APOL1 and Kidney Disease: New Insights Leading to Novel Therapies

Abstract

Our understanding of susceptibility to nondiabetic kidney disease in African Americans advanced substantially with the 2010 discovery of the powerful apolipoprotein L1 gene (APOL1) association.2Genovese G. Friedman D.J. Ross M.D. et al.Association of trypanolytic ApoL1 variants with kidney disease in African Americans.Science. 2010; 329: 841-845Crossref PubMed Scopus (1335) Google Scholar, 3Tzur S. Rosset S. Shemer R. et al.Missense mutations in the APOL1 gene are highly associated with end stage kidney disease risk previously attributed to the MYH9 gene.Hum Genet. 2010; 128: 345-350Crossref PubMed Scopus (439) Google Scholar Two renal risk variants in the APOL1 coding region are strongly associated with several progressive kidney diseases observed significantly more often in African Americans than in patients of other races. These variants likely arose some 10,000 years ago in Sub-Saharan Africa, selected for the protection they afford from Trypanosoma brucei rhodesiense–induced African sleeping sickness. APOL1 renal risk variants are present at high frequency among those with recent African ancestry and are virtually absent in others.Note from Editors: A version of this editorial originally appeared on the AJKD Blog1Freedman BI. NephMadness 2015: APOL1, The Champion. AJKD Blog. April 7, 2015. http://ajkdblog.org/2015/04/07/nephmadness-2015-apol1-the-champion. Accessed April 22, 2015.Google Scholaras an explanation of APOL1’s significance, and thus suitability to be champion of NephMadness 2015. NephMadness is an educational project styled as a tournament among key aspects of nephrology; from among 64 concepts, APOL1 emerged as the most notable recent advance in nephrology. Note from Editors: A version of this editorial originally appeared on the AJKD Blog1Freedman BI. NephMadness 2015: APOL1, The Champion. AJKD Blog. April 7, 2015. http://ajkdblog.org/2015/04/07/nephmadness-2015-apol1-the-champion. Accessed April 22, 2015.Google Scholaras an explanation of APOL1’s significance, and thus suitability to be champion of NephMadness 2015. NephMadness is an educational project styled as a tournament among key aspects of nephrology; from among 64 concepts, APOL1 emerged as the most notable recent advance in nephrology. The spectrum of APOL1-associated kidney diseases includes focal segmental glomerulosclerosis (FSGS), human immunodeficiency virus–associated nephropathy (HIVAN), hypertension-attributed kidney disease, severe lupus nephritis, and sickle cell nephropathy.4Fine D.M. Wasser W.G. Estrella M.M. et al.APOL1 risk variants predict histopathology and progression to ESRD in HIV-related kidney disease.J Am Soc Nephrol. 2012; 23: 343-350Crossref PubMed Scopus (86) Google Scholar, 5Palmer N.D. Freedman B.I. APOL1 and progression of nondiabetic nephropathy.J Am Soc Nephrol. 2013; 24: 1344-1346Crossref PubMed Scopus (19) Google Scholar Although FSGS often reflects nonspecific glomerular scarring seen with different disorders, it is now apparent that 70% of idiopathic FSGS cases in African Americans relate to APOL1 and constitute a single entity.6Kopp JB, Winkler CA, Zhao X, et al; for the FSGS-CT Study Consortium. Clinical features and histology of apolipoprotein L1-associated nephropathy in the FSGS clinical trial [published online ahead of print January 8, 2015]. J Am Soc Nephrol. http://dx.doi.org/10.1681/ASN.2013111242.Google Scholar, 7Kopp J.B. Nelson G.W. Sampath K. et al.APOL1 genetic variants in focal segmental glomerulosclerosis and HIV-associated nephropathy.J Am Soc Nephrol. 2011; 22: 2129-2137Crossref PubMed Scopus (554) Google Scholar Higher frequencies of solidified glomerulosclerosis, disappearing glomerulosclerosis, and thyroidization-type tubular atrophy are seen in those with 2 APOL1 renal risk variants.8Larsen C.P. Beggs M.L. Saeed M. et al.Histopathologic findings associated with APOL1 risk variants in chronic kidney disease.Mod Pathol. 2015; 28: 95-102Crossref PubMed Scopus (43) Google Scholar Although podocytes are critical cells in the pathogenesis of FSGS, APOL1-associated kidney diseases also manifest widespread cellular injury in the renal interstitium and vasculature. This suggests broad injury to multiple cell types in the kidney, not solely limited to podocytes.9Madhavan S.M. O'Toole J.F. Konieczkowski M. Ganesan S. Bruggeman L.A. Sedor J.R. APOL1 localization in normal kidney and nondiabetic kidney disease.J Am Soc Nephrol. 2011; 22: 2119-2128Crossref PubMed Scopus (185) Google Scholar, 10Ma L. Shelness G.S. Snipes J.A. et al.Localization of APOL1 protein and mRNA in the human kidney: nondiseased tissue, primary cells, and immortalized cell lines.J Am Soc Nephrol. 2015; 26: 339-348Crossref PubMed Scopus (94) Google Scholar In my opinion, the diagnosis of hypertension-attributed kidney disease in African American patients is frequently incorrect; APOL1-associated primary glomerulosclerosis is more often present. Hypertension accelerates progression of all kidney diseases and requires treatment to reduce cardiovascular risk. Despite current dogma, whether mild-to-moderate essential hypertension frequently initiates chronic kidney disease in African Americans remains controversial. In long-term trials, only 0.1% of participants with essential hypertension develop a doubling of serum creatinine concentration.11Tomson C.R. Petersen K. Heagerty A.M. Does treated essential hypertension result in renal impairment? A cohort study.J Hum Hypertens. 1991; 5: 189-192PubMed Google Scholar Moreover, for 95% of African Americans given the diagnosis of hypertension-attributed end-stage kidney disease, there is no evidence they had a normal glomerular filtration rate or urinalysis results when high blood pressure was initially detected; the vast majority also lack renal histology. Although this disorder is typically undetected for years, most African Americans who are clinically diagnosed with hypertension-attributed end-stage kidney disease are first seen by a nephrologist less than a year before initiating renal replacement therapy.12Schlessinger S.D. Tankersley M.R. Curtis J.J. Clinical documentation of end-stage renal disease due to hypertension.Am J Kidney Dis. 1994; 23: 655-660Abstract Full Text PDF PubMed Scopus (107) Google Scholar They present with advanced kidney disease and secondary hypertension. Physician bias is also evident in this diagnosis. When identical clinical histories were provided to nephrologists, they were twice as likely to diagnose “hypertensive nephropathy” in African Americans, in contrast to chronic glomerulonephritis in European Americans.13Perneger T.V. Whelton P.K. Klag M.J. Rossiter K.A. Diagnosis of hypertensive end-stage renal disease: effect of patient's race.Am J Epidemiol. 1995; 141: 10-15PubMed Google Scholar This combination of factors causes hypertension to be the second most commonly listed cause of end-stage kidney disease in the United States. Of course, the Centers for Medicare & Medicaid Services do not yet list APOL1-associated kidney disease as a potential cause of end-stage kidney disease on the Medical Evidence Report (the 2728 form). Familial clustering of disparate etiologies of end-stage kidney disease in African American families suggests an inherited basis for these kidney diseases, potentially relating to a single kidney disease gene.14Freedman B.I. Spray B.J. Tuttle A.B. Buckalew Jr., V.M. The familial risk of end-stage renal disease in African Americans.Am J Kidney Dis. 1993; 21: 387-393Abstract Full Text PDF PubMed Scopus (209) Google Scholar, 15Freedman B.I. Iskandar S.S. Appel R.G. The link between hypertension and nephrosclerosis.Am J Kidney Dis. 1995; 25: 207-221Abstract Full Text PDF PubMed Scopus (190) Google Scholar Family members appear to manifest susceptibility to progressive kidney disease. In those who lack an obvious inciting cause like lupus, HIV infection, or FSGS, their kidney disease is typically ascribed to the effects of hypertension with little supportive evidence. Results of the AASK (African American Study of Kidney Disease and Hypertension) confirm that hypertension-attributed kidney disease steadily progresses in the vast majority of participants despite aggressive control of blood pressures and use of high-dose angiotensin-converting enzyme inhibitors. APOL1 high-risk genotypes were subsequently found to predict kidney disease progression in AASK participants.16Parsa A. Kao W.H. Xie D. et al.AASK Study Investigators; CRIC Study InvestigatorsAPOL1 risk variants, race, and progression of chronic kidney disease.N Engl J Med. 2013; 369: 2183-2196Crossref PubMed Scopus (506) Google Scholar, 17Lipkowitz M.S. Freedman B.I. Langefeld C.D. et al.SK InvestigatorsApolipoprotein L1 gene variants associate with hypertension-attributed nephropathy and the rate of kidney function decline in African Americans.Kidney Int. 2013; 83: 114-120Crossref PubMed Scopus (169) Google Scholar This supports that the kidney disorder in many AASK participants is a primary APOL1-associated disorder within the FSGS spectrum; typically focal global glomerulosclerosis, interstitial fibrosis, and vascular changes are seen on kidney biopsy. When to screen and where to apply APOL1 genotype data in clinical practice is also controversial. A minority of individuals with 2 APOL1 renal risk variants ultimately develop chronic kidney disease (5% FSGS, ∼20% focal global glomerulosclerosis, and 50% HIVAN with uncontrolled HIV infection).7Kopp J.B. Nelson G.W. Sampath K. et al.APOL1 genetic variants in focal segmental glomerulosclerosis and HIV-associated nephropathy.J Am Soc Nephrol. 2011; 22: 2129-2137Crossref PubMed Scopus (554) Google Scholar As such, caution is urged before considering widespread genotyping; second hits appear necessary to produce clinical kidney disease, likely either gene-gene or gene-environment interactions.18Freedman B.I. Skorecki K. Gene-gene and gene-environment interactions in apolipoprotein L1 gene-associated nephropathy.Clin J Am Soc Nephrol. 2014; 9: 2006-2013Crossref PubMed Scopus (74) Google Scholar Several high-risk populations with recent African ancestry may ultimately benefit from genetic testing, but clinical trials are urgently needed to clearly define the benefits and the risks. In my opinion, evidence supports rapidly genotyping African American deceased kidney donors for APOL1 renal risk variants at the time of organ recovery.19Freedman B.I. Julian B.A. Should kidney donors be genotyped for APOL1 risk alleles?.Kidney Int. 2015; 87: 671-673Crossref PubMed Scopus (23) Google Scholar A recent multicenter study on kidney transplantation outcomes revealed that donor APOL1 genotypes had more impressive effects on kidney transplant survival than did the widely accepted metrics of cold ischemia time, panel reactive antibodies, and HLA matching.20Freedman BI, Julian BA, Pastan SO, et al. Apolipoprotein L1 gene variants in deceased organ donors are associated with renal allograft failure [published online ahead of print March 24, 2015]. Am J Transplant. http://dx.doi.org/10.1111/ajt.13223.Google Scholar The new Kidney Donor Profile Index (KDPI) treats all kidneys from African American deceased donors as being at equivalent high risk, yet data support that only 13% of African American deceased donors who possess 2 APOL1 renal risk variants are at high risk for shortened renal allograft survival.20Freedman BI, Julian BA, Pastan SO, et al. Apolipoprotein L1 gene variants in deceased organ donors are associated with renal allograft failure [published online ahead of print March 24, 2015]. Am J Transplant. http://dx.doi.org/10.1111/ajt.13223.Google Scholar Kidneys from donors with 2 APOL1 renal risk variants should not be discarded; many will function for prolonged periods. However, APOL1 genotyping will likely improve the organ allocation and informed-consent processes. The role for screening potential African American living-related kidney donors, particularly those with a positive family history of end-stage kidney disease, is not known. Although potential live donors may be more (or less) likely to donate given knowledge of their genotype, it is not clear what percentage would develop kidney disease after donor nephrectomy or what percentage of transplanted kidneys with 2 APOL1 renal risk variant kidneys would fail prematurely. It is critical that we perform trials to address these important concerns. The question of whether to screen all African Americans with hypertension (or all with nondiabetic kidney disease, or the general African American population) is also unclear. In the absence of effective treatments for APOL1-associated kidney disease, genetic information will not yet benefit these individuals. However, improved understanding of nondiabetic kidney disease and novel therapies will ultimately arise from this major molecular genetics breakthrough. It has been just 5 years since APOL1 was first identified as the cause of end-stage kidney disease in up to 40% of African Americans receiving renal replacement therapy. This finding dramatically changed the field of nephrology and our understanding of race-based risk for complex disease. New treatments for APOL1-associated kidney disease are on the horizon.21Nichols B. Jog P. Lee J.H. et al.Innate immunity pathways regulate the nephropathy gene Apolipoprotein L1.Kidney Int. 2015; 87: 332-342Crossref PubMed Scopus (207) Google Scholar It is likely that they will target the innate immune system or viral infections, because antiretroviral therapy has proven to be effective in reducing rates of HIVAN among genetically susceptible individuals. Nephrologists must start thinking outside of the box, beyond existing therapies. We must stop taking the reported causes of kidney disease in large registries at face value; instead, we should listen more closely to our patients and their families. In my practice, hypertensive members of African American families multiply affected with end-stage kidney disease often told me that they expected to need dialysis in the future. They felt that they had an inherited disorder and blood pressure medications would not change their fate. They proved to be correct; these patients understood their disease better than many of their physicians. We owe these families new treatments to address this refractory spectrum of nondiabetic kidney disease. Financial Disclosure: The author declares that he has no relevant financial interests.