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Diabetes and
Kidney Disease
Edgar V. Lerma
Vecihi Batuman
Editors
Second Edition

123
Diabetes and Kidney Disease
Edgar V. Lerma • Vecihi Batuman
Editors

Diabetes and Kidney Disease

Second Edition
Editors
Edgar V. Lerma Vecihi Batuman
Section of Nephrology Nephrology Section
University of Illinois at Chicago/Advocate Tulane University
Christ Medical Center, New Orleans, LA, USA
Oak Lawn, IL, USA

ISBN 978-3-030-86019-6    ISBN 978-3-030-86020-2 (eBook)

https://doi.org/10.1007/978-3-030-86020-2

© Springer Nature Switzerland AG 2014, 2022

This work is subject to copyright. All rights are reserved by the Publisher, whether the whole or part of
the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation,
broadcasting, reproduction on microfilms or in any other physical way, and transmission or information
storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology
now known or hereafter developed.
The use of general descriptive names, registered names, trademarks, service marks, etc. in this publication
does not imply, even in the absence of a specific statement, that such names are exempt from the relevant
protective laws and regulations and therefore free for general use.
The publisher, the authors and the editors are safe to assume that the advice and information in this book
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This Springer imprint is published by the registered company Springer Nature Switzerland AG
The registered company address is: Gewerbestrasse 11, 6330 Cham, Switzerland
To all my mentors and friends, at the
University of Santo Tomas Faculty of
Medicine and Surgery in Manila, Philippines,
and Northwestern University Feinberg School
of Medicine in Chicago, IL, who have in one
way or another, influenced and guided me to
become the physician that I am...
To all the medical students, interns, and
residents at Advocate Christ Medical Center,
whom I have taught or learned from,
especially those who eventually decided to
pursue Nephrology as a career...
To my parents and my brothers, without
whose unwavering love and support through
the good and bad times, I would not have
persevered and reached my goals in life …
Most especially, to my two lovely and
precious daughters Anastasia Zofia and
Isabella Ann, whose smiles and laughter
constantly provide me unparalleled joy and
happiness; and my very loving and
understanding wife Michelle, who has
always been supportive of my endeavors
both personally and professionally, and who
sacrificed a lot of time and exhibited
unwavering patience as I devoted a
significant amount of time and effort to this
project. Truly, they provide me with
motivation and inspiration.
—Edgar V. Lerma

To my former mentors, colleagues, residents,

fellows, and nurses – too many to name
individually. They made a career in
nephrology an exciting and fulfilling journey.
And to my family for their loving support and
encouragement.
—Vecihi Batuman
Contents

1 Historical Background of Diabetic Kidney Disease������������������������������    1

Vivian Fonseca, Arezu Bhatnagar, and Govind Datta Chamarthi
2 Diabetes and Kidney Disease: A Review of the Clinical Practice
Guidelines ������������������������������������������������������������������������������������������������   21
Nidhi Aggarwal, Sehrish Ali, and Sankar D. Navaneethan

Part I Natural Course, Pathogenesis, Morphology and Genetics

3 Diabetic Kidney Disease: Scope of the Problem������������������������������������   37
Jing Chen
4 Natural Course (Stages/Evidence-Based Discussion) ��������������������������   49
Dragana Lovre and Tina Kaur Thethi
5 Pathogenesis: Hemodynamic Alterations����������������������������������������������   75
Maria Jose Soler, Conxita Jacobs-Cachá, Manga Motrapu,
and Hans-Joachim Anders
6 Pathogenesis: Structural Changes in the Kidneys
in Type 1 and Type 2 Diabetes���������������������������������������������������������������� 105
Guillermo A. Herrera, Luis del Pozo-Yauner, Jeffrey J. Aufman,
and Elba A. Turbat-Herrera
7 Diabetes in Children and Adolescents���������������������������������������������������� 155
Mary Alice Rossi and Ihor V. Yosypiv

Part II Clinical Presentation and Associated Conditions

8 Screening, Early Diagnosis, Genetic Markers
and Predictors of Progression ���������������������������������������������������������������� 185
Jennifer Tuazon and Janis Cho

vii
viii Contents

9 Atypical Presentations ���������������������������������������������������������������������������� 219

Louis J. Imbriano, Nobuyuki Miyawaki, Joseph Mattana,
Shayan Shirazian, and John K. Maesaka
10 Albuminuria and Proteinuria ���������������������������������������������������������������� 243
Surya V. Seshan and Alluru S. Reddi
11 Hypertension and Diabetes �������������������������������������������������������������������� 263
William J. Elliott
12 Obesity and Metabolic Syndrome���������������������������������������������������������� 293
T. Alp Ikizler and Melis Sahinoz
13 Anemia and Diabetes ������������������������������������������������������������������������������ 305
Uzma Mehdi
14 Cardiovascular Disease and Diabetic Kidney Disease�������������������������� 327
Keith C. Ferdinand, Samar A. Nasser, and Ayan Ali
15 Dyslipidemia and Diabetes���������������������������������������������������������������������� 341
Anna Gluba-Brzózka, Jacek Rysz, Beata Franczyk,
and Maciej Banach
16 Bone Disease and Diabetes���������������������������������������������������������������������� 361
Stefana Catalina Bilha and Adrian Covic
17 Diabetic Retinopathy ������������������������������������������������������������������������������ 381
Azin Abazari, Nicola G. Ghazi, and Zeynel A. Karcioglu
18 Pregnancy and Diabetes�������������������������������������������������������������������������� 401
Anna Marie Burgner and Natalie McCall
19 Kidney Transplantation and Kidney Pancreas Transplantation �������� 417
Sixto Giusti and Vecihi Batuman
20 Diabetic Kidney Disease and Covid-19�������������������������������������������������� 431
Luis D’Marco

Part III Treatment and Prognosis

21 Glycemic Control ������������������������������������������������������������������������������������ 443
Armand A. Krikorian and Angela Pauline P. Calimag
22 Computerized Clinical Decision Support���������������������������������������������� 469
Shayan Shirazian, John K. Maesaka, Louis J. Imbriano,
and Joseph Mattana
23 Antihypertensive Therapies�������������������������������������������������������������������� 499
William J. Elliott
24 Diabetes and Kidney disease: metformin���������������������������������������������� 521
Luigi Gnudi and Carlo Alberto Ricciardi
Contents ix

25 Sodium-Glucose Cotransporter-2 (SGLT2) Inhibitors������������������������ 533

Ashish Kataria and Christos Argyropoulos
26 Glucagon-like Peptide-1 Receptor Agonists (GLP1-RA) �������������������� 563
Radica Z. Alicic, Emily J. Cox, Joshua J. Neumiller,
and Katherine R. Tuttle
27 Dipeptidyl Peptidase-4 (DPP4) Inhibitors �������������������������������������������� 583
Ngoc-Yen T. Pham, Christos Argyropoulos, and Nhan Dinh
28 Novel Treatments and the Future of DKD:
What Is on the Horizon? ������������������������������������������������������������������������ 601
Hongju Wu and Vecihi Batuman
29 Putting it All Together: Practical Approach
to the Patient with Diabetic Kidney Disease������������������������������������������ 637
Eudora Eng and Susan Quaggin
Index�������������������������������������������������������������������������������������������������������������������� 661
Contributors

Azin Abazari Department of Ophthalmology, Stony Brook University Medical

Center, Stony Brook, NY, USA
Nidhi Aggarwal Selzman Institute for Kidney Health, Section of Nephrology,
Department of Medicine, Baylor College of Medicine, Houston, TX, USA
Section of Nephrology, Michael E. DeBakey Veterans Affairs Medical Center,
Houston, TX, USA
Ayan Ali MD Candidate, Class of 2021, Tulane University School of Medicine,
New Orleans, LA, USA
Sehrish Ali Selzman Institute for Kidney Health, Section of Nephrology,
Department of Medicine, Baylor College of Medicine, Houston, TX, USA
Section of Nephrology, Michael E. DeBakey Veterans Affairs Medical Center,
Houston, TX, USA
Radica Z. Alicic Providence Medical Research Center, Providence Health Care,
Spokane, WA, USA
University of Washington School of Medicine, Seattle, WA, USA
Hans-Joachim Anders Department of Medicine IV, Renal Division, Hospital of
the Ludwig Maximilians University, Munich, Germany
Christos Argyropoulos Department of Internal Medicine, Division of Nephrology,
University of New Mexico School of Medicine, MSC 04-2785, 1 University of New
Mexico, Albuquerque, NM, USA
Jeffrey J. Aufman Department of Pathology, Largo Medical Center, Largo, FL, USA
Maciej Banach Department of Hypertension, Medical University of Lodz 90-549,
Lodz, Poland

xi
xii Contributors

Vecihi Batuman Dr A Rudolph and Ruth Ryder Huberwald Professor of Medicine,

John W Deming Department of Medicine, Tulane University Medical School, New
Orleans, LA, USA
Department of Medicine, Tulane University School of Medicine, New
Orleans, LA, USA
Arezu Bhatnagar Tulane University, School of Medicine, New Orleans, LA, USA
Stefana Catalina Bilha Endocrinology Department, “Sf. Spiridon” Clinical
Emergency Hospital, “Grigore T. Popa” University of Medicine and Pharmacy,
Iasi, Romania
Anna Marie Burgner Division of Nephrology and Hypertension, Vanderbilt
University Medical Center, Nashville, TN, USA
Angela Pauline P. Calimag Internal Medicine, Advocate Christ Medical Center,
Oak Lawn, IL, USA
Govind Datta Chamarthi Tulane University, School of Medicine, New
Orleans, LA, USA
Jing Chen Department of Medicine, Tulane University School of Medicine, New
Orleans, LA, USA
Janis Cho Division of Nephrology and Hypertension, Northwestern Medicine
Lake Forest Hospital, Lake Forest, IL, USA
Adrian Covic Nephrology Department, Dialysis and Renal Transplant Center,
“Dr. C.I. Parhon” University Hospital, “Grigore T. Popa” University of Medicine
and Pharmacy, Iasi, Romania
Emily J. Cox Providence Medical Research Center, Providence Health Care,
Spokane, WA, USA
Nhan Dinh Department of Internal Medicine, Division of Nephrology, University
of New Mexico School of Medicine MSC 04-2785, 1 University of New Mexico,
Albuquerque, NM, USA
Luis D’Marco Nephrology Department, Hospital Clínico Universitario,
Valencia, Spain
Instituto de Investigación Sanitaria de Valencia, Valencia, Spain
CEU Cardenal Herrera University, Valencia, Spain
William J. Elliott Department of Biomedical Sciences, Division of Pharmacology,
Pacific Northwest University of Health Sciences, University Parkway, Yakima,
WA, USA
Eudora Eng Department of Medicine, Division of Nephrology and Hypertension,
Northwestern University Feinberg School of Medicine, Chicago, IL, USA
Contributors xiii

Keith C. Ferdinand Gerald S. Berenson Endowed Chair in Preventive Cardiology,

Tulane University School of Medicine, New Orleans, LA, USA
Vivian Fonseca Department of Medicine, Section of Endocrinology, Tulane
University, New Orleans, LA, USA
Beata Franczyk Department of Nephrology, Hypertension and Family Medicine,
Medical University of Lodz, Lodz, Poland
Nicola G. Ghazi Department of Ophthalmology, The Gilbert and Rose-Marie
Chagoury School of Medicine, The Lebanese American University Medical Center-­
Rizk Hospital, Beirut, Lebanon
Sixto Giusti Assistant Profressor of Clinical Medicine, Tulane University Medical
School, New Orleans, LA, USA
Anna Gluba-Brzózka Department of Nephrology, Hypertension and Family
Medicine, Medical University of Lodz, Lodz, Poland
Luigi Gnudi School of Cardiovascular Medicine & Sciences, Section Vascular
Biology and Inflammation, British Heart Foundation Centre for Research
Excellence, Faculty of Life Sciences & Medicine, King’s College of London,
London, UK
Guillermo A. Herrera Department of Pathology, University of South Alabama,
College of Medicine-University Hospital, Mobile, AL, USA
T. Alp Ikizler Division of Nephrology and Hypertension, Vanderbilt University
Medical Center, Nashville, TN, USA
Louis J. Imbriano Department of Medicine, Division of Nephrology, NYU
Winthrop Hospital, Mineola, NY, USA
Conxita Jacobs-Cachá Nephrology Research Group, Vall d’Hebron Institut de
Recerca (VHIR), Department of Nephrology, Vall d’Hebron Hospital Universitari,
Barcelona, Spain
Zeynel A. Karcioglu Department of Ophthalmology, University of Virginia,
Charlottesville, VA, USA
Ashish Kataria Department of Internal Medicine, Division of Nephrology,
University of New Mexico School of Medicine, MSC 04-2785, 1 University of New
Mexico, Albuquerque, NM, USA
Armand A. Krikorian Internal Medicine, Endocrinology and Metabolism,
Advocate Christ Medical Center, Oak Lawn, IL, USA
Dragana Lovre Department of Medicine, Section of Endocrinology and
Metabolism, Tulane University Health Sciences Center and Southeast Louisiana
Veterans Health Care System, New Orleans, LA, USA
xiv Contributors

John K. Maesaka Department of Medicine, Division of Nephrology, NYU

Winthrop Hospital, Mineola, NY, USA
Joseph Mattana Department of Medicine, Frank H. Netter School of Medicine at
Quinnipiac University, St. Vincent’s Medical Center, Bridgeport, CT, USA
Department of Medicine, St. Vincent’s Medical Center, Bridgeport, CT, USA
Natalie McCall Division of Nephrology and Hypertension, Vanderbilt University
Medical Center, Nashville, TN, USA
Uzma Mehdi Department of Nephrology, Methodist Richardson Medical Center,
Dallas, TX, USA
Nobuyuki Miyawaki Department of Medicine, Division of Nephrology, NYU
Winthrop Hospital, Mineola, NY, USA
Manga Motrapu Department of Medicine IV, Renal Division, Hospital of the
Ludwig Maximilians University, Munich, Germany
Samar A. Nasser Department of Clinical Research & Leadership, School of
Medicine and Health Sciences, The George Washington University,
Washington, DC, USA
Sankar D. Navaneethan Selzman Institute for Kidney Health, Section of
Nephrology, Department of Medicine, Baylor College of Medicine,
Houston, TX, USA
Section of Nephrology, Michael E. DeBakey Veterans Affairs Medical Center,
Houston, TX, USA
Joshua J. Neumiller College of Pharmacy and Pharmaceutical Sciences,
Washington State University, Spokane, WA, USA
Ngoc-Yen T. Pham Department of Pharmacy, Department of Internal Medicine,
Division of Nephrology, University of New Mexico School of Medicine MSC
04-2785, 1 University of New Mexico, Albuquerque, NM, USA
Luis del Pozo-Yauner Department of Pathology, University of South Alabama,
College of Medicine-University Hospital, Mobile, AL, USA
Susan Quaggin Department of Medicine, Division of Nephrology and
Hypertension, Northwestern University Feinberg School of Medicine,
Chicago, IL, USA
Alluru S. Reddi Department of Medicine, Division of Nephrology & Hypertension,
Rutgers New Jersey Medical School, Newark, NJ, USA
Carlo Alberto Ricciardi School of Cardiovascular Medicine & Sciences, Section
Vascular Biology and Inflammation, British Heart Foundation Centre for Research
Excellence, Faculty of Life Sciences & Medicine, King’s College of London,
London, UK
Contributors xv

Mary Alice Rossi Department of Pediatrics, Tulane University School of Medicine,

New Orleans, LA, USA
Jacek Rysz Department of Nephrology, Hypertension and Family Medicine,
Medical University of Lodz, Lodz, Poland
Melis Sahinoz Division of Nephrology and Hypertension, Vanderbilt University
Medical Center, Nashville, TN, USA
Surya V. Seshan Department of Pathology and Laboratory Medicine, Weill Cornell
Medicine, New York, NY, USA
Shayan Shirazian Department of Medicine, Columbia University Irving Medical
Center, New York, NY, USA
Division of Nephrology, Department of Medicine, Columbia University Medical
Center, New York, NY, USA
Maria Jose Soler Nephrology Research Group, Vall d’Hebron Institut de Recerca
(VHIR), Department of Nephrology, Vall d’Hebron Hospital Universitari,
Barcelona, Spain
Tina Kaur Thethi Translational Research Institute, Advent Health,
Orlando, FL, USA
Jennifer Tuazon Division of Nephrology and Hypertension, Northwestern
University Feinberg School of Medicine, Chicago, IL, USA
Elba A. Turbat-Herrera Department of Pathology, University of South Alabama,
College of Medicine-University Hospital, Mobile, AL, USA
Katherine R. Tuttle Providence Medical Research Center, Providence Health
Care, Spokane, WA, USA
University of Washington School of Medicine, Seattle, WA, USA
Institute of Translational Health Sciences, Seattle, WA, USA
Hongju Wu Department of Medicine, Tulane University School of Medicine, New
Orleans, LA, USA
Ihor V. Yosypiv Department of Pediatrics, Tulane University School of Medicine,
New Orleans, LA, USA
Chapter 1
Historical Background of Diabetic Kidney
Disease

Vivian Fonseca, Arezu Bhatnagar, and Govind Datta Chamarthi

Introduction

Symptoms of diabetes are recorded as far back as 400 BC; the Indian physician
Sushruta describes diabetes in an ancient Hindi document as “madhumeha” or the
honeyed-urine disease [1]. Around 150 AD, the Greek physician Aretaeus of
Cappadocia wrote:
Diabetes is a remarkable disorder, and not one very common to man. It consists of a moist
and cold wasting of the flesh and limbs into urine... the secretion passes in the usual way,
by the kidneys and the bladder. It is of improbable, also, that something pernicious, derived
from other disease which attack the bladder and kidneys may sometimes prove the cause of
this affliction. The patients never cease making water, but the discharge is as incessant as a
sluice let off. This disease is chronic in character, and is slowly engendered, though the
patient does not survive long when it is completely established for the marasmus produced
is rapid and death is speedy [2].

For many centuries thereafter, diabetes mellitus was regarded as a disease of

the kidney.

V. Fonseca (*)
Department of Medicine, Section of Endocrinology, Tulane University,
New Orleans, LA, USA
e-mail: [email protected]
A. Bhatnagar · G. D. Chamarthi
Tulane University, School of Medicine, New Orleans, LA, USA
e-mail: [email protected]; [email protected]

© Springer Nature Switzerland AG 2022 1

E. V. Lerma, V. Batuman (eds.), Diabetes and Kidney Disease,
https://doi.org/10.1007/978-3-030-86020-2_1
2 V. Fonseca et al.

The Discovery of Diabetic Kidney Disease

Following the now famous paper published by Paul Kimmelstiel and Clifford
Wilson in 1936, many incorrectly assume that diabetic renal disease was recently
recognized. However, the discovery of diabetic kidney disease has been a gradual
process, and the meaning of diabetic renal disease has changed over time [3].
Erasmus Darwin [4] described it as urine that could be coagulated by heat, con-
firming the observations of Cotunnius [5] and Rollo [6] that the urine of some dia-
betics contained protein [7]. In the 1830s, research conducted by the “father of
nephrology” Richard Bright into the causes of kidney disease led to what became
known as Bright’s disease. Pierre-François Olive Rayer [8] and Wilhelm Griesinger
[9] were the first to hypothesize that diabetes might cause a form of Bright’s disease.
In the 1850s, much data on renal histology in patients with diabetes were pub-
lished. Lionel Beale examined the histology of enlarged diabetic kidneys and ana-
lyzed them chemically, showing an excess of fat present in the tubules. Luciano
Armanni (1875, cited by Ebstein) and Wilhelm Ebstein [10] described vacuolization
of renal tubular epithelium.
The concept of diabetic kidney disease continued to develop, and in 1883,
Ehrlich confirmed glycogen infiltration—a common postmortem finding in the pre-
insulin era. For the next 50 years, these tubular deposits of glycogen were the only
lesion believed to be specifically associated with diabetes, later called “nephro-
pathia diabetic” by Aschoff in 1911.
Kenzo Waku [11] published a description of diffuse capillary wall thickening
studied by silver staining in 8 of 13 diabetic patients, in a Japanese journal written
in German. No clinical details of the patients were provided, and the study gained
little attention. It was not until 1936, when Kimmelstiel and Wilson published their
paper “Intercapillary lesions in glomeruli of kidney” in The American Journal of
Pathology, that interest intensified in the study of diabetic vascular complications.

The Pathology of Diabetic Renal Disease

Paul Kimmelstiel (1900–1970), a native of Hamburg, Germany, came to the USA in

1933. Clifford Wilson (1906–1997), a relatively unknown British clinician, went to
Harvard University as a Rockefeller travelling fellow and met Kimmelstiel. Their
first paper [12] described glomerular lesions in eight patients who died of renal
failure. The lesions were attributed to diabetes mellitus because seven of the eight
patients were known to have the disease. Most of the patients had hypertension,
heavy albuminuria, and edema and were aged 48–68 years. The diabetic patients
had diabetes from a range of 10 months to 10 years. Their glomeruli showed uni-
form lesions involving large expansion of the intercapillary space. This expansion
1 Historical Background of Diabetic Kidney Disease 3

was shown to be continuous with the hyaline lesions of the afferent glomerular
arteriole. Kimmelstiel and Wilson did not emphasize the association of these lesions
with diabetes but suggested that the appearance was an acceleration of senile glo-
merulosclerosis. They noted that it was a rare finding and that it could complicate
glomerulonephritis.
Although Kimmelstiel and Wilson’s observations were received initially with
uncertainty, they stimulated interest in diabetic vascular pathology. After their pub-
lication, the eponym “Kimmelstiel–Wilson nodules” began to be applied to diabetic
renal lesions. However, it was Arthur Allen (1941) who clarified the link with dia-
betes [13]. He studied autopsies of 105 patients with diabetes (all of which were
over age 40), 100 patients with hypertension, 100 patients without hypertension or
diabetes, and 34 patients with glomerulonephritis. Thirty-four percent of the diabet-
ics showed the lesion, but otherwise it was seen in only three other patients.
Type 1 (insulin-dependent) and type 2 (non-insulin-dependent) diabetes are etio-
logically and epidemiologically distinct conditions and affect different divisions of
the population. However, there has been no major difference identified between the
nephropathies seen in both conditions, either pathophysiologically or in terms of
their management. They can thus be conveniently considered together. It should be
remembered, however, that patients with type 2 diabetes tend to be older and more
hypertensive and so more likely to have concomitant hypertensive and renovascular
disease [14].

Initial Studies of Renal Biopsies

Before 1950, renal histology samples were mostly obtained from autopsied patients.
The only way of analyzing kidney tissue from a live person was through an open
operation. In 1951, Danish physicians Poul Iversen and Claus Brun described a
method involving needle biopsy [15]. It became possible to obtain renal specimens
of diabetic patients in all stages of disease. By the end of the 1950s, there were a
large amount of data collected such as those published by Robert Kark in Chicago
[16]. These data revealed that patients with mild glomerular disease may have heavy
proteinuria and patients with less renal involvement may have complex lesions of
nodular glomerulosclerosis.
In 1957 the electron microscope [16] and in 1959 immunofluorescent protein
tracing [17] were used to study glomerular lesions in patients with diabetes mellitus.
Using these techniques, the hypothesis of a diffuse thickening of the basement
membrane in diabetics was proven. In 1956, Ruth Østerby-Hansen published a
study, [18] which showed that there was no thickening of the peripheral glomerular
basement membrane in early diabetic patients. This finding brought forth the pos-
sibility of treatment through modifying whatever was causing subsequent changes.
4 V. Fonseca et al.

Radioimmunoassay and the Concept of Microalbuminuria

In New York, in the 1950s, Rosalyn Yalow1 and Solomon Aaron Berson developed
the technique of radioimmunoassay, and they later published their findings [19].
The technique allowed for the precise measurement of minute amounts of proteins
and hormones. In 1960, Harry Keen and associates from Guy’s Hospital used the
technique to detect small amounts of albumin in the urine of diabetics. Their paper
[20] was published in The Lancet in 1963. Keen studied diabetics at all stages of
disease, including those who had no proteinuria on conventional testing. Keen real-
ized that elevated albumin excretion below the proteinuric level might be important
in the natural history of diabetic kidney disease, and the concept of microalbumin-
uria was developed.
In 1982, GianCarlo Viberti published findings that confirmed that microalbumin-
uria could predict the subsequent evolution of overt nephropathy with proteinuria in
type 1 diabetics, [21] and in 1984, Carl Erik Mogensen showed the same finding in
type 2 diabetics [22]. Concurrently, it became apparent that the reduction of blood
pressure could postpone renal failure [23].

 he Renin–Angiotensin–Aldosterone System and Diabetic

T
Kidney Disease

In the 1950s, Mann et al. documented the natural history of diabetic renal disease.
Death from renal failure that resulted from diabetic kidney disease usually occurred
in patients who had long-standing type 1 diabetes. However, after the 1970s with
improved treatments, much larger number of patients with type 2 diabetes began to
survive and develop end-stage renal disease. Attention began to shift from the treat-
ment to the prevention of diabetic kidney disease.
Pharmacologic blockade of the renin–angiotensin–aldosterone system (RAAS)
has become the standard of care for patients with type 2 diabetes mellitus and renal
involvement [24]. The history of the discovery of the RAAS began in 1898 with the
studies by Tigerstedt and Bergman, who reported the pressor effect of renal extracts;
they named the renal substance renin based on its origin [25]. Angiotensin-­
converting enzyme inhibitors (ACE-i) were the first class of clinically applicable
drugs that specifically block the RAAS. Originally, ACE-i were developed as anti-
hypertensives, in particular aimed at the treatment of high-renin hypertension. The
first proposals [26, 27] that the outcome of diabetic kidney disease could be
improved using RAAS blockade with ACE-i drugs began in the early 1980s. Brenner
and Zatz showed that rats with diabetes that were treated with ACE-i were protected
against nephropathy; however, conventional blood pressure lowering agents did not

1
By injecting radioactive iodine, they were able to track insulin and prove that type 2 diabetes is
due to an inefficient use of insulin. This discovery awarded them a Nobel Prize.
1 Historical Background of Diabetic Kidney Disease 5

[28]. The first controlled trial [29] of ACE-i in humans with diabetes appeared
in 1987.
In 1993, the landmark study using captopril was published [30]. The trial dem-
onstrated that captopril protected against deterioration of renal function in patients
with type 1 diabetes and diabetic kidney disease and was significantly more effec-
tive than blood pressure control alone. Captopril reduced the risk of doubling of the
serum creatinine by 48% when compared with standard antihypertensive therapy.
Both treatment groups had similar blood pressures; thus, the effect of captopril on
progression was determined to be independent of its antihypertensive properties, an
effect termed “renoprotection.”
In 2001, the Irbesartan diabetic kidney disease Trial, [31] designed to ascertain
whether the use of the angiotensin II receptor blocker irbesartan or the calcium
channel blocker amlodipine provided similar renoprotection in overt nephropathy
associated with type 2 diabetes, was published. Irbesartan was shown to reduce the
risk of doubling the serum creatinine by 33% when compared with standard antihy-
pertensive therapy and by 37% when compared with treatment with amlodipine.
Blood pressures were again similar across groups, indicating that these salutary
effects were a result of renoprotection. Similar results were reported using losartan
in the Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist
Losartan (RENAAL) trial [32].
Results of the Irbesartan in Patients with Type 2 Diabetes and Microalbuminuria
(IRMA 2) trial were also published in 2001. IRMA 2 studied the effects of the use
of irbesartan (300 or 150 mg/day versus placebo) to prevent progression from the
earlier stage of microalbuminuria to the later stage of overt nephropathy in patients
with hypertension and type 2 diabetes. The study demonstrated that patients receiv-
ing irbesartan (300 mg/day) had about one third the risk of developing overt
nephropathy compared with the patients not receiving (adjusted risk reduction 68%
at 300 mg/day) [33].

Value of Glycemic Control

Diabetes is the most common cause of ESRD in Western countries, and glycemic
control is correlated with the development and progression of diabetic kidney dis-
ease. Epidemiologic studies have demonstrated that diabetic kidney disease risk is
higher in patients with poor metabolic control [27, 34, 35]. Although genetic factors
modulate DN risk and some patients do not develop this complication despite sev-
eral years of poor glycemic control, there is evidence that hyperglycemia is a neces-
sary precondition for DN lesions. Two major early glomerular lesions, glomerular
basement membrane thickening and mesangial expansion, are not present at diagno-
sis of diabetes but are found 2–5 years after onset of hyperglycemia [34].
Studies in identical twins who are discordant for type 1 diabetes support the
concept that hyperglycemia is necessary for the development of diabetic glomeru-
lopathy. Twin studies show that the nondiabetic siblings had structurally normal
6 V. Fonseca et al.

kidneys, while their diabetic twin pair had glomerular lesions [36]. Moreover, nor-
mal kidneys from nondiabetic donors that are transplanted into patients with diabe-
tes develop lesions of DN [37, 38].
A number of articles now suggest a long-term survival advantage with simulta-
neous pancreas kidney (SPK) transplantation, compared with kidney transplanta-
tion alone for patients with end-stage renal disease caused by diabetic kidney
disease [39]. SPK offers the opportunity to test the ability of pancreas transplanta-
tion to prevent the development of diabetic glomerular lesions, because the renal
graft has never been exposed to hyperglycemia. Patients who have dual-organ trans-
plants almost always normalize their glycemic values afterward, and this is partly
why these patients live longer than those who get a kidney alone. In 1985, Bohman
et al. were the first to demonstrate that the development of diabetic glomerulopathy
was prevented in the recipients of SPK [40]. In 1993, the same group confirmed
prior observations when they reported data on a cohort of 20 SPK patients who were
followed for up to 6 years, compared with a group of 34 kidney transplant recipients
with diabetes [41]. More recent studies support the same observation [42, 43].

Treatment of Hyperglycemia

Almost 4000 years ago, “diabetes” or a disease describing it was well documented
in ancient records from Egypt, India, and across China. Interestingly, all recognized
that sweet copious amounts of urine and sweet-scented sweat were associated with
obesity and may have a hereditary component to it. They also noted that these phe-
notypic traits may possibly be occurring due to overindulgence of rich foods such
as milk which contains a lot of sugar in it.
With very limited resources in regard to the pathophysiology of diabetes, an
array of ancient medicines were used. These included oil of roses, dates, raw quinces
and gruel, jelly of viper’s flesh, broken red coral, sweet almonds, and fresh flowers
of blind nettles [44].
For the most part, diabetes was considered incurable at that time. Knowing now
that there are microvascular complications such as diabetic kidney disease, there is
much doubt as to whether people survived for that long, whether physicians of that
time stopped treatment or tailored treatment to best suit the various stages of this
dismal disease [45].
In type 1 diabetes, the Diabetes Control and Complications Trial (DCCT)
Research Group demonstrated that intensive treatment was associated with
decreased incidence of microalbuminuria and reduced progression to macroalbu-
minuria as compared with conventional treatment [46]. In type 2 diabetes, the UK
Prospective Diabetes Study (UKPDS) Group trial demonstrated a reduced incidence
of microalbuminuria in the intensively treated group as compared with conventional
treatment, but a parallel finding in macroalbuminuria was not significant [47].
1 Historical Background of Diabetic Kidney Disease 7

However, the Kumamoto study [48] and the Veterans Affairs Cooperative study [49]
both showed that intensive treatment was effective for primary prevention (decreased
incidence of microalbuminuria) and secondary prevention (reduced progression to
macroalbuminuria).
The Epidemiology of Diabetes Interventions and Complications (EDIC)/DCCT
follow-up study [50] and the UKPDS study also found that lowering HbA1c reduced
decline in GFR in type 1 and type 2 diabetes, respectively.

Intensive Glycemic Control

The benefit of intensive glycemic control for nephropathy is currently under debate.
Intensive treatment of hyperglycemia may prevent DN, including development of
microalbuminuria, but there is little evidence that it slows the progression of chronic
kidney disease [51].
In the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial,
assignment of the treatment group to an HbA1c goal of less than 6% led to increased
mortality and cessation of the trial [52]. Furthermore, in one analysis of data from
the ACCORD study, combined intensive glycemic and blood pressure control did
not produce an additive benefit on microvascular outcomes in patients with type 2
diabetes. This differs from the findings of the ADVANCE study, [53] which showed
that intensive glucose and BP controls were independently beneficial and their com-
bination produced synergistic benefits in nephropathy, new-onset microalbumin-
uria, and new-onset macroalbuminuria.

 he Impact of Glucose-Lowering Drugs on Diabetic Kidney

T
Disease Progression

While the impact of good glycemic control on nephropathy progression is generally

well accepted, none of the medications for hyperglycemia were shown to have a
specific beneficial effect on the kidney in the past. However, recently data has
emerged demonstrating that some drugs developed for lowering blood glucose can
decrease proteinuria and significantly slow the progression of chronic kidney dis-
ease (CKD). While some minor benefits have been seen with DPP-4 inhibitors and
thiazolidinediones, the effects of SGLT2 inhibitors and, to a lesser extent, GLP-1
receptor agonists are clinically impactful, and the use of the former has now been
incorporated into several clinical guidelines, [54] including the specific treatment of
diabetic kidney disease. Figure 1.1 [76] shows the evolution of treatment and man-
agement for diabetes.
8 V. Fonseca et al.

2005-amylin
agonist
1956-First sulfonylurea
available in US 2005-GLP 1 -R agonist

1956-Lente Insulin 1997-meglitinide

1918-Guanidine
(Synthalin) 1936-PZI Insulin 1995-AGI 2009-Bromocriptine

1915 1935 1955 1975 1995 2015

1922-Insulin first 1946-NPH 1996-TZD

administered to Insulin
human subject 1983-Recombinant 2013-SGLT-2i
human insulin
1923-Insulin 1984-2nd Generation
available in US 2006-DPP-4i
sulfonylureas
2008-Colesvalem

Fig. 1.1 Evolution of treatment and management for diabetes. (NB: PZI protamine zinc insulin,
NPH neutral protamine Hagedorn, AGI alpha glucosidase inhibitors, GLP-1R agonist glucagon-­
like peptide-1 receptor agonist, TZD thiazolidinediones, SGLT2i sodium glucose transporter inhib-
itors, DPP-4i dipeptidyl peptidase-4 inhibitors)

Sodium Glucose Transporter Inhibitors (SGLT2i)

Phlorizin, a molecule from the root bark of apple trees, has been studied for over a
century. In 1933, it was discovered to increase renal excretion of glucose, decrease
its reabsorption, and lower its overall levels in the body. Phlorizin seemed to be an
ideal alternative in managing glucose levels in those with diabetes mellitus (mecha-
nism of action; non-selective inhibitor of both Sodium Glucose Transporters (SGLT)
1 & 2). SGLT1 accounts for the dietary glucose uptake in the intestine and, SGLT2
is responsible for glucose reuptake in the tubular system of the kidney. SGLT1 reab-
sorbs the remainder of the filtered glucose [55]. Phlorizin’s dramatic reduction in
glucose reabsorption in the intestines, its negative effects on the body as well as, its
inadequate absorbance when taken orally, became quite evident.
For decades, researchers had many concerns about phlorizin and others in
the same class due to side effects thought to be related to its nonspecific inhibi-
tion of transporters in other organs. Finally, the development and approval of a
more specific SGLT2i, canagliflozin, in 2013 by the US Food and Drug
Administration (FDA) led to reassurance about such effects. Dapagliflozin and
empagliflozin followed in 2014 [56]. Several others in this class are now avail-
able worldwide.
Large-scale clinical trials mandated by the FDA, Empagliflozin- regulatory out-
come (EMPA-REG OUTCOME) and Cardiovascular Assessment Study (CANVAS),
examined SGLT2i’s effects in type 2 diabetics. These programs showed an approxi-
mate 35% reduction in the incidence of heart failure [55]. Furthermore, there were
reductions in mortality and major CV events. These trials also highlighted a
1 Historical Background of Diabetic Kidney Disease 9

reduction in the progression of nephropathy, a decrease in proteinuria and, a slower

decline in eGFR.
The Canagliflozin and Renal Events in Diabetes with Established Nephropathy
Clinical Evaluation (CREDENCE) trial demonstrated canagliflozin’s action on
inhibiting SGLT2 in advanced CKD due to diabetic kidney disease. The study
enrolled patients with significant proteinuria and eGFR as low as 30. Compared to
placebo it decreased creatinine levels, preventing progression of CKD, and reduced
the rates of mortality secondary to end-stage kidney disease (ESKD) and other car-
diovascular effects [57]. Importantly, the drug was continued in people whose eGFR
dropped below 30, and no harmful effects were seen, demonstrating possible bene-
fits at a stage where significant reduction in glucosuria was unlikely.
The Dapagliflozin and Prevention of Adverse Outcomes in Chronic Kidney
Disease (DAPA-CKD) trial that commenced in 2017 has recently halted due to its
overwhelming positive effects [58]. DAPA-CKD mirrors CREDENCE but on a
broader scale. Its population were those suffering from chronic renal disease with-
out diabetes. Dapagliflozin’s outcome also proved to delay further kidney damage
and decrease cardiovascular effects in those suffering with diabetes mellitus.
Interestingly, the beneficial effects on eGFR occurs despite an initial drop in
eGFR, possibly related to dehydration, which may be associated with incidences of
acute kidney injury in a few patients. In addition, and more likely, the effects are due
to a corrective action of SGLT2i on the impaired tubulo-glomerular feedback.
However, a meta-analysis by Menne et al. concluded that there was no increased
risk of AKI in patients taking SGLT2 inhibitors. In addition, they advise physicians
that the possibility of AKI should not deter them from prescribing them [59].
Thus, novel approach to treating hyperglycemia by working on the kidneys and
reducing the risks of associated macrovascular complications such as cardiovascu-
lar disease was established. The results of these trials have spawned many others as
well as mechanistic studies to understand the findings. Mechanisms proposed
include a reduction in BP, improved energetics in the renal cells, improved blood
flow through normalization of juxtaglomerular feedback, and a suppression of acti-
vation of intrarenal angiotensin production [60].

Glucagon-like Peptide-1 Receptor (GLP-1R) Agonists

Over 100 years ago, Moore et al. [61] discovered that gut extracts contain hormones
that regulate the function of the pancreas and administration of these hormones low-
ers glucose levels in urine. In 1932 Le Barre purified these extracts and called it
incretins. The invention of radioimmunoassay (RIA) by Berson and Yalow in 1960
which led to the ability to reliably measure insulin with RIA soon reopened the
incretin question. In 1964, [62] McIntyre showed that there was a higher plasma
insulin response to glucose given orally than to glucose given intravenously, hence
proving the incretin mechanism exists. This report proved a stimulus to studies
aimed at identifying and isolating these incretins.
10 V. Fonseca et al.

In 1973 John Brown [63] isolated GIP as an inhibitor of gastric acid secretions
but in subsequent studies showed that it is a commanding releaser of insulin during
hyperglycemia but could not explain the effect of GIP on insulin secretion after oral
glucose. Therefore, the search for other incretins continued. In 1983, Graeme Bell
[64] identified two glucagon-like peptides during the cloning and sequencing of
mammalian pre-proglucagon and named them GLP-1 and GLP-2, both of which
were expressed in the gut. But GLP-1 as such didn’t show a significant insulinotro-
pic effect. In 1987, Habener [65] and Holst [66] independently discovered that
GLP-1 was also synthesized in truncated form, which showed an even greater insu-
linotropic effect, and this led to the birth of GLP-1 drugs based on the incretin
concept. The results of the 1993 clinical study by M A Nauck showed that exoge-
nous GLP-1 [7-36 amide] caused normalization of fasting hypoglycemia, without
the stimulation of insulin secretion. The first GLP-1RA drug was exenatide and was
approved in 2005 [67, 68].
In recent years the efficacy of GLP-1 drugs in lowering blood glucose has been
very well established, and also many trials have shown that it has a consistent asso-
ciation in lowering systolic blood pressure and weight [69]. In 2016, the LEADER
trial [70] compared cardiovascular event outcomes in 9340 patients with type 2
diabetes with cardiovascular disease or cardiovascular risk factors randomly
assigned to subcutaneous liraglutide or placebo. After a median follow-up of
3.84 years, the study showed a significant difference between the groups, in death
from cardiovascular events (HR, 0.87), glycemic control (−0.4%), weight loss
(2.3 kg), and systolic blood pressure (−1.2 mmHg). In addition to these, the study
also showed a significant reduction in nephropathy events (HR, 0.78).
This result was driven by the significant reduction in new-onset microalbumin-
uria (HR, 0.74) in the liraglutide group. A short time after the LEADER trial, the
SUSTAIN-6 trial [71] showed very similar results with subcutaneous semaglutide.
There was a significant reduction in new or worsening nephropathy in the semaglu-
tide group compared to the placebo group (HR, 0.64). As seen in the LEADER trial,
this was driven by a reduction in new-onset microalbuminuria.
These studies have shown, when added to usual care, GLP-1RA results in lower
rates of development and progression of diabetic kidney disease. On the flip side,
some of the studies have shown patients to develop acute kidney injury as a side
effect of GLP-1RA treatment. However, this is thought to be due to nausea and
vomiting leading to dehydration, rather than a specific toxic effect on the kidney.
Some GLP-1RAs such as exenatide have this in their package insert suggesting that
they must be used with caution in patients with CKD. In 2019, oral semaglutide
became the first FDA-approved oral GLP-1RA drug, and already there are studies
looking for its impact in the clinical settings.
1 Historical Background of Diabetic Kidney Disease 11

Bardoxolone

Bardoxolone was initially developed as an anticancer drug. However, as clinical

studies progressed, data consistently showed that bardoxolone had a positive impact
on the estimated glomerular filtration rate (eGFR) of these patients [72]. Multiple
global trials have assessed its capabilities in alleviating or limiting the progression
of chronic kidney disease (CKD) in patients suffering with diabetic kidney disease.
The Bardoxolone Methyl Evaluation in Patients with Chronic Kidney Disease
and Type 2 Diabetes Mellitus (BEACON) trial was a multicenter, international,
phase 3 randomized, double-blind clinical trial that administered bardoxolone once
daily to one group and placebo to another group. Their aim was to see if bardoxo-
lone would increase the eGFR in those suffering with stage 4 chronic kidney dis-
ease. In total, 2185 patients were randomized into the study.
Among patients with type 2 diabetes mellitus and stage 4 chronic kidney disease,
bardoxolone methyl did not reduce the risk of ESRD or death from cardiovascular
causes. It in fact increased early-onset fluid overloading, especially in those suffer-
ing from heart failure or had prior history/hospitalization of heart failure. A higher
rate of cardiovascular events with bardoxolone methyl than with placebo prompted
immediate termination of the trial, [73] which was disappointing in light of benefits
seen in phase 2 trials.
The Phase 2 Study of Bardoxolone Methyl in Patients with Chronic Kidney
Disease and Type 2 Diabetes (TSUBAKI) study took place in Japan after BEACON
was terminated. This trial aimed to determine if patients without risk factors can
mitigate the risk for fluid overload and whether changes in eGFR with bardoxolone
methyl reflect true increases in GFR [74].
The outcome of this trial was extremely interesting to note, factoring in that the
incidence of cardiovascular events was deemed lower in CKD patients in Japan
versus in clinical trials in the USA. Additionally, the trial found no significant safety
concerns, such as fluid overloading and heart failure as were seen in BEACON [75].
Despite an early halt to the study, the BEACON trial did attest to the fact that
bardoxolone could preserve kidney function by delaying the progression of CKD
and thus end-stage renal disease. Patients who were randomly assigned to placebo
had a significant mean decline in eGFR from their baseline value (−0.9 ml per min-
ute per 1.73 m2; 95% CI, −1.2 to −0.5) as compared to those randomly assigned to
bardoxolone methyl, who were noted to have had a significant mean increase from
their baseline value (5.5 ml per minute per 1.73 m2; 95% CI, 5.2 to 5.9). The differ-
ence between the two groups was 6.4 ml per minute per 1.73 m2 (95% CI, 5.9 to 6.9;
P < 0.001) [73].
12 V. Fonseca et al.

Recent Updates

There seems to be widespread acceptance of SGLT2 inhibitors as an important class

of medications to slow the progression of CKD; indeed this benefit appears to occur
independent of glucose excretions. As discussed above multiple potential mecha-
nisms have been implicated. There has also been interest in the role of aldosterone
in progression of CKD. Although not approved for the indication and often associ-
ated with hyperkalemia, spironolactone has been used in the management of the
condition, though limited by side effects. A recent clinical trial with a novel nonste-
roidal mineralocorticoid receptor antagonist finerenone demonstrated significant
efficacy in slowing progression of CKD without large effects on BP reduction or
hyperkalemia [78].
Table 1.1 [77] highlights some of the major randomized clinical research trials
(RCT) throughout the years and their outcomes. Many of these trials resulted in
favorable outcomes including reductions in albuminuria and general kidney

Table 1.1 Landmark clinical trials in diabetes

Diabetes Follow-up
Study trial, year type (years) Design (RCT) Outcome
Diabetes control Type 1 6.5 years Intensive vs. Intensive glycemic control
and complications diabetes standard (HbA1c 7.3% vs. 9.1%) reduced
trial (DCCT), 1993 mellitus glycemic the incidence of micro- and
control macroalbuminuria by 39% and
54%, respectively
The Captopril Trial, Insulin-­ 4 years Captopril vs. Captopril slowed down the
1993 dependent placebo progression of kidney disease in
diabetes IDDM
mellitus
(IDDM)
UK prospective Type 2 10 years Intensive vs. Intensive vs. standard glycemic
diabetes study diabetes standard control (HbA1c 7.0% vs. 7.9%)
(UKPDS), 1998 mellitus glycemic reduced risk of
control microalbuminuria by 33%
Reduction of Type 2 3.4 years Losartan vs. Every 10 mmHg of systolic
endpoints in diabetes placebo blood pressure rise increased the
NIDDM with the mellitus risk of end-stage kidney disease
angiotensin II or death by 6.7%. Losartan
antagonist losartan decreased proteinuria by 35%
(RENAAL), 2001 (p < 0.001). Serum creatinine
doubling risk was reduced by
25% (p = 0.006) and end-stage
kidney disease by 28%
(p = 0.002)
1 Historical Background of Diabetic Kidney Disease 13

Table 1.1 (continued)

Diabetes Follow-up
Study trial, year type (years) Design (RCT) Outcome
Randomized Type 2 3.2 years Olmesartan Olmesartan reduced the time to
Olmesartan and diabetes vs. placebo microalbuminuria onset. Blood
diabetes mellitus pressure control was similar in
microalbuminuria both treatment arms
prevention study
(ROADMAP),
2001
Irbesartan diabetic Type 2 2.6 years Irbesartan vs. Irbesartan was Reno-protective
kidney disease trial diabetes amlodipine with a lower risk of serum
(IDNT), 2001 mellitus vs. placebo creatinine doubling (33%;
p = 0.003) and end-stage kidney
disease (23%; p = 0.07)
compared with amlodipine and
placebo
Ongoing Type 2 4.5 years Telmisartan/ Combination therapy was
Telmisartan alone diabetes lisinopril associated with an increased
and in combination mellitus combination composite outcome of dialysis.
with Ramipril vs. losartan Serum creatinine doubling and
global endpoint alone death (hazard ratio [HR] of
trial 1.09; 95% confidence interval
(ONTARGET), 1.01–1.18; p ≤ 0.037)
2008
Action to control Type 2 Terminated Intensive vs. Targeting HbA1c 6.0 vs.
cardiovascular risk diabetes at 3.5 years standard 7.0%–7.9% resulted in excess
in diabetes mellitus glycemic mortality
(ACCORD), 2008 control
A study of Type 2 Terminated Avosentan vs. Avosentan reduced proteinuria
cardiovascular diabetes at 4 months placebo compared with placebo group.
events in diabetes mellitus However, it had excess adverse
(ASCEND), 2010 cardiovascular events
Bardoxolone Type 2 Terminated Bardoxolone Bardoxolone methyl led to a
methyl evaluation diabetes at 9 months vs. placebo significant increase in
in patients with mellitus cardiovascular morbidity (HR
chronic kidney 1.83, 0 < 0.001)
disease and type 2
diabetes
(BEACON), 2011
Aliskiren trial in Type 2 Terminated RAS blockade The addition of aliskiren to
type 2 diabetes diabetes at 2.7 years plus aliskiren maximal angiotensin receptor
using mellitus vs. placebo blockers (ARBs) offered no
cardiovascular and additional benefit. In addition,
renal disease hyperkalemia and hypotension
endpoints were significantly increased in
(ALTITUDE), the treatment arm
2012
(continued)
14 V. Fonseca et al.

Table 1.1 (continued)

Diabetes Follow-up
Study trial, year type (years) Design (RCT) Outcome
Action in diabetes Type 2 5 years Intensive vs. Intensive glycemic control
and vascular diabetes standard (HbA1c 6.5% vs. 7.3%) reduced
disease mellitus glycemic risk of microalbuminuria,
(ADVANCE), 2013 control macroalbuminuria, and
end-stage kidney disease by 9%,
30%, and 65%, respectively
Veterans affairs Type 2 Terminated Losartan/ The combination therapy
nephropathy in diabetes at 2.2 years lisinopril offered no real benefit and
diabetes (VA mellitus combination resulted in an excessive risk of
NEPHRON-D), vs. losartan hyperkalemia and acute renal
2013 alone failure
Epidemiology of Type 1 18 years Intensive vs. Reno-protective effect of
diabetes diabetes standard intensive control persisted and
interventions and mellitus glycemic resulted in a 45% reduction risk
complications control of microalbuminuria at 18 years
(EDIC/DCCT),
2014
Canagliflozin on Type 2 Terminated Canagliflozin The relative risk for renal events
renal and diabetes at 2.6 years vs. placebo (doubling of creatinine or
cardiovascular mellitus end-stage kidney disease) was
outcomes in significantly lower in the
participants with treatment arm
diabetic kidney
disease
(CREDENCE),
2019
The Dapagliflozin With/ Terminated Dapagliflozin HR for the primary endpoint
and prevention of without at 3 years vs. placebo in was 0.61 (95% confidence
adverse outcomes type 2 patients taking interval [CI) 0.51–0.72;
in chronic kidney diabetes ACE-I or p = 0.000000028). The benefit
disease (DAPA-­ mellitus ARBs of dapagliflozin on the primary
CKD), 2017 endpoint was consistent in
patients with and without
diabetes
HR for secondary endpoints
were as follows: (a) worsening
renal function or death from
kidney failure, 0.56 (95% CI
0.45–0.68; p < 0.0001); (b)
hospitalization for heart failure
or cardiovascular death, 0.71
(95% CI 0.55–0.92; p = 0.0089);
and (c) all-cause mortality, 0.69
(95% CI 0.53–0.88; p = 0.0035)
1 Historical Background of Diabetic Kidney Disease 15

Table 1.1 (continued)

Diabetes Follow-up
Study trial, year type (years) Design (RCT) Outcome
Effect of 5734 type 2.6 years Finerenone During a median follow-up of
Finerenone on 2 DM with vs. placebo 2.6 years, a primary outcome
Chronic Kidney CKD All patients event occurred in 504 of 2833
Disease Outcomes on RAS patients (17.8%) in the
in Type 2 Diabetes blockers finerenone group and 600 of
(FIDELIO-DKD), 2841 patients (21.1%) in the
2020 placebo group (hazard ratio,
0.82; 95% confidence interval
[CI], 0.73 to 0.93; P = 0.001).
Overall, the frequency of
adverse events was similar in
the two groups. The incidence
of hyperkalemia-related
discontinuation of the trial
regimen was higher with
finerenone than with placebo
(2.3% and 0.9%, respectively).
In patients with CKD and type 2
diabetes, treatment with
finerenone resulted in lower
risks of CKD progression and
cardiovascular events than
placebo

function. However, with such stringent control of sugar levels with these types of
reno-protective medications, it also leads to serious adverse events countervailing
the benefits found. Awareness of treating diabetes and associated renal disease must
still be made when treating this cohort.

Conclusion

Over the last several decades we have accumulated substantial knowledge on the
natural history, pathophysiology, and progression of diabetic kidney disease.
Through data from worldwide clinical trials, innovative medical treatments have
been established to slow the progression of this disease. The advancement of mod-
ern medicine has certainly provided a much better prognosis and quality of life in
individuals suffering from this epidemic, diabetic kidney disease.
16 V. Fonseca et al.

References

1. Krall LP, Levine R, Barnett D. The history of diabetes. In: Kahn CR, Weir GC, editors. Joslin’s
diabetes mellitus. Philadelphia: Lea & Febiger; 1994.
2. Aretaeus, De causis et signis acutorum morborum (lib. 2) Francis Adams LL.D., Ed.
3. Stewart CJ. The discovery of diabetic nephropathy: from small print to Centre stage. J Nephrol.
2006;10:S75.
4. Darwin E. Zoonomia (The Laws of Organic Life). 1801.
5. Cotunnius D. De Ischiade Nervosa. Vienna, 1770.
6. Rollo J. Cases of the diabetes mellitus. 2nd ed. London: Dilly; 1798.
7. Cameron JS, Ireland JT, Watkins PJ. The kidney and renal tract. In: Keen HF, Jarrett J, editors.
Complications of diabetes. London: Edward Arnold Ltd.; 1975. p. 99.
8. Rayer P. In: Traite des Maladies du Rein, Vol. 2. Baillere, Tindall, and. Cox, editors. Paris; 1840.
9. Griesinger W. Studien uber diabetes. Archiv Physiologie Heilkunde. 1859;3:1–75.
10. Ebstein W. Weiteres über Diabetes mellitus, insbesondere über die Complicationdesselben mit
Typhus abdominalis. Deutsch Arch fklin Med. 1882;30:1–44.
11. Waku K. Ueber die Verunderung der Glomeruli der Diabetesniere. Tr Jap Path Soc.
1928;18:413–6.
12. Kimmelstiel P, Wilson C. Intercapillary lesions in glomeruli of kidney. Am J Pathol.
1936;12:83.
13. Allen AC. So-called intercapillary glomerulosclerosis—a lesion associated with diabetes.
Arch Pathol. 1941;32:33–51.
14. Foggensteiner L, Mulroy S, Firth J. Management of diabetic nephropathy. J R Soc Med.
2001;94(5):210–7. https://doi.org/10.1177/014107680109400504.
15. Iversen P, Brun C. Aspiration biopsy of the kidney. Am J Med. 1951;11(3):324–30.
16. Gellman DD, Pirani CL, Soothill JF, Muehrcke RC, Kark RM. Diabetic nephropathy. A clini-
cal and pathologic study based on renal biopsies. Medicine (Baltimore). 1959;38:321–67.
17. Irvine E, Rinehart JF, Mortimore GE, Hopper JJ. The ultrastructure of the renal glomerulus in
intercapillary glomerulosclerosis. Am J Pathol. 1956;32:647–53.
18. Østerby-Hansen R. A quantitative estimate of the peripheral glomerular basement membrane
in recent juvenile diabetes. Diabetologia. 1965;1:97–100.
19. Yalow RS, Berson SA. Immunoassay of endogenous plasma insulin in man. J Clin Invest.
1960;39:1157–75.
20. Keen H, Chlouverakis C. An immunoassay method for urinary albumin in low concentrations.
Lancet. 1963;ii:913–6.
21. Viberti GC, Hill RD, Argyropoulos A, Mahmud U, Keen H. Microalbuminuria as a predictor
of clinical nephropathy in insulin-dependent diabetics. Lancet. 1982;i:1430–2.
22. Mogensen DE. Microalbuminuria predicts clinical proteinuria and early mortality in maturity-­
onset diabetes. N Engl J Med. 1984;310:356–60.
23. Mogensen CE. Long-term antihypertensive treatment inhibiting progression of diabetic
nephropathy. Br Med J. 1982;285:685–8.
24. American Diabetes Association. Hypertension management in adults with diabetes. Diabetes
Care. 2004;27(Suppl 1):S65–7.
25. Basso N, Terragno NA. History about the discovery of the renin-angiotensin system.
Hypertension. 2001;38:1246–9.
26. Kofoed-Enevoldsen A, Borch-Johnsen K, Kreiner S, Nerup J, Deckert T. Declining incidence
of persistent proteinuria in type I (insulin-dependent) diabetics. Diabetes. 1987;36:205–9.
27. Krolewski AS, Warram JH, Chriestleib AR, Busick EJ, Kathan CR. The changing natural his-
tory of nephropathy in type I diabetes. Am J Med. 1985;78:785–94.
28. Zatz R, Brenner BM. Pathogenesis of diabetic nephropathy. The hemodynamic view. Am J
Med. 1985;80:443–53.
1 Historical Background of Diabetic Kidney Disease 17

29. Marre M, Chatellier G, Leblanc H, Guyene TT, Menard J, Passa P. Prevention of diabetic
nephropathy with enalapril in normotensive diabetics with microalbuminuria. Br Med
J. 1988;297:1092–5.
30. Lewis EJ, Hunsicker LG, Bain RP, Rohde RD. For the collaborative study group. The
effect of angiotensin-converting enzyme inhibition on diabetic nephropathy. N Engl J Med.
1993;329:1456–62.
31. Lewis EJ, Hunsicker LG, Clarke WR, et al. For the collaborative study group. Renoprotective
effect of the angiotensin-receptor antagonist irbesartan in patients with nephropathy due to
type 2 diabetes. N Engl J Med. 2001;345:851–60.
32. Brenner BM, Cooper ME. de Zeeuw D, et al., for the RENAAL study investigators. Effects of
losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropa-
thy. N Engl J Med. 2001;345:861–9.
33. Barnett AH. Inhibition of the renin-angiotensin system in diabetic patients—beyond HOPE. Br
J Cardiol. 2004;11:123–7.
34. Parving H-H, Mauer M, Ritz E. Diabetic nephropathy. In: Brenner BM, editor. Brenner and
rector’s the kidney. 7th ed. Philadelphia: WB Saunders; 2004. p. 1777–818.
35. The EURODIAB IDDM Complications Study Group. Microvascular and acute complica-
tions in insulin dependent diabetes mellitus: the EURODIAB IDDM complications study.
Diabetologia. 1994;37:278–85.
36. Steffes MW, Sutherland DER, Goetz FC, Rich SS, Mauer SM. Studies of kidney and muscle
biopsy specimens from identical twins discordant for type I diabetes mellitus. N Engl J Med.
1985;312:1282–7.
37. Mauer SM, Goetz FC, McHugh LE, Sutherland DE, Barbosa J, Najarian JS, Steffes MW. Long-­
term study of normal kidneys transplanted into patients with type I diabetes. Diabetes.
1989;38:516–23.
38. Mauer SM, Steffes MW, Connett J, Najarian JS, Sutherland DE, Barbosa J. The development
of lesions in the glomerular basement membrane and mesangium after transplantation of nor-
mal kidneys into diabetic patients. Diabetes. 1983;32:948–52.
39. Wiseman AC. Pancreas transplant options for patients with type 1 diabetes mellitus and
chronic kidney disease: simultaneous pancreas kidney or pancreas after kidney? Curr Opin
Organ Transplant. 2012;17(1):80–6.
40. Bohman S-O, Tyden G, Wilczek H, Lundgren G, Jaremko G, Gunnarsson R, Ostman J,
Groth G. Prevention of kidney graft diabetic nephropathy by pancreas transplantation in man.
Diabetes. 1985;34:306–8.
41. Wilczek HE, Jaremko G, Tyden G, Groth CG. Pancreatic graft protects a simultaneously trans-
planted kidney from developing diabetic nephropathy: a 1 to 6 year follow-up study. Transplant
Proc. 1993;1:1314–5.
42. Young BY, Gill J, Huang E, et al. Living donor kidney versus simultaneous pancreas-­kidney
transplant in type I diabetics: an analysis of the OPTN/UNOS database. Clin J Am Soc
Nephrol. 2009;4:845–52.
43. European Association for the Study of Diabetes (EASD) 48th Annual Meeting: Abstract 149.
Presented October 4, 2012.
44. Melissa Sattley, The history of diabetes mellitus. http://diabeteshealth.com/
read/2008/12/17/715/the-history-of-diabetes/ Accessed: May 2013.
45. Lakhtakia R. The history of diabetes mellitus. Sultan Qaboos Univ Med J. 2013;13(3):368–70.
46. Diabetes Complications and Control Trial Research Group. The effect of intensive treatment of
diabetes on the development and progression of long-term complications of insulin dependent
diabetes mellitus. N Engl J Med. 1993;329:977–86.
47. UKPDS Group. Intensive blood-glucose control with sulphonylureas or insulin compared with
conventional treatment and risk of complications in patients with type 2 diabetes. Lancet.
1998;352:837–53.
48. Ohkubo Y, Kishikawa H, Araki E, Miyata T, Isami S, Motoyoshi S, Kojima Y, Furuyoshi
N, Shichiri M. Intensive insulin therapy prevents the progression of diabetic microvascular
18 V. Fonseca et al.

c­ omplications in Japanese patients with non-insulin-dependent diabetes mellitus: a random-

ized prospective 6-year study. Diabetes Res Clin Pract. 1995;28:103–17.
49. Levin SR, Coburn JW, et al. Effect of intensive glycemic control on microalbuminuria in type
2 diabetes. Veterans affairs cooperative study on glycemic control and complications in type 2
diabetes feasibility trial investigators. Diabetes Care. 2000;23(10):1478–85.
50. Epidemiology of Diabetes Interventions and Complications (EDIC). Design, implementation,
and preliminary results of a long-term follow-up of the diabetes control and complications trial
cohort. Diabetes Care. 1999;22(1):99–111.
51. Coca SG, Ismail-Beigi F, Haq N, Krumholz HM, Parikh CR. Role of intensive glucose control
in development of renal end points in type 2 diabetes mellitus systematic review and meta-­
analysis. Arch Intern Med. 2012;172(10):761–9.
52. Gerstein HC, Miller ME, Byington RP, et al. Effects of intensive glucose lowering in diabetes
study group. Type 2 diabetes. N Engl J Med. 2008;358:2545–59.
53. Patel A, MacMahon S, Chalmers J, Neal B, Billot L, Woodward M, Marre M, Cooper M,
Glasziou P, Grobbee D, Hamet P, Harrap S, Heller S, Liu L, Mancia G, Mogensen CE, Pan
C, Poulter N, Rodgers A, Williams B, Bompoint S, de Galan BE, Joshi R, Travert F. Intensive
blood glucose control and vascular outcomes in patients with type 2 diabetes. N Engl J Med.
2008;358:2560–72.
54. Introduction: Standards of Medical Care in Diabetes—2020 Diabetes Care Jan 2020, 43
(Supplement 1) S1-S2; https://doi.org/10.2337/dc20-­Sint.
55. Rieg T, Vallon V. Development of SGLT1 and SGLT2 inhibitors. Diabetologia.
2018;61:2079–86. https://doi.org/10.1007/s00125-­018-­4654-­7.
56. https://www.niddk.nih.gov/news/archive/2016/story-discovery-sglt2-inhibitors-harnessing-­­
kidneys-help-treat-diabetes.
57. Perkovic V, Jardine MJ, et al. Canagliflozin and renal outcomes in type 2 diabetes and nephrop-
athy. N Engl J Med. 2019;380:2295–306. https://doi.org/10.1056/NEJMoa1811744.
58. https://www.astrazeneca.com/media-centre/press-releases/2020/farxiga-phase-iii-dapa-ckd-­­
trial-will-be-stopped-early-after-overwhelming-efficacy-in-patients-with-chronic-kidney-
disease.html.
59. Menne J, Dumann E, Haller H, Schmidt BMW. Acute kidney injury and adverse renal events
in patients receiving SGLT2-inhibitors: a systematic review and meta-analysis. PLoS Med.
2019;16(12):e1002983. https://doi.org/10.1371/journal.pmed.1002983.
60. Woods TC, Satou R, Miyata K, et al. Canagliflozin prevents intrarenal angiotensinogen aug-
mentation and mitigates kidney injury and hypertension in mouse model of type 2 diabetes
mellitus. Am J Nephrol. 2019;49(4):331–42. https://doi.org/10.1159/000499597.
61. Moore B. On the treatment of diabetes mellitus by acid extract of duodenal mucous membrane.
Biochem J. 1906;1(1):28–38. https://doi.org/10.1042/bj0010028.
62. McIntyre N, Holdsworth CD, Turner DS. New interpretation of oral glucose tolerance. Lancet.
1964;2(7349):20–1.
63. Dupre J, Ross SA, Watson D, Brown JC. Stimulation of insulin secretion by gastric inhibitory
polypeptide in man. J Clin Endocrinol Metab. 1973;37(5):826–8.
64. Bell GI, Santerre RF, Mullenbach GT. Hamster preproglucagon contains the sequence of glu-
cagon and two related peptides. Nature. 1983;302(5910):716–8.
65. Mojsov S, Weir GC, Habener JF. Insulinotropin: glucagon-like peptide I (7-37) co-encoded in
the glucagon gene is a potent stimulator of insulin release in the perfused rat pancreas. J Clin
Invest. 1987;79(2):616–9.
66. Holst JJ, Orskov C, Nielsen OV, Schwartz TW. Truncated glucagon-like peptide I, an insulin-­
releasing hormone from the distal gut. FEBS Lett. 1987;211(2):169–74.
67. Qualmann C, Nauck MA, Holst JJ, et al. Insulinotropic actions of intravenous glucagon-­
like peptide-1 (GLP-1) [7–36 amide] in the fasting state in healthy subjects. Acta Diabetol.
1995;32:13–6. https://doi.org/10.1007/BF00581038.
68. Nauck MA, Kleine N, Orskov C, Holst JJ, Willms B, Creutzfeldt W. Normalization of
fasting hyperglycaemia by exogenous glucagon-like peptide 1 (7-36 amide) in type 2
1 Historical Background of Diabetic Kidney Disease 19

(non-­
­ insulin-­dependent) diabetic patients. Diabetologia. 1993;36(8):741–4. https://doi.
org/10.1007/BF00401145.
69. Robinson LE, Holt TA, Rees K, et al. Effects of exenatide and liraglutide on heart rate, blood
pressure and body weight: systematic review and meta-analysis. BMJ Open. 2013;3:e001986.
https://doi.org/10.1136/bmjopen-­2012-­001986.
70. Mann JFE, Fonseca V, Mosenzon O, et al. Effects of Liraglutide versus placebo on cardiovas-
cular events in patients with type 2 diabetes mellitus and chronic kidney disease. Circulation.
2018;138(25):2908–18. https://doi.org/10.1161/CIRCULATIONAHA.118.036418.
71. Marso SP, Bain SC, Consoli A, Eliaschewitz FG, Jodar E, Leiter LA, et al. Semaglutide and
cardiovascular outcomes in patients with type 2 diabetes. N Engl J Med. 2016;375:1834–44.
72. Hong DS, Kurzrock R, Supko JG, He X, Naing A, Wheler J, et al. A phase I first-in-human trial
of bardoxolone methyl in patients with advanced solid tumors and lymphomas. Clin Cancer
Res. 2012;18:3396–406.
73. N Engl J Med 2013; 369:2492-2503. DOI: 10.1056/NEJMoa1306033.
74. https://doi.org/10.1016/j.kint.2019.05.033.
75. Tanaka K, Watanabe T, Takeuchi A, Ohashi Y, Nitta K, Akizawa T, et al. Cardiovascular events
and death in Japanese patients with chronic kidney disease. Kidney Int. 2017;91:227–34.
76. Cavaiola TS, Pettus JH. Management Of Type 2 Diabetes: Selecting Amongst Available
Pharmacological Agents. [Updated 2017 Mar 31]. In: Feingold KR, Anawalt B, Boyce A,
et al., editors. Endotext [Internet]. South Dartmouth (MA): MDText.com, Inc.; 2000. Available
from: https://www.ncbi.nlm.nih.gov/sites/books/NBK425702/
77. Chan GC, Tang SC. Diabetic nephropathy: landmark clinical trials and tribulations. Nephrol
Dial Transplant. 2016;31:359–68.
78. Bakris GL, et al. Effect of Finerenone on chronic kidney disease outcomes in type 2 diabetes.
N Engl J Med. 383:2219–29. https://doi.org/10.1056/NEJMoa2025.
Chapter 2
Diabetes and Kidney Disease: A Review
of the Clinical Practice Guidelines

Nidhi Aggarwal, Sehrish Ali, and Sankar D. Navaneethan

Introduction

Chronic kidney disease (CKD) among those with diabetes includes both diabetic
and nondiabetic kidney disease. Diabetes causes microvascular changes in the kid-
ney, leading to diabetic kidney disease (DKD). Diabetic kidney disease occurs in
approximately 30% of patients with type 1 diabetes (T1DM) and 40% of patients
with type 2 diabetes (T2DM). It is the leading cause of end-stage kidney disease
(ESKD) in the Western populations, contributing to almost 50% of all cases. Several
societies, such as the Kidney Disease: Improving Global Outcomes (KDIGO),
European Association for the Study of Diabetes in collaboration with the European
Society of Cardiology (ESC/EASD), and American Diabetes Association (ADA),
have issued clinical practice guidelines to guide clinicians manage diabetes in those
with CKD [1–3]. KDIGO clinical practice guidelines provide an assessment of the
strength of recommendation (strong, level 1; weak, level 2) and the quality of the
evidence (A, B, C, D). ESC/EASD guidelines are graded according to the strength
of recommendation (Class I, IIa, IIb, and III) and level of evidence (A, B, and C).
ADA publishes “Standards of Medical Care in Diabetes,” referred to as the Standards
of Care, in which recommendations are assigned ratings of A, B, or C (depending on
the quality of evidence in support of the recommendation) and E (based on expert
opinion) [3]. For these clinical practice guidelines, extensive literature search (such
as MEDLINE, SCOPUS, CENTRAL, etc.) using formal search criteria has been
adopted. In this chapter, we will discuss the following aspects of diagnosis and
treatment in patients with diabetes and CKD based on the evidence-based clinical

N. Aggarwal · S. Ali · S. D. Navaneethan (*)

Selzman Institute for Kidney Health, Section of Nephrology, Department of Medicine, Baylor
College of Medicine, Houston, TX, USA
Section of Nephrology, Michael E. DeBakey Veterans Affairs Medical Center,
Houston, TX, USA
e-mail: [email protected]; [email protected]; [email protected]

© Springer Nature Switzerland AG 2022 21

E. V. Lerma, V. Batuman (eds.), Diabetes and Kidney Disease,
https://doi.org/10.1007/978-3-030-86020-2_2
22 N. Aggarwal et al.

practice guidelines of these societies: (a) glycemic monitoring and targets, (b) use
of antihyperglycemic therapies, (c) blood pressure control and comprehensive man-
agement, (d) lifestyle interventions, and (e) the importance of self-management and
team-based care.

Glycemic Management

Given the significant role that hyperglycemia plays in the development of DKD,
adequate glycemic management is one of the most important and most challenging
aspects of diabetes management, especially in patients with CKD. Hemoglobin A1c
(HbA1c) may be inaccurate in patients with advanced kidney disease, especially in
dialysis patients. Insulin, which has significant metabolism and clearance by the
kidneys, may last longer in the body. Oral antihyperglycemic agents, which are
metabolized or cleared by the kidneys, may accumulate and lead to hypoglycemic
episodes. Many agents need dose adjustments or discontinuation with changes in
kidney function.

Glycemic Monitoring and Targets

Glycemic control in diabetics can be assessed by HbA1c measurement, self-­

monitoring of blood glucose (SMBG), and/or continuous glucose monitoring
(CGM). Early intensive diabetes control, as evidenced by lower HbA1c targets, is
associated with a lower risk of long-term diabetic microvascular complications and
mortality, both in T1DM and T2DM [4, 5]. The Diabetes Control and Complications
Trial (DCCT) showed that when compared to conventional diabetes therapy, inten-
sive therapy in T1DM was associated with a reduction in the incidence of microal-
buminuria and albuminuria. Long-term follow-up of DCCT treatment groups
showed a significant decrease in the development of impaired GFR and hyperten-
sion [4]. Meta-analysis of four large randomized controlled trials in T2DM
(ACCORD, ADVANCE, UKPDS, and VADT) showed beneficial effects of inten-
sive glycemic control with reduced incidence of microvascular complications
including microalbuminuria and macroalbuminuria [6].
All major societies recommend using HbA1c to monitor glycemic control
(Table 2.1). ADA recommends checking HbA1c at least twice a year in patients meet-
ing treatment goals and stable glycemic control, and quarterly in those not meeting
goals and/or in who the treatment has been modified (E) [7]. HbA1c goal of <7% is
recommended by ADA for most patients (A), with lower goals (<6.5%) based on pro-
vider judgment and patient preference in those with no significant hypoglycemia (C).
Higher targets (<8%) are recommended for those with advanced CKD, established
macrovascular complications, limited life expectancy, hypoglycemic unawareness,
risk of medication-induced hypoglycemia, and presence of other comorbidities, or in
2 Diabetes and Kidney Disease: A Review of the Clinical Practice Guidelines 23

Table 2.1 Guidelines recommendations for management of patients with diabetes and CKD
KDIGO
Topic ADA (2021) (2020) ESC and EASD (2019)
HbA1c target <7.0% (A) 6.5–8.0% <7% (IA)
<8%a (B) (1C)
First-line Metformin (A) + Metformin SGLT2i e (IB) or GLP1-­
hypoglycemic SGLT2ib (A) (1B) RAf (IIaB)
agent GLP1-RAc (A) SGLT2i (1A)
GLP1-RAd
(1B)
Physical activity 200–300 min/week (A) 150 min/ ≥150 min/week (IA)
level week (1D)
Protein intake 0.8 g/kg/day (A) 0.8 g/kg/day Less protein is
(2C) recommended
Sodium intake <2300 mg/day (B) <2000 mg/ <2300 mg/day (IA)
day (2C)
Blood pressure <140/90 mm hg (A) – Systolic blood
target pressure < 130 mm hg (IA)
Diastolic blood
pressure < 80 mm hg (IC)
Albuminuria RAAS blocker for UACR RAAS RAAS blocker (IA)
reduction ≥300 mg/g (A) or blocker (1B)
30–299 mg/g (B)
SGLT2i for UACR >300 mg/g
(A)
HbA1c hemoglobin A1c, SGLT2i sodium-glucose cotransporter 2 inhibitors, GLP-1RA glucagon-­
like peptide-1 receptor agonists; RAAS blocker renin-angiotensin-aldosterone system blocker,
UACR urine albumin-to-creatinine ratio
a
For those with history of severe hypoglycemia, limited life expectancy, advanced microvascular
or macrovascular complications, extensive comorbid conditions, or long-standing diabetes in
whom the goal is difficult to achieve
b
For those with eGFR ≥30 ml/min/1.73 m2 and albuminuria ≥30 mg/g creatinine
c
For those with CKD with increased risk of MACE
d
For those who have not achieved individualized glycemic targets despite use of metformin and
SGLT2i, or who are unable to use those medications
e
For those with eGFR 30–90 ml/min/1.73 m2
f
For those with eGFR ≥30 ml/min/1.73 m2

those who the goal is difficult to achieve despite the use of multiple agents (B). Similar
recommendations for an individualized target ranging from <6.5% to <8% are made
by KDIGO (1C). ESC/EASD also recommends a target of <7% to reduce microvas-
cular (1A) and macrovascular complications (IIa/C). HbA1c assessment may be inac-
curate in certain conditions, such as in the presence of hemoglobin variants, as well as
conditions that affect red blood cell turnover (hemolytic and other anemias, recent
blood transfusion, glucose-6-­phosphate dehydrogenase deficiency, use of erythropoi-
etin-stimulating agents, advanced CKD including ESKD, and pregnancy). Another
limitation of this test is that it does not provide a measure of glycemic variability or
hypoglycemia. KDIGO guidelines recommend that clinical judgment should be exer-
cised when using HgbA1c in such conditions.
24 N. Aggarwal et al.

Diabetic patients with markedly labile blood glucose values who are more prone
to hypoglycemic events, such as T1DM and T2DM with severe insulin deficiency,
need daily glucose monitoring. In such situations, SMBG by the patient is a useful
tool that aids in self-management and medication titration. CGM can play an impor-
tant role in assessing the safety and efficacy of treatment in patients who require
intensive insulin regimens. ESC/EASD (IIa/A) and KDIGO suggest using SMBG or
CGM to facilitate optimal glycemic control and avoid the risk of hypoglycemia, and
a glucose management indicator derived from CGM to assess glycemic control for
patients in whom HbA1c is not concordant with their clinical symptoms or mea-
sured glucose levels [1, 2]. For certain patient population, CGM metrics like “Time
in Range (TIR)” and “Time in Hypoglycemia” may be used in place of HbA1c as
glycemic targets and parameters for the reevaluation of the treatment regimen. With
the use of CGM, ADA recommends a goal TIR of >70% with a time below the range
of 4% as a parallel goal to HbA1c (B).

Medical Therapy for Hyperglycemia

The goal of therapy in diabetes is to manage hyperglycemia and prevent and treat its
associated microvascular and macrovascular complications. While drug therapy in
T1DM is essentially centered around insulin, more options are available to patients
with T2DM.

Older Agents

Apart from lifestyle modification, multiple oral and injectable antihyperglycemic

drugs are available for glycemic management in patients with T2DM. When select-
ing glucose-lowering medications for patients with T2DM and CKD, due consider-
ation should be given to a particular agent’s risk of hypoglycemia and limitations of
use in reduced GFR. Since DKD is a risk factor for developing cardiovascular dis-
ease (CVD), medication safety and efficacy in the prevention and treatment of CVD
should also be considered. Cost and patient preference will also guide the use of one
agent over the other.
For a long time, sulfonylureas and metformin were the primary oral agents. In
1998, the UK Prospective Diabetes Study showed the benefit of metformin in reduc-
ing the risk of mortality in overweight patients with T2DM by 36% compared to
conventional therapy. Also, metformin prevents weight gain, helps achieve weight
loss, and reduces cardiovascular events [8]. Compared with sulfonylureas, metfor-
min is associated with less risk of hypoglycemia, and in comparison to thiazolidin-
ediones, it has reduced incidences of edema, congestive heart failure, and weight
gain. Metformin is recommended as the first-line agent for treating T2DM patients
with CKD with eGFR ≥30 ml/min/1.73m2 by ADA (A) and KDIGO (1B). Based on
2 Diabetes and Kidney Disease: A Review of the Clinical Practice Guidelines 25

ESC/EASD guidelines, metformin should be considered in T2DM patients without

CVD and for those at moderate CVD risk (IIa). In patients with reduced eGFR
(<45 ml/min/1.73m2), the US Food and Drug Administration recommends that met-
formin should not be initiated and an existing dose should be reduced. Metformin
should be temporarily discontinued before the use of iodinated contrast in those
with eGFR between 30 and 60 ml/min/1.73m2. Its use is contraindicated in patients
when eGFR is <30 ml/min/1.73 m2 due to increased risk of lactic acidosis, which is
endorsed by clinical practice guidelines.
If the glycemic target is not achieved after about 3 months of treatment with
metformin, ADA recommends adding one of the six classes of antihyperglycemic
drugs: sulfonylureas, thiazolidinediones (TZD), sodium-glucose cotransporter 2
inhibitor (SGLT2i), glucagon-like peptide-1 receptor agonists (GLP-1RA), dipepti-
dyl peptidase-4 inhibitors (DPP-4i), or basal insulin. The choice of this additional
drug will be based on the specific effects of each class of medication, their side-­
effect profile, cost, level of kidney function, and patient factors (E). Medications
cleared by the kidneys such as sulfonylureas accumulate with reduced GFR and,
thus, increase the risk of hypoglycemia. Thiazolidinediones (pioglitazone and rosi-
glitazone) as well as saxagliptin (a DPP4i) are associated with an increased risk of
incident heart failure and are, therefore, not recommended for use in patients with
or at increased risk of heart failure (ESC/EASD, III).

Newer Agents

Several newer antihyperglycemic agents, including SGLT2i and GLP-1RA, have

been tested in large trials and have become available for clinical use in recent years.

Sodium-Glucose Cotransporter 2 Inhibitors (SGLT2i)

The most important of the newer classes of antihyperglycemic drugs are the SGLT2i.
SGLT2i directly affect the sodium-glucose cotransporter 2 in the proximal tubule of
the kidneys and thereby inhibit tubular glucose and sodium reabsorption and reduce
intraglomerular pressure albuminuria, oxidative stress, and inflammation in the kid-
ney and, ultimately, reduce risk of CKD progression and CVD events [9]. Besides,
they cause modest volume contraction, systemic blood pressure reduction, and
weight loss. Major adverse effects are diabetic ketoacidosis, lower extremity ampu-
tations, and genital mycotic infections. They can cause an initial decrease in GFR
due to hemodynamic effects, but this is usually reversible and rarely needs therapy
discontinuation. Long-term use of SGLT2i is associated with the preservation of
GFR. Several large cardiovascular outcomes trials with SGLT2i in patients with
T2DM at high risk of CVD or existing CVD (EMPA-REG OUTCOME, CANVAS,
DECLARE-TIMI 58) have examined kidney effects as secondary outcomes [10–
12]. Recent trials, focused on primary kidney outcomes using SGLT2i (CREDENCE
26 N. Aggarwal et al.

and DAPA-CKD), have shown beneficial results with these medications and have
established SGLT2i as an important class of medications in the management of
DKD [13, 14]. Canagliflozin can be used in patients with reduced GFR (above
30 ml/min/1.73m2). Dapagliflozin has been studied in populations with eGFR down
to 25 ml/min/1.73m2 and has also shown efficacy in nondiabetic CKD [14].
Based on the results of these trials, the use of an SGLT2i is recommended by
KDIGO (1A), ADA (A), and ESC/EASD (IB) for patients with T2DM and DKD
with eGFR ≥30 ml/min/1.73m2 and urinary albumin/creatinine of >300 mg/g [1, 2,
15]. ADA guidelines recommend that when an additional agent required to be added
to metformin or metformin cannot be used or tolerated, an SGLT2i or GLP-1RA
should be considered. Unless contraindicated, KDIGO recommends using metfor-
min along with an SGLT2i as the first-line therapy in patients with T2DM and CKD
(1A). For patients not meeting their glycemic targets despite using other antihyper-
glycemic agents and who can tolerate further lowering of HbA1c, KDIGO suggests
adding an SGLT2i. For patients meeting their glycemic target or at risk of hypogly-
cemia with further lowering of A1c, agents other than metformin can be reduced to
allow the addition of SGLT2i.

Glucagon-Like Peptide-1 Receptor Agonists (GLP-1RA)

GLP-1RA stimulate the incretin hormone pathway and thereby enhance the glucose-­
dependent insulin secretion, suppress postprandial glucagon release, slow the gas-
tric emptying, and improve satiety through effects on the central regulation of
feeding. These actions assist in improving glycemic control, weight loss, and reduc-
ing blood pressure. Independent of the glucose-lowering effects, GLP-1RA also
have direct nephro-protective effects. These agents inactivate sodium hydrogen
exchanger 3 in the brush border of the proximal tubular cells of kidneys and pro-
mote secretion of atrial natriuretic peptide, thereby inducing natriuresis and diuresis
and thus improving blood pressure.
In large cardiovascular outcomes trials (ELIXA, LEADER, SUSTAIN-6,
REWIND) in patients with or at high risk of CVD, GLP1-RAs such as lixisenatide
[16], liraglutide [17, 18], semaglutide [19], and dulaglutide [20] have shown benefi-
cial kidney effects as secondary outcomes (preservation of eGFR and prevention of
worsening albuminuria). Based on the data from these trials, and independent of the
glycemic targets, ADA recommends using an SGLT2i or GLP-1RA with cardiovas-
cular benefit in patients with established atherosclerotic CVD, established kidney
disease, or heart failure (A) [21]. KDIGO also recommends using a long-acting
GLP-1RA as an agent of choice in patients who cannot achieve glycemic target
despite the use of metformin and SGLT2i (1B). Efficacy of SGLT2i in improving
glycemic control is reduced at eGFR <45 ml/min/1.73m2. To achieve additional
glycemic control at that level, a long-acting GLP-1RA should be considered [1].
Liraglutide, semaglutide, and dulaglutide are minimally cleared by kidneys and,
therefore, do not require any dose adjustment even with eGFR as low as 15 ml/
2 Diabetes and Kidney Disease: A Review of the Clinical Practice Guidelines 27

min/1.73m2. For T2DM patients who need the addition of an injectable agent on top
of oral agents to achieve glycemic target, ADA recommends preferred use of
GLP-1RA over insulin (B).

Insulin Use in Type 2 DM

Insulin use in T2DM is recommended by ADA (E) for those patients who present
with significantly elevated blood glucose levels (≥300 mg/dl), or HbA1c levels of
>10%, or symptoms of hyperglycemia (polyuria, polydipsia), or those with cata-
bolic features (weight loss, hypertriglyceridemia, ketosis) [21]. Many patients with
long-standing T2DM may eventually require insulin therapy in addition or instead
of other agents. Basal long-acting insulin can be added to metformin or other oral
drugs to improve glycemic control. It helps to reduce hepatic glucose production
and controls hyperglycemia overnight and between meals. Some patients may also
require the addition of doses of prandial short-acting insulin. In patients with a sub-
stantial reduction of kidney function, insulin doses can be titrated by patients based
on self-monitoring of glucose levels to avoid hypoglycemia.

Hypertension Control in DKD

Hypertension is common comorbidity among patients that have both diabetes and
CKD. Approximately 58–70% of patients that are diagnosed with diabetes also
have a diagnosis of hypertension. Additionally, many patients have been known to
develop hypertension before displaying signs of kidney disease [22]. Alternatively,
with declining eGFR, the incidence of developing hypertension increases. Thus,
optimal control of hypertension in patients with DKD is crucial to CVD risk reduc-
tion and slowing the progression of kidney disease.

Hypertension Management

Treatment of hypertension in patients with DKD involves both pharmacologic and

non-pharmacologic measures to reduce cardiovascular risk and delay complica-
tions. Non-pharmacologic interventions include lifestyle and dietary modifications,
physical activity, and lipid control, which have been discussed in other sections of
this chapter.
Managing hypertension via RAAS inhibition in patients with DKD remains the
cornerstone of pharmacological therapy. RAAS inhibition is achieved using ACE
inhibitors (ACEi) or angiotensin receptor blockers (ARB) to improve albuminuria,
cardiovascular risk reduction, and reduction of DKD progression [23–25]. KDIGO
28 N. Aggarwal et al.

clinical practice guidelines recommend using either ACEi or ARB in their maxi-
mally tolerated doses in patients with DKD and hypertension (1B). After initiation
of therapy with either agent, kidney function is to be monitored. Unless an increase
in serum creatinine by >30% is observed within 4 weeks, the agent is to be contin-
ued [1]. ESC/EASD guidelines also recommend using either ACEi or ARB in their
maximally tolerated doses for treatment of hypertension to achieve a blood pressure
target of 120/80 mm Hg or at least targeting 130/80 mm Hg in patients with diabetes
(IA) [2]. ADA guidelines encourage lifestyle intervention for patients with blood
pressure ≥ 120/80 mm Hg with initiation of antihypertensive therapy once blood
pressure is ≥140/90 (A). Initial antihypertensive therapy is recommended with
ACEi or ARB, at its maximum tolerated dose (C) [26].
Given the advantages of RAAS inhibition with monotherapy, treatment of DKD
and hypertension with dual agents has also been studied. However, long-term stud-
ies including the Ongoing Telmisartan Alone and in Combination with Ramipril
Global Endpoint Trial (ONTARGET) and the Veterans Affairs Nephropathy in
Diabetes (VA NEPHRON-D) have failed to show an improvement in cardiovascular
outcomes with dual agents. Rather they have shown an increased risk of acute kid-
ney injury and hyperkalemia [27, 28]. If optimal hypertension control is not achieved
with single agent RAAS blocker, other agents including diuretics, calcium channel
blockers (CCB), and/or beta-blockers may be used. CCB in combination with ACEi
or ARB may help improve BP in addition to albuminuria [29]. If hypertension per-
sists, despite management with three antihypertensive agents, the use of mineralo-
corticoid receptor antagonist may be considered as they have also been shown to
help reduce BP and improve albuminuria [30].

Albuminuria Management

Proteinuria is a hallmark finding in patients with DKD and has been independently
associated with increased cardiovascular risk and kidney disease progression.
Consequently, in patients with DKD that are normotensive, ACEi or ARB may be
considered if albuminuria is present to minimize this risk as suggested in the
RENAAL (Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist
Losartan) and INNOVATION (The Incipient to Overt: Angiotensin II Blocker,
Telmisartan, Investigation on Type 2 Diabetic Nephropathy) trials [25, 31].
Conversely, if non-albuminuria and normotension is present, RAAS inhibition is
not likely to help and has not been shown to reduce the incidence of either CKD
progression or albuminuria [32]. ADA recommends ACEi or ARB for albuminuria
≥300 mg/g (A) or 30–299 mg/g (B) [26]. SGLT2i is another agent to be considered
per ADA clinical practice for urinary albumin creatinine >300 mg/g (A) [15].
KDIGO guidelines also recommend treatment with an ACEi or ARB for patients
with diabetes, hypertension, and albuminuria (1B) [1]. ESC and EASD guidelines
recommend treatment with ACEi or ARB for patients with hypertension and diabe-
tes, especially with albuminuria or left ventricular hypertrophy (IA) [2]. If
2 Diabetes and Kidney Disease: A Review of the Clinical Practice Guidelines 29

albuminuria is <30 mg/24 h, other agents including diuretics and dihydropyridine

calcium channel blockers may be considered, which have also demonstrated a
reduction in cardiovascular risk.

Lifestyle Management

Tobacco Cessation

Tobacco use is a risk factor for developing CKD and CVD and is one of the leading
causes of mortality worldwide [33, 34]. Avoiding tobacco products may provide
health benefits and reduce the incidence of these disease processes and mortality.
Although no randomized control trials have examined the effects of tobacco cessa-
tion on patients with diabetes and kidney disease, a small randomized trial did show
increased BP values and DKD progression in smokers [35]. Additionally, a prospec-
tive cohort study reported a higher cardiovascular risk in current or prior smokers
with diabetes and kidney disease [36]. Numerous other studies have shown an asso-
ciation between tobacco cessation and decreased albuminuria in patients with CKD,
and retardation of diabetic kidney disease [37, 38]. Hence, recently released KDIGO
clinical practice guidelines recommend tobacco cessation for those with diabetes
and kidney disease (1D) [1, 2].

Dietary Modifications

A well-balanced diet is an essential factor in maintaining optimal health. ADA rec-

ommends weight loss and the Dietary Approaches to Stop Hypertension (DASH)
diet in patients with BP > 120/80 and DM (A) [26]. This diet focuses on low sodium
and increased potassium intake. However, as a patient’s kidney disease progresses,
the importance of limiting certain foods that may lead to various electrolyte abnor-
malities and volume imbalances increases. Limiting foods rich in potassium or
phosphorus is often necessary in CKD to prevent hyperkalemia or hyperphosphate-
mia. Additionally, increased protein intake can lead to increased acid load, which
can be associated with worsening metabolic acidosis in patients with advanced kid-
ney disease. ADA recommends protein intake of approximately 0.8 g/kg body
weight per day in patients with CKD and diabetes (A) [15]. KDIGO also recom-
mends restricting dietary protein intake in patients with diabetes and CKD to 0.8 g/
kg/day (2C) to help limit glomerular hyperfiltration and reduce kidney disease pro-
gression [1, 39]. For patients that are on kidney replacement therapy, ADA recom-
mends increasing protein intake to avoid malnutrition (B) [15]. KDIGO recommends
a protein intake of 1–1.2 g/kg/day to counteract their high catabolic state and nega-
tive nitrogen balance [1]. KDIGO and ESC/EASD guidelines recommend patients
with DKD to have a diet rich in vegetables, fruits, whole grains, fibers, legumes,
30 N. Aggarwal et al.

plant-based proteins, unsaturated fats, and nuts (IA). On the other hand, processed
foods, carbohydrates, and alcohol consumption should be limited [1, 2].
Another risk factor that leads to increased blood pressure, worsening CV func-
tion, and kidney disease progression is sodium [40]. Increased sodium intake pro-
motes water reabsorption contributing to hypervolemia. Consequently, sodium
restriction has been studied considerably in many trials over recent years [41, 42].
Restricting sodium in the diet improves the effect of RAAS blockade and improves
blood pressure, which is associated with decreased CV events, reduced stroke risk,
and decreased CKD progression [43, 44]. Additionally, limiting sodium intake may
improve hypervolemia in addition to proteinuria [45]. KDIGO recommends limit-
ing sodium intake to less than 2 g per day in patients with diabetes and CKD (2C)
[1]. ADA recommends sodium restriction to 2.3 g per day in patients with prediabe-
tes and diabetes (B) [46]. ESC/EASD guidelines recommend limiting sodium intake
to <2.3 g per day in patients with DKD (IA) [2].

Physical Activity and Exercise

Exercise and physical activity have a positive correlation with a healthy lifestyle.
However, many of the patients with CKD and DM are sedentary or have low levels
of physical activity, which places them at an even higher risk of CVD and mortality.
Many studies have shown a benefit of physical activity in CKD patients, including
improved blood pressure, increased capacity, cognitive benefits, CV function, and
improved quality of life [47, 48]. Although there is limited data on physical activity
in patients with diabetes and CKD, increased physical activity likely brings similar
advantages in this population in addition to reducing HbA1c levels [49, 50]. ADA
clinical practice encourages 200–300 min of physical activity per week (A) [51].
ESC/EASD guidelines recommend aerobic and resistance training for at least
150 min per week (IA) to improve glycemic control, lipid levels, and hypertension
[2]. In line with the 2019 American College of Cardiology/American Heart
Association guidelines, KDIGO clinical practice guidelines also recommend at
least 150 min per week of accumulated moderate-intensity physical activity in
patients with DKD (1D) [1, 52].

Self-management Programs and Team-Based Care

Self-management skills are critical for those with diabetes and kidney disease.
Several diabetes self-management educational programs have been developed to
empower and enable individuals to build self-management knowledge and skills.
Overall goals of these programs are to reduce long-term microvascular and macro-
vascular complications, severe hypoglycemia, and diabetic ketoacidosis and to opti-
mize well-being, quality of life, and treatment satisfaction. These programs can be
2 Diabetes and Kidney Disease: A Review of the Clinical Practice Guidelines 31

delivered face-to-face as one-to-one or group-based programs or via technology

platforms by different members of health-care teams. Systematic reviews in the
general population with diabetes have shown that reducing clinical risk factors in
self-management education programs is likely to offer cost savings in the long-­
term. Therefore, KDIGO clinical practice guidelines recommend a structured self-
management educational program be implemented for the care of people with
diabetes and CKD (1C) [1]. These guidelines also recognize the importance of
team-based care and suggest that policymakers and institutional decision-makers
should implement team-based, integrated care focused on risk evaluation and patient
empowerment to provide comprehensive care in patients with diabetes and CKD.

References

1. KDIGO. 2020 clinical practice guideline for diabetes Management in Chronic Kidney Disease.
Kidney Int. 2020;98(4s):S1–s115.
2. Cosentino F, Grant PJ, Aboyans V, Bailey CJ, Ceriello A, Delgado V, et al. 2019 ESC
Guidelines on diabetes, pre-diabetes, and cardiovascular diseases developed in collaboration
with the EASD: The Task Force for diabetes, pre-diabetes, and cardiovascular diseases of
the European Society of Cardiology (ESC) and the European Association for the Study of
Diabetes (EASD). Eur Heart J. 2019;41(2):255–323.
3. Introduction: Standards of Medical Care in Diabetes—2021. Diabetes Care.
2021;44(Supplement 1):S1–2.
4. de Boer IH. Kidney disease and related findings in the diabetes control and complica-
tions trial/epidemiology of diabetes interventions and complications study. Diabetes Care.
2014;37(1):24–30.
5. Laiteerapong N, Ham SA, Gao Y, Moffet HH, Liu JY, Huang ES, et al. The legacy effect in
type 2 diabetes: impact of early glycemic control on future complications (The Diabetes &
Aging Study). Diabetes Care. 2019;42(3):416–26.
6. Zoungas S, Arima H, Gerstein HC, Holman RR, Woodward M, Reaven P, et al. Effects of
intensive glucose control on microvascular outcomes in patients with type 2 diabetes: a meta-­
analysis of individual participant data from randomised controlled trials. Lancet Diabetes
Endocrinol. 2017;5(6):431–7.
7. Glycemic targets: standards of medical Care in Diabetes—2021. Diabetes Care.
2021;44(Supplement 1):S73–84.
8. UK Prospective Diabetes Study (UKPDS) Group. Effect of intensive blood-glucose control
with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34).
Lancet. 1998;352(9131):854–65.
9. Zelniker TA, Braunwald E. Cardiac and renal effects of sodium-glucose co-transporter 2 inhib-
itors in diabetes: JACC state-of-the-art review. J Am Coll Cardiol. 2018;72(15):1845–55.
10. Zinman B, Wanner C, Lachin JM, Fitchett D, Bluhmki E, Hantel S, et al. Empagliflozin, car-
diovascular outcomes, and mortality in type 2 diabetes. N Engl J Med. 2015;373(22):2117–28.
11. Neal B, Perkovic V, Mahaffey KW, de Zeeuw D, Fulcher G, Erondu N, et al. Canagliflozin and
cardiovascular and renal events in type 2 diabetes. N Engl J Med. 2017;377(7):644–57.
12. Wiviott SD, Raz I, Bonaca MP, Mosenzon O, Kato ET, Cahn A, et al. Dapagliflozin and car-
diovascular outcomes in type 2 diabetes. N Engl J Med. 2019;380(4):347–57.
13. Perkovic V, Jardine MJ, Neal B, Bompoint S, Heerspink HJL, Charytan DM, et al. Canagliflozin
and renal outcomes in type 2 diabetes and nephropathy. N Engl J Med. 2019;380(24):2295–306.
14. Heerspink HJL, Stefansson BV, Correa-Rotter R, Chertow GM, Greene T, Hou FF, et al.
Dapagliflozin in patients with chronic kidney disease. N Engl J Med. 2020;383(15):1436–46.
32 N. Aggarwal et al.

15. Microvascular complications and foot care: standards of medical Care in Diabetes—2021.
Diabetes Care. 2021;44(Supplement 1):S151–67.
16. Pfeffer MA, Claggett B, Diaz R, Dickstein K, Gerstein HC, Køber LV, et al. Lixisenatide
in patients with type 2 diabetes and acute coronary syndrome. N Engl J Med.
2015;373(23):2247–57.
17. Marso SP, Daniels GH, Brown-Frandsen K, Kristensen P, Mann JFE, Nauck MA, et al.
Liraglutide and cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2016;375(4):311–22.
18. Mann JFE, Ørsted DD, Brown-Frandsen K, Marso SP, Poulter NR, Rasmussen S, et al.
Liraglutide and renal outcomes in type 2 diabetes. N Engl J Med. 2017;377(9):839–48.
19. Marso SP, Bain SC, Consoli A, Eliaschewitz FG, Jódar E, Leiter LA, et al. Semaglutide and car-
diovascular outcomes in patients with type 2 diabetes. N Engl J Med. 2016;375(19):1834–44.
20. Gerstein HC, Colhoun HM, Dagenais GR, Diaz R, Lakshmanan M, Pais P, et al. Dulaglutide
and cardiovascular outcomes in type 2 diabetes (REWIND): a double-blind, randomised
placebo-­controlled trial. Lancet. 2019;394(10193):121–30.
21. Pharmacologic approaches to glycemic treatment: standards of medical Care in Diabetes—2021.
Diabetes Care. 2021;44(Supplement 1):S111–24.
22. Van Buren PN, Toto R. Hypertension in diabetic nephropathy: epidemiology, mechanisms, and
management. Adv Chronic Kidney Dis. 2011;18(1):28–41.
23. Lewis EJ, Hunsicker LG, Bain RP, Rohde RD. The effect of angiotensin-converting-­
enzyme inhibition on diabetic nephropathy. The collaborative study group. N Engl J Med.
1993;329(20):1456–62.
24. Lewis EJ, Hunsicker LG, Clarke WR, Berl T, Pohl MA, Lewis JB, et al. Renoprotective effect
of the angiotensin-receptor antagonist irbesartan in patients with nephropathy due to type 2
diabetes. N Engl J Med. 2001;345(12):851–60.
25. Keane WF, Brenner BM, de Zeeuw D, Grunfeld JP, McGill J, Mitch WE, et al. The risk of
developing end-stage renal disease in patients with type 2 diabetes and nephropathy: the
RENAAL study. Kidney Int. 2003;63(4):1499–507.
26. 10. Cardiovascular disease and risk management: standards of medical Care in Diabetes-2021.
Diabetes Care. 2021;44(Suppl 1):S125–50.
27. Mann JF, Schmieder RE, McQueen M, Dyal L, Schumacher H, Pogue J, et al. Renal outcomes
with telmisartan, ramipril, or both, in people at high vascular risk (the ONTARGET study): a
multicentre, randomised, double-blind, controlled trial. Lancet. 2008;372(9638):547–53.
28. Fried LF, Emanuele N, Zhang JH, Brophy M, Conner TA, Duckworth W, et al. Combined
angiotensin inhibition for the treatment of diabetic nephropathy. N Engl J Med.
2013;369(20):1892–903.
29. Toto RD. Management of hypertensive chronic kidney disease: role of calcium channel block-
ers. J Clin Hypertens (Greenwich). 2005;7(4 Suppl 1):15–20.
30. Alexandrou ME, Papagianni A, Tsapas A, Loutradis C, Boutou A, Piperidou A, et al. Effects of
mineralocorticoid receptor antagonists in proteinuric kidney disease: a systematic review and
meta-analysis of randomized controlled trials. J Hypertens. 2019;37(12):2307–24.
31. Makino H, Haneda M, Babazono T, Moriya T, Ito S, Iwamoto Y, et al. Prevention of transition
from incipient to overt nephropathy with telmisartan in patients with type 2 diabetes. Diabetes
Care. 2007;30(6):1577–8.
32. Haller H, Ito S, Izzo JL Jr, Januszewicz A, Katayama S, Menne J, et al. Olmesartan for the delay
or prevention of microalbuminuria in type 2 diabetes. N Engl J Med. 2011;364(10):907–17.
33. Pan A, Wang Y, Talaei M, Hu FB. Relation of smoking with Total mortality and cardiovas-
cular events among patients with diabetes mellitus: a meta-analysis and systematic review.
Circulation. 2015;132(19):1795–804.
34. Smoking prevalence and attributable disease burden in 195 countries and territories,
1990-2015: a systematic analysis from the global burden of disease study 2015. Lancet.
2017;389(10082):1885–906.
35. Sawicki PT, Mühlhauser I, Bender R, Pethke W, Heinemann L, Berger M. Effects of smok-
ing on blood pressure and proteinuria in patients with diabetic nephropathy. J Intern Med.
1996;239(4):345–52.
2 Diabetes and Kidney Disease: A Review of the Clinical Practice Guidelines 33

36. Xia J, Wang L, Ma Z, Zhong L, Wang Y, Gao Y, et al. Cigarette smoking and chronic kidney
disease in the general population: a systematic review and meta-analysis of prospective cohort
studies. Nephrol Dial Transplant. 2017;32(3):475–87.
37. Sawicki PT, Didjurgeit U, Mühlhauser I, Bender R, Heinemann L, Berger M. Smoking is
associated with progression of diabetic nephropathy. Diabetes Care. 1994;17(2):126–31.
38. Gambaro G, Bax G, Fusaro M, Normanno M, Manani SM, Zanella M, et al. Cigarette smoking
is a risk factor for nephropathy and its progression in type 2 diabetes mellitus. Diabetes Nutr
Metab. 2001;14(6):337–42.
39. Klahr S, Buerkert J, Purkerson ML. Role of dietary factors in the progression of chronic renal
disease. Kidney Int. 1983;24(5):579–87.
40. Mozaffarian D, Fahimi S, Singh GM, Micha R, Khatibzadeh S, Engell RE, et al. Global sodium
consumption and death from cardiovascular causes. N Engl J Med. 2014;371(7):624–34.
41. Lambers Heerspink HJ, Holtkamp FA, Parving HH, Navis GJ, Lewis JB, Ritz E, et al.
Moderation of dietary sodium potentiates the renal and cardiovascular protective effects of
angiotensin receptor blockers. Kidney Int. 2012;82(3):330–7.
42. Cook NR, Cutler JA, Obarzanek E, Buring JE, Rexrode KM, Kumanyika SK, et al. Long term
effects of dietary sodium reduction on cardiovascular disease outcomes: observational follow-
­up of the trials of hypertension prevention (TOHP). BMJ. 2007;334(7599):885–8.
43. Health effects of dietary risks in 195 countries, 1990-2017: a systematic analysis for the Global
Burden of Disease Study 2017. Lancet. 2019;393(10184):1958–72.
44. Humalda JK, Navis G. Dietary sodium restriction: a neglected therapeutic opportunity in
chronic kidney disease. Curr Opin Nephrol Hypertens. 2014;23(6):533–40.
45. McMahon EJ, Bauer JD, Hawley CM, Isbel NM, Stowasser M, Johnson DW, et al. A random-
ized trial of dietary sodium restriction in CKD. J Am Soc Nephrol. 2013;24(12):2096–103.
46. 5. Facilitating behavior change and Well-being to improve health outcomes: standards of med-
ical Care in Diabetes-2021. Diabetes Care. 2021;44(Suppl 1):S53–72.
47. Thompson S, Wiebe N, Padwal RS, Gyenes G, Headley SAE, Radhakrishnan J, et al. The
effect of exercise on blood pressure in chronic kidney disease: a systematic review and meta-­
analysis of randomized controlled trials. PLoS One. 2019;14(2):e0211032.
48. Heiwe S, Jacobson SH. Exercise training in adults with CKD: a systematic review and meta-­
analysis. Am J Kidney Dis. 2014;64(3):383–93.
49. Afsar B, Siriopol D, Aslan G, Eren OC, Dagel T, Kilic U, et al. The impact of exercise on phys-
ical function, cardiovascular outcomes and quality of life in chronic kidney disease patients: a
systematic review. Int Urol Nephrol. 2018;50(5):885–904.
50. Vanhees L, Geladas N, Hansen D, Kouidi E, Niebauer J, Reiner Z, et al. Importance of charac-
teristics and modalities of physical activity and exercise in the management of cardiovascular
health in individuals with cardiovascular risk factors: recommendations from the EACPR. Part
II. Eur J Prev Cardiol. 2012;19(5):1005–33.
51. 8. obesity management for the treatment of type 2 diabetes: standards of medical care in dia-
betes-­2021. Diabetes Care. 2021;44(Suppl 1):S100–10.
52. Arnett DK, Khera A, Blumenthal RS. 2019 ACC/AHA guideline on the primary preven-
tion of cardiovascular disease: part 1, lifestyle and behavioral factors. JAMA Cardiol.
2019;4(10):1043–4.
 Part I
Natural Course, Pathogenesis,
Morphology and Genetics
Chapter 3
Diabetic Kidney Disease: Scope
of the Problem

Jing Chen

Diabetes is the leading cause of chronic kidney disease (CKD) and end-stage kidney
disease (ESKD) in the United States and worldwide [1, 2]. Approximately 30–40%
of persons with diabetes develop diabetic nephropathy, manifested as albuminuria
and/or decreased glomerular filtration rate [3]. Higher levels of albuminuria and
lower levels of estimated glomerular filtration rate (eGFR) independently increase
the risk for cardiovascular events, ESKD, and death [4, 5].

Epidemiology of Diabetic Kidney Disease

Prevalence of diabetes has reached epidemic proportions in the world. According to

the International Diabetes Federation, the global diabetes prevalence in 2019 is esti-
mated to be 9.3% (463 million people), rising to 10.2% (578 million) by 2030 and
10.9% (700 million) by 2045. The prevalence is higher in urban (10.8%) than rural
(7.2%) areas and in high-income (10.4%) than low-income countries (4.0%). The
prevalence of diabetes in women in 2019 is estimated to be 9.0% and 9.6% in men.
The increase of diabetes prevalence with age leads to a prevalence of 19.9%
(111.2 million) in people aged 65–79 years. The global prevalence of impaired glu-
cose tolerance is estimated to be 7.5% (374 million) in 2019 and projected to reach
8.0% (454 million) by 2030 and 8.6% (548 million) by 2045 [6]. In the United
States, 31 million adults aged 20–79 years had diabetes in 2019, and the number is
expected to rise to 34.4 million by 2030 and 36.0 million by 2045 [6].
With the global epidemic of diabetes, diabetic kidney disease has become an
important clinical and public health challenge. In 2017, the age-standardized global

J. Chen (*)
Department of Medicine, Tulane University School of Medicine, New Orleans, LA, USA
e-mail: [email protected]

© Springer Nature Switzerland AG 2022 37

E. V. Lerma, V. Batuman (eds.), Diabetes and Kidney Disease,
https://doi.org/10.1007/978-3-030-86020-2_3
38 J. Chen

Table 3.1 Prevalence (95% confidence interval) of diabetic versus nondiabetic kidney disease
versus in the US population, NHANES 2009–2014
CKD UACR ≥300 mg/g eGFR <60 ml/min per 1.73 m2
Diabetes, % 25 (21 to 28) 4.6 (3.4 to 5.8) 12 (9 to 15)
No diabetes, % 5.3 (4.6 to 5.9) 0.3 (0.2 to 0.5) 2.5 (2.0 to 3.0)
Data are adopted from Zelnick et al. [8]
NHANES National Health and Nutrition Examination Survey, CKD chronic kidney disease, UACR
urine albumin-to-creatinine ratio, eGFR estimated glomerular filtration rate

prevalence of diabetic kidney disease (DKD) in men and women was 15.48/1000
and 16.50/1000, respectively [7]; and there were an estimated 219,451 deaths that
were attributed to DKD among men and women, respectively. These deaths
accounted for about 34% of all CKD deaths among men in 2017 and 36% in women.
These proportions have increased since 1990, where DKD deaths were 29% of all
CKD deaths in men and 32% of all CKD deaths in women [7]. According to data
from National Health and Nutrition Examination Survey from 2009 to 2014, the
estimated prevalence of CKD (eGFR <60 ml/min per 1.73 m2; albumin-to-creati-
nine ratio ≥ 30 mg/g, or both) for those with diabetes versus without diabetes was
25% versus 5.3% in the United States, respectively; albumin-to-­ creatinine
ratio ≥ 30 mg/g was 16% versus 3.0%, respectively; and eGFR <60 ml/min per
1.73 m2 was 12% versus 2.5%, respectively (Table 3.1). Approximately 24% of
CKD among all US adults was attributable to diabetes after adjusting for demo-
graphics [8].
Despite that the prevalence of diabetes in the United States has increased over the
last 20 years from 6% to 10%, the proportion of people with diabetes who also have
CKD has remained relatively stable (approximately 25% to 30%) [8, 9]. However,
the distribution of clinical manifestations of diabetic kidney disease has changed
[9]. The prevalence of persistent moderately to severely increased albuminuria in
diabetic patients decreased from approximately 21% during the period from 1988 to
1994 to 16% during the period from 2009 to 2014. By contrast, the prevalence of
decreased eGFR (<60 mL/min/1.73 m2) increased from 9% to 14%. The lower
prevalence of albuminuria over time was observed only among adults younger than
65 years and non-Hispanic whites, whereas the prevalence of reduced eGFR
appeared to increase without significant differences by age or race/ethnicity [9]. The
lack of decline in albuminuria prevalence among blacks and Mexican Americans
may be attributable in part to less frequent use of proven diabetes therapies [10].
The CKD awareness remains extremely poor. Only 10% of people with stage 3
CKD (eGFR 30 to 59 mL/min/1.73 m2) are aware of their diagnosis in the United
States; although this proportion is higher among people with stage 4 CKD (eGFR
15 to 29 mL/min/1.73 m2), less than 60% of patients overall are aware of their dis-
ease [1, 11]. One in two (50.1%) people living with diabetes do not know that they
have diabetes in the world [6].
The costs for diabetic nephropathy to individual and society are considerable. In
the United States, the total Medicare spending on both chronic kidney disease and
ESRD patients was in excess of $120 billion in 2017. For identified CKD (not
3 Diabetic Kidney Disease: Scope of the Problem 39

ESRD), the total Medicare expenditure was $84 billion. Spending for ESRD patients
totaled $35.9 billion, accounting for 7.2% of the overall Medicare-paid claims in the
fee-for-service system [12]. The cost of diabetic kidney disease was recently ana-
lyzed using information from 5968 studies in French or English published between
January 1, 2000, and October 23, 2015; an average cost per patient and per year
ranged from US $1095 to US $16,384 [13]. The cost of diabetic nephropathy pro-
gression using information from the Kaiser Permanente Northwest health mainte-
nance organization suggested that annual medical costs were 37% higher following
progression from normoalbuminuria to microalbuminuria ($10,188 vs. $7424) and
41% higher following progression from microalbuminuria to macroalbuminuria
($12,371 vs. $8753) [14].
In summary, the prevalence of diabetic kidney disease is high. Diabetic nephrop-
athy accounts for nearly half of all incident cases of end-stage renal disease in the
United States. In addition, diabetic kidney disease is associated with increased mor-
tality from cardiovascular disease and all causes. Medicare and non-Medicare
spending on diabetic nephropathy and consequent end-stage renal disease is sub-
stantial in the United States. Therefore, the prevention of diabetic nephropathy is
important to improve health outcomes of persons with diabetes and to reduce the
societal burden of chronic kidney disease.

Obesity, Metabolic Syndrome, and Diabetic Nephropathy

The growing prevalence of obesity and metabolic syndrome (the cluster of risk fac-
tors including hypertension, insulin resistance, and dyslipidemia) is the major driv-
ing force for the continued increase in the prevalence of type 2 diabetes. These
disorders likely interact to exacerbate the kidney damage (Fig. 3.1).

Obesity Insulin Resistance Metabolic Syndrome

Diabetes

SNS Activation Tubular NaCl Reabsorption RAAS Activation Hyperglycemia

Hypertension Oxidative stress Endothelial Dysfunction Inflammation

Albuminuria and Glomerulopathy

Fig. 3.1 Interaction of obesity-, metabolic syndrome-, and diabetes-related kidney disease
Abbreviations: SNS, sympathetic nervous system; RAAS, renin-angiotensin-aldosterone system
Another Random Scribd Document
with Unrelated Content
 Mrs. Broderick: I will not go in it! I would sooner make any shift
and die by the side of the wall. Sure heaven is the best place,
heaven and this world we’re in now!
Sibby: Don’t be giving up now, ma’am. Here is Mr. Nestor
coming, and if any one will give you an advice he is the one will do
it. Why wouldn’t he, he being, as he is, an educated man, and such
a great one to be reading books.
Mrs. Broderick: So he is too, and keeps it in his mind after. It’s a
wonder to me a man that does be reading to keep any memory at
all.
Nally: It’s easy for him to carry things light, and his pension paid
regular at springtime and harvest.
(Nestor comes in reading “Tit-Bits.”)
Nestor: There was a servant girl in Austria cut off her finger
slicing cabbage....
All: The poor thing!
Nestor: And her master stuck it on again with glue. That now
was a very foolish thing to do. What use would a finger be stuck
with glue that might melt off at any time, and she to be stirring the
pot?
Sibby: That is true indeed.
Nestor: Now, if I myself had been there, it is what I would have
advised....
Sibby: That’s what I was saying, Mr. Nestor. It is you are the
grand adviser. What now will you say to poor Mrs. Broderick that has
a summons out against her this day for up to ten pounds?
Nestor: It is what I am often saying, it is a very foolish thing to
be getting into debt.
Mrs. Broderick: Sure what way could I help it? It’s a very done-up
town to be striving to make a living in.
Nestor: It would be a right thing to be showing a good example.
 Mrs. Broderick: They would want that indeed. There are more die
with debts on them in this place than die free from debt.
Nestor: Many a poor soul has had to suffer from the weight of
the debts on him, finding no rest or peace after death.
Sibby: The Magistrates are gone into the Courthouse, Mrs.
Broderick. Why now wouldn’t you go up to the bank and ask would
the manager advance you a loan?
Mrs. Broderick: It is likely he would not do it. But maybe it’s as
good for me go as to be sitting here waiting for the end.
(Puts on hat and shawl.)
Nestor: I now will take charge of the shop for you, Mrs.
Broderick.
Mrs. Broderick: It’s little call there’ll be to it. The time a person is
sunk that’s the time the custom will go from her. (She goes out.)
Nally: I’ll be taking a ramble into the Court to see what are the
lads doing. (Goes out.)
Sibby: (Following them.) I might chance some customers there
myself.
(Goes out calling—oranges, good oranges.)
Nestor: (Taking a paper from his pocket, sitting down, and
beginning to read.) “Romantic elopement in high life. A young lady
at Aberdeen, Missouri, U.S.A., having been left by her father an
immense fortune....”
(Stops to wipe his spectacles, puts them on again and looks for
place, which he has lost. Cooney puts his head in at door
and draws it out again.)
Nestor: Come in, come in!
Cooney: (Coming in cautiously and looking round.) Whose house
now might this be?
 Nestor: To the Widow Broderick it belongs. She is out in the town
presently.
Cooney: I saw her name up over the door.
Nestor: On business of her own she is gone. It is I am minding
the place for her.
Cooney: So I see. I suppose now you have good cause to be
minding it?
Nestor: It would be a pity any of her goods to go to loss.
Cooney: I suppose so. Is it to auction them you will or to sell
them in bulk?
Nestor: Not at all. I can sell you any article you will require.
Cooney: It would be no profit to herself now, I suppose, if you
did?
Nestor: What do you mean saying that? Do you think I would
defraud her from her due in anything I would sell for her at all?
Cooney: You are not the bailiff so?
Nestor: Not at all. I wonder any person to take me for a bailiff!
Cooney: You are maybe one of the creditors?
Nestor: I am not. I am not a man to have a debt upon me to any
person on earth.
Cooney: I wonder what it is you are at so, if you have no claim
on the goods. Is it any harm now to ask what’s this your name is?
Nestor: One Joseph Nestor I am, there are few in the district but
know me. Indeed they all have a great opinion of me. Travelled I did
in the army, and attended school and I young, and slept in the one
bed with two boys that were learning Greek.
Cooney: What way now can I be rightly sure that you are Joseph
Nestor?
Nestor: (Pulling out envelope.) There is my pension docket. You
will maybe believe that.
Cooney: (Examining it.) I suppose you may be him so. I saw your
name often before this.
 Nestor: Did you now? I suppose it may have travelled a good
distance.
Cooney: It travelled as far as myself anyway at the bottom of
letters that were written asking relief for the owner of this house.
Nestor: I suppose you are her brother so, Michael Cooney?
Cooney: If I am, there are some questions that I want to put and
to get answers to before my mind will be satisfied. Tell me this now.
Is it a fact Mary Broderick to be living at all?
Nestor: What would make you think her not to be living and she
sending letters to you through the post?
Cooney: I was saying to myself with myself, there was maybe
some other one personating her and asking me to send relief for
their own ends.
Nestor: I am in no want of any relief. That is a queer thing to say
and a very queer thing. There are many worse off than myself, the
Lord be praised!
Cooney: Don’t be so quick now starting up to take offence. It is
hard to believe the half the things you hear or that will be told to
you.
Nestor: That may be so indeed; unless it is things that would be
printed on the papers. But I would think you might trust one of your
own blood.
Cooney: I might or I might not. I had it in my mind this long time
to come hither and to look around for myself. There are seven
generations of the Cooneys trusted nobody living or dead.
Nestor: Indeed I was reading in some history of one Ulysses that
came back from a journey and sent no word before him but slipped
in unknown to all but the house dog to see was his wife minding the
place, or was she, as she was, scattering his means.
Cooney: So she would be too. If Mary Broderick is in need of
relief I will relieve her, but if she is not, I will bring away what I
brought with me to its own place again.
 Nestor: Sure here is the summons. You can read that, and if you
will look out the door you can see by the stir the Magistrates are
sitting in the Court. It is a great welcome she will have before you,
and the relief coming at the very nick of time.
Cooney: It is too good a welcome she will give me I am thinking.
It is what I am in dread of now, if she thinks I brought her the
money so soft and so easy, she will never be leaving me alone, but
dragging all I have out of me by little and little.
Nestor: Maybe you might let her have but the lend of it.
Cooney: Where’s the use of calling it a lend when I may be sure I
never will see it again? It might be as well for me to earn the value
of a charity.
Nestor: You might do that and not repent of it.
Cooney: It is likely I’ll be annoyed with her to the end of my
lifetime if she knows I have as much as that to part with. It might be
she would be following me to Limerick.
Nestor: Wait now a minute till I will give you an advice.
Cooney: It is likely my own advice is the best. Look over your
own shoulder and do the thing you think right. How can any other
person know the reasons I have in my mind?
Nestor: I will know what is in your mind if you will tell it to me.
Cooney: It would suit me best, she to get the money and not to
know at the present time where did it come from. The next time she
will write wanting help from me, I will task her with it and ask her to
give me an account.
Nestor: That now would take a great deal of strategy.... Wait now
till I think.... I have it in my mind I was reading in a penny novel ...
no but on the “Gael” ... about a boy of Kilbecanty that saved his old
sweetheart from being evicted.
Cooney: I never heard my sister had any old sweetheart.
Nestor: It was playing Twenty-five he did it. Played with the
husband he did, letting him win up to fifty pounds.
 Cooney: Mary Broderick was no cardplayer. And if she was itself
she would know me. And it’s not fifty pounds I am going to leave
with her, or twenty pounds, or a penny more than is needful to free
her from the summons to-day.
Nestor: (Excited.) I will make up a plan! I am sure I will think of
a good one. It is given in to me there is no person so good at
making up a plan as myself on this side of the world, not on this side
of the world! I will manage all. Leave here what you have for her
before she will come in. I will give it to her in some secret way.
Cooney: I don’t know. I will not give it to you before I will get a
receipt for it ... and I’ll not leave the town till I’ll see did she get it
straight and fair. Into the Court I’ll go to see her paying it.
(Sits down and writes out receipt.)
Nestor: I was reading on “Home Chat” about a woman put a
note for five pounds into her son’s prayer book and he going a
voyage. And when he came back and was in the church with her it
fell out, he never having turned a leaf of the book at all.
Cooney: Let you sign this and you may put it in the prayer book
so long as she will get it safe. (Nestor signs. Cooney looks
suspiciously at signature and compares it with a letter and then
gives notes.)
Nestor: (Signing.) Joseph Nestor.
Cooney: Let me see now is it the same handwriting I used to be
getting on the letters. It is. I have the notes here.
Nestor: Wait now till I see is there a prayer book.... (Looks on
shelf). Treacle, castor oil, marmalade.... I see no books at all.
Cooney: Hurry on now, she will be coming in and finding me.
Nestor: Here is what will do as well.... “Old Moore’s Almanac.” I
will put it here between the leaves. I will ask her the prophecy for
the month. You can come back here after she finding it.
Cooney: Amn’t I after telling you I wouldn’t wish her to have
sight of me here at all? What are you at now, I wonder, saying that.
I will take my own way to know does she pay the money. It is not
my intention to be made a fool of.
(Goes out.)
Nestor: You will be satisfied and well satisfied. Let me see now
where are the predictions for the month. (Reads.) “The angry
appearance of Scorpio and the position of the pale Venus and Jupiter
presage much danger for England. The heretofore obsequious
Orangemen will refuse to respond to the tocsin of landlordism. The
scales are beginning to fall from their eyes.”
(Mrs. Broderick comes in without his noticing her. She gives a
groan. He drops book and stuffs notes into his pocket.)
Mrs. Broderick: Here I am back again and no addition to me
since I went.
Nestor: You gave me a start coming in so noiseless.
Mrs. Broderick: It is time for me go to the Court, and I give you
my word I’d be better pleased going to my burying at the Seven
Churches. A nice slab I have there waiting for me, though the man
that put it over me I never saw him at all, and he a far off cousin of
my own.
Nestor: Who knows now, Mrs. Broderick, but things might turn
out better than you think.
Mrs. Broderick: What way could they turn out better between this
and one o’clock?
Nestor: (Scratching his head.) I suppose now you wouldn’t care
to play a game of Twenty-five?
Mrs. Broderick: I am surprised at you, Mr. Nestor, asking me to
go cardplaying on such a day and at such an hour as this.
Nestor: I wonder might some person come in and give an order
for ten pounds’ worth of the stock?
Mrs. Broderick: Much good it would do me. Sure I have the most
of it on credit.
 Nestor: Well, there is no knowing. Some well-to-do person now
passing the street might have seen you and taken a liking to you
and be willing to make an advance or a loan.
Mrs. Broderick: Ah, who would be taking a liking to me as they
might to a young girl in her bloom.
Nestor: Oh, it’s a sort of thing might happen. Sure age didn’t
catch on to you yet; you are clean and fresh and sound. What’s this
I was reading in “Answers.” (Looks at it.) “Romantic elopement....”
Mrs. Broderick: I know of no one would be thinking of me for a
wife ... unless it might be yourself, Mr. Nestor....
Nestor: (Jumping up and speaking fast and running finger up and
down paper.) “Performance of Dick Whittington.” ... There now,
there is a story that I read in my reading, it was called Whittington
and the Cat. It was the cat led to his fortune. There might some
person take a fancy to your cat....
Mrs. Broderick: Ah, let you have done now. I have no cat this
good while. I banished it on the head of it threatening the jackdaw.
Nestor: The jackdaw?
Mrs. Broderick: (Fetches cage from inner room.) Sure I reared it
since the time it fell down the chimney and I going into my bed. It is
often you should have seen it, in or out of its cage. Hero his name
is. Come out now, Hero.
(Opens cage.)
Nestor: (Slapping his side.) That is it ... that’s the very thing.
Listen to me now, Mrs. Broderick, there are some might give a good
price for that bird. (Sitting down to the work.) It chances now there
is a friend of mine in South Africa. A mine owner he is ... very rich ...
but it is down in the mine he has to live by reason of the Kaffirs ... it
is hard to keep a watch upon them in the half dark, they being
black.
Mrs. Broderick: I suppose....
 Nestor: He does be lonesome now and again, and he is longing
for a bird to put him in mind of old Ireland ... but he is in dread it
would die in the darkness ... and it came to his mind that it is a
custom with jackdaws to be living in chimneys, and that if any birds
would bear the confinement it is they that should do it.
Mrs. Broderick: And is it to buy jackdaws he is going?
Nestor: Isn’t that what I am coming to. (He pulls out notes.)
Here now is ten pounds I have to lay out for him. Take them now
and good luck go with them, and give me the bird.
Mrs. Broderick: Notes is it? Is it waking or dreaming I am and I
standing up on the floor?
Nestor: Good notes and ten of them. Look at them! National
Bank they are.... Count them now, according to your fingers, and
see did I tell any lie.
Mrs. Broderick: (Counting.) They are in it sure enough ... so long
as they are good ones and I not made a hare of before the
magistrates.
Nestor: Go out now to the Court and show them to Timothy
Ward, and see does he say are they good. Pay them over then, and
its likely you will be let off the costs.
Mrs. Broderick: (Taking shawl.) I will go, I will go. Well, you are a
great man and a kind man, Joseph Nestor, and that you may live a
thousand years for this good deed.
Nestor: Look here now, ma’am, I wouldn’t wish you to be
mentioning my name in this business or saying I had any hand in it
at all.
Mrs. Broderick: I will not so long as it’s not pleasing to you. Well,
it is yourself took a great load off me this day! (She goes out.)
Nestor: (Calling after her.) I might as well be putting the jackdaw
back into the cage to be ready for the journey. (Comes into shop.) I
hope now he will be well treated by the sailors and he travelling over
the sea.... Where is he now.... (Chirrups.) Here now, come here to
me, what’s this your name is.... Nero! Nero! (Makes pounces behind
counter.) Ah, bad manners to you, is it under the counter you are
gone!
(Lies flat on the floor chirruping and calling, Nero! Nero! Nally
comes in and watches him curiously.)
Nally: Is it catching blackbeetles you are, Mr. Nestor? Where are
they and I will give you a hand....
Nestor: (Getting up annoyed.) It’s that bird I was striving to
catch a hold of for to put him back in the cage.
Tommy Nally: (Making a pounce.) There he is now. (Puts bird in
cage.) Wait now till I’ll fasten the gate.
Nestor: Just putting everything straight and handy for the widow
woman I am before she will come back from the settlement she is
making in the Court.
Nally: What way will she be able to do that?
Nestor: I gave her advice. A thought I had, something that came
from my reading. (Taps paper.) Education and reading and going in
the army through the kingdoms of the world; that is what fits a man
now to be giving out advice.
Tommy: Indeed, it’s good for them to have you, all the poor
ignorant people of this town.
Cooney: (Coming in hurriedly and knocking against Nally as he
goes out.) What, now, would you say to be the best nesting place in
this town. Nests of jackdaws I should say.
Nestor: There is the old mill should be a good place. To the west
of the station it is. Chimneys there are in it. Middling high they are.
Wait now till I’ll tell you of the great plan I made up....
Cooney: What are you asking for those rakes in the corner? It’s
no matter, I’ll take one on credit, or maybe it is only the lend of it I’ll
take. ... I’ll be coming back immediately. (He goes out with rake.)
Sibby: (Coming in excitedly.) If you went bird-catching, Mr.
Nestor, tell me what way would you go doing it?
 Nestor: It is not long since I was reading some account of that ...
lads that made a trade of it ... nets they had and they used to be
spreading them in the swamps where the plover do be feeding....
Sibby: Ah, sure where’s the use of a plover!
Nestor: And snares they had for putting along the drains where
the snipe do be picking up worms.... But if I myself saw any person
going after things of the sort, it is what I would advise them to stick
to the net.
Sibby: What now is the price of that net in the corner?
Nestor: (Taking it down.) It is but a little bag that is, suitable for
carrying small articles; it would become your oranges well.
Twopence I believe, Sibby, is what I should charge you for that.
Sibby: (Taking money out of handkerchief.) Give it to me so!
Here I’ll get the start of you, Timothy Ward, anyway.
(She takes it and goes out, almost overturning Timothy Ward,
who is rushing in.)
Nestor: Well, Timothy, did you see the Widow Broderick in the
Court?
Ward: I did see her. It is in it she is, now, looking as content as in
the coffin, and she paying her debt.
Nestor: Did she give you any account of herself?
Ward: She did to be sure, and to the whole Court; but look here
now, I have no time to be talking. I have to be back there when the
magistrates will have their lunch taken. Now you being so clever a
man, Mr. Nestor, what would you say is the surest way to go
catching birds?
Nestor: It is a strange thing now, I was asked the same question
not three minutes ago. I was just searching my mind. It seems to
me I have read in some place it is a very good way to go calling to
them with calls; made for the purpose they are. You have but to sit
under a tree or whatever place they may perch and to whistle ...
suppose now it might be for a curlew.... (Whistles.)
 Timothy Ward: Are there any of those calls in the shop?
Nestor: I would not say there are any made for the purpose, but
there might be something might answer you all the same. Let me
see now.... (Gets down a box of musical toys and turns them over.)
Ward: Is there anything now has a sound like the croaky screech
of a jackdaw?
Nestor: Here now is what we used to be calling a corncrake....
(Turns it.) Corncrake, corncrake ... but it seems to me now that to
give it but the one creak, this way ... it is much like what you would
hear in the chimney at the time of the making of the nests.
Ward: Give it here to me!
(Puts a penny on counter and runs out.)
Tommy Nally: (Coming in shaking with excitement.) For the love
of God, Mr. Nestor, will you give me that live-trap on credit!
Nestor: A trap? Sure there is no temptation for rats to be settling
themselves in the Workhouse.
Nally: Or a snare itself ... or any sort of a thing that would make
the makings of a crib.
Nestor: What would you want, I wonder, going out fowling with a
crib?
Nally: Why wouldn’t I want it? Why wouldn’t I have leave to
catch a bird the same as every other one?
Nestor: And what would the likes of you be wanting with a bird?
Nally: What would I want with it, is it? Why wouldn’t I be getting
my own ten pounds?
Nestor: Heaven help your poor head this day!
Nally: Why wouldn’t I get it the same as Mrs. Broderick got it?
Nestor: Well, listen to me now. You will not get it.
Nally: Sure that man is buying them will have no objection they
to come from one more than another.
 Nestor: Don’t be arguing now. It is a queer thing for you, Tommy
Nally, to be arguing with a man like myself.
Nally: Think now all the good it would do me ten pound to be put
in my hand! It is not you should be begrudging it to me, Mr. Nestor.
Sure it would be a relief upon the rates.
Nestor: I tell you you will not get ten pound or any pound at all.
Can’t you give attention to what I say?
Nally: If I had but the price of the trap you wouldn’t refuse it to
me. Well, isn’t there great hardship upon a man to be bet up and to
have no credit in the town at all.
Nestor: (Exasperated, and giving him the cage.) Look here now, I
have a right to turn you out into the street. But, as you are silly like
and with no great share of wits, I will make you a present of this
bird till you try what will you get for it, and till you see will you get
as much as will cover its diet for one day only. Go out now looking
for customers and maybe you will believe what I say.
Nally: (Seizing it.) That you may be doing the same thing this
day fifty years! My fortune’s made now! (Goes out with cage.)
Nestor: (Sitting down.) My joy go with you, but I’m bothered
with the whole of you. Everyone expecting me to do their business
and to manage their affairs. That is the drawback of being an
educated man!
(Takes up paper to read.)
Mrs. Broderick: (Coming in.) I declare I’m as comforted as Job
coming free into the house from the Court!
Nestor: Well, indeed, ma’am, I am well satisfied to be able to do
what I did for you, and for my friend from Africa as well, giving him
so fine and so handsome a bird.
Mrs. Broderick: Sure Finn himself that chewed his thumb had not
your wisdom, or King Solomon that kept order over his kingdom and
his own seven hundred wives. There is neither of them could be put
beside you for settling the business of any person at all.
 (Sibby comes in holding up her netted bag.)
Nestor: What is it you have there, Sibby?
Sibby: Look at them here, look at them here.... I wasn’t long
getting them. Warm they are yet; they will take no injury.
Mrs. Broderick: What are they at all?
Sibby: It is eggs they are ... look at them. Jackdaws’ eggs.
Nestor: (Suspiciously.) And what call have you now to be bringing
in jackdaws’ eggs?
Sibby: Is it ten pound apiece I will get for them do you think, or
is it but ten pound I will get for the whole of them?
Nestor: Is it drink, or is it tea, or is it some change that is come
upon the world that is fitting the people of this place for the asylum
in Ballinasloe?
Sibby: I know of a good clocking hen. I will put the eggs under
her.... I will rear them when they’ll be hatched out.
Nestor: I suppose now, Mrs. Broderick, you went belling the case
through the town?
Mrs. Broderick: I did not, but to the Magistrates upon the bench
that I told it out of respect to, and I never mentioned your name in
it at all.
Sibby: Tell me now, Mrs. Broderick, who have I to apply to?
Mrs. Broderick: What is it you are wanting to apply about?
Sibby: Will you tell me where is the man that is after buying your
jackdaw?
Mrs. Broderick: (Looking at Nestor.) What’s that? Where is he, is
it?
Nestor: (Making signs of silence.) How would you know where he
is? It is not in a broken little town of this sort such a man would be
stopping, and he having his business finished.
Sibby: Sure he will have to be coming back here for the bird. I
will stop till I’ll see him drawing near.
 Nestor: It is more likely he will get it consigned to the shipping
agent. Mind what I say now, it is best not be speaking of him at all.
(Timothy Ward comes in triumphantly, croaking his toy. He has
a bird in his hand.)
Ward: I chanced on a starling. It was not with this I tempted
him, but a little chap that had him in a crib. Would you say now, Mr.
Nestor, would that do as well as a jackdaw? Look now, it’s as
handsome every bit as the other. And anyway it is likely they will
both die before they will reach to their journey’s end.
Nestor: (Lifting up his hands.) Of all the foolishness that ever
came upon the world!
Ward: Hurry on now, Mrs. Broderick, tell me where will I bring it
to the buyer you were speaking of. He is fluttering that hard it is
much if I can keep him in my hand. Is it at Noonan’s Royal Hotel he
is or is it at Mack’s?
Nestor: (Shaking his head threateningly.) How can you tell that
and you not knowing it yourself?
Ward: Sure you have a right to know what way did he go, and he
after going out of this.
Mrs. Broderick: (Her eyes apprehensively on Nestor.) Ah, sure,
my mind was tattered on me. I couldn’t know did he go east or
west. Standing here in this place I was, like a ghost that got a knock
upon its head.
Ward: If he is coming back for the bird it is here he will be
coming, and if it is to be sent after him it is likely you will have his
address.
Mrs. Broderick: So I should, too, I suppose. Where now did I put
it? (She looks to Nestor for orders, but cannot understand his signs,
and turns out pocket.) That’s my specs ... that’s the key of the box
... that’s a bit of root liquorice.... Where now at all could I have left
down that address?
Ward: There has no train left since he was here. Sure what does
it matter so long as he did not go out of this. I’ll bring this bird to
the railway. Tell me what sort was he till I’ll know him.
Mrs. Broderick: (Still looking at Nestor.) Well, he was middling tall
... not very gross ... about the figure now of Mr. Nestor.
Ward: What aged man was he?
Mrs. Broderick: I suppose up to sixty years. About the one age,
you’d say, with Mr. Nestor.
Ward: Give me some better account now; it is hardly I would
make him out by that.
Mrs. Broderick: A grey beard he has hanging down ... and a bald
poll, and grey hair like a fringe around it ... just for all the world like
Mr. Nestor!
Nestor: (Jumping up.) There is nothing so disagreeable in the
whole world as a woman that has too much talk.
Mrs. Broderick: Well, let me alone. Where’s the use of them all
picking at me to say where did I get the money when I am under
orders not to tell it?
Ward: Under orders?
Mrs. Broderick: I am, and strong orders.
Ward: Whose orders are those?
Mrs. Broderick: What’s that to you, I ask you?
Ward: Isn’t it a pity now a woman to be so unneighbourly and
she after getting profit for herself?
Mrs. Broderick: Look now, Mr. Nestor, the way they are going on
at me, and you saying no word for me at all.
Ward: How would he say any word when he hasn’t it to say? The
only word could be said by any one is that you are a mean grasping
person, gathering what you can for your own profit and keeping
yourself so close and so compact. It is back to the Court I am going,
and it’s no good friend I’ll be to you from this out, Mrs. Broderick!
Mrs. Broderick: Amn’t I telling you I was bidden not to tell?
Sibby: You were. And is it likely it was you yourself bid yourself
and gave you that advice, Mrs. Broderick? It is what I think the bird
was never bought at all. It is in some other way she got the money.
Maybe in a way she does not like to be talking of. Light weights,
light fingers! Let us go away so and leave her, herself and her
money and her orders! (Timothy Ward goes out, but Sibby stops at
door.) And much good may they do her.
Mrs. Broderick: Listen to that, Mr. Nestor! Will you be listening to
that, when one word from yourself would clear my character! I leave
it now between you and the hearers. Why would I be questioned
this way and that way, the same as if I was on the green table
before the judges? You have my heart broke between you. It’s best
for me to heat the kettle and wet a drop of tea.
(Goes to inner room.)
Sibby: Tell us the truth now, Mr. Nestor, if you know anything at
all about it.
Nestor: I know everything about it. It was to myself the notes
were handed in the first place. I am willing to take my oath to you
on that. It was a stranger, I said, came in.
Sibby: I wish I could see him and know him if I did see him.
Nestor: It is likely you would know a man of that sort if you did
see him, Sibby Fahy. It is likely you never saw a man yet that owns
riches would buy up the half of this town.
Sibby: It is not always them that has the most that makes the
most show. But it is likely he will have a good dark suit anyway, and
shining boots, and a gold chain hanging over his chest.
Nestor: (Sarcastically.) He will, and gold rings and pins the same
as the King of France or of Spain.
(Enter Cooney, hatless, streaked with soot and lime,
speechless but triumphant. He holds up a nest with
nestlings.)
Nestor: What has happened you, Mr. Cooney, at all?
Cooney: Look now, what I have got!
 Nestor: A nest, is it?
Cooney: Three young ones in it!
Nestor: (Faintly.) Is it what you are going to say they are
jackdaws!
Cooney: I followed your directions....
Nestor: How do you make that out?
Caoney: You said the mill chimneys were full of them....
Nestor: What has that to do with it?
Cooney: I left my rake after me broken in the loft ... my hat went
away in the millrace ... I tore my coat on the stones ... there has
mortar got into my eye....
Nestor: The Lord bless and save us!
Cooney: But there is no man can say I did not bring back the
birds, sound and living and in good health. Look now, the open
mouths of them! (All gather round.) Three of them safe and living....
I lost one climbing the wall. ... Where now is the man is going to
buy them?
Sibby: (Pointing at Nestor.) It is he that can tell you that.
Cooney: Make no delay bringing me to him. I’m in dread they
might die on me first.
Nestor: You should know well that no one is buying them.
Sibby: No one! Sure it was you yourself told us that there was!
Nestor: If I did itself there is no such a man.
Sibby: It’s not above two minutes he was telling of the rings and
the pins he wore.
Nestor: He never was in it at all.
Cooney: What plan is he making up now to defraud me and to
rob me?
Sibby: Question him yourself, and you will see what will he say.
Cooney: How can I ask questions of a man that is telling lies?
 Nestor: I am telling no lies. I am well able to answer you and to
tell you the truth.
Cooney: Tell me where is the man that will give me cash for
these birds, the same as he gave it to the woman of this house?
Sibby: That’s it, that is it. Let him tell it out now.
Cooney: Will you have me ask it as often as the hairs of my
head? If I get vexed I will make you answer me.
Nestor: It seems to me to have set fire to a rick, but I am well
able to quench it after. There is no man in South Africa, or that came
from South Africa, or that ever owned a mine there at all. Where is
the man bought the bird, are you asking? There he is standing
among us on this floor. (Points to Cooney.) That is himself, the very
man!
Cooney: (Advancing a step.) What is that you are saying?
Nestor: I say that no one came in here but yourself.
Cooney: Did he say or not say there was a rich man came in?
Sibby: He did, surely.
Nestor: To make up a plan....
Cooney: I know well you have made up a plan.
Nestor: To give it unknownst....
Cooney: It is to keep it unknownst you are wanting!
Nestor: The way she would not suspect....
Cooney: It is I myself suspect and have cause to suspect! Give
me back my own ten pounds and I’ll be satisfied.
Nestor: What way can I give it back?
Cooney: The same way as you took it, in the palm of your hand.
Nestor: Sure it is paid away and spent....
Cooney: If it is you’ll repay it! I know as well as if I was inside
you you are striving to make me your prey! But I’ll sober you! It is
into the Court I will drag you, and as far as the gaol!
Nestor: I tell you I gave it to the widow woman....
 (Mrs. Broderick comes in.)
Cooney: Let her say now did you.
Mrs. Broderick: What is it at all? What is happening? Joseph
Nestor threatened by a tinker or a tramp!
Nestor: I would think better of his behaviour if he was a tinker or
a tramp.
Mrs. Broderick: He has drink taken so. Isn’t drink the terrible
tempter, a man to see flames and punishment upon the one side
and drink upon the other, and to turn his face towards the drink!
Cooney: Will you stop your chat, Mary Broderick, till I will drag
the truth out of this traitor?
Mrs. Broderick: Who is that calling me by my name? Och! Is it
Michael Cooney is in it? Michael Cooney, my brother! O Michael,
what will they think of you coming into the town and much like a rag
on a stick would be scaring in the wheatfield through the day?
Cooney: (Pointing at Nestor.) It was going up in the mill I
destroyed myself, following the directions of that ruffian!
Mrs. Broderick: And what call has a man that has drink taken to
go climbing up a loft in a mill? A crooked mind you had always, and
that’s a sort of person drink doesn’t suit.
Cooney: I tell you I didn’t take a glass over a counter this ten
year.
Mrs. Broderick: You would do well to go learn behaviour from Mr.
Nestor.
Cooney: The man that has me plundered and robbed! Tell me
this now, if you can tell it. Did you find any pound notes in “Old
Moore’s Almanac”?
Mrs. Broderick: I did not to be sure, or in any other place.
Nestor: She came in at the door and I striving to put them into
the book.
Cooney: Look are they in it now, and I will say he is not tricky,
but honest.
 Nestor: You needn’t be looking....
Mrs. Broderick: (Turning over the leaves.) Ne’er a thing at all in it
but the things that will or will not happen, and the days of the
changes of the moon.
Cooney: (Seizing and shaking it.) Look at that now! (To Nestor.)
Will you believe me now telling you that you are a rogue?
Nestor: Will you listen to me, ma’am....
Cooney: No, but listen to myself. I brought the money to you.
Nestor: If he did he wouldn’t trust you with it, ma’am.
Cooney: I intended it for your relief.
Nestor: In dread he was you would go follow him to Limerick.
Mrs. Broderick: It is not likely I would be following the like of him
to Limerick, a man that left me to the charity of strangers from
Africa!
Cooney: I gave the money to him....
Nestor: And I gave it to yourself paying for the jackdaw. Are you
satisfied now, Mary Broderick?
Mrs. Broderick: Satisfied, is it? It would be a queer thing indeed I
to be satisfied. My brother to be spending money on birds, and his
sister with a summons on her head. Michael Cooney to be passing
himself off as a mine-owner, and I myself being the way I am!
Cooney: What would I want doing that? I tell you I ask no birds,
black, blue or white!
Mrs. Broderick: I wonder at you now saying that, and you with
that clutch on your arm! (Cooney indignantly flings away nest.)
Searching out jackdaws and his sister without the price of a needle
in the house! I tell you, Michael Cooney, it is yourself will be
wandering after your burying, naked and perishing, through winds
and through frosts, in satisfaction for the way you went wasting your
money and your means on such vanities, and she that was reared on
the one floor with you going knocking at the Workhouse door! What
good will jackdaws be to you that time?
 Cooney: It is what I would wish to know, what scheme are the
whole of you at? It is long till I will trust any one but my own eyes
again in the whole of the living world.
(She wipes her eyes indignantly. Tommy Nally rushes in the
bird and cage still in his hands.)
Nally: Where is the bird buyer? It is here he is said to be. It is
well for me get here the first. It is the whole of the town will be here
within half an hour; they have put a great scatter on themselves
hunting and searching in every place, but I am the first!
Nestor: What is it you are talking about?
Nally: Not a house in the whole street but is deserted. It is much
if the Magistrates themselves didn’t quit the bench for the pursuit,
the way Tim Ward quitted the place he had a right to be!
Nestor: It is some curse in the air, or some scourge?
Nally: Birds they are getting by the score! Old and young! Where
is the bird-buyer? Who is it now will give me my price?
(He holds up the cage.)
Cooney: There is surely some root for all this. There must be
some buyer after all. It’s to keep him to themselves they are
wanting. (Goes to door.) But I’ll get my own profit in spite of them.
(He goes outside door, looking up and down the street.)
Mrs. Broderick: Look at what Tommy Nally has. That’s my bird.
Nally: It is not, it’s my own!
Mrs. Broderick: That is my cage!
Nally: It is not, it is mine!
Mrs. Broderick: Wouldn’t I know my own cage and my own bird?
Don’t be telling lies that way!
Nally: It is no lie I am telling. The bird and the cage were made a
present to me.
 Mrs. Broderick: Who would make a present to you of the things
that belong to myself?
Nally: It was Mr. Nestor gave them to me.
Mrs. Broderick: Do you hear what he says, Joseph Nestor? What
call have you to be giving a present of my bird?
Nestor: And wasn’t I after buying it from you?
Mrs. Broderick: If you were it was not for yourself you bought it,
but for the poor man in South Africa you bought it, and you
defrauding him now, giving it away to a man has no claim to it at all.
Well, now, isn’t it hard for any man to find a person he can trust?
Nestor: Didn’t you hear me saying I bought it for no person at
all?
Mrs. Broderick: Give it up now, Tommy Nally, or I’ll have you in
gaol on the head of it.
Nally: Oh, you wouldn’t do such a thing, ma’am, I am sure!
Mrs. Broderick: Indeed and I will, and have you on the treadmill
for a thief.
Nally: Oh, oh, oh, look now, Mr. Nestor, the way you have made
me a thief and to be lodged in the gaol!
Nestor: I wish to God you were lodged in it, and we would have
less annoyance in this place!
Nally: Oh, that is a terrible thing for you to be saying! Sure the
poorhouse itself is better than the gaol! The nuns preparing you for
heaven and the Mass every morning of your life....
Nestor: If you go on with your talk and your arguments it’s to
gaol you will surely go.
Nally: Milk of a Wednesday and a Friday, the potatoes steamed
very good.... It’s the skins of the potatoes they were telling me you
do have to be eating in the gaol. It is what I am thinking, Mr. Nestor,
that bird will lie heavy on you at the last!
Nestor: (Seizing cage and letting the bird out of the door.) Bad
cess and a bad end to it, and that I may never see it or hear of it
again!
 Mrs. Broderick: Look what he is after doing! Get it back for me!
Give it here into my hands I say! Why wouldn’t I sell it secondly to
the buyer and he to be coming to the door? It is in my own pocket I
will keep the price of it that time!
Nally: It would have been as good you to have left it with me as
to be sending itself and the worth of it up into the skies!
Mrs. Broderick: (Taking Nestor’s arm.) Get it back for me I tell
you! There it is above in the ash tree, and it flapping its wings on a
bough!
Nestor: Give me the cage, if that will content you, and I will
strive to entice it to come in.
Cooney: (Coming in.) Everyone running this way and that way. It
is for birds they are looking sure enough. Why now would they go
through such hardship if there was not a demand in some place?
Nestor: (Pushing him away.) Let me go now before that bird will
quit the branch where it is.
Cooney: (Seizing hold of him.) Is it striving to catch a bird for
yourself you are now?
Nestor: Let me pass if you please. I have nothing to say to you at
all.
Cooney: Laying down to me they were worth nothing! I knew
well you had made up some plan! The grand adviser is it! It is to
yourself you gave good advice that time!
Nestor: Let me out I tell you before that uproar you are making
will drive it from its perch on the tree.
Cooney: Is it to rob me of my own money you did and to be
keeping me out of the money I earned along with it!
(Threatens Nestor with “Moore’s Almanac,” which he has
picked up.)
Sibby: Take care would there be murder done in this place!
(She seizes Nestor, Mrs. Broderick seizes Cooney. Tommy Nally
wrings his hands.)
 Nestor: Tommy Nally, will you kindly go and call for the police.
Cooney: Is it into a den of wild beasts I am come that must go
calling out for the police?
Nestor: A very unmannerly person indeed!
Cooney: Everyone thinking to take advantage of me and to make
their own trap for my ruin.
Nestor: I don’t know what cause has he at all to have taken any
umbrage against me.
Cooney: You that had your eye on my notes from the first like a
goat in a cabbage garden!
Nestor: Coming with a gift in the one hand and holding a dagger
in the other!
Cooney: If you say that again I will break your collar bone!
Nestor: O, but you are the terrible wicked man!
Cooney: I’ll squeeze satisfaction out of you if I had to hang for it!
I will be well satisfied if I’ll kill you!
(Flings “Moore’s Almanac” at him.)
Nestor: (Throwing his bundle of newspapers.) Oh, good jewel!
Ward: (Coming in hastily.) Whist the whole of you, I tell you! The
Magistrates are coming to the door! (Comes in and shuts it after
him.)
Mrs. Broderick: The Lord be between us and harm! What made
them go quit the Court?
Ward: The whole of the witnesses and of the prosecution made
off bird-catching. The Magistrates sent to invite the great mine-
owner to go lunch at Noonan’s with themselves.
Cooney: Horses of their own to stick him with they have. I
wouldn’t doubt them at all.
Ward: He could not be found in any place. They are informed he
was never seen leaving this house. They are coming to make an
investigation.
 Nestor: Don’t be anyway uneasy. I will explain the whole case.
Ward: The police along with them....
Cooney: Is the whole of this district turned into a trap?
Ward: It is what they are thinking, that the stranger was made
away with for his gold!
Cooney: And if he was, as sure as you are living, it was done by
that blackguard there!
(Points at Nestor.)
Ward: If he is not found they will arrest all they see upon the
premises....
Cooney: It is best for me to quit this.
(Goes to door.)
Ward: Here they are at the door. Sergeant Carden along with
them. Hide yourself, Mr. Nestor, if you’ve anyway to do it at all.
(Sounds of feet and talking and knock at the door. Cooney
hides under counter. Nestor lies down on top of bench,
spreads his newspaper over him. Mrs. Broderick goes
behind counter.)
Nestor: (Raising paper from his face and looking out.) Tommy
Nally, I will give you five shillings if you will draw “Tit-Bits” over my
feet.

Curtain
 THE WORKHOUSE WARD

Persons
Mike McInerney
PAUPERS
Michael Miskell
Mrs. Donohoe, A COUNTRYWOMAN

THE WORKHOUSE WARD

Scene: A ward in Cloon Workhouse. The two old men in their beds.

Michael Miskell: Isn’t it a hard case, Mike McInerney, myself and

yourself to be left here in the bed, and it the feast day of Saint
Colman, and the rest of the ward attending on the Mass.
Mike McInerney: Is it sitting up by the hearth you are wishful to
be, Michael Miskell, with cold in the shoulders and with speckled
shins? Let you rise up so, and you well able to do it, not like myself
that has pains the same as tin-tacks within in my inside.
Michael Miskell: If you have pains within in your inside there is no
one can see it or know of it the way they can see my own knees that
are swelled up with the rheumatism, and my hands that are twisted
in ridges the same as an old cabbage stalk. It is easy to be talking
about soreness and about pains, and they maybe not to be in it at
all.
 Mike McInerney: To open me and to analyse me you would know
what sort of a pain and a soreness I have in my heart and in my
chest. But I’m not one like yourself to be cursing and praying and
tormenting the time the nuns are at hand, thinking to get a bigger
share than myself of the nourishment and of the milk.
Michael Miskell: That’s the way you do be picking at me and
faulting me. I had a share and a good share in my early time, and
it’s well you know that, and the both of us reared in Skehanagh.
Mike McInerney: You may say that, indeed, we are both of us
reared in Skehanagh. Little wonder you to have good nourishment
the time we were both rising, and you bringing away my rabbits out
of the snare.
Michael Miskell: And you didn’t bring away my own eels, I
suppose, I was after spearing in the Turlough? Selling them to the
nuns in the convent you did, and letting on they to be your own. For
you were always a cheater and a schemer, grabbing every earthly
thing for your own profit.
Mike McInerney: And you were no grabber yourself, I suppose,
till your land and all you had grabbed wore away from you!
Michael Miskell: If I lost it itself, it was through the crosses I met
with and I going through the world. I never was a rambler and a
card-player like yourself, Mike McInerney, that ran through all and
lavished it unknown to your mother!
Mike McInerney: Lavished it, is it? And if I did was it you yourself
led me to lavish it or some other one? It is on my own floor I would
be to-day and in the face of my family, but for the misfortune I had
to be put with a bad next door neighbour that was yourself. What
way did my means go from me is it? Spending on fencing, spending
on walls, making up gates, putting up doors, that would keep your
hens and your ducks from coming in through starvation on my floor,
and every four footed beast you had from preying and trespassing
on my oats and my mangolds and my little lock of hay!
Michael Miskell: O to listen to you! And I striving to please you
and to be kind to you and to close my ears to the abuse you would
be calling and letting out of your mouth. To trespass on your crops is
it? It’s little temptation there was for my poor beasts to ask to cross
the mering. My God Almighty! What had you but a little corner of a
field!
Mike McInerney: And what do you say to my garden that your
two pigs had destroyed on me the year of the big tree being
knocked, and they making gaps in the wall.
Michael Miskell: Ah, there does be a great deal of gaps knocked
in a twelvemonth. Why wouldn’t they be knocked by the thunder,
the same as the tree, or some storm that came up from the west?
Mike McInerney: It was the west wind, I suppose, that devoured
my green cabbage? And that rooted up my Champion potatoes? And
that ate the gooseberries themselves from off the bush?
Michael Miskell: What are you saying? The two quietest pigs ever
I had, no way wicked and well ringed. They were not ten minutes in
it. It would be hard for them eat strawberries in that time, let alone
gooseberries that’s full of thorns.
Mike McInerney: They were not quiet, but very ravenous pigs
you had that time, as active as a fox they were, killing my young
ducks. Once they had blood tasted you couldn’t stop them.
Michael Miskell: And what happened myself the fair day of
Esserkelly, the time I was passing your door? Two brazened dogs
that rushed out and took a piece of me. I never was the better of it
or of the start I got, but wasting from then till now!
Mike McInerney: Thinking you were a wild beast they did, that
had made his escape out of the travelling show, with the red eyes of
you and the ugly face of you, and the two crooked legs of you that
wouldn’t hardly stop a pig in a gap. Sure any dog that had any life in
it at all would be roused and stirred seeing the like of you going the
road!
Michael Miskell: I did well taking out a summons against you that
time. It is a great wonder you not to have been bound over through
your lifetime, but the laws of England is queer.
 Mike McInerney: What ailed me that I did not summons yourself
after you stealing away the clutch of eggs I had in the barrel, and I
away in Ardrahan searching out a clocking hen.
Michael Miskell: To steal your eggs is it? Is that what you are
saying now? (Holds up his hands.) The Lord is in heaven, and Peter
and the saints, and yourself that was in Ardrahan that day put a
hand on them as soon as myself! Isn’t it a bad story for me to be
wearing out my days beside you the same as a spancelled goat.
Chained I am and tethered I am to a man that is ramsacking his
mind for lies!
Mike McInerney: If it is a bad story for you, Michael Miskell, it is a
worse story again for myself. A Miskell to be next and near me
through the whole of the four quarters of the year. I never heard
there to be any great name on the Miskells as there was on my own
race and name.
Michael Miskell: You didn’t, is it? Well, you could hear it if you
had but ears to hear it. Go across to Lisheen Crannagh and down to
the sea and to Newtown Lynch and the mills of Duras and you’ll find
a Miskell, and as far as Dublin!
Mike McInerney: What signifies Crannagh and the mills of Duras?
Look at all my own generations that are buried at the Seven
Churches. And how many generations of the Miskells are buried in
it? Answer me that!
Michael Miskell: I tell you but for the wheat that was to be sowed
there would be more side cars and more common cars at my father’s
funeral (God rest his soul!) than at any funeral ever left your own
door. And as to my mother, she was a Cuffe from Claregalway, and
it’s she had the purer blood!
Mike McInerney: And what do you say to the banshee? Isn’t she
apt to have knowledge of the ancient race? Was ever she heard to
screech or to cry for the Miskells? Or for the Cuffes from
Claregalway? She was not, but for the six families, the Hyneses, the
Foxes, the Faheys, the Dooleys, the McInerneys. It is of the nature
of the McInerneys she is I am thinking, crying them the same as a
king’s children.
Michael Miskell: It is a pity the banshee not to be crying for
yourself at this minute, and giving you a warning to quit your lies
and your chat and your arguing and your contrary ways; for there is
no one under the rising sun could stand you. I tell you you are not
behaving as in the presence of the Lord!
Mike McInerney: Is it wishful for my death you are? Let it come
and meet me now and welcome so long as it will part me from
yourself! And I say, and I would kiss the book on it, I to have one
request only to be granted, and I leaving it in my will, it is what I
would request, nine furrows of the field, nine ridges of the hills, nine
waves of the ocean to be put between your grave and my own grave
the time we will be laid in the ground!
Michael Miskell: Amen to that! Nine ridges, is it? No, but let the
whole ridge of the world separate us till the Day of Judgment! I
would not be laid anear you at the Seven Churches, I to get Ireland
without a divide!
Mike McInerney: And after that again! I’d sooner than ten pound
in my hand, I to know that my shadow and my ghost will not be
knocking about with your shadow and your ghost, and the both of
us waiting our time. I’d sooner be delayed in Purgatory! Now, have
you anything to say?
Michael Miskell: I have everything to say, if I had but the time to
say it!
Mike McInerney: (Sitting up.) Let me up out of this till I’ll choke
you!
Michael Miskell: You scolding pauper you!
Mike McInerney: (Shaking his fist at him.) Wait a while!
Michael Miskell: (Shaking his fist.) Wait a while yourself!
(Mrs. Donohoe comes in with a parcel. She is a countrywoman
with a frilled cap and a shawl. She stands still a minute.
The two old men lie down and compose themselves.)
 Mrs. Donohoe: They bade me come up here by the stair. I never
was in this place at all. I don’t know am I right. Which now of the
two of ye is Mike McInerney?
Mike McInerney: Who is it is calling me by my name?
Mrs. Donohoe: Sure amn’t I your sister, Honor McInerney that
was, that is now Honor Donohoe.
Mike McInerney: So you are, I believe. I didn’t know you till you
pushed anear me. It is time indeed for you to come see me, and I in
this place five year or more. Thinking me to be no credit to you, I
suppose, among that tribe of the Donohoes. I wonder they to give
you leave to come ask am I living yet or dead?
Mrs. Donohoe: Ah, sure, I buried the whole string of them.
Himself was the last to go. (Wipes her eyes.) The Lord be praised he
got a fine natural death. Sure we must go through our crosses. And
he got a lovely funeral; it would delight you to hear the priest
reading the Mass. My poor John Donohoe! A nice clean man, you
couldn’t but be fond of him. Very severe on the tobacco he was, but
he wouldn’t touch the drink.
Mike McInerney: And is it in Curranroe you are living yet?
Mrs. Donohoe: It is so. He left all to myself. But it is a lonesome
thing the head of a house to have died!
Mike McInerney: I hope that he has left you a nice way of living?
Mrs. Donohoe: Fair enough, fair enough. A wide lovely house I
have; a few acres of grass land ... the grass does be very sweet that
grows among the stones. And as to the sea, there is something from
it every day of the year, a handful of periwinkles to make kitchen, or
cockles maybe. There is many a thing in the sea is not decent, but
cockles is fit to put before the Lord!
Mike McInerney: You have all that! And you without ere a man in
the house?
Mrs. Donohoe: It is what I am thinking, yourself might come and
keep me company. It is no credit to me a brother of my own to be in
this place at all.
 Mike McInerney: I’ll go with you! Let me out of this! It is the
name of the McInerneys will be rising on every side!
Mrs. Donohoe: I don’t know. I was ignorant of you being kept to
the bed.
Mike McInerney: I am not kept to it, but maybe an odd time
when there is a colic rises up within me. My stomach always gets
better the time there is a change in the moon. I’d like well to draw
anear you. My heavy blessing on you, Honor Donohoe, for the hand
you have held out to me this day.
Mrs. Donohoe: Sure you could be keeping the fire in, and stirring
the pot with the bit of Indian meal for the hens, and milking the
goat and taking the tacklings off the donkey at the door; and maybe
putting out the cabbage plants in their time. For when the old man
died the garden died.
Mike McInerney: I could to be sure, and be cutting the potatoes
for seed. What luck could there be in a place and a man not to be in
it? Is that now a suit of clothes you have brought with you?
Mrs. Donohoe: It is so, the way you will be tasty coming in
among the neighbours at Curranroe.
Mike McInerney: My joy you are! It is well you earned me! Let
me up out of this! (He sits up and spreads out the clothes and tries
on coat.) That now is a good frieze coat ... and a hat in the fashion
... (He puts on hat.)
Michael Miskell: (Alarmed.) And is it going out of this you are,
Mike McInerney?
Mike McInerney: Don’t you hear I am going? To Curranroe I am
going. Going I am to a place where I will get every good thing!
Michael Miskell: And is it to leave me here after you you will?
Mike McInerney: (In a rising chant.) Every good thing! The goat
and the kid are there, the sheep and the lamb are there, the cow
does be running and she coming to be milked! Ploughing and seed
sowing, blossom at Christmas time, the cuckoo speaking through the
dark days of the year! Ah, what are you talking about? Wheat high
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