NIDDK 

Recent Advances & Emerging Opportunities 

January 2024 

Kidney, Urologic, and 

Hematologic Diseases 

U.S. Department of Health and Human Services 

National Institutes of Health 

National Institute of Diabetes & Digestive & Kidney Diseases 

This is a chapter from the NIDDK’s Annual Report. The full Report includes highlights of research on 

these and many other areas across the NIDDK’s mission and is available at: 

www.niddk.nih.gov/about-niddk/strategic-plans-reports/niddk-recent-advances-emerging-opportunities
NIDDK Recent Advances & Emerging Opportunities 2024 

KIDNEY, UROLOGIC, AND 

HEMATOLOGIC DISEASES....................................77

Understanding the Molecular Pathways 

to Kidney Injury.................................................................80

“Kidney Atlas” Helps Illustrate Changes 

That Occur With Kidney Injury........................80

Probing the Molecular Events Linking 

Kidney Injury to Fibrosis....................................80

Investigating Polycystic Kidney Disease ...............81

Resolving Key Details of Polycystic 

Kidney Disease Genetics ..................................81

New Technologies Help Uncover an 

Unexpected Role of Glucose in 

Polycystic Kidney Disease ................................81

Expanding Knowledge of 

Kidney Transplantation .............................................82

Kidneys From Deceased Organ 

Donors With or Without Acute 

Kidney Injury Show Similar 

Transplant Outcomes.........................................82

Discovering Genetic Risk Factors for 

Diabetic Kidney Disease.................................................82

A Potential Explanation for Differences 

in Susceptibility to Kidney 

Complications of Diabetes ...............................82

Understanding the Spectrum of 

Urologic Disease Symptoms and 

Treatment Responses..................................................83

New Insights Into Overactive Bladder 

Urinary Symptoms..............................................83

Discovering the Risks of Developing 

Symptoms Due to Ureteral 

Stent Placement..................................................84

Exploring the Biology of Blood Disorders 

to Find New Avenues for Treatment............................84

Identification of New Potential 

Therapeutic Approach to 

Blood Disorders ..................................................84

Feature: Lower Urinary Tract Symptoms 

Network (LURN): Development and Use of 

Improved Assessments of Urinary Symptoms..........86

Feature: Alternatives to Race-Based 

Kidney Function Calculations..................................88

Feature: Improving Kidney Stone 

Measurements With Automated Systems ................90

Personal Perspective: Contributing to 

Research Toward Achieving Equity in 

African American Kidney Transplant Outcomes......92

Kidney, Urologic, and Hematologic Diseases Toc_2024-kuh
NIDDK Recent Advances & Emerging Opportunities 2024: Kidney, Urologic, and Hematologic Diseases 77

Acute kidney injury can cause long term damage by promoting fibrosis, which is the formation of scar tissue. This 

scarring process modifies genetic activity by turning genes on or off in cells. These changes can affect the kidney’s ability 

to function properly but do not happen uniformly across all cells. Described within this chapter, researchers recently 

examined how two types of acute injury change the array of activated genes in cells across the kidney. In the above 

constructed image, cells of the injured kidney are sorted via a technique called UMAP plotting into clusters based on 

similar gene expression, indicated by the different colors. Cells from structures in the kidney known as proximal tubules 

(PT), which have three segments known as S1, S2, and S3, were found to exist in a healthy state (green clusters) or to have 

genetic activity consistent with injury (red), active repair (orange), or failed repair (brown). The research also identified 

two novel states of injury (type 1 and type 2) with distinct activation profiles that had not been previously characterized. 

These two subsets had metabolic changes that could differentially affect the cells’ ability to repair and recover. 

Recognizing and understanding this heterogeneity in genetic activity following injury allows for a better understanding 

of specific repair mechanisms that promote healing and limit damage from fibrosis. Ultimately, this could lead to new 

treatments to help prevent chronic kidney disease.

Reprinted from Cell Metabolism 34, Li, H., Dixon, E. E., Wu, H. & Humphreys, B. D. Comprehensive single-cell transcriptional profiling defines shared and 

unique epithelial injury responses during kidney fibrosis, 1977-1998.e9, Copyright 2022, with permission from Elsevier.
NIDDK Recent Advances & Emerging Opportunities 2024: Kidney, Urologic, and Hematologic Diseases 78

Normal, healthy kidneys filter about 200 quarts of blood 

each day, generating about 2 quarts of excess fluid, salts, 

and waste products that are excreted as urine. Loss of 

function of these organs, either for a short period of time 

or as a consequence of a gradual, long-term decline in 

kidney function, is a life-threatening condition. 

An estimated 35.5 million American adults have impaired 

kidney function—also called chronic kidney disease 

(CKD).1 However, up to 9 of every 10 adults with CKD 

are not aware that they have the disease.1 CKD has 

two main causes: high blood pressure and diabetes. The 

increases in obesity and type 2 diabetes in the United 

States in recent years—especially among children and 

adolescents—have grave implications for the Nation’s 

health, as young people with these conditions are more 

likely to face serious health complications at an earlier 

age than people who historically have developed these 

conditions later in life. CKD can also result from other 

factors, as noted below.

CKD, especially if undetected, can progress to irreversible 

kidney failure, a condition known as end-stage kidney 

disease (ESKD). People with ESKD require dialysis or a 

kidney transplant to live. In 2021, over 808,000 patients 

in the United States and its territories were living with 

ESKD.2

 Over 541,000 had previously received either 

hemodialysis or peritoneal dialysis, and over 251,000 were 

living with a kidney transplant.2 Racial and ethnic minority 

populations in the United States, particularly African 

Americans, Hispanic and Latino Americans, and American 

Indians and Alaska Natives, bear a disproportionate 

burden of CKD and ESKD. ESKD prevalence in 2021 was 

about four times greater in African Americans; over twice 

as high in American Indians, Alaska Natives, and Hispanic 

Americans; and 1.6 times greater in Asian Americans, 

compared to Whites.2

 NIDDK supports a significant body 

of research aimed at understanding the biology underlying 

CKD and developing treatment strategies.

In addition to research on kidney disease related to 

diabetes and high blood pressure, NIDDK also supports 

studies of inherited diseases—such as polycystic kidney 

disease, congenital kidney disorders, and focal segmental 

glomerulosclerosis—and immune-related kidney 

diseases, such as IgA nephropathy and hemolytic uremic 

syndrome. One feature common to kidney diseases 

arising from varying causes is the deposition of fibrotic 

scar tissue in the kidney. Research supported by NIDDK 

has enhanced our understanding of the origin of this 

scar tissue, how it can impair kidney function, and how it 

might be prevented or treated.

Diseases of the kidneys, urologic system, and blood are among the most critical health problems 

in the United States. They affect millions of Americans, and their impact is felt across the 

lifespan. To improve our understanding of the causes of these diseases, and to identify potential 

new prevention and treatment strategies, NIDDK supports basic and clinical research studies 

of the kidney and urinary tract and of the blood and blood-forming organs. The overall goal of 

NIDDK’s research programs is to improve the health of people who have or are at risk for kidney, 

urologic, and hematologic (blood) diseases.

Kidney, Urologic, 

and Hematologic Diseases

1 Centers for Disease Control and Prevention. Chronic Kidney Disease in 

the United States, 2023. Atlanta, GA: U.S. Department of Health and 

Human Services, Centers for Disease Control and Prevention; 2023.

 2 United States Renal Data System. 2023 USRDS Annual Data Report: 

Epidemiology of kidney disease in the United States. National Institutes of 

Health, National Institute of Diabetes and Digestive and Kidney Diseases, 

Bethesda, MD, 2023.

An estimated 35.5 million American adults have 

chronic kidney disease.
NIDDK Recent Advances & Emerging Opportunities 2024: Kidney, Urologic, and Hematologic Diseases 79

Urologic diseases and conditions affect people of all 

ages, result in significant health care expenditures, 

and can lead to substantial disability and impaired 

quality of life. Areas of NIDDK-supported research 

include the causes of and treatments for urologic 

diseases and disorders, such as urinary tract 

infections and urinary stone disease, two of the most 

common and costly urologic conditions affecting 

people in the United States. Urinary incontinence 

(UI) is another prevalent problem. Based on U.S. 

medical insurance claims over several years, the 

annual prevalence of UI among individuals 65 and 

older ranged from 7.0 to 7.8 percent for women 

and from 3.6 to 4.0 percent for men. Among those 

aged 18 to 64, UI prevalence ranged from 0.9 to 1.2 

percent for women while the prevalence was 0.2 

percent for men.3 These estimates may be lower 

than the actual prevalence of UI due to stigma 

surrounding the condition. Many suffer in silence 

due to embarrassment and lack of knowledge about 

treatment options available. 

Many people are also living with one of a cluster of 

disorders collectively called urologic chronic pelvic pain 

syndrome (UCPPS). The two most common examples of 

UCPPS are interstitial cystitis/bladder pain syndrome 

(IC/BPS)—also known as IC/painful bladder syndrome 

(PBS)—and chronic prostatitis/chronic pelvic pain 

syndrome (CP/CPPS). IC/BPS is a debilitating, chronic, 

and painful urologic disorder. Based on a large, national 

interview survey, it is estimated that among U.S. women 

18 years or older, three to eight million have pelvic 

pain and other symptoms, such as urinary urgency or 

frequency, that are associated with IC/BPS.4

 Using a 

community-based epidemiologic survey, researchers 

have estimated that among U.S. men ages 30 to 

79 years old, 1.3 percent have persistent urologic 

symptoms, such as pain with bladder filling and/or pain 

relieved by bladder emptying, that are associated with 

IC/BPS.5 NIDDK-supported basic and clinical research 

on IC/BPS and on CP/CPPS is focused on elucidating 

the causes of these conditions, identifying important 

subsets of patients to aid diagnostic stratification, and 

improving treatment and interventions. 

Research on UCPPS is one example of how NIDDK 

is seeking a broad-based understanding of symptoms 

affecting the lower urinary tract (LUTS), including pain, 

bladder leakage, and problems urinating. For the wide 

range of LUTS, we still need to learn more about causes 

and contributing factors to improve management and 

treatment of symptoms. NIDDK is supporting research 

to better understand factors that contribute to bladder 

health over the lifespan, with the ultimate goal of 

preventing LUTS.

NIDDK’s hematology research program uses a broad 

approach to enhance understanding of the normal 

and abnormal function of blood cells and the bloodforming (hematopoietic) system in order to develop 

effective treatment strategies. Blood diseases and 

disorders—some of which cause severe, debilitating 

pain, and premature death—affect millions of Americans. 

These inherited and acquired diseases can affect red 

and white blood cells, platelets, bone marrow, or blood 

vessels. Research efforts include studies of a number 

of nonmalignant blood diseases, including sickle cell 

disease, the thalassemias, aplastic anemia, iron deficiency 

anemia, hemolytic anemias, thrombocytopenia, the 

anemia of inflammation and of chronic diseases, 

hemochromatosis, HIV-associated blood-related 

dysfunction, and bone marrow failure. NIDDK also 

supports research on the basic biology of adult blood 

(hematopoietic) stem cells, which are used clinically 

in bone marrow transplants and may have broader 

application in gene therapy research.

Racial and ethnic minority populations 

in the United States, particularly African 

Americans, Hispanic and Latino Americans, 

and American Indians and Alaska Natives, bear 

a disproportionate burden of chronic kidney 

disease and end-stage kidney disease.

Among U.S. women 18 years or older, three 

to eight million have pelvic pain and other 

symptoms, such as urinary urgency or 

frequency, associated with interstitial cystitis/

bladder pain syndrome.

3 Urologic Diseases in America. 2023. Urologic Diseases in America: 

Annual Data Report. National Institutes of Health, National Institute of 

Diabetes and Digestive and Kidney Diseases, Bethesda, MD, 2023. 

4 Berry SH, et al. Prevalence of symptoms of bladder pain syndrome/

interstitial cystitis among adult females in the United States. J Urol 186: 

540-544, 2011. 

5 Link CL, et al. Prevalence and psychosocial correlates of symptoms 

suggestive of painful bladder syndrome: results from the Boston Area 

Community Health (BACH) survey. J Urol 180: 599-606, 2008. 
NIDDK Recent Advances & Emerging Opportunities 2024: Kidney, Urologic, and Hematologic Diseases 80

UNDERSTANDING THE MOLECULAR 

PATHWAYS TO KIDNEY INJURY

“Kidney Atlas” Helps Illustrate Changes That Occur 

With Kidney Injury: Researchers have compared healthy 

and diseased kidney tissue at the cellular and molecular 

level to create the most comprehensive “kidney atlas” to 

date. The work, supported in part by NIDDK’s Kidney 

Precision Medicine Project (KPMP), will help researchers 

delve into the mechanisms of kidney injury and healing. 

The kidney is a complex organ composed of multiple 

cell types, each of which has a specific role. Acute 

kidney injury (AKI) occurs when the kidney is damaged 

by factors such as low blood flow, certain medications, 

or infection. While the kidney typically continues 

to function following injury, some people with AKI 

progress to chronic kidney disease (CKD). In CKD the 

kidneys gradually lose their ability to excrete excess salt, 

eliminate waste, and balance water levels. This can lead 

to end-stage kidney disease, which must be treated with 

dialysis or may even require a kidney transplant. The 

atlas helps investigators understand the changes that 

occur in specific kidney cell populations due to different 

stresses and further differentiates distinct disease states 

to identify optimal treatment approaches.

In the study, kidney samples provided by male and 

female donors who were healthy or had AKI or CKD 

were analyzed for the types of cells present, what 

region of the kidney these cells were in, and how the 

cells adapted to their local environment. Damaged 

tissue was analyzed for which molecular repair 

pathways were turned on, what types of immune cells 

were present, and what cell types were communicating 

with each other through chemical signals. Additionally, 

the research distinguished pathways that led to injury 

resolution versus those that became “maladaptive,” 

causing long-lasting inflammation and irreversible 

damage (called fibrosis). The data, available to 

investigators through the KPMP Kidney Tissue Atlas 

at www.kpmp.org, represent a collection of threedimensional renderings and kidney maps that can help 

scientists from around the globe understand the kidney 

in health, injury, and disease.

This work could significantly improve our 

understanding of why some people overcome AKI 

while others experience a progressive loss of kidney 

function that develops into CKD. Furthermore, it 

helps distinguish distinct disease states that we now 

collectively treat as AKI or CKD, which could allow 

for more targeted therapeutics that not only halt 

disease progression but reverse kidney damage as 

well. Ultimately, KPMP research aspires to form the 

basis for new treatments for kidney diseases that are 

personalized, effective, and safe.

Lake BB, Menon R, Winfree S,...Jain S. An atlas of healthy and injured cell 

states and niches in the human kidney. Nature 619: 585–594, 2023.

Probing the Molecular Events Linking Kidney 

Injury to Fibrosis: New research has utilized cuttingedge methods to analyze the way different types of 

cells respond to kidney injuries that lead to fibrosis 

in two mouse models of kidney injury. Acute kidney 

injury (AKI) often leads to chronic kidney disease—and 

sometimes to kidney failure—by triggering events 

that lead to kidney fibrosis, or scarring. Clarifying the 

molecular links between injury and fibrosis in the kidney 

might therefore suggest new and better ways to treat 

people with AKI to prevent long-term kidney damage. 

To identify the processes involved, scientists used 

male mice in which one kidney was injured either by a 

temporary blockage of blood flow or by a temporary 

block of the path for urine to drain from the kidney. 

Using 24 kidneys from mice with one injury type or 

the other, they used high-throughput methods that 

allowed them to record details of genetic activity in 

over 300,000 cells, including 50 different cell types. 

These experiments revealed a wide variety of cellular 

responses in the different types of kidney injury. The 

animals with AKI caused by blood flow restriction 

were more likely to recover their kidney function than 

those with AKI from temporary urinary obstruction, 

and researchers found differences in genetic activity 

in various cell types that might help explain the 

unequal outcomes. Comparing these changes to 

cellular responses from other mouse models as well as 

human kidney disease states allowed the researchers 

to verify that many were relevant to human disease. 

Study scientists assembled their data into an atlas 

of genetic activity profiles of various cell types from 

the two injury states, which is available on the web 

as a useful resource for future research. This atlas 

is improving our understanding of the pathways that 

lead to kidney fibrosis and could one day lead to 

In a breakthrough toward understanding 

and treating kidney injury, researchers have 

compared healthy and diseased kidney tissue 

at the cellular and molecular level to create the 

most comprehensive “kidney atlas” to date.
NIDDK Recent Advances & Emerging Opportunities 2024: Kidney, Urologic, and Hematologic Diseases 81

treatments that help prevent chronic kidney disease 

from developing in people who experience AKI.

Li H, Dixon EE, Wu H, and Humphreys BD. Comprehensive single-cell 

transcriptional profiling defines shared and unique epithelial injury 

responses during kidney fibrosis. Cell Metab 34: 1977-1998.e9, 2022.

INVESTIGATING POLYCYSTIC 

KIDNEY DISEASE 

Resolving Key Details of Polycystic Kidney Disease 

Genetics: Researchers helped clarify what genetic 

variations can cause polycystic kidney disease (PKD) 

by examining specific gene sequences in more than 

170,000 people in a regional health care system who 

agreed to participate. In PKD, numerous kidney cysts 

form that interfere with the organ’s function. As the 

disease progresses it often leads to kidney failure and 

complications such as high blood pressure, cysts in the liver, 

and problems with blood vessels in the brain and heart. 

The most common form of PKD—autosomal dominant 

PKD, or ADPKD—usually occurs when someone has a 

disease-causing variant in either the gene PKD1 or the gene 

PKD2. However, although some specific variations in these 

genes are known to cause disease, many other PKD1 and 

PKD2 variants are of uncertain significance. Importantly, 

a significant number of people with ADPKD have been 

found to have only normal versions of PKD1 and PKD2, and 

previous research has implicated rare variants in at least 10 

other genes as potentially being able to cause the disease.

To shed more light on the genetic causes of ADPKD, 

scientists used a technique that allowed them to zero in 

on the key portions of each gene previously suggested 

to have a role in causing the disease. They examined 

the gene sequences in consenting participants—more 

than 170,000 people—among whom 235 had a diagnosis 

of ADPKD. This allowed them to identify genetic 

variants in PKD1 and PKD2 that truly are likely to cause 

ADPKD—including previously unknown variations—while 

ruling out some of the previous suspects. Variations in 

PKD1 turned out to be causing the disease in a bit more 

than half of those with ADPKD, while PKD2 variations 

accounted for 14 percent, and variations in other genes 

accounted for an additional 8 percent. Importantly, it 

was not possible to identify the genetic cause of ADPKD 

in almost a quarter of the participants with the disease, 

suggesting there is much more to discover about its 

causes. Because 93 percent of the study participants 

were of European ancestry, it will be important to extend 

this research in a study with a more diverse group of 

participants. These findings potentially improve on 

scientists’ ability to predict who will develop ADPKD, 

and who might benefit from treatments currently in 

development.

Chang AR, Moore BS, Luo JZ,....Mirshahi T. Exome sequencing of a clinical 

population for autosomal dominant polycystic kidney disease. JAMA 328: 

2412–2421, 2022.

New Technologies Help Uncover an Unexpected Role 

of Glucose in Polycystic Kidney Disease: Using an 

innovative new method to simulate a micro-environment 

within the kidney, scientists have discovered that glucose 

(sugar) absorption contributes to the growth of cysts in 

polycystic kidney disease (PKD). PKD is a genetic disorder 

that causes many fluid-filled cysts to grow in a person’s 

kidneys, leading to chronic kidney disease, high blood 

pressure, and often kidney failure. When waste products 

are initially filtered out of the blood in the kidney, water 

and important nutrients go along for the ride. These 

valuable materials are largely reabsorbed as they pass 

through tiny structures called tubules. It is within these 

tubules that cysts form in PKD. Because tubules are 

enclosed within the kidney, it is difficult to research the 

mechanisms behind PKD cyst formation in humans or 

using animal models. Previous studies have led to the 

development of microscopic structures outside of a living 

organism, called kidney organoids, which contain not 

only the tubules, but the other components of the blood 

filtration system. Importantly, kidney organoids from cells 

with PKD-causing mutations develop tubular cysts, just 

as they would in a person. Organoids are typically grown 

in static fluid conditions, but because of the constant 

exchange of fluid within the kidney, an understanding of 

the impact of liquid flow on PKD organoids is needed. 

This understanding could provide needed insight into the 

mechanisms of cyst formation in the kidney. 

For this research study, scientists grew organoids and 

attached them to special microscope slides called chips 

that contain small channels to provide a fluid-flow 

environment similar to that of a living kidney. They 

observed via microscope that the PKD organoid cysts 

grew twice as fast in fluid-flow conditions as they did 

New research potentially improves on scientists’ 

ability to predict who will develop polycystic 

kidney disease, and who might benefit from 

treatments currently in development.
NIDDK Recent Advances & Emerging Opportunities 2024: Kidney, Urologic, and Hematologic Diseases 82

when the liquid around them was motionless. The 

researchers discovered that cyst growth rate was closely 

linked to their exposure to glucose, a nutrient normally 

reabsorbed by the tubules. They found that the PKD 

cysts absorbed and expanded in response to glucose 

and subsequently showed that this expansion could 

be reversed with the use of a drug that inhibits tubular 

reabsorption of glucose. Equipped with the insight gained 

from the PKD organoid-on-chip model, the researchers 

were then able to confirm the uptake of fluorescent 

glucose in PKD cysts within the kidneys of a PKD mouse 

model, suggesting that the same phenomenon occurs in 

living PKD kidneys.

The novel organoid-on-chip PKD model used in this 

study provided new insight into the impact of fluid 

flow and glucose uptake on the formation of PKD cysts 

within the kidney. With further research, safety studies, 

and clinical trials, these findings suggest that glucose 

uptake-inhibiting drugs might one day help prevent the 

progression of PKD in people with the disease.

Li SR, Gulieva RE, Helms L,...Freedman BS. Glucose absorption drives 

cystogenesis in a human organoid-on-chip model of polycystic kidney 

disease. Nat Commun 13: 7918, 2022.

EXPANDING KNOWLEDGE 

OF KIDNEY TRANSPLANTATION

Kidneys From Deceased Organ Donors With or Without 

Acute Kidney Injury Show Similar Transplant Outcomes:

Findings from a national cohort study showed that kidneys 

from deceased donors with acute kidney injury (AKI) were 

not clinically different than kidneys from donors with no 

or resolved AKI, in terms of graft survival and function. 

Kidney transplantation significantly improves quality of 

life and eliminates costs associated with chronic dialysis, 

but innovative approaches are urgently needed to expand 

the donor pool because many people are on a waitlist and 

often never make it to transplant. To fill this gap, this study 

provides evidence for the benefits of transplanting kidneys 

from deceased donors with AKI, suggesting they are an 

underutilized resource that could help improve long-term 

health outcomes for those in dire need of new kidneys.

AKI is an often-reversible condition in which one’s kidneys 

suddenly stop functioning properly. AKI can lead to 

thickening and scarring of the kidney tissue and increases 

risk of chronic kidney disease, but whether kidneys 

transplanted from donors with AKI can go on to function 

as well as those from donors without AKI needs further 

research. In this study, researchers analyzed data from over 

7,000 donors with ongoing AKI and over 13,000 adults who 

received kidney transplants from the donors from 2007 

to 2016. When they compared the results to outcomes 

from people who received kidneys with no or resolved AKI, 

they did not find any clinically meaningful differences in 

either kidney function over 12 months or in failure rates 

of transplanted kidneys within 3 years. The data also 

showed that kidneys from donors with AKI and diabetes 

had slightly worse transplant outcomes, compared to 

kidneys with AKI but without diabetes. The researchers also 

found that during the study period, nearly 3,000 kidneys 

were discarded from donors with ongoing AKI who were 

under age 65 and had neither hypertension nor diabetes, 

suggesting that more widespread use of kidneys from 

potential donors with AKI could help expand the donor pool.

These findings show that even severe, ongoing AKI that 

persisted at the time of kidney donation does not have 

a significant adverse effect on transplant outcomes, 

and that kidneys from donors with AKI are too often 

discarded, needlessly limiting the pool of kidneys that 

could be safely and effectively transplanted into people 

awaiting the procedure. Continued research will be 

important to confirm the long-term outcomes and to 

increase the clinical practice of transplanting kidneys 

from deceased donors with AKI for those who are 

waiting for kidney transplants. 

Sonnenberg EM, Hsu JY, Cohen JB,...Reese PP. Acute kidney injury in 

deceased organ donors and kidney transplant outcomes. Ann Surg 276: 

e982-e990, 2022. 

DISCOVERING GENETIC RISK FACTORS FOR 

DIABETIC KIDNEY DISEASE

A Potential Explanation for Differences in Susceptibility 

to Kidney Complications of Diabetes: New research 

in mice has identified a genetic factor that might help 

explain why some people with diabetes are more prone 

than others to kidney complications of the disease. 

Between 10 and 30 percent of people with either 

type 1 or type 2 diabetes develop diabetic kidney disease 

Kidneys from donors with acute kidney injury 

often get discarded, but there may be an 

opportunity for these organs to serve as safe 

and effective organ transplants and expand the 

donor pool.
NIDDK Recent Advances & Emerging Opportunities 2024: Kidney, Urologic, and Hematologic Diseases 83

(DKD), making diabetes a major risk factor for loss of 

kidney function. But because most people with diabetes 

do not develop DKD, there is considerable interest in 

understanding what puts some people at higher risk 

than others. One of the early events in development of 

DKD is loss of a type of kidney cells called podocytes, 

which act as the first filter for blood. These cells permit 

water, salts, and other small molecules in the blood to 

exit the bloodstream, while blocking larger compounds 

like proteins from coming along for the ride. When 

podocytes disappear, protein levels start to fall in the 

blood, and rise in the urine—hallmarks of kidney disease. 

Podocytes also disappear in a strain of mice that are 

susceptible to DKD, but they remain present in a 

different strain of mice with kidneys that stay healthy 

even when the animals have diabetes. Looking for 

differences between the two strains, researchers noticed 

that the mice that lose their podocytes after developing 

diabetes were producing more of a protein called 

xanthine oxidoreductase (Xor). They found that this was 

due to a difference in a region of DNA that helps regulate 

how much of the protein is produced when glucose 

levels rise (as in diabetes). To see if this difference was 

important, the scientists created a mouse strain that had 

the genetic predisposition to create excess Xor but was 

otherwise identical to the DKD-resistant animals. When 

experimentally given diabetes, these mice rapidly lost 

their podocytes, suggesting that elevated Xor might be 

an important factor in contributing to DKD. If levels of 

Xor turn out to have a similar impact on podocytes and 

kidney health in people with diabetes, future work might 

focus on trying to develop a medication that can safely 

inhibit Xor’s effects in hopes of one day preventing DKD 

or slowing its progression in those at risk for the disease.

Wang Q, Qi H, Wu Y,...Daehn I. Genetic susceptibility to diabetic kidney 

disease is linked to promoter variants of XOR. Nat Metab 5: 607-625, 2023.

UNDERSTANDING THE SPECTRUM OF 

UROLOGIC DISEASE SYMPTOMS AND 

TREATMENT RESPONSES

New Insights Into Overactive Bladder Urinary 

Symptoms: Recent findings suggest that two 

manifestations of overactive bladder (OAB) may reflect 

a spectrum of symptom severity rather than two 

distinct subtypes. People with OAB may experience 

a variety of symptoms including increased urge to 

urinate (urinary urgency or UU), frequent urination, 

urine leakage (urgency urinary incontinence or UUI), 

and nocturia (nighttime frequent urination). Some 

hypothesize that UU and UUI represent different 

degrees of OAB symptoms (i.e., they are the same 

condition), while others hypothesize that they are two 

separate subtypes of OAB. Though OAB is a relatively 

common condition, there is limited understanding of 

the characteristics that distinguish people with UU from 

those with UUI, making the clinical management of 

these burdensome and painful conditions challenging. 

Increased knowledge about these conditions could 

help identify if some people respond better to certain 

treatments, enabling a more personalized and targeted 

approach to treatment.

In this observational study, people with lower urinary 

tract symptoms who were enrolled in the Symptoms 

of Lower Urinary Tract Dysfunction Research Network 

study were characterized as experiencing either UUonly or UUI based on their answers to a questionnaire 

about their urinary symptoms. Of the 683 participants 

who reported urinary urgency at their initial visit, 

one-third were characterized with UU alone and twothirds were characterized with UUI. At their initial 

appointment and at 3- and 12-month follow-ups, 

participants also answered questions to assess their 

urological pain, other urological symptoms, and quality 

of life. Individuals experiencing UU-only reported 

fewer symptoms like severe urgency and urinary 

frequency; lower levels of anxiety, depression, and 

stress; and better sleep and higher physical activity 

than those with UUI. Additionally, individuals with 

UUI reported a lower quality of life than those with UU 

alone. Interestingly, the researchers did not observe 

differences in urological pain between people with UUonly and people with UUI. The study investigators also 

observed that some people transitioned between UUonly and UUI after 12 months, whereas some improved 

to the point of having no urgency at all. These results 

suggested that UUI may be a more severe form of UU, 

rather than two different subtypes of OAB.

While this study provides new information about the 

symptoms of UU and UUI, further research is needed 

to definitively characterize the relationship between 

these conditions. A limitation of this study is that 

participants were followed for only 12 months. Longer 

observations of people with UU and UUI will provide 

better insight into their long-term impact on health and 

well-being. Further, since the population included was 

predominantly White, observations of more diverse 
NIDDK Recent Advances & Emerging Opportunities 2024: Kidney, Urologic, and Hematologic Diseases 84

groups will help determine whether these findings 

apply to all people living with OAB.

Lai HH, Wiseman JB, Helmuth ME,...Kenton K; for the Symptoms of 

Lower Urinary Tract Dysfunction Research Network (LURN). Phenotyping 

of urinary urgency patients without urgency incontinence, and their 

comparison to urgency incontinence patients: findings from the LURN 

study. J Urol 209: 233-242, 2023.

Discovering the Risks of Developing Symptoms Due 

to Ureteral Stent Placement: Kidney stones are small, 

hard structures that are sometimes found in the kidneys 

or in the tubes known as ureters that move urine from 

the kidney to the bladder. When stones are too large 

to pass through, they can cause blockages. Physicians 

often recommend a surgery called a ureteroscopy (URS) 

in which a small tube containing a camera is used to 

look inside the ureters and kidneys to find, and in some 

cases remove, the cause of the blockage. Sometimes the 

surgeon may temporarily leave a tiny tube called a stent 

inserted in the ureters to assist in holding them open 

to facilitate urine flow and passage of any stones after 

surgery, promoting healing. Unfortunately, these stents 

often cause discomfort and may themselves lead to 

urinary difficulties in some people. However, identifying 

individuals who are most at risk of experiencing severe 

stent-related symptoms has been difficult. The NIDDKsupported Urinary Stone Disease Research Network, 

therefore, conducted and published the findings of the 

Study to Enhance Understanding of Stent-Associated 

Symptoms, or STENTS, with the goal of improving 

understanding of stent-related symptoms and risk 

factors for developing them. 

STENTS researchers enrolled 424 people who 

underwent a URS and stent placement at four hospitals 

across the United States. Before surgery, participants 

filled out four short questionnaires to report pain 

intensity, level of pain interference on daily activities, 

urinary symptoms such as incontinence, increased 

frequency and difficulty urinating, and the level of bother 

due to those symptoms. These questionnaires were 

repeated 1, 3, and 5 days after the URS, on the day of 

stent removal, and 30 days after stent removal. The 

study researchers found that while they observed a peak 

in pain and urinary symptoms 1 day post-surgery with a 

steady decline until day 5, the level of daily interference 

and bother due to pain and urinary symptoms persisted 

longer. Surprisingly, no specific surgical factors, such as 

surgery length or method, were associated with higher 

pain and urinary symptoms or their impact. Instead, 

they found that painful past stent experiences were 

associated with higher pain intensity and interference, 

higher body mass index was associated with higher 

urinary symptoms and bother, and younger age and 

history of depression were associated with higher levels 

of all symptoms and their impact. A month after stent 

removal, however, all reported symptoms were below 

pre-surgery levels.

Further investigation of stent-related symptoms 

is needed since these results may not be broadly 

representative, as the study population was primarily 

White, and the surgeries were performed at academic 

medical centers. However, the knowledge gained from 

this study can lead to new strategies, such as options 

for stent-less ureteroscopies, more informed patient 

counseling, and new potential therapies to improve 

experiences of patients with kidney stones.

Harper JD, Desai AC, Maalouf NM,...Scales CD Jr; for the Urinary Stone 

Disease Research Network (USDRN). Risk factors for increased stentassociated symptoms following ureteroscopy for urinary stones: results from 

STENTS. J Urol 209: 971-980, 2023.

EXPLORING THE BIOLOGY OF BLOOD 

DISORDERS TO FIND NEW AVENUES FOR 

TREATMENT

Identification of a New Potential Therapeutic Approach 

to Blood Disorders: Scientists detailed a novel way to 

restart production of fetal hemoglobin (HbF), suggesting 

a new potential therapeutic approach for some blood 

disorders. Thalassemias and sickle cell disease are 

inherited blood disorders that affect hemoglobin, a protein 

that carries oxygen through the body. Around birth, 

production of HbF is turned off and shifts to production of 

“adult” hemoglobin (HbA). In this research, investigators 

studied hemoglobin genes and their regulation and 

identified how HbF is turned on in response to highaltitude conditions of low oxygen (hypoxia), an example 

of a condition in which more red blood cells are needed 

rapidly. This research identifies a new therapeutic 

approach to blood disorders of hemoglobin.

Researchers gained more insight into individual 

risk factors for pain and urinary symptoms 

among people with stents placed after surgery 

for urinary stones.
NIDDK Recent Advances & Emerging Opportunities 2024: Kidney, Urologic, and Hematologic Diseases 85

The scientists found that a protein called hypoxiainducible factor 1α (HIF1α) can turn on production of 

HbF in an adult human blood cell line. Using cuttingedge molecular and genetic strategies, they found that 

HIF1α binds specific sequences of DNA in regions 

known to regulate hemoglobin genes and recruits 

additional proteins to stimulate production of HbF. 

They uncovered molecular changes in HIF1α, as well 

as changes in how it interacts with other proteins, that 

occur in the developmental switch from production of 

HbF to HbA. They hypothesized that reversing these 

changes might re-induce HbF production. To test 

whether this approach could be a potential therapeutic 

strategy, the scientists treated cells with a drug known 

to boost red blood cell levels. They found that treating 

healthy adult donor cells or cells from donors with sickle 

cell disease with this drug increased production of HbF 

to levels similar to those induced by treatment with 

hydroxyurea, which is used to treat sickle cell disease. 

Treatment of the cells from a donor with sickle cell with 

the drug also reduced the sickling characteristic of 

the disease. 

The exciting finding that stabilization of HIF1α can 

induce production of HbF in human blood cells provides 

important new knowledge in understanding the 

regulation of hemoglobin production and indicates a 

potential therapeutic strategy to restart HbF production 

in people affected by blood disorders. Additional 

research will be needed to test whether this strategy can 

be translated from the bench to the clinic. 

Feng R, Mayuranathan T, Huang P,...Weiss MJ. Activation of γ-globin 

expression by hypoxia-inducible factor 1α. Nature 610: 783–790, 2022.
NIDDK Recent Advances & Emerging Opportunities 2024: Kidney, Urologic, and Hematologic Diseases 86

Lower Urinary Tract Symptoms 

Network (LURN): Development and 

Use of Improved Assessments of 

Urinary Symptoms

Symptoms affecting the lower urinary tract, such 

as urinary incontinence, frequent urination, and 

bladder pain, are common among adults and often 

have negative impacts on a person’s quality of life. 

Gaining a comprehensive understanding of the full 

spectrum of lower urinary tract symptoms (LUTS) and 

their impact on people dealing with them will allow 

for better diagnoses and development of improved 

treatment options. 

LUTS are typically assessed using questionnaires 

that allow individuals to self-report and rank their 

symptoms, and sometimes their quality of life, via 

a point scale to determine their symptom severity 

scores. When used alongside other clinical tests and 

physical examinations, these assessments can help 

guide clinicians in their recommendations. Several 

questionnaires have been developed to assess LUTS, 

however many of them are either limited in their 

scope, focusing on specific disorders, or were originally 

developed to assess sex and/or gender-specific 

symptoms. For example, the American Urological 

Association Symptom Index was initially designed 

to assess symptoms of benign prostatic hyperplasia 

in men, while the Pelvic Floor Distress Inventory 

evaluates the impact of LUTS and other symptoms on 

the quality of life of women with pelvic floor disorders. 

Additionally, many of the available questionnaires do 

not assess the full range of LUTS. 

In 2012, NIDDK established the Symptoms of Lower 

Urinary Tract Dysfunction Research Network (LURN) 

with the long-term goals of better understanding 

different LUTS subtypes and improving measurement 

of patient experiences of LUTS. To achieve these aims, 

LURN researchers first developed the Comprehensive 

Assessment of Self-Reported Urinary Symptoms 

(CASUS), which is a 93-question survey measuring a 

broad variety of symptoms in both men and women 

with LUTS. 

For use in a clinical or research setting, an optimal 

questionnaire must be simple and brief enough to 

ensure that people can fully understand and complete 

it, yet comprehensive enough to gather meaningful 

information. Therefore, using the CASUS as a 

starting point, LURN researchers along with a panel 

of clinicians used a multi-step process to develop two 

shorter-form questionnaires: the LURN Symptom 

Index 10 (SI-10) and the LURN Symptom Index 29 

(SI-29). The SI-10 is primarily intended for clinical 

use and is composed of 10 core questions, while the 

SI-29, which consists of 29 core questions, is primarily 

designed for research. Both questionnaires cover 

five key symptom areas of LUTS: urinary urgency, 

incontinence, urination difficulty, night-time frequent 

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NIDDK Recent Advances & Emerging Opportunities 2024: Kidney, Urologic, and Hematologic Diseases 87

urination (referred to as nocturia), and pain. When 

tested for validity against commonly used LUTS 

measurement questionnaires, both SI-10 and SI-29 

provided scores that were comparable to those of the 

established surveys while also providing assessment of 

a broader range of symptom areas. 

The LURN questionnaires have already proven to 

be valuable resources in both research and clinical 

settings, facilitating assessment of LUTS symptoms 

and their impact on people’s lives. Several hospitals 

have integrated the SI-10 questionnaire into their 

electronic health record systems, providing clinicians 

with more insight into the symptoms that their 

patients experience. 

Recognizing that addressing disparities in urological 

health requires ensuring these tools are accessible 

to diverse patient populations, LURN researchers 

optimized each question during questionnaire 

development to promote easy translation into other 

languages. In fact, the NIDDK-supported Prevention 

of Lower Urinary Tract Symptoms (PLUS) Research 

Consortium developed a Spanish translation of the 

SI-10 for inclusion in its RISE FOR HEALTH study 

of women’s bladder health. In addition, Turkish 

translations of both questionnaires and a Hindi version 

of the SI-29 are available for download on the LURN 

website, and more translations are planned for the 

future. By making the questionnaires available in 

multiple languages, LURN scientists are helping ensure 

that their research will be both broadly applicable and 

widely available, thus improving comprehensive LUTS 

assessment in diverse communities.

More research will be necessary to fully understand 

and optimally treat the complex array of diseases 

and conditions that contribute to LUTS. Through 

development of the CASUS, SI-29, and SI-10 

questionnaires, LURN has laid a key foundation for 

that work by providing comprehensive tools that 

are yielding new insights that may one day improve 

diagnostic and treatment approaches for LUTS.

For more information, visit

https://nih-lurn.org/Resources/Questionnaires.

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NIDDK Recent Advances & Emerging Opportunities 2024: Kidney, Urologic, and Hematologic Diseases 88

Alternatives to Race-Based Kidney 

Function Calculations

Race has long been used as a biological variable 

in health research, under the mistaken belief that 

racial categories correlate with genetic traits that 

account for population-level biological differences. 

However, we now know that more genetic variation 

exists within race categories than between them, 

and that race correlates poorly with the spectrum 

of biological variability that exists among 

human beings. 

Accordingly, NIDDK-supported research is leading 

to a change in the way kidney disease is diagnosed 

and monitored by removing race as a variable from 

the equations used to estimate glomerular filtration 

rate (GFR). Estimated GFR remains a primary tool to 

assess kidney function and to classify the severity of 

kidney disease. Estimated GFR also helps determine 

prognosis and treatment, such as when hemodialysis 

or a transplant may be needed and how to optimize 

the dosage of certain drugs.

Because measuring someone’s GFR directly is 

expensive, difficult, and burdensome on the 

person being tested, GFR is normally estimated by 

using an inexpensive blood test to determine the 

concentration of a compound called creatinine. 

Because creatinine is synthesized at a constant rate 

by one’s muscles and filtered out of the blood by the 

kidneys, its concentration in the blood is strongly 

linked to kidney function. For several reasons, 

however, creatinine is not a perfect biomarker of 

a person’s actual kidney function. For example, its 

synthesis rate is determined by how much muscle 

a person has, and its blood concentration is also 

affected to a degree by how much meat they eat. As 

a result, a person’s real GFR might be a bit higher or 

lower than their estimated GFR, but the estimates are 

generally close.

However, the original study data used to develop 

estimated GFR calculations came overwhelmingly from 

participants of European descent. Subsequent work 

showed that the relationship between creatinine level 

and real GFR, on average, was the same for people 

from most other groups. Researchers discovered, 

though, that for unknown reasons creatinine levels 

tend to be slightly higher in Black study participants 

than in participants from other populations, at any 

given directly measured GFR. As a result, for many 

years estimated GFR calculations have taken into 

consideration whether the person being tested is 

“Black” or “non-Black.”

This practice is problematic. Race was created for 

social and political reasons, and thus has no biological 

basis. Indeed, race categories do not align with the 

continuum of human genetic and biological variability. 

For example, many individuals who identify as Black 

do not, in fact, have a higher creatinine to GFR ratio 

than is found in other groups. Therefore, applying the 

“correction factor” for Black race sometimes leads to 

overestimation of GFR, potentially aggravating the 

significant health disparities that exist in kidney health 

outcomes. For example, a person who identifies as 

Black could be erroneously excluded from receiving a 

kidney transplant because the equation overestimates 

their GFR, making it appear that their kidneys are more 

functional than they are. Further, the physiological 

reason why some Black people have a higher 

creatinine to true GFR ratio remains unknown, so 

there is no way to test for it. Thus, it is unclear who, 

exactly, does have a higher creatinine to true GFR 

ratio and thus should receive a correction factor for 

determination of estimated GFR. 

Recent NIDDK-supported research from the Chronic 

Renal Insufficiency Cohort Study and the Chronic 

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NIDDK Recent Advances & Emerging Opportunities 2024: Kidney, Urologic, and Hematologic Diseases 89

Kidney Disease Epidemiology Collaboration has 

sought to address these issues by identifying new, 

better methods for assessing kidney function. For 

example, one group investigated whether genetic 

ancestry analysis might be useful for helping 

determine who the correction factor should apply to. 

While the use of ancestry did improve accuracy at the 

population level, it is both impractical and not always 

applicable at the individual level. Other approaches 

that considered body composition (e.g., how muscular 

a person is) or urinary creatinine excretion rates 

marginally improved accuracy. Another group 

tested an alternative formula for estimating GFR 

from creatinine that corrects somewhat for age and 

sex, but that does not use race as a modifier. On 

average, this approach slightly underestimated GFR 

for participants who identified as Black, and slightly 

overestimated GFR for people who considered 

themselves non-Black. 

Encouragingly, both studies also found that estimating 

GFR based on blood levels of a compound called 

cystatin C, which does not vary by a person’s race, 

could help improve the accuracy of kidney function 

tests. One of the studies found that the most 

accurate, least biased results were obtained using 

equations that utilize both markers—creatinine and 

cystatin C. Thus, NIDDK-supported research has 

informed recent recommendations to use both serum 

creatinine and cystatin C to estimate GFR in adults, 

when cystatin C is available. Using the combined 

serum creatinine-cystatin C equation is particularly 

important when the estimated GFR value is close to a 

critical decision point, such as when determining drug 

dosing or kidney transplant eligibility.

At present, however, laboratory and reimbursement 

infrastructure are not yet adequate to support 

routine ordering of cystatin C tests in clinical 

settings for all people for whom GFR should be 

more accurately assessed. Therefore, two leading 

kidney health advocacy groups—the American 

Society of Nephrology and the National Kidney 

Foundation—have called for measures to improve 

the availability of cystatin C testing, as well as more 

research to find still better approaches for assessing 

kidney health. In the meantime, they have called for 

adoption of the improved creatinine-only based GFR 

estimation method that uses age and sex—but not 

race—as modifiers. 

Thus, NIDDK-supported research is improving the 

equitable and accurate assessment of kidney function. 

NIDDK remains committed to research that builds 

on that improvement and to the overarching goal of 

reducing disparities in kidney disease. 

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NIDDK Recent Advances & Emerging Opportunities 2024: Kidney, Urologic, and Hematologic Diseases 90

Improving Kidney Stone 

Measurements With 

Automated Systems

Urinary stones, also called kidney stones, are pebblelike structures that form due to buildup of minerals 

from urine in the kidneys. About 11 percent of men 

and 6 percent of women in the United States have 

kidney stones at least once during their lifetime. If 

small enough, kidney stones can pass through the 

urinary tract freely, while larger stones can cause 

symptoms such as severe pain, bleeding, and urinary 

blockage. Treatment courses for kidney stones are 

informed by the size and location of stones and 

can involve simply monitoring for their passage, 

using methods to break them into smaller pieces, or 

surgically removing the stones. Reliable and precise 

measurement methods are therefore crucial for 

accurate diagnosis and treatment of kidney stones.

Multiple tests are used collectively to diagnose 

kidney stones, including lab tests like blood and 

urinary analyses to measure levels of certain 

minerals, and imaging tests like x-rays and computed 

tomography (CT) scans to visualize the location of 

the stones. Some stones can be missed by x-rays 

depending on their size and location. Therefore, CT 

scans, which consist of x-rays taken at multiple angles 

that are computer processed to produce detailed 

images, are more commonly used to visualize kidney 

stones. While CT scans are better able to detect 

stones, they require manual input to determine the 

size and other characteristics of kidney stones and 

to measure the anatomy surrounding them. This 

need for human input introduces variability and less 

precise measurements, as the same stone may be 

characterized differently from one person to the 

next. This variability can make it difficult to assess 

factors such as the likelihood of a stone passing 

and the measurement of changes in stone size over 

time. A more automated measurement process could 

help to ensure reliable kidney stone measurements 

and reduce the need for the tedious, more variable 

manual process. 

NIDDK supports research to develop automated, 

more reliable measurement tools for kidney stone 

detection. For example, the Center for Machine 

Learning in Urology (CMLU), which is a joint venture 

of Children’s Hospital of Pennsylvania and University 

of Pennsylvania, aims to use machine learning with 

CT imaging to improve prediction of kidney stone 

passage. In a recent advance from the CMLU, 

scientists described the ability of their machinelearning algorithm to accurately measure kidney 

stones and compared it to the manual measurements 

of three different researchers. Of the 94 children 

and adults included in the study, both manual 

measurers and the algorithm were able to detect 

that 42 of the patients had kidney stones. However, 

the algorithm was shown to provide more reliable 

measurements of stones and regions of the urinary 

tract than manual input. The algorithm also had a 

quicker average measuring time of 12 seconds—

regardless of the number of stones—compared to 

increased manual input times with the presence of 

more stones. Another NIDDK-funded program, the 

O’Brien Urology Research Center at Mayo Clinic, has 

supported the development of a semi-automated 

software system called qSAS. The system, which is 

currently in use for CT research at the Mayo Clinic 

and is freely available to other research groups, 

provides standardized stone characterization with 

minimal manual input. 

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NIDDK Recent Advances & Emerging Opportunities 2024: Kidney, Urologic, and Hematologic Diseases 91

Automated CT scan image measurement processes can 

lessen, and in some cases remove, the variability that 

comes from manual measuring, while providing more 

accurate assessments. Machine-learning CT imaging 

tools like the one developed by CMLU researchers 

have an added advantage of automatic continued 

refinement as more data points are entered. With 

further validation and optimization, the quicker and 

more reliable measurements offered by these new 

technologies have the potential to ensure more precise 

research and diagnosis of kidney stones. 

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NIDDK Recent Advances & Emerging Opportunities 2024: Kidney, Urologic, and Hematologic Diseases 92

Contributing to Research Toward 

Achieving Equity in African American 

Kidney Transplant Outcomes

Chronic kidney disease (CKD) is characterized by 

a long-term decrease in the ability of a person’s 

kidneys to effectively filter toxins from the blood. 

CKD can often lead to end-stage kidney disease 

(ESKD), also known as kidney failure. Treatment 

options for ESKD are either dialysis, which typically 

involves filtration of toxins from the blood by 

a machine, or kidney transplantation. Though 

beneficial, dialysis can be burdensome and draining, 

typically requiring 4-hour visits to a dialysis center 

3 days per week. However, transplantation, if 

available, can provide better quality of life and 

enhanced survival to recipients.

African Americans experience disproportionately 

higher rates of ESKD compared to other racial groups 

in the United States. NIDDK-supported research 

contributed to the discovery that one factor impacting 

this disparity is a greater presence of specific high-risk 

genetic variations in the APOL1 gene among people 

with recent African ancestry. Two variants of this 

gene have been shown to account for nearly all the 

additional risk of ESKD in African Americans who 

do not have diabetes. However, it is not completely 

clear whether donated kidneys with two of these 

high-risk APOL1 variants have worse outcomes after 

transplantation. 

To address this, NIDDK, with additional support 

from the National Institute of Allergy and Infectious 

Diseases and the National Institute on Minority Health 

and Health Disparities, started the APOL1 Long-term 

Kidney Transplantation Outcomes Network (APOLLO) 

in 2017. APOLLO is an observational study that 

involves extensive collaboration of many organizations, 

including the United Network for Organ Sharing, organ 

procurement organizations, and kidney transplant 

centers across the United States. The aim of the study 

is to determine the impact of APOL1 gene variations 

on outcomes of transplants with kidneys from both 

living and deceased African American donors. (See 

inset for the story of a kidney donor and kidney 

transplant recipient participating in APOLLO.)

THE LINK BETWEEN AFRICAN 

ANCESTRY AND APOL1-RELATED 

KIDNEY DISEASE RISK

Like many other sustained genetic mutations, 

the variations found in the APOL1 gene likely aid 

in human adaptation to a specific environment. 

Studies have shown that the proteins of the same 

two APOL1 variants that result in increased risk 

of kidney disease likely protect people against 

infection with the parasites that cause a disease 

called sleeping sickness in humans. Scientists 

believe that the predominance of these parasites 

in sub-Saharan Africa has contributed to the high 

prevalence of the APOL1 variants in people with 

recent African ancestry.

Only people who inherit the high-risk variants 

from both parents appear to have increased risk 

of ESKD associated with APOL1. However, most 

people who inherit two high-risk variants will never 

experience ESKD or even develop kidney disease. 

The mechanism by which the variant APOL1 genes 

lead to development of kidney disease is not fully 

understood, but other factors – including certain 

immune responses or infection with HIV (human 

immunodeficiency virus) might play a role. 

PERSONAL PERSPECTIVE
NIDDK Recent Advances & Emerging Opportunities 2024: Kidney, Urologic, and Hematologic Diseases 93

APOLLO: ASSESSING THE INTERSECTION 

OF APOL1 AND AFRICAN AMERICAN 

DONOR KIDNEY TRANSPLANTATION 

Because of the burden of dialysis treatment, kidney 

transplants provide people with ESKD greater quality 

of life. However, there are many more people who 

need a kidney than there are donor organs available. 

Unfortunately, many African American donor kidneys 

are not used. This occurs for a variety of reasons, 

including observations that kidneys transplanted 

from African American donors typically function for 

shorter periods of time and may have viral infections 

that kidneys from donors of other groups do not. 

Kidneys from African American donors are also 

more likely to be transplanted into African American 

recipients, meaning that these potential recipients are 

disproportionately impacted by the decreased pool 

of viable kidneys. If APOL1 high-risk variants among 

African Americans contribute to the lower rates of 

available kidneys, a genetic test of the donor could 

be used to determine the risk of kidney transplant 

failure instead of race. In that case, more kidneys 

could become available for donation, and there may be 

better outcomes for the recipients. 

The ongoing APOLLO long-term observational study 

is the first forward-looking study of APOL1 and kidney 

transplant risk, meaning that participant outcomes 

and health will be observed over time instead of 

assessed retroactively. In APOLLO, kidney donors and 

recipients will be genetically tested to determine their 

APOL1 gene type. The outcomes of kidney transplant 

recipients, primarily the length of time to transplant 

failure, will be observed over a span of several years 

and assessed according to the number of donor and/or 

recipient APOL1 high-risk variants involved. 

Although most of the kidney transplant recipients 

participating in APOLLO receive organs from deceased 

donors, some of the donors are living. As such, the 

study will also observe the health outcomes of these 

donors. Some evidence suggests that living kidney 

donors who have two high-risk APOL1 variants may 

have a higher risk of developing kidney disease at some 

point, long after donation. While the outcomes of 

living kidney donors will be observed throughout the 

main APOLLO study, the supplemental Living-donor 

Extended Time Outcome (LETO) study will assess 

donor outcomes as well. The LETO arm of APOLLO 

will look back at the kidney health outcomes of kidney 

donors from 15 to 20 years ago to assess any risk of 

APOL1 high-risk variants to living kidney donors.

Working alongside the researchers to develop and 

steer the study is APOLLO’s Community Advisory 

Council, which is made up of African American living 

kidney donors, kidney recipients, and their family 

members. An important goal of the Community 

Advisory Council and the researchers alike is to 

provide understandable education to the broad patient 

community. They have, therefore, collaborated to 

develop many videos, pamphlets, and other resources 

explaining the link between APOL1 gene variants and 

kidney disease, as well as the purpose, plans, and 

hopes of APOLLO. (For more information, please 

see: www.apollocommunity.net/community-education.) 

Findings from APOLLO have the potential to lead to 

a nationwide reworking of the current assessments 

for kidney donations, which could provide a second 

chance at life for many more people awaiting kidneys. 

PERSONAL PERSPECTIVE
NIDDK Recent Advances & Emerging Opportunities 2024: Kidney, Urologic, and Hematologic Diseases 94

Deryl’s and Tanya’s Story

Deryl didn’t learn that he had chronic kidney disease 

(CKD) until he was in his forties, but knowing what 

he knows now, he believes that there were hints of it 

throughout his life. Since he was a child, he says, “I 

knew something was wrong.... I believed my kidneys 

were not functioning properly based on personal 

frequent occurrences. I remember my mom asking 

if I wanted to go to the doctor. I always said no 

because of the embarrassment of the situation.” His 

life completely changed in 2020, after a severe case 

of COVID-19 when he developed end-stage kidney 

disease (ESKD) and needed a kidney transplant. 

Hope soon came from his cousin, Tanya, who was 

ready and willing to donate one of her kidneys. 

Remembering when she learned of her cousin’s need 

for a kidney, she says, “I think that it was just kind 

of a no-brainer for me to say, ‘Oh, OK, well I’ll get 

tested.’” The subsequent journey, including their 

participation in NIDDK’s APOL1 Long-term Kidney 

Transplantation Outcomes Network (APOLLO), 

resulted in a new beginning and a family’s passion to 

advance health equity in kidney transplantation. 

LEARNING ABOUT AND 

LIVING WITH CKD

Having played basketball for most of his life and now 

coaching a high school basketball team in Highland, 

Illinois, Deryl has always lived an athletic lifestyle 

without any other major health issues. He remembers 

receiving his first bit of insight into his kidney 

disease as a transfer student athlete at Kansas State 

University. “The only thing I knew was when I was 

in college the doctor said, ‘You have protein in your 

urine,’” he remembers. “The doctor said that I could 

have a more serious problem down the line. I was 

told I had [high] blood pressure also,” he says. “I was 

told to try and eat certain food items in moderation. 

It was difficult....” Overall, though, he says, “I didn’t 

know what it really meant and the effects that it could 

cause. There was no cure.” Detection of protein in a 

person’s urine can be an early sign of kidney disease. 

However, Deryl did not let that stop him. He recalls 

telling himself, “You’re an 18-year-old young man 

and student athlete. Only thing that I know is all my 

coaches told me to play hard, and I believed playing 

and working hard was a cure-all.” 

And that is exactly how Deryl lived a lot of his 

life. After college he went on to have a successful 

professional basketball career for over 10 years. 

In fact, it wasn’t until he went to his doctor for 

a routine exam as an Indiana State University 

basketball coach in his forties that he learned he had 

kidney damage and was diagnosed with CKD. The 

diagnosis was important to Deryl: “When you have 

a condition, it’s important to have knowledge and, if 

possible, treat it. In my case, I was affected by CKD 

on and off the court.” 

Cousins Deryl and Tanya are participating in the APOLLO study, which 

aims to improve African American kidney donation and transplant 

outcomes

PERSONAL PERSPECTIVE
NIDDK Recent Advances & Emerging Opportunities 2024: Kidney, Urologic, and Hematologic Diseases 95

While kidney damage due to CKD can be slowed 

through lifestyle changes like blood pressure 

management, weight loss, and diet changes, there 

are currently no known ways to reverse CKD-related 

damage. Deryl made many adjustments to manage 

his CKD, although he says that it wasn’t easy. 

His hard work changing his diet paid off, though, 

and he managed to avoid needing dialysis. All of 

that changed when, in 2020 at the height of the 

COVID-19 pandemic, Deryl contracted the illness, 

which resulted in his ESKD.

THE LONG ROAD TO A NEW KIDNEY

Tanya, Deryl’s cousin, works as a lawyer and 

has dedicated her life to providing justice to her 

community as the head of a civil legal aid clinic in 

Chicago. Tanya says that as her parents’ only child, 

she, Deryl, and his sister “grew up more like siblings 

than cousins.” So, she sprang into action when 

she received a call from his sister saying that Deryl 

needed a kidney transplant. Deryl’s sister already 

knew then that she wasn’t a match to donate a kidney 

to her brother, so Tanya decided to get tested.

Matching a living donor to a transplant recipient is a 

complex, multi-step process. It involves tests to assess 

the health of both donor and recipient, determine 

blood type compatibility, and, most critically, to predict 

the chance of the recipient’s body rejecting the donor 

organ. Once Tanya learned she was a match, she and 

Deryl’s sister waited to tell him, not wanting to get his 

hopes up prematurely. “We just wanted to make sure 

that there was a plan, that I had gone through all of the 

education, that I had passed all the things that I needed 

to pass,” Tanya says. 

Despite finding a donor fairly quickly, it would 

take over a year before Deryl could receive his 

cousin’s kidney. Deryl’s medical team found that 

his parathyroid hormone levels were elevated—a 

complication that can commonly occur in people with 

ESKD—and wanted his levels to decrease before they 

could safely perform the surgery. In the interim, he 

had to begin dialysis. “I was on dialysis for 14 months,” 

says Deryl. “We were not expecting me to be on 

dialysis that long.” He remembers the challenges of 

maintaining a normal life during this time: “I did dialysis 

from 5:00 a.m. to 9:00 a.m., and then I went to work, 

coached my high school team, and ran my DJ business 

with bookings on the weekends. And there were days 

that I was super weak at work and barely making it, so 

it was very difficult.” 

In 2021, Deryl finally got the OK to undergo surgery. 

To Tanya and Deryl, even the date of the surgery 

was a good sign. “They give us a surgery date of 

December 1, which happens to be our maternal 

grandmother’s birthday,” Tanya says. “We all see this 

as a positive sign from God—it’s all going to go well.” 

Both of their surgeries did, indeed, go well. When 

speaking of his medical team who performed the 

transplant, Deryl says, “You ever seen the ‘Dream 

Team’ in basketball? They became my Dream Team.” 

APOLLO: GAINING INSIGHT AND 

“CLOSURE” THROUGH KNOWLEDGE

It was in the time leading up to his kidney transplant 

surgery that Deryl and Tanya first learned about 

APOLLO. The Transplant Center at SSM Health 

Saint Louis University Hospital where Deryl received 

his transplant was a Clinical Center participating in 

APOLLO. He spoke to the Principal Investigator 

at the Center, Dr. Krista Lentine, who provided 

information about enrolling in the study. Speaking 

about his decision to enroll, Deryl recalls thinking, 

“Maybe I can help someone else. Maybe someone 

else with kidney disease.” He also says that he 

“started to want to know even more” regarding his 

kidney health. 

When Tanya learned of her cousin’s need 

for a kidney, she says, “I think that it was 

just kind of a no-brainer for me to say, 

‘Oh, OK, well I’ll get tested.’”

PERSONAL PERSPECTIVE
NIDDK Recent Advances & Emerging Opportunities 2024: Kidney, Urologic, and Hematologic Diseases 96

The primary outcome measured for APOLLO is the 

success or failure of participant kidney transplants—

as tracked by electronic medical records and the 

United Network for Organ Sharing—over a span of 

up to 4.5 years. Participant visits are infrequent 

and consist of an initial visit and an additional visit 

to collect blood and urine samples, all of which are 

saved in the APOLLO Central Laboratory. These 

samples will allow APOLLO researchers to assess 

secondary study measurements of kidney health, 

such as the presence of protein in the urine and 

changes in participants’ estimated kidney function. 

Another important component of APOLLO is 

providing information and health education to the 

patient community about APOL1 variants and the 

risk for kidney disease. Though study participants 

have the opportunity to learn their—or in the case 

of deceased donors, their family member’s—APOL1

genetic results 3 to 4 years after their enrollment, 

they are not prevented from getting tested 

themselves sooner outside of APOLLO. It was 

through this outside testing that Deryl learned that 

he had received a high-risk APOL1 variant from 

both of his parents. “It gave me closure,” he says, 

referring to now having a better understanding 

of the medical issues with his kidneys that he’d 

experienced throughout his life. 

Speaking about her thoughts on the impact that 

APOLLO could have on outcomes for African 

Americans with kidney disease, Tanya says, “For me, 

it’s huge, because of the work that I do.” She views 

her participation in APOLLO and her and Deryl 

sharing their story as a type of justice for the African 

American community, saying, “Justice gets construed 

as what we see in the criminal justice system or 

in a court of law, but justice takes many forms.” 

She continues by saying that African Americans 

“have generations of not trusting our health care 

professionals, so I’m hoping that studies like this will 

give people some more agency.” The advice that she 

would give anyone considering donating a kidney: 

“Get information. Be educated about it and not so 

quick to assume that you know everything there is 

to know about donating.”

Throughout his journey with CKD and ESKD, Deryl 

saw the value of learning all he could about his own 

health. Providing his advice to anyone living with 

kidney disease, he says that people should learn and 

be informed about their own health, as it is important 

“to be front and center on your medical situation.” 

Since his transplant, he now has much more energy 

to do the things he loves, like spending time with his 

family, playing and coaching basketball, and sharing 

his love of music through his side job as a DJ. His 

days look a lot different now. “This morning,” he says, 

“I got up at 4:45 a.m. I played basketball from 5:30 

a.m. to 7:00 a.m. I came back home... showered, 

went to work, got in by 7:45 a.m., worked a full day, 

got on the phone with you, will talk to a couple clients 

tonight, [my son’s] got football later today.... I'm able 

to power right through the day.” 

The participation of Deryl, Tanya, and many others 

in APOLLO may one day lead to more organs for 

transplants, improve the health of people with ESKD, 

and advance health equity in kidney transplantation.

PERSONAL PERSPECTIVE

Speaking about his decision to 

enroll in the APOL1 Long-term 

Kidney Transplantation Outcomes 

Network (APOLLO), Deryl recalls thinking, 

“Maybe I can help someone else. Maybe 

someone else with kidney disease."