Few medical specialties have been impacted by precision medicine to the extent that nephrology has. Genotyping often identifies the true cause of kidney disease in patients and family members. The majority of chronic nephropathy in children and up to 20% of cases in adults have an inherited basis [1]. Unfortunately, etiologies of kidney failure reported in large national databases remain inaccurate and few patients undergo kidney biopsy [2,3]. This flawed epidemiology, with more than 75% of incident cases of kidney failure in the United States currently ascribed to the effects of diabetes mellitus and hypertension, hindered the search for true causes of kidney disease.

Many epidemiologists and statisticians analyzing kidney failure registry data were not nephrologists; therefore, they were unable to appreciate the natural history of chronic kidney disease (CKD) from early stages and could not recognize inaccurate diagnoses [4]. Hypertension researchers then repeatedly tested whether blood pressure lowering using select agents would slow the progression of mislabeled “hypertensive nephropathy.” Because researchers didn’t appreciate that diagnoses were incorrect, blood pressure-lowering trials have consistently failed to slow progression of putative hypertensive nephropathy [5]. The National Institutes of Health (NIH)-sponsored African American Study of Kidney Disease and Hypertension Trial (AASK) and Systolic Blood Pressure Intervention Trial (SPRINT) prove this point [6,7]. In AASK, intensive blood pressure lowering with high-dose angiotensin converting enzyme inhibitors failed to significantly slow progression of kidney disease in nondiabetic African Americans recruited to have “hypertensive kidney disease.” Nearly 60% of AASK participants met the endpoints of dialysis, doubling of serum creatinine concentration or death (with few deaths) [6]. The NIH SPRINT also revealed that intensive blood pressure lowering to less than 120 mmHg in hypertensive patients with less than 1 g of proteinuria per day failed to slow progression of CKD [7]. SPRINT further showed that intensive blood pressure lowering failed to reduce the incidence of new onset CKD in hypertensive individuals. Paradoxically, a statistically significant 3.5-fold increase in risk for a sustained 30% reduction in estimated glomerular filtration rate (eGFR) from ≥60 mL/min/1.73 m² was observed in intensively treated SPRINT participants [7,8]. These NIH trials targeted blood pressure lowering to levels that are protective from cardiovascular target organ involvement, as well as used high-dose renin-angiotensin system (RAS) blockade. Despite this, many participants unfortunately required renal replacement therapy. These large and expensive major clinical trials failed to provide cures for hypertensive patients with CKD.

African Americans in families with multiple members on dialysis often knew that blood pressure control alone would not be curative. They informed physicians, “There is something different about my family that predisposes to kidney failure. Our risk is independent of lowering blood pressures or blood sugars.” Unfortunately, they were powerless to change long-held perceptions in the medical field [9,10]. In fact, these patients were correct and this ultimately led to the identification of the powerful effects of the apolipoprotein L1 kidney failure gene (APOL1) [11,12]. Since the discovery of APOL1, additional gene variants causing CKD have been detected and will yield novel directed therapies.

Relative to European, Asian, and Hispanic American populations, African Americans have threefold higher incidence rates of virtually all common forms of kidney failure [13]. Although the reasons for their higher risk were not clear, it was typically attributed to having more severe high blood pressure and hyperglycemia, different diets, perceived poorer medical compliance, and environmental factors including lack of access to adequate healthcare. Unfortunately, poor access to healthcare is present in many patients and must be rectified.

In contrast to other populations, several etiologies of kidney disease were often present in single African American families [9]. First- and second-degree relatives frequently had biopsy-proven focal segmental glomerulosclerosis (FSGS; or non-biopsied chronic glomerular disease with nephrotic range-proteinuria), human immunodeficiency virus (HIV)-associated nephropathy (HIVAN), lupus nephritis, sickle cell nephropathy, kidney disease attributed to type 2 diabetes mellitus (often with short diabetes durations and absence of retinopathy or neuropathy), and so-called “hypertensive nephropathy” with low-level proteinuria [9]. Despite a wealth of contradictory evidence, hypertensive individuals with low-level or absent proteinuria are often labeled with hypertensive nephropathy (or arteriolar nephrosclerosis) attributed to the effects of mild-to-moderate hypertension as in AASK [3]. Two new International Classification of Diseases, 10th Revision (ICD-10) codes for APOL1-mediated kidney disease (AMKD) and family history of AMKD were released in October 2025 [2]. These codes finally permit physicians to provide correct diagnoses in patients when appropriate genotyping is performed. This will be a major step forward in correcting the epidemiology of CKD in registry data. More than 35% of African Americans with kidney failure possess two APOL1 risk variants, and Fig. 1 displays the estimated proportions of kidney disease comprising these patients.

After decades of unsuccessful efforts to identify genes underlying human kidney disease in animal models [14], broad searches for inherited causes in humans began in the 1990s. Candidate gene testing, family-based linkage analysis, and association testing in unrelated individuals were initial analytic methods, ultimately leading to genome-wide association studies [15]. Discovery of APOL1 came from a new methodology known as admixture mapping or mapping by admixture linkage disequilibrium [16]. Ancestry informative markers on human chromosome 22q were linked with kidney failure and the non-muscle myosin heavy chain 9 gene (MYH9) was initially thought to produce the signal [17,18]. Two years later, after the 1000 Genomes Project data became available, the adjacent APOL1 was identified as the causal gene [11,12]. The APOL1 G1 and G2 risk variants are in linkage disequilibrium with MYH9 risk haplotypes.

Initial studies of APOL1 association in African Americans included patients with FSGS and solidified glomerulosclerosis (nondiabetic kidney failure misattributed to hypertension) [11,12]. Shortly thereafter, the APOL1 kidney disease spectrum expanded to include collapsing glomerulopathy [19–21], severe lupus nephritis [22,23], sickle cell nephropathy [24], earlier failure of transplanted kidneys from APOL1 high-risk genotype donors [25–27], and faster progression of many etiologies of CKD including membranous nephropathy [28] and diabetic kidney disease (DKD) [29,30]. These disorders were present in multiply affected African American families with kidney failure, demonstrating that APOL1 was the gene responsible for familial clustering of disparate kidney diseases.

Approximately 80% of individuals who possess two APOL1 risk variants will not develop kidney disease [31], and the 20% who do likely have second hits or modifying factors that contribute [32]. Modifiers include environmental factors, such as interferon exposure, or inherited factors such as the protective APOL1 p.N264K variant [21,33]. Individuals with two APOL1 risk variants, including at least one G2, are protected from developing FSGS if they possess the p.N264K variant [33]. Many patients with idiopathic FSGS and solidified glomerulosclerosis likely have modifying factors that initiated kidney disease; however, they have yet to be identified.

Familial clustering of FSGS is recognized throughout the world. Major causative genes in adults include α-actinin 4 (ACTN4), transient receptor potential cation channel 6 (TRPC6), inverted formin 2 (INF2), and type IV collagen alpha chains 3 and 4 (COL4A3 and COL4A4) [34]. Podocin (NPHS2) and nephrin (NPHS1) mutations are common autosomal recessive causes in childhood, including steroid-resistant forms of nephrotic syndrome [34].

Genovese et al. [11] analyzed 192 African Americans with biopsy-proven FSGS (versus 176 controls) from Brigham and Women’s Hospital and the NIH FSGS Genetic Study. Powerful genetic association (hazard ratio, 10.5) was detected between APOL1 G1 and G2 risk variants with FSGS. The association was also present in the Wake Forest University School of Medicine cohort of 1,002 African Americans with hypertension-attributed kidney failure (versus 923 controls), with a hazard ratio of 7.3. Tzur et al. [12] also reported an association between APOL1 G1 with nondiabetic kidney failure in African American and Hispanic Black populations.

Cases from these reports form the foundation of the current APOL1 nephropathy spectrum. Most have biopsy-proven FSGS with heavy proteinuria (nephrotic range or nephrotic syndrome), FSGS with sub-nephrotic proteinuria, or non-biopsied solidified glomerulosclerosis with minimal (or absent) proteinuria. Solidified glomerulosclerosis is the most common kidney disease mediated by APOL1. These patients typically present with reduced kidney function, normal urinalysis (or mild proteinuria), and mild-moderate hypertension. As discussed, they have historically been mislabeled hypertensive kidney disease [3,10]. It is now clear that hypertension develops secondary to kidney disease; high blood pressure is neither an initiating (nor a modifying) factor in AMKD.

Collapsing glomerulopathy, like FSGS and solidified glomerulosclerosis, is more common in individuals with recent African ancestry. In some cases, collapsing glomerulopathy develops after therapeutic interferon administration and improves after cessation of the drug [21]. Nichols et al. [21] reported that this phenomenon relates to APOL1 and upregulated gene expression by interferon, as well as by interferon-independent pathways including toll-like receptors. It is now appreciated that collapsing glomerulopathy develops in individuals with two APOL1 risk variants during states of high endogenous interferon production, such as severe viral infections and systemic lupus erythematosus (SLE) [35–37]. Interferon is likely the second hit causing kidney disease during HIV and coronavirus disease-2019 (COVID-19) infection. HIVAN and COVID-19–associated nephropathy (COVAN) take the form of collapsing glomerulopathy, typically with heavy proteinuria. These are important disorders with the potential to rapidly cause kidney failure. HIV viral suppression with antiretroviral therapy halts early-stage HIVAN and preventing severe COVID-19 infection with vaccination may prevent COVAN [38]. Treating (preventing) second hits appears to be one avenue to effectively treat some forms of AMKD.

In contrast to FSGS, collapsing glomerulopathy, and solidified glomerulosclerosis, several multisystem disorders with potential kidney involvement are not directly caused by APOL1; however, affected individuals with two APOL1 risk variants progress more rapidly to kidney failure (Table 1). These include SLE, sickle cell nephropathy, membranous nephropathy, and DKD.

Although severe lupus nephritis with kidney failure is associated with APOL1 [23], a report in patients with milder lupus nephritis failed to detect an association on chromosome 22q [39]. This speaks to the rapid progression of nephritis in the subset of patients with SLE and two APOL1 risk variants. DKD is another disorder with variable histologic and clinical manifestations, where two APOL1 risk variants speed progression to kidney failure [29,30]. African American families with members on dialysis, now known to have AMKD, often include individuals with coexisting type 2 diabetes mellitus and kidney failure [9]. Some likely had underlying FSGS with heavy proteinuria and coincident type 2 diabetes mellitus. However, others had classic forms of DKD with mesangial matrix expansion and nodular glomerulosclerosis with other glomeruli revealing AMKD [40]. Analyses in patients with diabetes from the CRIC (Chronic Renal Insufficiency Cohort) revealed that those with two APOL1 risk variants lost kidney function more quickly than those with fewer than two risk variants [29].

The diverse spectrum of APOL1 kidney disease is akin to other syndromes resulting from mutations in single genes. Multiple clinical phenotypes can also be caused by mutations in the COL4A, these include Alport syndrome, FSGS, immunoglobulin A nephropathy, cystic kidney disease, or absence of a clinical phenotype [41].

Transplanted kidneys from African American deceased donors were known to fail more rapidly than kidneys from other donors [42]. This observation was seen irrespective of the recipient’s ancestry. African American live kidney donors were also more likely to develop post-donation kidney failure compared to other live donors [43]. Although the cause of these observations was uncertain, it resulted in the Kidney Donor Risk Index (KDRI) downgrading the quality of all kidneys from deceased donors with recent African ancestry (African Americans) [44]. This index used the social factor “Black race” instead of a biological factor (APOL1 genotype) and frequently caused falsely low-quality assessments in African American deceased donor kidneys [45]. As a result, many good-quality kidneys were discarded based on inaccurate quality assessments [46].

One year after the discovery of the APOL1 association with native kidney disease, it became evident that shorter allograft survival from transplanted African American kidneys was related to possession of two APOL1 risk variants in donors [25]. Kidneys from African American deceased donors with zero or one APOL1 risk variant had similar outcomes to European American kidneys and demonstrate that donor ancestry is not the key factor, only donor genetic variation at APOL1 [26,27]. Although one report suggested APOL1 genotypes of transplant recipients could be involved in transplant outcomes [47], others support primary effects of donor genotype (or lack of recipient genotype effect) [48].

Much has changed in kidney transplantation since this discovery (Fig. 2). Additional changes are expected based on results from the NIH APOL1 Long-term Kidney Transplant Outcomes (APOLLO) Consortium [49]. The KDRI equation was recently revised by removing “donor race” as a risk factor [50]. This came after recomputed KDRI results from 1,149 kidney transplants from African American deceased donors revealed that replacing the donor race variable with APOL1 genotypes better defined kidney transplant outcomes [45]. Substantial improvements in KDRI scores were observed in 85%–90% of kidneys based on APOL1. In addition, live kidney donor candidates with African ancestry now receive information about APOL1 from their transplant physicians. Based on recent results [51], an Expert Opinion Panel commissioned by the American Society of Transplantation’s Living Donor Community of Practice suggested that live kidney donor candidates self-reporting African ancestry, including African Americans, Afro-Caribbeans, Hispanic Blacks, and Africans, should be informed about APOL1 and the risk of kidney failure [52]. Additionally, guidance suggested that candidates be informed that genetic testing may be offered for risk stratification and genetic counselling is available. Thus, more open discussions about APOL1 in live kidney donation are occurring in the United States.

If prospective APOLLO results confirm retrospective reports in deceased donor kidney transplantation, APOL1 genotyping will be valuable in organ allocation decisions from African ancestry donors. Genotyping for APOL1 can be rapidly performed; results would be available at the same time as donor human leukocyte antigen genotyping and testing for HIV and hepatitis infections. APOL1 genotypes could be used to guide organ allocation, and determine which recipients should be offered kidneys from donors with two risk variants. It may prove better to transplant such kidneys as expanded-criterion donor kidneys. In this scenario, they could be offered to recipients with more comorbidities, who are informed about their potential for shorter graft function. In contrast, healthier recipients with renal-limited kidney disease and longer expected survival would preferentially receive kidneys from donors with fewer than two risk variants. APOLLO is also likely to provide more information on whether kidney recipient APOL1 genotypes impact risk for earlier graft failure. APOLLO includes the largest number of DNA samples from deceased organ donors with African ancestry matched with the recipients of their kidneys.

APOL1 risk variants injure kidney cells, in part, via podocyte toxicity, mitochondrial dysfunction, metabolic reprogramming, and inflammatory signaling (Fig. 3) [53]. Although G1 and G2 risk variants protect from African sleeping sickness, the G0 non-risk allele appears to have beneficial effects on cellular respiration [54]. G0 variants improve oxygen consumption rates and likely support cells during conditions where substantial ATP production is required; these include nutrient deprivation, hypoxic stress, or increased bioenergetic load of an activated immune response.

APOL1 expression in different kidney cell types produces variable phenotypes. Risk variant expression in podocytes leads to proteinuria with an FSGS pattern of injury [55]. In contrast, endothelial cell expression produces hypertension with ischemic kidney injury and lower proteinuria [56]. Studies in patient derived kidney organoids demonstrate that APOL1 risk variant expression primarily affects podocyte populations, with upregulation triggered by inflammatory cytokines such as interferon gamma (IFN-γ) [57].

Induction of APOL1 by inflammation and/or immune activation often precedes or accelerates nephropathy in patients with two APOL1 risk variants [21]. Cytokines like IFN-γ induce APOL1 expression, while APOL1 risk variants in turn amplify inflammatory pathways. Recent literature points to dysregulated interferon signaling as a trigger for APOL1 expression in podocytes [57].

Podocyte injury is central to many forms of APOL1 kidney disease. APOL1 risk variants can induce pore forming or membrane disruptive activities under conditions leading to cytotoxic gain-of-function effects [58–61]. Expression in podocytes leads to altered ion flux and permeability resulting in cytotoxic stress, dysregulation of intracellular trafficking and organelle function, and activation of cell death pathways including necrosis, pyroptosis, or autophagy related injury. Podocytes rely heavily on stable actin dynamics, and APOL1 risk variant expression disrupts cytoskeletal arrangement and slit diaphragm signaling. This predisposes to foot process effacement, a hallmark of FSGS [62].

Translocation of APOL1 to the endoplasmic reticulum (ER) appears to be critical for cytotoxicity [63,64]. Although the mechanisms by which APOL1 induces ER stress remain unclear, risk variants may act as misfolded proteins [65]. Gerstner et al. [66] challenged this assumption, as their control transgene lacking 9 amino acids in the pore-forming domain of APOL1 did not impact ER stress in a Drosophila model and suggests other mechanisms may be responsible.

Mitochondrial impairment appears to be central to APOL1-mediated injury [54,57,67,68]. APOL1 risk variant expression reduces oxidative phosphorylation, suppresses tricarboxylic acid cycle activity, and upregulates glycolysis and hypoxia related signaling. This leads to loss of mitochondrial branches with reduced branch length, failure to increase maximal respiratory rate after IFN-γ stimulation and opening of the mitochondrial permeability transition pore. Collectively, findings demonstrate early metabolic reprogramming that precedes overt cell dysfunction. Podocytes require high mitochondrial output to maintain cytoskeletal and filtration functions, and they become energy-deficient under APOL1 risk variant driven shifts toward glycolysis. These metabolic changes were verified in human biopsy-derived kidney tissue and induced pluripotent stem cell-derived organoid models. Mechanistically, mitochondrial depolarization, impaired fusion/fission dynamics, and altered lipid metabolism contribute to progressive podocyte fatigue and apoptosis [57].

It has become apparent that offering APOL1 genotyping to patients with recent African ancestry (African Americans, Africans, Afro-Caribbeans, and Hispanic Blacks) is useful to accurately diagnose their cause of CKD. Clinicians often did not pursue genetic testing in the past; they were awaiting potential therapies and clinical trials. Physicians have long treated patients with non-targeted RAS inhibition and blood pressure- and blood sugar-lowering therapies. Agents like sodium-glucose co-transporter 2 inhibitors, glucagon-like peptide-1 receptor agonists and dual endothelin and angiotensin II receptors are useful for slowing progression of many forms of CKD; however, limited data exist on their efficacy in patients with two APOL1 risk variants [69,70].

The situation in patients with two risk variants is changing. Four clinical trials are testing agents that inhibit the production of APOL1 protein or block its effect (Fig. 4). Vertex Pharmaceuticals and Maze Therapeutics are testing small-molecule inhibitors of APOL1 protein. The Vertex phase 2a inaxaplin (VX-147) study published results in 16 patients with biopsy-proven FSGS, eGFR ≥27 mL/min/1.73 m², and urine protein-to-creatinine ratio (UPCR) >0.7–10.0 g/g. Participants saw a rapid fall in UPCR of 47.6% (95% confidence interval, –60.0 to –31.3) after 13 weeks on therapy [71].

AstraZeneca is testing a novel APOL1 antisense oligonucleotide (ASO) called AZD2373 (opemalirsen) in the phase 2a APPRECIATE study of patients with nondiabetic CKD, eGFR ≥25 mL/min/1.73 m², and urine albumin-to-creatinine ratio >300 mg/g. AZD2373 phase 1 study results revealed dose-dependent decreases in plasma APOL1 protein concentration. Administering AZD2373 to APOL1 transgenic mice also prevents the development of kidney disease after interferon administration and AZD2373 reduced liver and kidney APOL1 expression in this model [72]. Other APOL1 ASOs arrest progression of established nephropathy in transgenic mice [73]. Finally, baricitinib, an inhibitor of the janus kinase pathway, is being studied because activation of this pathway may contribute to cellular toxicity in APOL1 kidney disease [60].

Conventional therapies for CKD have proven ineffective in slowing or preventing kidney disease in individuals who possess two APOL1 risk variants. The most common labels applied to CKD in such patients include hypertensive nephropathy or unspecified chronic glomerulosclerosis. It is critical that clinicians recognize that many patients with recent African ancestry have kidney disease related to APOL1 and these individuals can be enrolled in clinical trials that may provide direct benefit, as well as help others in the future [2]. As a result, there has been a dramatic increase in genotyping for APOL1 and other variants causing CKD. This information provides great hope for novel therapies to cure these diseases.

In 2010, the discovery of the APOL1 kidney disease spectrum in patients with two risk variants clarified questions that had been unanswered for decades [11,12]. Much remains to be learned about disease mechanisms and modifying factors, but novel therapies directed against APOL1 messenger RNA (mRNA) and protein have been developed and may successfully treat diseases in this spectrum [74].

The risk for CKD in individuals who possess a single APOL1 risk variant remains uncertain. The 2010 report by Genovese et al. [11] revealed a weak effect of possessing one risk variant, although not nearly as strong as two. Based on that, autosomal recessive inheritance with variable penetrance clearly predominates. Individuals with HIV infection in Africa are at high risk for HIVAN if they possess only one risk variant [75], and data from Brazil and the H3Africa Study also support this observation [76,77]. It will be important to clarify whether possessing one risk variant is a major contributor to CKD in the US, as 39% of African Americans possess one copy. These individuals are currently considered carriers (not high risk themselves), capable of transmitting a risk variant to their offspring. Transplanted kidneys from deceased organ donors with two APOL1 risk variants are known to fail earlier after engraftment; however, there does not appear to be an increased risk from donor kidneys with one risk variant. If one risk variant proves to be an important contributor to risk for nephropathy, it will profoundly impact the field of transplantation for recipients of these kidneys and living donors with one risk variant.

Recent discovery of the APOL1 p.N264K protective variant made it important to include this variant in genotyping for accurately determining risk for FSGS [33]. The p.N264K variant has a low frequency in the African American population, and its protection appears limited to those who have high-risk genotypes including a G2 variant. Unfortunately, few patients in clinical practice are re-classified as low risk based on possessing p.N264K. The search to identify additional genetic and environmental modifiers of risk continues, especially the second hits causing approximately 20% of individuals with two APOL1 risk variants to develop FSGS and hypertension-attributed kidney disease (solidified glomerulosclerosis).

Assuming efficacy and safety of novel therapies undergoing clinical trials in patients with proteinuric APOL1 kidney diseases like FSGS, an exciting avenue for future research will be determining their effectiveness in patients with two APOL1 risk variants with lower levels of proteinuria (the commonest diseases in the spectrum, including hypertension-attributed CKD or solidified glomerulosclerosis). The role of these therapies in patients with sickle cell nephropathy, lupus nephritis, and membranous nephropathy who have two APOL1 risk variants will also be important to clarify. Although APOL1 does not cause kidney sickle cell nephropathy, lupus nephritis, or membranous nephropathy, affected patients with two APOL1 risk variants have more rapid kidney disease progression to kidney failure. Therefore, the novel therapies may slow the progression of these disorders to renal replacement therapy. The same is true for patients with diabetes mellitus and reduced eGFR who possess two APOL1 risk variants. There may also be a role for novel APOL1 mRNA and protein-directed therapies in recipients of donor kidneys with two APOL1 risk variants and living kidney donors with high-risk genotypes for preventing (or treating) post-kidney donation nephropathy.

It has been just 16 years since the discovery of the powerful spectrum of kidney diseases caused by APOL1 in individuals possessing recent African ancestry. In this short time, novel therapies directed against APOL1 mRNA and APOL1 protein small molecule inhibitors have shown great promise. It is crucial that nephrologists genotype individuals with CKD and recent African ancestry for APOL1 to improve the epidemiology of CKD in this population, enable affected individuals to enroll in clinical trials, and inform family members and the general community about APOL1 and its risk for severe kidney disease [2].