Research in Diseases, Disorders, and Health Conditions
Chronic Diseases and Organ Systems
Normal, healthy kidneys filter about 200 quarts of blood each day, generating about two quarts of excess fluid, salts, and waste products that are excreted as urine. Loss of function of these organs, due to a variety of causes, can result in life-threatening complications. In people with polycystic kidney disease, fluid-filled cysts form in the kidneys and other organs and can, as they grow over time, compromise kidney function. There is no treatment that can restore kidney function once it has been lost; patients require either dialysis or a transplant to survive.
NIH’s basic and clinical research on kidney development and disease include research on the causes of kidney disease, the underlying mechanisms leading to progression of kidney disease to end-stage renal disease that requires replacement of kidney function through dialysis or transplantation, and the identification and testing of possible treatments to prevent development or halt progression of kidney disease. As the lead NIH IC for kidney disease, NIDDK supports studies of inherited diseases, such as polycystic kidney disease, congenital kidney disorders, and immune-related kidney diseases, including IgA nephropathy and hemolytic uremic syndrome. Focal Segmental Glomerulosclerosis (FSGS) is a cause of nephrotic syndrome in children and adolescents, as well as an important cause of kidney failure in adults and accounts for about a sixth of the cases of nephrotic syndrome .
NIDDK-supported clinical trials are exploring new treatment options and identifying novel links between kidney disease and its many co-morbid conditions, including cardiovascular disease. For example, NIDDK and NHLBI are co-sponsoring the Co-sponsored by NIDDK and NHLBI, the Chronic Renal Insufficiency Cohort Study166is evaluating long-term cardiovascular risk and outcomes of over 3,700 persons with chronic kidney disease. In a recent finding, scientists reported that high levels of FGF-23, a hormone that regulates phosphate metabolism, are associated with an increased risk of kidney failure and death among people with chronic kidney disease. This study is part of a broader effort by NIH to identify biomarkers that can allow physicians to better predict how various diseases are likely to progress in different patients and thereby personalize treatments to improve their health.167
The Chronic Kidney Disease in Children Study168 examines over 500 children with mild to moderately decreased kidney function in order to identify risk factors for further decrease in kidney function; closely monitor brain development; examine risk factors for heart disease; and look at the long-term effects of poor growth in this group.169 170 In order to identify and validate biomarkers, which should stimulate bench to bedside translation and may enhance researchers’ ability to evaluate promising new therapies in clinical trials, NIDDK supports the Chronic Kidney Disease Biomarker Consortium. NIDDK is also studying acute kidney injury (also called acute renal failure), which is a relatively common complication in hospitalized patients. The Assessment, Serial Evaluation, and Subsequent Sequelae in Acute Kidney Injury, a study of the natural history of patients with acute kidney injury, will provide important information about the natural history of acute kidney injury and recovery.171
NIA collaborates with NIDDK to support research on renal function and chronic kidney disease in aging. Projects include basic, clinical, and translational research on chronic kidney disease (CKD) and its consequences in aging and in older persons, focusing on biology and pathophysiology of CKD in animal models; etiology and pathophysiology of CKD in the elderly; epidemiology and risk factors for the development of CKD with advancing age; and/or diagnosis, medical management and clinical outcomes of CKD in this population.172
166 For more information, see https://porter.cceb.upenn.edu:7778/servlet/page?_pageid=55,138&_dad=portal30&_schema=PORTAL30 .
167 Isakova T, et al. JAMA. 2011;305(23):2432–9. PMID: 21673295.
168 For more information, see https://statepi.jhsph.edu/ckid/ .
169 For more information, see https://healthcare.utah.edu/clinicaltrials/current/hemodialysis-fistula-maturation-hfm-study.html .
170 For more information, see https://rarediseasesnetwork.epi.usf.edu/NEPTUNE/index.htm .
171 For more information, see https://www2.niddk.nih.gov/Research/Resources/KidneyResources.htm.
172 For more information, see https://grants.nih.gov/grants/guide/pa-files/PA-09-165.html and https://grants.nih.gov/grants/guide/pa-files/PA-09-166.html.
NIAID, along with NHLBI and NIDDK, supports the Clinical Trials in Organ Transplantationprogram173 which aims to enhance the understanding of, and ultimately reduce the immune-mediated morbidity and mortality of organ transplantation, including kidney transplantation. NIAID and NHLBI also fund the Clinical Trials in Organ Transplantation in Children,174 which aims to improve short- and long-term graft and patient survival in children who have undergone heart, lung, and kidney transplantation. The Immune Tolerance Network175, a clinical research consortium sponsored by NIAID, is dedicated to the clinical evaluation of novel therapies that are designed to promote immune system tolerance in autoimmune and allergic diseases, and therefore, prevent rejection of transplanted tissues, cells, and organs (including kidney).
NCI and NIDDK researchers are collaborating in research regarding focal segmental glomerulosclerosis (FSGS), the leading cause of primary nephrotic syndrome in adults and the leading cause of end-stage renal disease in children, as well as HIV-associated nephropathy (HIVAN), a disorder that occurs in 10 percent of untreated HIV-infected persons of African descent but is rarely observed in non-Africans.
Previous studies have found that African Americans with two variants of the APOL1 gene have about a 4 percent lifetime risk of developing FSGS. These findings explain nearly all of the excess risk of non-diabetic kidney failure in African Americans. 176 Recently, APOL1 variants have been shown in experiments to destroy trypanosomes that carry African sleeping sickness, a degenerative and potentially fatal disease affecting tens of thousands of people in sub-Saharan Africa.177 In another study, the cellular distribution of APOL1 was observed to differ in samples taken from normal kidneys compared to samples taken from patients with FSGS or HIV-associated kidney disease, most notably in a subset of smooth muscle cells that surround the arteries leading to the glomerulus. This observation suggests that a previously unrecognized problem with blood vessels may play an important role in kidney disease.178
In a clinical trial to treat FSGS in children and young adults, researchers found no difference between two different drug regimens to treat this form of kidney disease, which is stubbornly resistant to standard therapy. The trial was the largest clinical trial of pediatric and adult patients with steroid-resistant FSGS. The results of this investigation underscore the importance of continued research to identify new markers of disease progression (biomarkers) and other factors that contribute to this disease, which may provide new targets for therapy and allow physicians to more closely monitor a patient’s response to treatment.179 Scientists have identified a factor circulating in the blood of some patients with FSGS that may play an important role in the disease’s initiation, progression, and recurrence. Levels of serum-soluble urokinase receptor were found to correlate with risk of FSGS and risk of recurrent FSGS following a kidney transplant. This discovery, once replicated by others, may have important implications both for research and for decisions regarding patient care.180
The Renin-Angiotensin-Aldosterone System (RAAS) is an endocrine system housed in the kidney and also expressed in other organs, including the heart and brain. RAAS plays an important role in the control of blood pressure (BP) and renal function. The first rat gene knockout model of RAAS was generated using a new technology called zinc-finger nucleases (ZFNs). The Ren-/- rat showed a greatly reduced blood pressure, having no plasma renin activity and no renin protein expressed in the juxtaglomerular cells in the kidney. The creation of a knockout rat will permit significant mechanistic research in this important system.181
In regard to public health information campaigns, NIDDK’s National Kidney Disease Education Program (NKDEP)182 raises awareness about the problem of kidney disease and steps such as control of diabetes or high blood pressure that should be taken to treat chronic kidney disease and prevent kidney failure.
NIDDK will continue its multi-faceted approach to research into kidney diseases, including:
173 For more information, see https://www.ctotstudies.org/ .
174 For more information, see https://www.ctotc.org/ .
175 For more information, see https://www.immunetolerance.org/ .
176 Kao WH, et al. Nat Genet. 2008;40(10):1185–92. PMID: 18794854; Kopp JB, et al. Nat Genet. 2008;40(10):1175–84. PMID: 18794856. See also https://www.nih.gov/news/health/sep2008/niddk-14.htm.
177 Genovese G, et al. Science. 2010;329(5993):841–5. PMID: 20647424.
178 Madhavan SM, et al. J Am Soc Nephrol. 2011;22(11):2119–28. PMID: 21997392.
179 Gipson DS, et al. Kidney Int. 2011;80(8):868–78. PMID: 21734640.
180 Wei C, et al. Nat Med. 2011;17(8):952–60. PMID: 21804539.
181 Moreno C, et al. Hypertension. 2011;57(3):614–9. PMID: 21242461.
182For more information, see https://nkdep.nih.gov/.