Barry I. Freedman, MD, FACP is John H. Felts, III Distinguished Professor and Chief, Section on Nephrology at Wake Forest School of Medicine. His research focuses on identifying genes underlying chronic kidney disease, type 2 diabetes mellitus, cardiovascular and bone disease, as well as race-based disparities in kidney disease and atherosclerosis. Dr. Freedman chaired the NIDDK Family Investigation in Nephropathy and Diabetes (FIND) UO1 Consortium and is past chair of the Board of Directors for ESRD Network 6.

Our understanding of non-diabetic nephropathy susceptibility in African Americans advanced substantially with the recent discovery of the powerful apolipoprotein L1 gene (APOL1) association. Two coding renal risk variants in APOL1 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 due to 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.

The APOL1 nephropathy spectrum includes focal segmental glomerulosclerosis (FSGS), HIV-associated nephropathy (HIVAN), “hypertension-attributed” nephropathy, severe lupus nephritis, and sickle cell nephropathy. Although FSGS often reflects non-specific glomerular scarring seen with different disorders, it is now apparent that 70% of idiopathic FSGS cases in African Americans relate to APOL1 and comprise a single entity. Higher frequencies of solidified glomerulosclerosis (GS), disappearing GS, and thyroidization-type tubular atrophy are seen in those with two APOL1 renal risk variants. 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.

In my opinion, the diagnosis “hypertension-attributed” nephropathy 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 (CKD) in African Americans remains controversial. In long-term trials, only 0.1% of participants with essential hypertension develop a doubling of serum creatinine concentration. Moreover, 95% of African Americans given the diagnosis “hypertensive end-stage kidney disease (ESKD)” lacked evidence of a normal GFR and urinalysis 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” ESKD are first seen by a nephrologist less than one year before initiating renal replacement therapy. They present with advanced nephropathy 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. This combination of factors causes hypertension to be the second most-commonly listed cause of ESKD in the United States. Of course, APOL1-associated nephropathy is not yet listed as causing ESKD on the Centers for Medicare and Medicaid Services 2728 form.

Familial clustering of disparate etiologies of ESKD in African American families suggests an inherited basis for these kidney diseases, potentially relating to a single nephropathy gene. Family members appear to manifest susceptibility to progressive nephropathy. 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 African American Study of Kidney Disease and Hypertension (AASK) trial confirm that “hypertension-attributed” nephropathy steadily progresses in the vast majority of participants despite aggressive control of blood pressures and use of high dose ACE inhibition. APOL1 high-risk genotypes were subsequently found to predict nephropathy progression in AASK participants. This supports that the kidney disorder in many AASK participants is a primary APOL1–associated disorder within the FSGS spectrum, typically focal global glomerulosclerosis (FGGS), 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 two APOL1 renal risk variants ultimately develop CKD (5% FSGS, ~20% FGGS, and 50% HIVAN with uncontrolled HIV infection). 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. Several high-risk populations with recent African ancestry may ultimately benefit from genetic testing. 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. A recent multi-center study on kidney transplant outcomes revealed that donor APOL1 genotypes had more impressive effects on renal allograft survival than did the widely accepted metrics of cold ischemia time, panel reactive antibodies, and HLA matching. The new Kidney Donor Profile Index (KDPI) gives kidneys from African American deceased donors “1 point” toward higher risk; yet data supports that only 13% of African American deceased donors who possess two APOL1 renal risk variants are at high risk for shortened renal allograft survival. APOL1 two-renal-risk-variant donor kidneys 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 ESKD, 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 nephropathy after donor nephrectomy or what percentage of transplanted APOL1 two-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 non-diabetic CKD or the general African American population) is also unclear. In the absence of effective treatments for APOL1-associated nephropathy, genetic information will not yet benefit these individuals. However, improved understanding of non-diabetic nephropathy and novel therapies will ultimately arise from this major molecular genetics breakthrough. It has been less than five years since APOL1 was first identified as the cause of ESKD 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 CKD are on the horizon. It is likely that they will target the innate immune system or viral infections, because anti-retroviral 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 multiply-affected African American ESKD families often told me that they expected to need dialysis in the future. They felt that they had an inherited disorder and the blood pressure medications I was prescribing would not change their fate. They proved to be correct; these patients understood their disease better than many of their physicians. I feel that I owe these families new treatments to address this refractory spectrum of non-diabetic kidney disease.

See the final standings! | For more on NephMadness 2015 | #NephMadness on Twitter