Foreword

I want to start this chapter by telling you a story: how and why I have been continually amazed and enthusiastic about learning every day a new issue about kidney physiology and pathophysiology and how this book starts a new era in Mexico by demonstrating how basic science can improve from using the laboratory results in our understanding of Kidney's health and the earliest identification and effective treatment of kidney diseases.

My interest in the kidneys started in my early days at medical school 53 years ago, since 1979, during and after my postdoctoral studies at the laboratory of nephrology and Mineral Metabolism at Washington University School of Medicine in Saint Louis, Missouri, where two outstanding professors Dr. Saulo Klahr and Eduardo Slatopolsky involved me under the tutorial of Kevin Martin and Ezequiel Bellorin-Font in the development of the area on mineral, bone metabolism and the intracellular pathways of action of parathyroid hormone throughout their proximal tubular receptors and intracellular signaling. After returning to the Nephrology and Mineral Metabolism at the National Institute of Nutrition, I coordinated and developed the mineral metabolism laboratory and clinical services.

A lifetime perspective of the last 5 decades in Mexico

Let me start a journey remembering some examples of the teaching strategies of my mentors, Dr. José Carlos Peña and Jaime Herrera, in the nephrology specialty training in the late 1970s: for example, to have a precise determination of glomerular filtration rate (GFR), we did use the inulin clearance rate if the clinical decision making needed such precision. The urinary collection during a 24-hour interval was used in several decision-making processes, including the Creatinine Clearance, to not only determine GFR but to define the fractional excretion of different substances or the metabolic balance of several substances in specific protocols conducted in an excellent clinical research service. Except for inulin determination, most tests performed lacked specificity, and their scientific basis was derived mainly from observational and metabolic studies. Looking at the conclusions we derived from their results in those days, I feel that they allowed us to use very intuitive reasoning due to their design. Their precision and reproducibility were difficult to standardize and, therefore, to perform in any clinical setting. Nonetheless, we made an excellent diagnosis, mainly with respect to the physiology and metabolic aspects of KD.

The characterization of the immune system was also in its very early years. Therefore, its role in CKD etiology and evolution was suspected, and the evidence was merely observational. During these decades, an enormous change has been achieved, and it is a consequence of basic research translated to clinical nephrology under the leadership of Dr. Donato Alarcon, Federico Chavez Peon, coworkers, and many groups in the transplant community.

In the early 1980s, the science of membrane receptors, membrane channels, transporters, and co-transporters was another considerable progress when applied to clinical nephrology. The mineral and bone metabolism system, the acidification system, and arterial hypertension, among other areas, greatly benefited from this research, and there are important groups around Mexico developing this area.

From 1990 to date, another big area of development in nephrology was the genomic, transcriptional, metabolomic, and microbiome research areas.

In this route of more than half a century, nephrology as a specialty of internal medicine was started around the world, and in Mexico, it happened in 1972. Not to forget are the advances in dialysis procedures and the quality-of-life improvements made possible since 1979 by fundamental scientific research on peritoneal membrane physiology and its adaptations to the procedure. The hemodialysis efficacy was also improved due to the development of biocompatible membranes, up-to-date purification of water, and better dialysates.

This book comes together as an example of the collaboration and enthusiasm of at least 10 different institutional groups around the country; they work as a community where CKD, AKD, ESRD, and transplantation are potent stimuli for their work.

The renal circulatory system is pivotal for these mechanisms to act in precise coordination

Over these decades, the kidneys have always been a great laboratory where the multiple functions covered by the two kidneys are paramount to the whole-body economy and health. The anatomic place where nature allocated them is strategic. Humans, a species that stands on two feet and in a vertical position and walks as a bipod, need a barometric sensor system and a unique propulsion of blood. This peculiarity, combined with the non-permeable characteristics of our skin, is also related to the volume control of the intra and extracellular compartments. In a few words, the Kidney, the central nervous system, and the heart have evolved in the human species with a very complex system for precisely regulating fluid and volume control. The strategic position of the kidneys in the retroperitoneum and under the diaphragm allows them to have an excellent mechanism for sensing and adjusting both fluid and volume, with a super specialized mechanism: a. the renin-angiotensin; b. the vasopressin; and c. renal innervation is also an essential component.

Another consequence of humans is having non-permeable skin, which obligates the body to have precise water and mineral homeostasis conservation mechanisms. The role of the kidneys in this area is of great importance; a precise balance between ingestion, metabolic needs, and excretion depends on the coordinated function of many different systems for secretion, reabsorption, transport, and cotransport of the monovalent and divalent ions coordinated with glucose, nitrogen, and ammonium either in the proximal or distal tubule where acidification is also regulated and, therefore, the metabolic acid-base balance of the whole body.

The urine concentration and sodium/chloride balance are coordinated in the renal medulla where the loops of Henle and distal /collecting ducts are to be studied.

Also, the kidney interstitium was elucidated and understood in the last two decades, along with the role of erythropoietin and anemia of CKD, inflammation, fibrosis , and tissue death.

Hence, this book is a unique opportunity to invite you to focus our attention on the great opportunity that the contemporary clinical practice of nephrology already has in several areas, namely earliest detection of Kidney Diseases (KD) and the mechanisms involved in the damage of kidney tissues, acute kidney injuries, the effect of different toxic exposures on kidney function, the mechanisms of tissue death and fibrosis as well as the mechanisms of action of specific treatments/therapeutic interventions among others, thanks to the advances generated by the results of very well focused basic scientific research.

The kidneys are bright organs; they play a role in the human body's health

You will enjoy analyzing the contributions of my co-authors, which can be addressed considering the focus of their interest in some of the issues summarized in the contents table.

A group of chapters are focused on genomic sciences and the Kidney, namely the pleiotropic aspects of CKD, the genetic influence on cell differentiation, kidney/urinary tract cancers, epigenetics of CKD, and their relationships with microbiota. A fascinating area related to stem cell science is the integration of new organs, including functional kidneys, and forecasting a new era in successful organ transplantation.

Examples of how inflammation and metabolic syndromes affect energy utilization are exemplified by the chapters analyzing mitochondria and oxidative stress (oxygen and ROS), for example, in diabetic kidney damage.

Arterial hypertension, sodium balance, acid-base metabolism, and nephrolithiasis are also areas where co-authors had incursion and generated new insights into the pathophysiology and treatment options.

An emerging area regarding mechanisms of kidney damage is related to the toxic effects of different chemicals to which people are exposed, either due to the natural contamination of the habitat or anthropogenic activities.

Regarding clinical nephrology, this book discusses the science related to the diagnosis and association of CKD with metabolic syndrome, type 2 diabetes mellitus, systemic arterial hypertension, nephrolithiasis, renal tubular acidosis, polycystic kidney disease, and acute kidney injuries.

CKD in Mexico and the world;A global burden lacking fundamental strategies to be controlled, diminished, or ideally avoided

When getting accurate data on the number of Mexican citizens living with CKD, we will face the results of small population studies from which only a gross estimation can be done. This latter is explained by the complexity of our fragmented health system, which makes it almost impossible to adopt a uniform policy for early detection, classification, and, very importantly, successful intervention of this disease.

Therefore, the Mexican scenario shows late identification and ineffective intervention of CKD, leading to a growing and uncontrolled number of patients facing the irreversible end stage of kidney disease (ESKD) and the need for the high cost of dialysis treatment to survive. This resource does not cover the whole ESKD population.

There is enough international evidence of the catastrophic costs implied of the yearly expenses of the different options to treat ESKD when hemo and peritoneal dialysis are unavoidable treatments for survival.

In Mexico, these data are available only for the significant health provider system: the Mexican Institute of Social Security (IMSS), where formal workers are covered, and a significant percentage of ESKD patients receive either hemo and/or peritoneal dialysis. Note that there is a significant and underestimated ESKD population of IMSS beneficiaries who do not receive dialysis.

The direct and indirect expenses of such programs are catastrophic for the IMSS. If they are extrapolated to the estimated ESKD population not covered by IMSS, it is easy to realize that they are catastrophic for the whole country. What do we mean when considering a cost catastrophic for any health system? There is an example for you to analyze before you go through this publication. In 2020, the direct cost of the IMSS dialysis programs, just the costs related to the treatment session or the peritoneal supplies for approximately 60,000 ESKD patients, equals the expenses to attend all the millions of births attended at IMSS facilities in the whole IMSS population. In addition, there are indirect costs bearable by this population, namely of the complications of treatment, hospitalizations, and death. They almost cost three times more than the direct cost just described.

I hope these examples provide enough reasons to be enthusiastic about fostering the kind of scientific research presented throughout this book, which is focused on the early identification of renal tissue damage, the options to prevent it and stop deterioration, and lastly, avoiding fibrosis and tissue death.

In the last three decades, a significant effort has been made to identify the presence of CKD in high-risk populations; there are many worldwide spread programs with this purpose, one of which has been active in Mexico, the Kidney Early Evaluation Program (KEEP) of the International Kidney Foundation which allows estimating the “remnant glomerular reserve.” This program is well designed to identify clinical antecedents correctly to establish the kind of risk present, correlating with clinical anthropometry, classifying the stage of CKD estimating glomerular filtration rate using standardized determination of serum creatinine and different validated formulas as well as glomerular integrity through the albumin/creatinine ratio in one sporadic urine sample.

Although it is very “glomerulocentric,” it has been demonstrated to be very useful as a clinical tool to conscientize the patient and, in very few cases, to provide a photograph of the size of the CKD problem to a specific health system, which ultimately is responsible for providing access to effective treatment options; all oriented to stop the deterioration of such glomerular remnant function and to slow the need of dialysis, ideally to recover functional glomerulus.

Using this model in the year 2010 in the Mexican state of Jalisco, it became evident that we were able to screen nearly 8000 citizens with type 2 diabetes (DM2) covered by the public health state services in only two weeks, adapting a validated version of the KEEP protocol. As a result of this campaign, we did generate consciousness of the kind of care that the individual patient needs to have according to the CKD remnant “kidney” reserve, as well as those that did not have CKD; in this case, the patients became aware that they can develop this undesirable complication of DM2 if they do not adhere to appropriate medical care and control of their disease.

We also established and finished a course online designed to train general practitioners (GPs) in taking medical care of this DM2 population in their primary care clinics; the course was peer-reviewed, and the intervention protocol was validated to treat each deterioration stage. These GPs identified approximately 100 CKD patients in their own DM2 registry. We also asked for the nephrologist evaluation online in a very well-programmed schedule.

The Health Care Authorities of Jalisco stopped the program because there were several logistical problems regarding accessibility to laboratory testing and medications. Nonetheless, the program yielded a model to be pursued at the non-IMSS covered population affected by DM2, which is most of the population in the country, nearly 60% of the adult population older than 20 years old.

These results were compared with those obtained in other Mexican States where the Mexican Kidney Foundation (FMR) openly invited the public to participate in KEEP testing events. Those with known risk factors for developing CKD were accepted, regardless of whether they have IMSS or other insurance coverage. The results were significantly similar, if not almost identical, to those we obtained in the Jalisco scenario.

With these data, it is easy to speculate on how many people are affected by one or more of the Metabolic Syndrome components identified by the Nationwide Health and Nutrition Survey conducted by the National Institute of Public Health (INSP, ENSANUT), which may have developed CKD and classify them according to the KDOQUI/EPI criteria in the whole country.

Although imprecise, the figure is of millions of cases with CKD in the 20-year and older adult group, which are affected by CKD, of which 96% are in the early stages of the disease. Therefore, a significant opportunity exists to establish a fundamental public policy to face this challenge through systematic early identification, classification, and protocolized interventions, briefly a cost-efficient policy that should decrease the burden to the nation represented by CKD and ESKD.

Let us finish this section by mentioning that many new biomarkers identified and understood by recent scientific research can identify when a kidney starts deteriorating its integrity; KEEP accepts a patient as having CKD.

Which will be the best-case scenario for CKD in Mexico?

As we have reviewed in this chapter, I hope you became aware of the significant avenues opened today for the research community regarding the importance of kidney integrity in the health sustainability of anyone, with a large emphasis on people with one or more components of metabolic syndrome as several chapters of this book endorse.

Let's drive the route on the contemporary issues that syndemic entities like metabolic syndrome present to an integrated science community to develop effective and sustainable public policies to solve these problems; it is mandatory to acknowledge that they have conditionings that are not only related to a specific disease state but also include many socio-economic, ambient, and geographical factors. Therefore, the research on these multifactorial human conditions needs to establish a compelling inter- and transdisciplinary approach .

The interinstitutional and interdisciplinary nature of the present publications must encourage their institutions to promote transdisciplinary involvement; this is more feasible in universities where many disciplines and specialties are available. Recent efforts by the National Council of Science and Technology (CONACyT) have encouraged this approach, which has been demonstrated to be particularly cumbersome but necessary if feasible; long-term policies are to be implemented.

Meanwhile, the example given in this publication is excellent; basic scientists working on specific mechanisms of CKD and AKD and interacting with nephrology specialists have made a tremendous effort that is unique to my knowledge in Mexico.