Innovations in Nephrology Breakthrough Technologies in

Kidney Disease Care

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vi Foreword

revolutionary perspectives that exhibit our modern (and encouraging) reality of

nephrology. From this, a panorama is meticulously crafted, presenting the broader
scope of innovation—through data, painstaking amounts of research, and even busi-
ness opportunities in nephrology endeavors—in a manner made palatable to the
medical community at large. Alas, a roadmap to the “new.”
Perhaps something of a misquote, it is said that Henry Ford—a figurehead in the
innovation of the modern automobile—claimed that, had he listened to the griev-
ances of men in the era preceding vehicular domination, he would have been in the
business of breeding faster horses. Indeed, the long-term necessities of the client
most frequently outweigh his short-term desires, and it is this idea that functions as
the primary impetus for innovation; instead of mere product or service improve-
ments, we must always consider that the common man rarely has the insight to
envision the “radical innovations” to come, and thus we should prepare appropri-
ately by examining his necessities though a visionary lens as captains of our respec-
tive fields. In this book, the reader will certainly not encounter any “faster horses.”
Instead, the past, present, and future of nephrology will be reconciled through a
natural evolution of innovative concepts, technological progress, and advancements
in technique from a framework of scientific development.
Above the constantly fluid stream of innovation, change, and progress this book
will come to represent in the field of nephrology, its waters will one day inevitably
yield into a stagnance of its own, completing the very cycle of innovation it pro-
motes by cocooning itself into a timeless snapshot of the ideas, expectations, and
(why not?) dreams of an era. After all, innovation predicates its own obsolescence.

Department of Internal Medicine José A. Moura-Neto

Bahiana School of Medicine and Public Health
Salvador, Bahia, Brazil
Contents

1 
From Hippocrates to Robotics: A Journey Through the
History of Nephrology ����������������������������������������������������������������������������    1
Geraldo Bezerra da Silva Junior, Gustavo Marques Fernandes
Bezerra, José A. Moura-Neto, Edison Souza, José Hermógenes
Rocco Suassuna, and Masaomi Nangaku
2 
Genetic Engineering of the Kidney��������������������������������������������������������   17
Constanca Figueiredo and Rainer Blasczyk
3 
Stem Cells: Use in Nephrology����������������������������������������������������������������   29
Silviene Novikoff, Niels Olsen Saraiva Câmara, and Patricia
Semedo-Kuriki
4 
Proteomics and Biomarkers for Kidney Diseases Diagnosis����������������   69
Somkanya Tungsanga, Thana Thongsricome, Trairak Pisitkun,
and Asada Leelahavanichkul
5 Single Cell Transcriptomics��������������������������������������������������������������������   87
Yoshiharu Muto, Haikuo Li, and Benjamin D. Humphreys
6 
Gut Microbiota and Chronic Kidney Disease �������������������������������������� 103
Antonio Augusto Ferreira Carioca, Suiani da Silva Sales, and
Bárbara Rebeca Cordeiro de Melo
7 
Artificial Food and the Future of Nutrition for Kidney Health���������� 115
Fabiana Baggio Nerbass and Denise Mafra
8 
Novel Drugs for Kidney Diseases Treatment ���������������������������������������� 127
Gdayllon Cavalcante Meneses, Ranieri Sales de Souza Santos,
Alice Maria Costa Martins, and Elizabeth De Francesco Daher
9  Printing in Nephrology���������������������������������������������������������������������� 141
3D
Toshihiro Nonaka, Yukiko Nagaishi, Daiki Murata, Hideo Hara,
and Koichi Nakayama

vii
viii Contents

10 Kidney-on-a-Chip������������������������������������������������������������������������������������ 157
Jonathan Himmelfarb, Masatomo Chikamori, and Hiroshi Kimura
11 
Innovations in Maintenance Dialysis Therapy�������������������������������������� 165
José A. Moura-Neto, Jyoti Baharani, Sudhir Bowry, Carsten Hornig,
Christian Apel, Arduino Arduini, José Carolino Divino-Filho, and
Bernard Canaud
12 
Dialysis for Business and Society: From a Shareholder to a
Stakeholder Perspective in Dialysis Units Management���������������������� 191
José A. Moura-Neto
13 
Generation of Whole Kidney and Other Possible
Strategies to Renal Replacement Therapy in the Future �������������������� 201
Shuichiro Yamanaka and Takashi Yokoo
14 
Bioartificial Kidneys, Renal Epithelial Cell Systems,
and Biomimetic Membrane Devices������������������������������������������������������ 217
Christopher J. Pino and H. David Humes
15 
Artificial Intelligence in Nephrology������������������������������������������������������ 237
Artur Quintiliano Bezerra da Silva, Jose Bruno de Almeida,
and Gianna Mastroianni Kirsztajn
16 
PathoSpotter: Computational Intelligence Applied to
Nephropathology�������������������������������������������������������������������������������������� 253
Luciano Oliveira, Paulo Chagas, Angelo Duarte, Rodrigo Calumby,
Emanuele Santos, Michele Angelo, and Washington dos Santos
17 
Internet of Things and Wearables for Kidney Diseases������������������������ 273
Wendley Souza da Silva, Leila Maria Rodrigues de Sousa,
Gustavo Marques Fernandes Bezerra, Leonardo Pontes Andrade,
and Geraldo Bezerra da Silva Junior
18 
Conversational Assistants and their Applications in
Health and Nephrology���������������������������������������������������������������������������� 283
Elizabeth Sucupira Furtado, Francisco Oliveira, and Vládia Pinheiro
19 
Mobile Health in Nephrology������������������������������������������������������������������ 305
Christielle Lidianne Alencar Marinho, Orlando Vieira Gomes,
Geraldo Bezerra da Silva Junior, Juliana Gomes Ramalho de
Oliveira, and Paulo Adriano Schwingel
20 
Telenephrology: A Resource for Universalizing Access to
Kidney Care, Perspectives from Latin America������������������������������������ 321
Carlos Zúñiga-San Martín
21 
Innovations in Intensive Care Nephrology�������������������������������������������� 343
Prit Kusirisin, Piyanut Kaewdoungtien, Peerapat Thanapongsatorn,
Sadudee Peerapornratana, and Nattachai Srisawat
Contents ix

22 Innovations in Kidney Transplantation ������������������������������������������������ 365

Tainá Veras de Sandes-Freitas, Renato Labanca Delgado Perdigão,
Andressa dos Santos Portas, Aline Rios Freitas de Almeida,
and Helady Sanders-Pinheiro
23 
Development and Implementation of Unmanned
Aerial Vehicles for Donor Organ Transportation �������������������������������� 379
Shani S. Kamberi, Samuel J. Gavzy, Nicole Shockcor, and Joseph
R. Scalea
24 
Implementation and Development of a Robotic
Surgery Program�������������������������������������������������������������������������������������� 389
Gisele Maia Jünger and José Eduardo Fernandes Távora
25 
Robotics and the Avant-Garde Role of Urologic Surgery�������������������� 399
Tomás Bernardo Costa Moretti, Ricardo Miyaoka,
and Wilmar Azal Neto
26 
Caregiver Robots in Nephrology: Is It Feasible?���������������������������������� 421
Maria Lúcia do Carmo Cruz Robazzi, Ana Carolina Queiroz Godoy
Daniel, Cassandra Alves de Oliveira Silva, Ciro Gatti Cirillo,
Eugenia Velludo Veiga, Joel Paulo Russomano Veiga,
Leidiane Miranda Sacramento, Liliana Amorim Alves Scandiuzi,
Maria Adelaide Silva Paredes Moreira, Mayara Rocha Siqueira
Sudré, and Rosalina Aparecida Partezani Rodrigues
27 
Preclinical Randomized Controlled Trials in Nephrology ������������������ 453
Yutian Lei and Hans-Joachim Anders
28 
Alternative Clinical Trial Designs for Nephrology Research �������������� 461
Neeru Agarwal, Murilo Guedes, Roberto Pecoits-Filho,
and Meg Jardine
29 
Consumer Involvement in Research and
Decision-Making in Nephrology ������������������������������������������������������������ 493
Nicole Scholes-Robertson, Talia Gutman, Chandana Guha,
Adeera Levin, Daniel Gallego, Kelly Malheiros, and Allison Tong
30 
Social Media and Interaction Between Healthcare
Professionals and the Kidney Patient���������������������������������������������������� 511
Rolando Claure-Del Granado, Fernanda Arce-Amaré,
Edgar V. Lerma, and Jonathan Chávez-Iñiguez
31 
Innovations in Nephrology Education���������������������������������������������������� 523
Augusto Cesar Soares dos Santos Junior
and Daniel Costa Chalabi Calazans
Index������������������������������������������������������������������������������������������������������������������ 533
Chapter 1
From Hippocrates to Robotics: A Journey
Through the History of Nephrology

Geraldo Bezerra da Silva Junior, Gustavo Marques Fernandes Bezerra,

José A. Moura-Neto, Edison Souza, José Hermógenes Rocco Suassuna,
and Masaomi Nangaku

1.1 Introduction

The term nephrology comes from the Greek “nephrós” (kidney) + “logos” (lan-
guage, word), meaning “study of the kidneys,” of their physiology and diseases. The
history of nephrology is entwined with the history of modern medicine [1]. It is a
relatively new medical specialty, having been considered for the first time as a dis-
cipline in the 1950s, with an initial focus on the pathophysiology and electrolyte
disturbance therapy [1]. In this chapter, we present some historical landmarks of
nephrology, its trajectory in the world, from ancient times to the advent of robotics,
highlighting some perspectives for the future, as this book will present the main
innovations that have been applied to nephrology and which has the potential to be
a reality in the near future.

G. B. da Silva Junior (*) · G. M. F. Bezerra

School of Medicine, University of Fortaleza, Fortaleza, Ceará, Brazil
e-mail: [email protected]; [email protected]
J. A. Moura-Neto
Bahiana School of Medicine and Public Health, Salvador, Bahia, Brazil
E. Souza
School of Medicine, Rio de Janeiro State University, Rio de Janeiro, Brazil
e-mail: [email protected]
J. H. R. Suassuna
School of Medicine, Rio de Janeiro State University, Rio de Janeiro, Brazil
National Academy of Medicine, Rio de Janeiro, Brazil
M. Nangaku
Division of Nephrology and Endocrinology, University of Tokyo School of Medicine,
Tokyo, Japan
e-mail: [email protected]

© The Author(s), under exclusive license to Springer Nature 1

Switzerland AG 2022
G. Bezerra da Silva Junior, M. Nangaku (eds.), Innovations in Nephrology,
https://doi.org/10.1007/978-3-031-11570-7_1
2 G. B. da Silva Junior et al.

1.2 Hippocrates and the Kidneys

Hippocrates (460–370 BC), the “father of Medicine,” had several aphorisms, includ-
ing some about kidney disease [2]:
• “Colorless urine is bad.”
• “Bubbles on the surface of urine indicate kidney disease and prolonged suffering.”
• “Kidney and bladder diseases are difficult to cure in the elderly.”
Some of these observations are important even in contemporary nephrology,
such as the association between foam in urine and proteinuria [3], colorless urine as
evidence of concentration or tubular defect [4], and many other impressions that
would be confirmed through science development and research.

1.3 The Kidneys in the Bible

There are some descriptions of the kidneys in the Bible. The kidney is mentioned
more than 30 times as a site of temperament, emotions, and vigor and as a site of
punishment for faults [5]. There are also reports of rhabdomyolysis in the Bible,
possibly caused by poisoning due to the consumption of birds of the Coturnix cotur-
nix species (common quail) [6].

1.4 Historical Landmarks of Nephrology

Galen (131–200 AD), based on experiments, was the first to demonstrate that the
kidney is a urine excreting organ. He published the treatise “De Pulsis et urinis,”
which described the variations of pulse, fever, and urine in different diseases, show-
ing association with prognosis [7].
Maurus (thirteenth century) defined urine as the result of three consecutive diges-
tions of bodily fluids, with the separation of the pure part from the impure one by
the body. Urine would be the impure part. The analysis of urine was performed by
the physician, based on color, concentration and sediment. Corbeil (also in the thir-
teenth century) classified the several colors of urine, which allowed the dissemina-
tion of uroscopy by European medical schools and its routine use until the eighteenth
century [2].
With the development of the microscope, in the sixteenth century, with the contri-
butions of Galileo Galilei (1564–1642), who first introduced the experimental
method, and Marcello Malpighi (1628–1694), pioneer of the microscopic anatomy
[8], several scientists started to analyze urine, looking for elements that cause calculi.
In the seventeenth and eighteenth centuries, the description of several elements found
in urinary microscopy associated with lithiasis was performed. In the eighteenth cen-
tury, the first description of albumin was made in the urine of patients with edema.
1 From Hippocrates to Robotics: A Journey Through the History of Nephrology 3

The anatomical-functional bases of the kidneys were described by Malpighi,

William Bowman (1812–1892) [9, 10], Carl Ludwig (1816–1895) (DAVIS 1996),
and Jakob Henle (1809–1885) [11]. Robert Tigerstedt (1853–1923) discovered
renin [12], which, in 1939, was evidenced to be an enzyme responsible for the pro-
duction of angiotensin II [11], of which inhibition/blockade is currently one of the
main bases of hypertension treatment and kidney “protection” strategies.
In 1840, Pierre Rayer (1793–1867) published the book Traité des maladies des
reins, which correlated data from pathological anatomy, urinary alterations, and
clinical manifestations [2].
Richard Bright (1789–1858), considered the “father of nephrology,” also corre-
lated clinical findings with anatomical alterations found in autopsies (“Reports of
medical cases”)—an association between edema, urinary, and renal alterations [13].
In the late nineteenth century, Claude Bernard (1813–1878) developed the con-
cept of the internal environment [14]. The circulatory system is responsible for con-
necting the internal environment to interfaces with the external environment,
specialized for the exchange of gases, which are the lungs, for the absorption of
solutions, after processing the multiple components of diet, which are the intestines
and, finally, an interface for the controlled excretion of solutes and solvents, com-
prising the kidneys. According to Claude Bernard, our physical and mental capaci-
ties would result from the renal competence to counteract the external environment
through the mobilization of its regulatory mechanisms, which protect our biological
integrity [14].
In the beginning of the nineteenth century, Bostock and Christison evidenced
elevated levels of urea in the blood of patients with kidney disease [15]. In 1847,
creatinine was discovered by Justus von Liebig, being measured for the first time by
Max Jaffé (1841–1911) [16], in Germany, in 1886 [17]. George Michael Edebohls
(1853–1908) performed the first surgical kidney biopsy, making an incision in the
renal capsule or performing a complete bilateral decapsulation [18, 19].

1.5 Twentieth Century Landmarks in Nephrology

Thomas Addis (1881–1949) standardized the method of urine collection, cell count
definition (“Addis count”), quantification of proteinuria, and measurement of serum
creatinine as a marker of kidney function [20].
During the twentieth century, there was the development of kidney biopsy tech-
niques, the use of immunofluorescence, and the classification of glomerulopathies.
In the 1940s, Albert Hewett Coons and colleagues first described immunofluores-
cence techniques to detect pneumococcal antigens. In the 1950s, these principles
were first applied to renal biopsies and demonstrated by R.C. Mellors. Another
important achievement in this century was demonstrated by nephrologist Nils
Alwall (1904–1986), from Sweden. He worked in the same period as Willem Kolff,
aiming to build an “artificial kidney,” and was the pioneer of the ultrafiltration pro-
cess, also being the first to perform percutaneous kidney biopsies in the world, in
4 G. B. da Silva Junior et al.

1944 [18]. The first report of percutaneous kidney biopsy, however, was published
in 1950 by Antonino Pérez Ara, a physician from Cuba, but in a local journal [21].
In 1951, Homer W. Smith recognized the importance of methods for measuring
renal clearance, in addition to elucidating the tubular transport capacity, secretion,
and reabsorption of several substances, such as urea and creatinine. In the same
decade, Marilyn Farquhar, Robert Vernier, and Robert Good published the first
paper describing the implications of a new electron microscopy technique for the
study of glomerular pathologies [11].
The twentieth century also saw the emergence of several techniques and tech-
nologies that persist to this day. Several studies and first performances of trans-
plants, peritoneal dialysis, vascular accesses, arteriovenous fistulas, among others,
were carried out, which will be discussed later in this chapter.

1.6 Hypertension Historical Landmarks

After discovering much of the renal microscopic anatomy and the renin-angiotensin
system in 1874, Frederick Horatio Akbar Mahomed, an English physician, made the
first connection between kidney disease (acute and chronic) and hypertension,
observing that “before any changes in the kidney or the appearance of albumin in
the urine, the first observable change is high pressure in the arterial system” [22].
In 1934, Harry Goldblatt, after formulating the hypothesis that blood flow reduc-
tion and the consequent renal ischemia could cause hypertension, developed an
experimental model of hypertension. For that purpose, he designed a device to
clamp the renal arteries of dogs, aiming to demonstrate the high pressure induced by
ischemia. The only ones that caused an increase in blood pressure were the renal
arteries [23].
In the 1970s, Brazilian physician and pharmacologist Sérgio Henrique Ferreira
and colleagues identified angiotensin antagonists (ARBs) and angiotensin
II-converting enzyme inhibitors (ACEi), two classes of inhibitors of the renin-­
angiotensin system [24]. In 1985, Taugma et al. proved for the first time that ACE
inhibitors could provide renal protection [11]. Currently, it is known that these two
drug classes are the main nephroprotective drugs and great allies in the treatment of
hypertension.

1.7 The Development of Nephrology as a Medical Specialty

in the Twentieth Century

Until the early 1950s, nephrology was not a medical specialty [25]. Shortly after
World War II (1939–1945), the first national organizations interested in kidney dis-
eases started to emerge in Europe, with emphasis on the 1948 Societé de Pathologie
Rénale, which in 1959 was renamed Societé de Néphrologie [26], in France, the
1 From Hippocrates to Robotics: A Journey Through the History of Nephrology 5

Renal Association, in 1950, in the United Kingdom [27] and the Società Italiana di
Nephrologia, in 1957 [28], in Italy, the first to use the name Nephrology.
The International Society of Nephrology (ISN), conceived and initially chaired
by Professor Jean Hamburguer, was founded in 1960, after the I International
Congress of Nephrology, held in Switzerland. The ISN focuses its efforts on advanc-
ing science, providing education and assistance in nephrology worldwide and cur-
rently has approximately 10,000 members in over 150 countries [11].
Some months before the creation of the ISN, the Brazilian Society of Nephrology
(SBN, Sociedade Brasileira de Nefrologia) was founded on August 2, 1960 [29].
Two years later, in 1962, SBN held its first congress, in the city of Rio de Janeiro, at
the National Academy of Medicine. The institution's main missions comprise:
spreading scientific knowledge of nephrology, supporting professionals in the spe-
cialty and ensure universal access to renal health, and currently Brazil is the country
with the highest number of nephrologists in Latin America.

1.8 Technologies Applied to Nephrology

1.8.1 Hemodialysis

The history of hemodialysis can be considered to have started in 1830, when physi-
cist Thomas Graham verified that separating two fluids with substances dissolved in
them using a cellulose membrane, an exchange between them occurred. The physi-
cist called the phenomenon “dialysis” and the membranes “semi-permeable.” In
1913, John Abel made the first “artificial kidney” in dogs without kidneys. The
experiment with dogs consisted in a series of cellulose tubes dipped in saline solu-
tion, which was where the dogs’ blood circulated. The problems with this experi-
ence were the fragility of the membranes, the lack of heparin, and frequent
infections [30].
In 1917, during World War I, the observation of war wounded soldiers with ure-
mia due to acute renal disease led the German physician Georg Haas to change the
prototype of the “artificial kidney”—he increased the area of the membranes, man-
aging to sterilize the components of the entire extracorporeal circuit with ethanol. In
1926, he attempted to use dialysis for the first time in human beings. This first
experiment consisted in taking 1/2 l of blood from a patient with uremia and circu-
lating it through the system tubes for 1/2 h, bathed in saline solution, and reinfusing
the patient, without success. During this dialysis, Haas performed, for the first time,
a temporary vascular access through a glass cannula to connect the extracorporeal
circulation from the radial artery to the cubital vein [31].
In 1936, with the commercialization of cellophane, there was an improvement in
dialysis, but still without much success. In 1940, still during World War II, a Dutch
physician called Willem Johan Kolff, born in 1911, considered the “father of hemo-
dialysis,” made the “artificial kidney,” which consisted of a tube with 40 m of cel-
lophane, wrapped in a cylinder, which was surrounded by a tank containing a
6 G. B. da Silva Junior et al.

solution. The patient's blood circulated inside the tube, and with each rotation of the
cylinder, it plunged into the tank. Kolff's kidney was an innovation, as it used a
blood propulsion system in the circuit (after being adapted from an automobile
water pump), allowing for the first time its use in a patient undergoing continuous
dialysis [32], as shown in Fig. 1.1. The first patient survived treatment in 1945 after
15 attempts [33].
The first Brazilian artificial kidney was designed and built by Dr. Tito Ribeiro de
Almeida (1913–1998), at Hospital das Clínicas, School of Medicine, University of
São Paulo, in 1949. The first hemodialysis session performed in Brazil took place
on May 19 in the same year. This machine was used until 1954, when the first
imported artificial kidney arrived in Brazil [29]. Until the mid-1950s, dialysis was
still considered experimental and was carried out in approximately six hospitals
around the world, with dubious results. Dialysis procedures were basically aimed at
acute kidney injury patients until 1960.

Fig. 1.1 Under German occupation of the Netherlands, in the small town of Kampen, Kolff built
a horizontal rotating drum artificial kidney with a sewing machine motor (a), attached to a bicycle
chain that turned a drum (b), on which circulating blood within cellophane tubing was exposed to
dialysate in a 100-liter porcelain tank (c) with the tubing mounted on a drum built of wooden slats
(d). Reproduced with permission from Friedman [32]. © 2009 John Wiley & Sons, Inc
1 From Hippocrates to Robotics: A Journey Through the History of Nephrology 7

In that decade, Belding Scribner, Wayne Quinton, and David Dillard at the
University of Washington in Seattle (USA) developed a Teflon arteriovenous shunt,
which allowed, for the first time, long-term hemodialysis for patients with chronic
kidney disease (CKD) [34]. In the same decade, Brescia and colleagues were the
first to describe, in 1966, the arteriovenous fistula for maintenance hemodialy-
sis [35].
In the late 1960s, the first hollow fiber dialyzer was developed by Benjamin
Lipps and John A. Sargent at Dow Chemical Company, California (USA)—a revo-
lutionary advance. The first human dialysis test using this hollow fiber prototype
dialyzer was performed in August 1967 by Richard Stewart [36, 37].
The concept of Kt/V was developed by Frank Gotch and John A. Sargent from a
later analysis of the National Cooperative Dialysis Study (NCDS) published in
1985. Despite some controversy, Kt/V still stands as an important parameter for
nephrologists to prescribe and monitor the adequacy of dialysis treatment [38].
Another milestone in hemodialysis was the development of erythropoiesis stim-
ulating agents in the late 1980s. Epoetin alfa was first approved by the United States
FDA in June 1989. After that, some studies and guidelines tried to establish a target
for hemoglobin levels in CKD patients. In 2006, the CREATE study—conducted in
Europe, Asia, and Mexico—and the CHOIR study—conducted in the United
States—failed to demonstrate the advantage in achieving high hemoglobin levels
[39]. A new class of drugs for CKD anemia treatment would emerge in the twenty-­
first century: the hypoxia-inducible factor (HIF) prolyl hydroxylase inhibitors,
which had the approval for clinical use in the late 2010s [40, 41].
Dialysis treatment showed remarkable improvement in the late twentieth cen-
tury and, incorporating technological innovations, left behind the status of
extremely rudimentary procedure to the safety of modern machines equipped with
numerous sensors, intelligent monitoring systems, performance evaluation, and
automated disinfection, providing patient safety and allowing the early detection of
problems.

1.8.2 Peritoneal Dialysis

The first peritoneal dialysis in human beings took place in 1923 under the super-
vision of George Ganter [42]. Even submitted to a procedure that used electro-
lyte solutions stored in glasses, coupled to rubber tubes and a needle at the end,
the patient showed good blood results; however, she died after hospital dis-
charge, making Ganter conclude that the treatment should not have been inter-
rupted [42].
In 1965, Henry Tenckhoff improvised a flexible peritoneal dialysis catheter,
using a technique that is applied, even with modifications, to this day. Moreover,
this type of catheter takes its name from him, being called Tenckhoff catheter [11].
Continuous Ambulatory Peritoneal Dialysis (CAPD) was first described in 1978
by biomedical engineer Robert Popovich and by nephrologist Jack Moncrief. The
8 G. B. da Silva Junior et al.

technique was tested in nine patients over 136 weeks and allowed good control of
edema and protein loss, in addition to helping control the peritonitis [11, 43]. A
year earlier, in 1977, Greek nephrologist Dimitrios Oreopoulos used, instead of
glass containers, plastic bags in the CAPD, which resulted in a dramatic recovery
of the tested patient and allowed the application of this technique at home level
[11, 44].

1.8.3 Kidney Transplant

The first successful kidney transplants were described by Emerich Ullmann in

March 1902. The Austrian surgeon performed an autotransplantation to a dog and a
xenotransplantation from a dog to a goat. Subsequently, in 1906, the first docu-
mented attempts at kidney transplantation in humans were carried out by French
surgeon Mathieu Jaboulay. The procedures, which were unsuccessful, were per-
formed having a pig and a goat as donors [11].
The first record of a kidney transplantation from a deceased human donor was
performed in 1933 by the surgeon Yurii Voronoy, in a territory that now belongs to
Ukraine [45], and he was one of the first to observe possible problems due to immu-
nological characteristics related to graft rejection [45]. On June 17, 1950, the first
successful kidney transplant was performed by Richard Lawler in the USA. The
compatible allograft lasted 10 months and the patient lived for an additional 5 years,
possibly with residual kidney function [46]. In 1954, at the Brigham and Women’s
Hospital, in Boston, USA, Joseph E. Murray and John P. Merrill performed the first
successful living-donor kidney transplant between twin siblings. The recipient lived
for another 8 years after the procedure. In 1960, Peter Medawar and Frank Burnet
won the Nobel Prize in Medicine for their pioneering in defining rejections and the
study of immunosuppressants [46].
In Latin America, the first kidney transplant was in Argentina [47]. In Brazil, the
era of transplants started in 1964, at Hospital dos Servidores do Estado, in Rio de
Janeiro [48]. The Brazilian Association of Organ Transplants (ABTO, Associação
Brasileira de Transplantes de Órgãos) was founded on April 14, 1987, with the
purpose of promoting and stimulating the development of actions related to human
organ and tissue transplants in the country, among others (ABTO). The National
Transplant System (SNT, Sistema Nacional de Transplantes), established in 1997,
is the entity responsible for controlling and monitoring the process of organ and tis-
sue donation and transplant in Brazil and is the largest public and universal organ
transplant system in the world.
Currently there are huge disparities in access to kidney transplant in the world,
where the lower socioeconomic populations have the lowest chances of achieving a
transplant [49]. Xenotransplantation emerges as an option for this problem, and the
techniques are currently very advanced [50, 51].
1 From Hippocrates to Robotics: A Journey Through the History of Nephrology 9

1.8.4 New Technologies

From the 1980s onward, new technologies emerged to add to the practice of nephrol-
ogy. In 1985, the first robotic surgery was performed in humans, and this area has
shown considerable progress, especially in the 1990s. In 2000, the da Vinci robotic
surgery system obtained approval by the FDA for general laparoscopic procedures
and became the first operative surgical robot in the USA [52]. This method has been
applied in kidney transplants, with faster donor and recipient recovery [53]. The first
successful robotic assisted kidney transplantation (RAKT) was performed in France
in the beginning of this century [54]. In more recent years (2018–2020), large case
series have been published with successful robotic assisted kidney transplant [55].
In 1992, nephrologist Burton Rose created the “UpToDate in Nephrology and
Hypertension” platform. Subsequently, he decided to expand the product and con-
vinced leaders from other specialties to do so, renaming the program “UpToDate in
Medicine,” which later became simply “UpToDate.” Currently, the platform has
numerous updated articles on several areas of medicine and more than two million
users in approximately 200 countries [56], becoming one of the most important
online update platforms in medicine in the world.
Telemedicine can be considered as existing practice since the advent of “new”
communications methods, such as telegraph in 1844 and telephone in 1876, provid-
ing patients with the possibility to contact their physicians in a faster and cheaper
way [57]. With the growth of the internet and, consequently, of digital health,
nephrology has also acquired new technologies. One of the main tools is telene-
phrology, which, just like telemedicine as a whole, is based on consultations and
other virtual strategies. It is currently being applied in several countries with evi-
dence of success, allowing the nephrologist to contact other specialties and patients,
as well as providing effective care for conditions such as CKD [58]. There are suc-
cessful experiences in telenephrology around the world [59–61], and an unprece-
dent increase in telemedicine application was seen with the emergence of COVID-19
pandemic [62, 63].
Another currently widely used strategy, especially with the emergence of smart-
phones, tablets, and other mobile devices, is applications. These can be used in
many areas, and therefore, there are many health-oriented applications. Consequently,
this scenario extends to nephrology. Lee et al. [64] identified 177 applications
related to CKD. The most common functionalities were CKD information and CKD
self-management (57%), e-consultation (25%), CKD nutrition education (24%),
and estimated glomerular filtration rate (eGFR) calculators (19%) [64]. Moreover,
the self-management function is common among the applications, as a study by
Ong et al. [65], carried out in 2016 based on blood pressure (BP) monitoring of
patients with CKD, showed a reduction in the users’ systolic (SBP) and diastolic
blood pressure (DBP) [65].
Another technology that promises to have an impact in healthcare sector is arti-
ficial intelligence (AI), defined as “machines that mimic cognitive functions that
10 G. B. da Silva Junior et al.

humans associate with the human mind, such as learning and problem-solving,” or,
in a simpler definition, intelligence made by machines, with minimal human use
[66]. AI is generally applied through a method called “Machine Learning,” which
allows the computer to learn without being programmed with algorithms. In addi-
tion, this tool already has important applications in nephrology, such as the IBM
Watson system, from the Italian Society of Nephrology, which answers questions
about calcimimetics based on scientific documents (https://sinitaly.org/watson/).
Moreover, one can mention the PathoSpotter, created in Brazil, which contributes to
the identification of glomerular pathologies and can be very useful for renal
biopsy [67].
With the first steps toward creating advanced AI, as well as the advancement of
telemedicine, it is possible to look at the future of nephrology with great optimism
[53]. Furthermore, with the increase in the use of smartphones and their applica-
tions, social networks, research sites, among others, the increasing patient empow-
erment is expected over the years [58, 68].
From the 1990s onward, new discoveries and historic landmarks emerged. In
2012, John B. Gurdon and Shinya Yamanaka received the Nobel Prize in Physiology
or Medicine for discovering the ability of mature cells to become pluripotent when
reprogrammed (iPS cells), which has been widely applied in nephrology research
[69]. Moreover, the study by Katalin Susztak [70], based on the RNA sequencing of
nephron cells, identified clusters of cells that had not been discovered before, which
may be essential to elucidate and treat kidney diseases. In 2010, two variants of the
APOL1 protein gene coding sequence on chromosome 22 were discovered and
shown to have the highest association with CKD [71]. There are currently several
studies on gene editing, and one of the most exciting system of gene editing is the
so-called clustered regularly interspaced short palindromic repeats (CRISPR),
which can be applied in the treatment of many genetic diseases of the kidneys [72].
Other technologies are being developed in the area of nephrology, such as the
implantable bioartificial kidney, which aims to simulate kidney function, as well as
others, such as 3D bioprinting, kidney-on-a-chip, kidney organoids, and others [53].
These and other tools, despite demanding a wide range of studies in bioengineering,
nanotechnology, and cell studies, promise to revolutionize nephrology and bring
more quality of life to patients (Fig. 1.2).
 Homer W. Smith Nephr ologis t
(1895-1962) Dr. Burt on R ose
1

Recognized the importance cr eat ed what Discover of 2 coding

of renal clearance w ould bec ome
variations of APOL1
methods, elucidated UpToDat e
1992 genes that showed
reabsorption and strong relation
secretion of substances to CKD.
1951 2010
Jean Hamburger First robotic-assisted
(1909-1992) kidney transplantion
First temporarily 2001
successful kidney transplant
(the patient died 22 days later)
1952
Nils Alwall Joseph Murray Erythropoietin
(1904-1986) (1919-2012) stimulating agents Large case series
Pioneer of the First successful (ESAs) for CKD-associated of robotics assistance
ultrafiltration process, Marilyn Farquhar (1928-2019),
kidney transplant anemia, FDA approval in kidney transplantation
he performed Robert L. Vernier (?-2014)
1954 1989 2018-2020
the first human & Robert A. Good (1922-2003)
kidney biopsy First described a new electron
1944 microscope technique to study
glomerular pathology
1957 First robotic
First kidney surgery
transplant in (PUMA 560)
Willem Kolff Latin America 1985
Hippocrates (1911-2009) (Argentina) Increment in
(460-370 BC) Considered the 1957 Telenephrology due to
Aphorisms linking “father of hemodialysis”, COVID-19 pandemic
urine abnormalities created an “artificial kidney” 2020
and kidney disease (Kolff’s kidney) Foundation of the
1943 Brazilian Society of
Frank Gotch/
Nephrology (SBN)
John Sargent
and International
Concept of Kt/V
Society of Nephrolgoy
1985 First fully virtual
(ISN)
Bible ISN World Congress
1960
More than 30 citations; of Nephrology
Kidneys as site of 2021
emotions and place Yurii Voronoy
of punishment for First International
(1895-1961) Congress of Nephrology,
faults; Description First human-to-human Foundation of
of rhabdomyolysis Geneve & Evian, the Asian
kidney transplantation Switzerland
1933 Pacific Society
Peter Medawar/ 1960 of Nephrology
Frank Burnet (APSN)
First kidney
Galen (129-200 AD) Nobel Prize 1983
xenotransplant,
“De pulsis et uninis” in Medicine;
Georg Haas from a pig genetically
Pulse, fever and urine pioneers in
(1886-1971) engineered to a human
in different diseases describing rejection
First performed (NYC, USA)
and the study of
dialysis and first Belding Scribner 2021
immunosuppressants Robert Popovich
temporary vascular (1921-2003),
1960 (1939-2012)
Marcello Malpighi access Wayne Quinton (1921-2015) Developed the
(1628-1694) 1926 & David Dillard (1923-1993) continuous ambulatorial
First description of Developed an external Post-COVID19 era:
peritoneal dialysis
the glomerulus Teflon AV shunt hybrid congresses;
(CAPD)
1666 1960 digital nephrology;
1978
Georg Ganter advances in robotics
(1885-1940) 2022 on
Richard Bright First peritoneal
(1789-1858) dialysis
Clinical description of 1923
kidney disease
First kidney
(became known as
transplantation Sérgio Henrique
Bright’s disease)
performed in Brazil Ferreira (1934-2016)
1827
(Rio de Janeiro) Discovered the
Mathieu Jaboulay 1964 ACE inhibitors
(1860-1913) 1974
First kidney
William Bowman transplants
Foundation of the
(1816-1892) in humans
European Renal Association -
First description 1906
European Dialysis and
of the nephron Transplant Association
1842 (ERA-EDTA), now nominated Foundation of the
ERA. Latin American Society
Emerich Ullmann
1964 of Nephrology and
(1861-1937)
First successful renal Hypertension (SLANH)
autotransplantation Kenneth C. Appell 1970
Carl Ludwig Frederik Mahomed 1902 (1919-2012)
(1816-1895) (1853-1923) Developed the first
Max Jaffé
First theory about First link between AV fistula for
(1841-1911)
filtration and hypertension and maintenance
First measurement
reabsorption kidney disease hemodialysis
of serum creatinine
From Hippocrates to Robotics: A Journey Through the History of Nephrology

1842 1874 1965

1886

Foundation of the
American Society of
Jakob Henle
Nephrology (ASN)
(1809-1885) Henry Tenckhoff 1966
Discover of (1930-2017)
Henle’s loop Developed a flexible
1862 Robert Tigerstedt
peritoneal dialysis cateter
(1853-1923)
1965
Discover of renin
1890
11

Fig. 1.2 A “journey” through the history of nephrology, from Hippocrates to robotics (ancient times—2022)
12 G. B. da Silva Junior et al.

1.9 Conclusion

Nephrology is a medical specialty that since ancient times challenged researchers to

overcome barriers, and as science develops, technology is applied to this area of
medicine. Nephrology currently has effective therapies, such as dialysis, kidney
transplant, and immunosuppressant use, which have prolonged the survival kidney
patients. With the development of science, the pathophysiology of kidney diseases
has been better understood. The main pathological entity of the specialty, “renal
failure,” has been acquiring new dimensions and nomenclatures (acute kidney
injury/acute kidney disease/chronic kidney disease). Treatment of acute kidney
injury has improved significantly in recent years, and there has been a significant
reduction in mortality of patients with this condition. Chronic kidney disease has
been reaching epidemic levels worldwide, acquiring the status of a public health
problem. Nephrology is a specialty closely related to public health policies, since
most patients cannot afford treatment, and government should subside treatment
payment. The digital era arises with several technologies applied to the healthcare
sector, and promising innovative tools could provide disruptive methods for the
management of kidney diseases.

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