The Impact of APOL1 on Chronic Kidney Disease and Hypertension
2019; Elsevier BV; Volume: 26; Issue: 2 Linguagem: Inglês
10.1053/j.ackd.2019.01.003
ISSN1548-5609
AutoresTodd W. Robinson, Barry I. Freedman,
Tópico(s)Cynara cardunculus studies
ResumoEssential hypertension is a clinical diagnosis based on the presence of an elevated systemic blood pressure on physical examination without a clear inciting cause. It has multiple etiologies and is not a homogeneous disorder. Hypertension contributes to the development and progression of atherosclerotic cardiovascular diseases, and antihypertensive treatment reduces the risk of fatal and nonfatal myocardial infarction, stroke, and congestive heart failure. Although hypertension is frequently present in nondiabetic individuals with low levels of proteinuria and chronic kidney disease, reducing blood pressures in this population does not reliably slow nephropathy progression. Many of these patients with recent African ancestry have the primary kidney disease "solidified glomerulosclerosis" that is strongly associated with renal-risk variants in the apolipoprotein L1 gene (APOL1). This kidney disease contributes to secondarily elevated blood pressures. The APOL1-associated spectrum of nondiabetic nephropathy also includes proteinuric kidney diseases, idiopathic focal segmental glomerulosclerosis, collapsing glomerulopathy, severe lupus nephritis, and sickle cell nephropathy. This article reviews relationships between mild to moderate essential hypertension and chronic kidney disease with a focus on the role of APOL1 in development of hypertension. Available evidence strongly supports that APOL1 renal-risk variants associate with glomerulosclerosis in African Americans, which then causes secondary hypertension, not with essential hypertension per se. Essential hypertension is a clinical diagnosis based on the presence of an elevated systemic blood pressure on physical examination without a clear inciting cause. It has multiple etiologies and is not a homogeneous disorder. Hypertension contributes to the development and progression of atherosclerotic cardiovascular diseases, and antihypertensive treatment reduces the risk of fatal and nonfatal myocardial infarction, stroke, and congestive heart failure. Although hypertension is frequently present in nondiabetic individuals with low levels of proteinuria and chronic kidney disease, reducing blood pressures in this population does not reliably slow nephropathy progression. Many of these patients with recent African ancestry have the primary kidney disease "solidified glomerulosclerosis" that is strongly associated with renal-risk variants in the apolipoprotein L1 gene (APOL1). This kidney disease contributes to secondarily elevated blood pressures. The APOL1-associated spectrum of nondiabetic nephropathy also includes proteinuric kidney diseases, idiopathic focal segmental glomerulosclerosis, collapsing glomerulopathy, severe lupus nephritis, and sickle cell nephropathy. This article reviews relationships between mild to moderate essential hypertension and chronic kidney disease with a focus on the role of APOL1 in development of hypertension. Available evidence strongly supports that APOL1 renal-risk variants associate with glomerulosclerosis in African Americans, which then causes secondary hypertension, not with essential hypertension per se. Clinical Summary•Despite weak evidence supporting the role of mild to moderate essential hypertension as an initiator of chronic kidney disease, the 2017 United States Renal Data System Annual Data Report lists hypertension as the primary cause of end-stage renal disease in 24.6% of incident European-American and 37.9% of incident African-American patients.•Two renal histologic patterns predominate in nondiabetic patients with chronic kidney disease, hypertension, and low-level proteinuria: (1) arteriolar nephrosclerosis with intima-medial proliferation of cells and collagen deposition in the preglomerular arterioles, ultimately resulting in glomerular ischemia and obsolescent glomerulosclerosis; and (2) solidified glomerulosclerosis associated with the apolipoprotein L1 gene (APOL1) in patients with recent African ancestry.•Although a kidney biopsy or APOL1 genotyping is required to establish whether arteriolar nephrosclerosis or APOL1-associated solidified glomerulosclerosis is present, aggressive blood pressure control with renin-angiotensin-aldosterone system blockade fails to slow the progression of either kidney disease in hypertensive patients.•A preponderance of evidence supports a major role of APOL1 renal-risk variants in the development and progression of glomerulosclerosis and other primary kidney diseases, not with hypertension per se. •Despite weak evidence supporting the role of mild to moderate essential hypertension as an initiator of chronic kidney disease, the 2017 United States Renal Data System Annual Data Report lists hypertension as the primary cause of end-stage renal disease in 24.6% of incident European-American and 37.9% of incident African-American patients.•Two renal histologic patterns predominate in nondiabetic patients with chronic kidney disease, hypertension, and low-level proteinuria: (1) arteriolar nephrosclerosis with intima-medial proliferation of cells and collagen deposition in the preglomerular arterioles, ultimately resulting in glomerular ischemia and obsolescent glomerulosclerosis; and (2) solidified glomerulosclerosis associated with the apolipoprotein L1 gene (APOL1) in patients with recent African ancestry.•Although a kidney biopsy or APOL1 genotyping is required to establish whether arteriolar nephrosclerosis or APOL1-associated solidified glomerulosclerosis is present, aggressive blood pressure control with renin-angiotensin-aldosterone system blockade fails to slow the progression of either kidney disease in hypertensive patients.•A preponderance of evidence supports a major role of APOL1 renal-risk variants in the development and progression of glomerulosclerosis and other primary kidney diseases, not with hypertension per se. Querying PubMed for the key words "hypertension and chronic kidney disease" in August 2018 returned more than 22,000 publications. Many describe distinct pathophysiologic processes that can produce chronic kidney disease (CKD) and/or elevate the systemic blood pressure. In contrast, others present "hypertension-attributed nephropathy" and "essential hypertension" as homogeneous clinical syndromes. This is an inaccurate assessment; a multitude of genetic factors, environmental exposures, and coexisting diseases acting in concert contribute to alterations in kidney function, systolic blood pressure (SBP), and diastolic blood pressure (DBP).1Limou S. Vince N. Parsa A. Lessons from CKD-related genetic association studies-Moving Forward.Clin J Am Soc Nephrol. 2018; 13: 140-152Crossref PubMed Scopus (18) Google Scholar, 2Ko Y.A. Yi H. Qiu C. et al.Genetic-variation-driven gene-Expression changes Highlight genes with important functions for kidney disease.Am J Hum Genet. 2017; 100: 940-953Abstract Full Text Full Text PDF PubMed Scopus (55) Google Scholar A continuum of blood pressure exists in the general population. Graded increases in the risk of adverse cardiovascular disease (CVD) outcomes and death occur in those with higher systemic pressures.3Kearney P.M. Whelton M. Reynolds K. Muntner P. Whelton P.K. He J. Global burden of hypertension: analysis of worldwide data.Lancet. 2005; 365: 217-223Abstract Full Text Full Text PDF PubMed Scopus (3983) Google Scholar Mortality rates are also increased in those with very low blood pressures, likely reflecting comorbid conditions. An equally high blood pressure in 2 individuals of the same age and ancestral background does not guarantee that they have similar pathophysiologic processes underlying their disorders or that they will respond equally to a given class of antihypertensive medications. These individuals likely face different risks for development of kidney disease, CVD, and cerebrovascular disease. The disease process referred to as "essential hypertension" is a physical examination finding reflecting a high SBP and/or DBP without an obvious cause. The term essential is synonymous with idiopathic. If a pathophysiologic cause was evident, patients would have secondary hypertension. Hypertension is reportedly the primary etiology of end-stage renal disease (ESRD) in 24.6% of incident European-American and 37.9% of incident African-American patients initiating chronic dialysis.4USRDS. USRDS Annual Data ReportEpidemiology of kidney disease in the United States. National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases, Chapter 1. Bethesda, MD2016Google Scholar Accelerated and malignant forms of hypertension, atheroembolic kidney disease, and renovascular hypertension are clearly documented as causes of CKD that develop in hypertensive individuals. Kidney function can decline rapidly in these disorders. However, the concept that mild to moderate essential hypertension is a common initiator of CKD is tenuous at best.5Freedman 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 (193) Google Scholar, 6Freedman B.I. Cohen A.H. Hypertension-attributed nephropathy: what's in a name?.Nat Rev Nephrol. 2016; 12: 27-36Crossref PubMed Scopus (52) Google Scholar The discovery of association between the apolipoprotein L1 gene (APOL1) and nondiabetic nephropathy in populations with recent African ancestry supports that CKD typically develops first and is followed by elevations in systemic blood pressures.7Genovese 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 (1413) Google Scholar, 8Tzur 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 (460) Google Scholar This manuscript reviews the studies that have assessed the association between APOL1 renal-risk variants (RRVs) with hypertension and CKD and that support this conclusion. The landmark National Institutes of Health–sponsored Systolic Blood Pressure Intervention Trial (SPRINT) and African American Study of Kidney Disease and Hypertension Trial (AASK) prospectively evaluated the effects of blood pressure reduction on risk of development and progression of CKD, as well as effects on CVD and mortality.9SPRINT Research Group A randomized trial of intensive versus standard blood-pressure control.N Engl J Med. 2015; 373: 2103-2116Crossref PubMed Scopus (3932) Google Scholar, 10Wright Jr., J.T. Bakris G. Greene T. et al.Effect of blood pressure lowering and antihypertensive drug class on progression of hypertensive kidney disease: results from the AASK trial.JAMA. 2002; 288: 2421-2431Crossref PubMed Scopus (1632) Google Scholar, 11Appel L.J. Wright Jr., J.T. Greene T. et al.Intensive blood-pressure control in hypertensive chronic kidney disease.N Engl J Med. 2010; 363: 918-929Crossref PubMed Scopus (438) Google Scholar Effects of APOL1 RRVs on outcomes were also retrospectively assessed in these trials. The effect of reducing SBP to a target below 120 mm Hg (intensive treatment) vs to a target below 140 mm Hg (standard treatment) was assessed in SPRINT. In all, 9361 nondiabetic participants aged >50 years with an SBP > 130-180 mm Hg and at high risk for CVD were randomly assigned to the 2 treatment arms. To study individuals at increased risk for CVD, the trial included participants aged ≥75 years, those with prior CVD events (excluding stroke), with 10-year risk of CVD ≥15% based on the Framingham risk score, or with CKD defined as an estimated glomerular filtration rate (eGFR) of 20 to <60 mL/min/1.73 m2 with <1 g proteinuria per day (patients with polycystic kidney disease were excluded). SPRINT results underscore that intensive blood pressure treatment significantly reduces the frequency of major fatal and nonfatal CVD events, as well as death from all causes in high-risk patients with hypertension. In contrast, renal outcomes in the intensively treated arm of SPRINT were less favorable than outcomes for CVD and mortality.12Cheung A.K. Rahman M. Reboussin D.M. et al.Effects of intensive BP control in CKD.J Am Soc Nephrol. 2017; 28: 2812-2823Crossref PubMed Scopus (264) Google Scholar, 13Beddhu S. Rocco M.V. Toto R. et al.Effects of intensive systolic blood pressure control on kidney and cardiovascular outcomes in Persons without kidney disease: a secondary analysis of a randomized trial.Ann Intern Med. 2017; 167: 375-383Crossref PubMed Scopus (68) Google Scholar SPRINT used a "composite renal outcome" to evaluate the 2646 participants with CKD at baseline. This was defined as first occurrence of a reduction in eGFR of ≥50%, need for chronic dialysis (defined as ≥90 days), or need for kidney transplantation. The CKD subgroup consisted of 1330 SPRINT participants randomized to intensive antihypertensive treatment and 1316 randomized to standard antihypertensive treatment. The composite renal outcome in the intensive vs the standard treatment arm was not significantly different (hazard ratio [HR], 0.89; 95% confidence interval [CI], 0.4-1.87; P = 0.76). In isolation, neither a ≥50% reduction in eGFR (HR, 0.87; 95% CI, 0.36-2.07; P = 0.75) nor initiation of long-term dialysis (HR, 0.57; 95% CI, 0.19-1.54; P = 0.27) was significantly impacted by intensive blood pressure lowering, and no participant received a kidney transplant. In the 6677 SPRINT participants without CKD at baseline (3332 intensive treatment and 3345 standard treatment), significantly higher rates of incident declines (≥30%) in eGFR to <60 mL/min/1.73 m2 were seen with intensive blood pressure lowering (HR, 3.49; 95% CI, 2.44-5.10; P < 0.001). Incident albuminuria, defined as doubling of the urine albumin-to-creatinine ratio from 10 mg/g, showed nonsignificant trends toward better outcomes in the intensive treatment arm for participants with and without CKD at baseline (HR, 0.72; 95% CI, 0.48-1.07; P = 0.11 and HR, 0.81; 95% CI, 0.63-1.04; P = 0.10, respectively). Hypertensive and nondiabetic SPRINT participants with stage 3 CKD and <1 gm proteinuria per day appeared to derive no renal benefit from intensive blood pressure control. These patients, many labeled with "hypertensive nephrosclerosis" in the medical record, are unlikely to be offered a kidney biopsy due to low levels of proteinuria. Their risk of developing a ≥50% decrement in eGFR or starting dialysis was no different from that with SBP targets <120 mm Hg or <140 mm Hg. Albuminuria tended to be lower in the group targeting intensive blood pressure control, and this may reflect more frequent use (or higher doses) of renin-angiotensin-aldosterone system (RAAS) blocking agents. Incident CKD developed more often in SPRINT participants without nephropathy at baseline targeted for intensive lowering of blood pressure. In those without CKD at baseline, the differences in adjusted mean eGFR between the intensive and standard treatment groups, respectively, were −3.32 mL/min/1.73 m2 at 6 months and −4.50 mL/min/1.73 m2 at 18 months; this difference remained stable for the remainder of the follow-up period. At 3 years, an incident CKD event developed in 3.7% of intensively treated participants compared with 1.0% in the standard treatment arm (HR, 3.54; 95% CI, 2.50-5.02). However, even with the higher rates of incident CKD, SPRINT showed significant reductions in CVD events and mortality with intensive blood pressure treatment. Intensive blood pressure control clearly reduces CVD events and saves lives in high-risk nondiabetic individuals with hypertension. However, SPRINT demonstrated that intensive blood pressure control fails to slow the progression of established nephropathy in nondiabetic individuals with low levels of proteinuria. In addition, more hypertensive participants without CKD developed nephropathy with a target SBP of <120 mm Hg.13Beddhu S. Rocco M.V. Toto R. et al.Effects of intensive systolic blood pressure control on kidney and cardiovascular outcomes in Persons without kidney disease: a secondary analysis of a randomized trial.Ann Intern Med. 2017; 167: 375-383Crossref PubMed Scopus (68) Google Scholar This was not likely a purely hemodynamic effect because it persisted throughout the trial. The SPRINT Alzheimer's, Seniors and Kidney Study (SPRINT ASK) will be performing an additional assessment of kidney function 1 year after the final study visit, results are expected soon. SPRINT included 2571 African Americans who provided DNA samples and consented to genetic testing.14Freedman B.I. Rocco M.V. Bates J.T. et al.APOL1 renal-risk variants do not associate with incident cardiovascular disease or mortality in the Systolic Blood Pressure Intervention Trial.Kidney Int Rep. 2017; 2: 713-720Abstract Full Text Full Text PDF PubMed Scopus (18) Google Scholar, 15Langefeld C.D. Divers J. Pajewski N.M. et al.Apolipoprotein L1 gene variants associate with prevalent kidney but not prevalent cardiovascular disease in the Systolic Blood Pressure Intervention Trial.Kidney Int. 2015; 87: 169-175Abstract Full Text Full Text PDF PubMed Scopus (63) Google Scholar Similar to the 13% frequency of APOL1 high risk for CKD genotypes (G1G1, G2G2, or G1G2) in the general African-American population, approximately 14% of African Americans in SPRINT had 2 APOL1 RRVs. These high-risk genotypes were associated with prevalent CKD and albuminuria at baseline among African Americans in SPRINT, but not with CVD. After a median 39-month follow-up, no association was observed between the composite CVD outcome (or its components) and APOL1 renal-risk genotypes. A nonsignificant trend (P = 0.11) toward APOL1 association with incident CKD was observed, reflecting a sustained 30% decrease in eGFR to <60 mL/min/1.73 m2. SPRINT broke new ground in understanding the relationships between initiation and progression of CKD based on antihypertensive treatment targets. Results were consistent with the findings in the AASK Trial and the subsequent AASK Cohort Study.10Wright Jr., J.T. Bakris G. Greene T. et al.Effect of blood pressure lowering and antihypertensive drug class on progression of hypertensive kidney disease: results from the AASK trial.JAMA. 2002; 288: 2421-2431Crossref PubMed Scopus (1632) Google Scholar, 11Appel L.J. Wright Jr., J.T. Greene T. et al.Intensive blood-pressure control in hypertensive chronic kidney disease.N Engl J Med. 2010; 363: 918-929Crossref PubMed Scopus (438) Google Scholar In contrast to SPRINT, AASK specifically enrolled African Americans who were thought to have kidney disease related to the effects of high blood pressure. The hypothesis was that by aggressively lowering blood pressures and using high-dose RAAS blocking agents, specifically angiotensin-converting enzyme inhibitors, the progression of presumed hypertensive kidney disease in AASK participants could be slowed. Despite impressive reductions in blood pressure, nearly 60% of AASK participants developed a primary study outcome within 10 years; this included doubling of the serum creatinine concentration, initiation of dialysis, or death. In fact, few AASK participants died, and most who met the primary study outcome had a renal event. AASK demonstrated that aggressive blood pressure control was ineffective in slowing the progression of established nephropathy attributed to the effects of hypertension in African Americans; it included different classes of antihypertensive medications and prescription of high-dose RAAS blockade. Genetic analyses in AASK revealed that participants were enriched with APOL1 renal-risk genotypes, and these were the major predictor of risk for progression of nephropathy. APOL1 renal-risk genotypes are known to be associated with a spectrum of diseases related to focal segmental glomerulosclerosis (FSGS); these include solidified glomerulosclerosis with minimal to absent proteinuria (the disorder often erroneously attributed to hypertension), collapsing glomerulopathy, severe lupus nephritis, sickle cell nephropathy, and more rapid failure of renal allografts based on the kidney donors' genotype.6Freedman B.I. Cohen A.H. Hypertension-attributed nephropathy: what's in a name?.Nat Rev Nephrol. 2016; 12: 27-36Crossref PubMed Scopus (52) Google Scholar, 16Freedman B.I. Locke J.E. Reeves-Daniel A.M. Julian B.A. Apolipoprotein L1 gene effects on kidney Transplantation.Semin Nephrol. 2017; 37: 530-537Abstract Full Text Full Text PDF PubMed Scopus (18) Google Scholar It is apparent that many African-American AASK participants who had progressive CKD had a primary kidney disease and not nephropathy related to hypertension.17Lipkowitz M.S. Freedman B.I. Langefeld C.D. et al.Apolipoprotein L1 gene variants associate with hypertension-attributed nephropathy and the rate of kidney function decline in African Americans.Kidney Int. 2013; 83: 114-120Abstract Full Text Full Text PDF PubMed Scopus (183) Google Scholar, 18Parsa A. Kao W.H. Xie D. et al.APOL1 risk variants, race, and progression of chronic kidney disease.N Engl J Med. 2013; 369: 2183-2196Crossref PubMed Scopus (532) Google Scholar Many cases with minimal or no proteinuria appear to have been caused by APOL1, including solidified glomerulosclerosis and FSGS as reported in an AASK kidney biopsy study.6Freedman B.I. Cohen A.H. Hypertension-attributed nephropathy: what's in a name?.Nat Rev Nephrol. 2016; 12: 27-36Crossref PubMed Scopus (52) Google Scholar, 19Fogo A. Breyer J.A. Smith M.C. et al.Accuracy of the diagnosis of hypertensive nephrosclerosis in African Americans: a report from the African American study of kidney disease (AASK) trial. AASK Pilot study investigators.Kidney Int. 1997; 51: 244-252Abstract Full Text PDF PubMed Scopus (209) Google Scholar Secondary hypertension is a well-established manifestation of longstanding CKD from glomerular, tubulointerstitial, and vascular etiologies. Nonetheless, many patients continue to be mislabeled as having CKD or ESRD due to mild to moderate essential hypertension based on their clinical presentation and compounded by the lack of knowledge of APOL1 genotypes. The Mount Sinai BioMe Biobank repository was analyzed to assess blood pressures in African Americans based on APOL1.20Nadkarni G.N. Galarneau G. Ellis S.B. et al.Apolipoprotein L1 variants and blood pressure Traits in African Americans.J Am Coll Cardiol. 2017; 69: 1564-1574Crossref PubMed Scopus (32) Google Scholar A total of 5200 African-American biobank participants were included in this study, and replication cohorts consisted of an additional 1623 BioMe participants, 1809 Vanderbilt BioVU participants, and 567 Northwestern NUgene Biobank participants. Blood pressure and APOL1 RRV associations were evaluated in the discovery and replication cohorts and in a model adjusted for age, sex, body mass index, and eGFR. These investigators found that in the 14-16% of African-American patients with 2 APOL1 RRVs, there was an additive effect on SBP and age at diagnosis of hypertension. Individuals with 2 APOL1 RRVs were diagnosed with hypertension 2 to 5 years earlier than those with 0 or 1 RRV. In the fully-adjusted analysis, BioMe participants aged 20 to 29 years had an increase in SBP of 0.94 mmHg per copy of an APOL1 RRV. In addition, individuals in this age group experienced declines in eGFR approximately 10 years later, which became evident in the 30- to 39-year age range. This suggested that hypertension predated and may have led to the decline in eGFR. As such, the authors proposed that the earliest effect of APOL1 might be on hypertension and not CKD. The BioMe analysis, including samples and data from a biobank and electronic medical record of prevalent patients, is the sole report of APOL1 association primarily with hypertension. Table 1 summarizes results from 13 other population-based, clinical and research cohorts that assessed APOL1 associations with blood pressure, hypertension, and CKD. Nearly all support primary association between APOL1 and kidney disease and/or reduced eGFR.Table 1Studies Reporting Hypertension and CKD Phenotypes Based on APOL1 Renal-Risk GenotypesSample/CohortAPOL1 Association with Hypertension/Blood PressureAPOL1 Association With ↓eGFR/CKDReferencePediatric Nephrology Clinic, St. Louis, MONoYes21Anyaegbu E.I. Shaw A.S. Hruska K.A. Jain S. Clinical phenotype of APOL1 nephropathy in young relatives of patients with end-stage renal disease.Pediatr Nephrol. 2015; 30: 983-989Google ScholarAfrican American Study of Kidney Disease and Hypertension, AASKNoYes17Lipkowitz M.S. Freedman B.I. Langefeld C.D. et al.Apolipoprotein L1 gene variants associate with hypertension-attributed nephropathy and the rate of kidney function decline in African Americans.Kidney Int. 2013; 83: 114-120Abstract Full Text Full Text PDF PubMed Scopus (183) Google Scholar, 18Parsa A. Kao W.H. Xie D. et al.APOL1 risk variants, race, and progression of chronic kidney disease.N Engl J Med. 2013; 369: 2183-2196Crossref PubMed Scopus (532) Google ScholarCardiovascular Health Study, CHSNoYes22Mukamal K.J. Tremaglio J. Friedman D.J. et al.APOL1 genotype, kidney and cardiovascular disease, and death in older adults.Arterioscler Thromb Vasc Biol. 2016; 36: 398-403Crossref PubMed Scopus (67) Google ScholarJackson Heart Study, JHSNoYes23Ito K. Bick A.G. Flannick J. et al.Increased burden of cardiovascular disease in carriers of APOL1 genetic variants.Circ Res. 2014; 114: 845-850Crossref PubMed Scopus (121) Google ScholarAfrican American-Diabetes Heart Study, AA-DHSaAll participants had type 2 diabetes mellitus.NoNo24Freedman B.I. Langefeld C.D. Lu L. et al.APOL1 associations with nephropathy, atherosclerosis, and all-cause mortality in African Americans with type 2 diabetes.Kidney Int. 2015; 87: 176-181Abstract Full Text Full Text PDF PubMed Scopus (59) Google ScholarAA-DHS Memory in Diabetes, AA-DHS MINDaAll participants had type 2 diabetes mellitus.NoYes25Freedman B.I. Gadegbeku C.A. Bryan R.N. et al.APOL1 renal-risk variants associate with reduced cerebral white matter lesion volume and increased gray matter volume.Kidney Int. 2016; 90: 440-449Abstract Full Text Full Text PDF PubMed Scopus (11) Google ScholarAtherosclerosis Risk In Communities, ARICNoYes26Grams M.E. Rebholz C.M. Chen Y. et al.Race, APOL1 risk, and eGFR decline in the general population.J Am Soc Nephrol. 2016; 27: 2842-2850Crossref PubMed Scopus (93) Google ScholarCoronary Artery Risk Development in Young Adults, CARDIANoYesbAssociation with albuminuria (not eGFR).27Chen T.K. Estrella M.M. Vittinghoff E. et al.APOL1 genetic variants are not associated with longitudinal blood pressure in young black adults.Kidney Int. 2017; 92: 964-971Abstract Full Text Full Text PDF PubMed Scopus (13) Google ScholarSystolic Blood Pressure Intervention Trial, SPRINTNoYes9SPRINT Research Group A randomized trial of intensive versus standard blood-pressure control.N Engl J Med. 2015; 373: 2103-2116Crossref PubMed Scopus (3932) Google ScholarMulti-Ethnic Study of Atherosclerosis, MESANoNo28Chen T.K. Katz R. Estrella M.M. et al.Association between APOL1 genotypes and risk of cardiovascular disease in MESA (Multi-Ethnic study of atherosclerosis).J Am Heart Assoc. 2017; 6: e007199Google ScholarReasons for Geographic and Racial Differences in Stroke, REGARDSNoNo29Gutierrez O.M. Judd S.E. Irvin M.R. et al.APOL1 nephropathy risk variants are associated with altered high-density lipoprotein profiles in African Americans.Nephrol Dial Transplant. 2016; 31: 602-608Crossref PubMed Scopus (18) Google ScholarLiving Kidney Donors, Detroit, MINoYes30Doshi M.D. Ortigosa-Goggins M. Garg A.X. et al.APOL1 genotype and renal function of black living donors.J Am Soc Nephrol. 2018; 29: 1309-1316Crossref PubMed Scopus (87) Google ScholarWomen's Health Initiative, WHIYescBlood pressure association confounded by ↓eGFR.Yes23Ito K. Bick A.G. Flannick J. et al.Increased burden of cardiovascular disease in carriers of APOL1 genetic variants.Circ Res. 2014; 114: 845-850Crossref PubMed Scopus (121) Google ScholarBioMe Biobank, New York, NYYesdBlood pressures rose before fall in eGFR.Yes20Nadkarni G.N. Galarneau G. Ellis S.B. et al.Apolipoprotein L1 variants and blood pressure Traits in African Americans.J Am Coll Cardiol. 2017; 69: 1564-1574Crossref PubMed Scopus (32) Google ScholarAbbreviations: CKD, chronic kidney disease; eGFR, estimated glomerular filtration rate.a All participants had type 2 diabetes mellitus.b Association with albuminuria (not eGFR).c Blood pressure association confounded by ↓eGFR.d Blood pressures rose before fall in eGFR. Open table in a new tab Abbreviations: CKD, chronic kidney disease; eGFR, estimated glomerular filtration rate. Relationships between APOL1 and blood pressure were examined in 2 small African-American cohorts with detailed phenotypes: hypertensive children and living kidney donors. The APOL1 genotype, hypertension, and a family history of ESRD were analyzed in 93 pediatric and young adult African Americans with severe hypertension or FSGS.21Anyaegbu E.I. Shaw A.S. Hruska K.A. Jain S. Clinical phenotype of APOL1 nephropathy in young relatives of patients with end-stage renal disease.Pediatr Nephrol. 2015; 30: 983-989Google Scholar APOL1 high-risk genotypes were significantly associated with CKD and a family history of ESRD in these young individuals. In all, 66% of those with a family history of ESRD had 2 APOL1 RRVs, as did 83% of pediatric cases previously diagnosed as having "hypertension-attributed CKD". In contrast, hypertensive African-American children with a normal eGFR, no proteinuria, and no family history of ESRD universally lacked 2 APOL1 RRVs. The cohort of African-American living kidney donors also showed similar predonation and postdonation blood pressures and frequencies of hypertension, irrespective of APOL1 genotype.30Doshi M.D. Ortigosa-Goggins M. Garg A.X. et al.APOL1 genotype and renal function of black living donors.J Am Soc Nephrol. 2018; 29: 1309-1316Crossref PubMed Scopus (87) Google Scholar Significantly lower predonation and postdonation eGFRs were present in the donors with APOL1 renal-risk genotypes. Both cohort studies support the hypothesis that hypertension was primarily a manifestation of underlying CKD and did not initiate nephropathy. The previously discussed AASK10Wright Jr., J.T. Bakris G. Greene T. et al.Effect of blood pressure lowering and antihypertensive drug class on progression of hypertensive kidney disease: results from the AASK trial.JAMA. 2002; 288: 2421-2431Crossref PubMed Scopus (1632) Google Scholar and SPRINT trials9SPRINT Research Group A randomized trial of intensive versus standard blood-pressure control.N Engl J Med. 2015; 373: 2103-2116Crossref PubMed Scopus (3932) Google Scholar had intervention arms that randomized hypertensive participants with nondiabetic CKD to intensive pharmacologic control of blood pressure. In AASK participants randomized to the aggressive blood pressure control arm (mean arterial blood pressure [MABP] ≤92 mm Hg), there was no observed benefit in slowing the rate of progression of kidney failure compared with those randomized to MABP 102-107 mm Hg. A subset of 675 AASK participants with clinically diagnosed "hypertensive nephropathy" had APOL1 genotyping. All had baseline CKD defined as an iothalamate GFR of 20-65 mL/min/1.73 m2 and subnephrotic or absent proteinuria.17Lipkowitz M.S. Freedman B.I. Langefeld C.D. et al.Apolipoprotein L1 gene variants associate with hypertension-attributed nephropathy and the rate of kidney function decline in African Americans.Kidney Int. 2013; 83: 114-120Abstract Full Text Full Text PDF PubMed Scopus (183) Google Scholar The investigators, along with an accompanying editorial,31Skorecki K.L. Wasser W.G. Hypertension-misattributed kidney disease in African Americans.Kidney Int. 2013; 83: 6-9Abstract Full Text Full Text PDF PubMed Scopus (27) Google Scholar concluded that the progression of kidney disease in AASK participants with nondiabetic CKD was strongly associated with APOL1, and systemic blood pressures had no effect. There were also no significant differences in SBP, DBP, or MABP 1 year after randomization based on the presence of 2 APOL1 RRVs vs 0 or 1. In the contemporary SPRINT, a post hoc analysis of 2568 African-American participants focused on APOL1 genotype and incident CVD events.14Freedman B.I. Rocco M.V. Bates J.T. et al.APOL1 renal-risk variants do not associate with incident cardiovascular disease or mortality in the Systolic Blood Pressure Intervention Trial.Kidney Int Rep. 2017; 2: 713-720Abstract Full Text Full Text PDF PubMed Scopus (18) Google Scholar SPRINT participants were all hypertensive and uniformly lacked diabetes mellitus. CVD events assessed included a composite of myocardial infarction, acute coronary syndrome, and stroke, as well as heart failure and CVD-related death. Results were adjusted for demographic characteristics and to which blood pressure intervention group participants were randomized. In African Americans with APOL1 renal-risk genotypes, baseline SBP and DBP were similar to those of African Americans who had 0 or 1 APOL1 RRV. As expected, those with 2 APOL1 RRVs had a lower baseline eGFR and significantly more proteinuria. No significant relationship was observed between APOL1 RRVs and the composite primary CVD end point. Several large cardiovascular and diabetes complication studies recorded blood pressures and performed APOL1 genotyping in African Americans. The Cardiovascular Health Study (CHS) assessed a population-based cohort of Americans older than 65 years, and a subgroup was genotyped for APOL1.22Mukamal K.J. Tremaglio J. Friedman D.J. et al.APOL1 genotype, kidney and cardiovascular disease, and death in older adults.Arterioscler Thromb Vasc Biol. 2016; 36: 398-403Crossref PubMed Scopus (67) Google Scholar Genotypes were assessed for association with subclinical atherosclerosis, incident CVD, mortality, and kidney disease after more than 13 years of follow-up. In CHS, 91 African Americans had 2 APOL1 RRVs. Their outcomes were compared with those of 707 other African Americans with 0 or 1 RRV and approximately 5000 European Americans (presumably lacking APOL1 RRVs). African Americans in the APOL1 renal-risk genotype group had more albuminuria and a strong association with reduced eGFR. Moreover, higher mortality was observed in the APOL1 high-risk genotype group, with higher rates of myocardial infarction. Albuminuria and risk for myocardial infarction and mortality were similar between African Americans with 0 or 1 APOL1 RRV and European Americans. Although the CHS analysis involved an older sample with few African Americans having 2 APOL1 RRVs, no associations between APOL1 genotype and hypertension or blood pressure were evident. In contrast to CHS, the Coronary Artery Risk Development in Young Adults study enrolled 1330 younger African Americans.27Chen T.K. Estrella M.M. Vittinghoff E. et al.APOL1 genetic variants are not associated with longitudinal blood pressure in young black adults.Kidney Int. 2017; 92: 964-971Abstract Full Text Full Text PDF PubMed Scopus (13) Google Scholar As in the general population, 13% had 2 APOL1 RRVs. The mean age at recruitment was 24 years. After 25 years of follow-up, assessment of changes in blood pressure, adjusted for demographic, socioeconomic, and hypertension risk factors, medications, and kidney function were performed. From young adulthood to midlife, African Americans had greater increases in blood pressure than their European-American counterparts, but the difference was not associated with APOL1 genotype. In the Coronary Artery Risk Development in Young Adults study, APOL1 genotypes were not associated with eGFR computed with cystatin-c; however, there was a significantly higher baseline urine albumin-to-creatinine ratio in African Americans with 2 APOL1 RRVs than that in African Americans with 0 or 1 RRV. Community-based studies are reviewed next. The observational Jackson Heart study (JHS) recruited participants from urban and rural communities in the proximity of Jackson, Mississippi.23Ito K. Bick A.G. Flannick J. et al.Increased burden of cardiovascular disease in carriers of APOL1 genetic variants.Circ Res. 2014; 114: 845-850Crossref PubMed Scopus (121) Google Scholar Replication was performed in the Women's Health Initiative cohort. In a subgroup analysis of JHS, APOL1 was genotyped in 1959 randomly selected African-American participants, and associations between APOL1 and renal and CVD phenotypes were analyzed. CKD was more often present in the APOL1 high-risk genotype group. There were no significant differences in the baseline distributions of age, gender, type 2 diabetes mellitus, and presence of hypertension among JHS participants with or without APOL1 renal-risk genotypes. JHS participants with 2 APOL1 RRVs had an increased risk of CVD, which persisted after adjustment for CVD and CKD risk factors. APOL1 renal-risk genotypes were associated with both low eGFR and hypertension in the Women's Health Initiative, suggesting the potential for confounding between these end points.23Ito K. Bick A.G. Flannick J. et al.Increased burden of cardiovascular disease in carriers of APOL1 genetic variants.Circ Res. 2014; 114: 845-850Crossref PubMed Scopus (121) Google Scholar APOL1 genotypes were associated with declines in eGFR, without concurrent association with high blood pressure in the Atherosclerosis Risk In Communities (ARIC) cohort.26Grams M.E. Rebholz C.M. Chen Y. et al.Race, APOL1 risk, and eGFR decline in the general population.J Am Soc Nephrol. 2016; 27: 2842-2850Crossref PubMed Scopus (93) Google Scholar ARIC prospectively evaluated 15,140 individuals and had a 25-year follow-up period. In subgroup analyses, investigators assessed APOL1 association with eGFR in the context of clinical events such as acute kidney injury, hypertension, diabetes, hospitalizations, and mortality. Although most ARIC participants were European American, approximately 20% were African American. There were no statistically significant differences in baseline SBP or prevalence of hypertension in African Americans with or without APOL1 high-risk genotypes. However, African Americans with 2 (and 1) APOL1 RRVs had a higher risk of total and pre-ESRD hospitalizations, acute kidney injury, ESRD, hypertension, diabetes mellitus, CVD, and all-cause mortality compared with European Americans. In the fully-adjusted analyses (irrespective of APOL1 genotype), African Americans had higher risk of incident hypertension, diabetes, and ESRD than European Americans but lower risk of total hospitalizations and incident CVD. The Multi-Ethnic Study of Atherosclerosis primary prevention cohort enrolled individuals without prevalent CVD, and 1746 of 6814 African-American participants had APOL1 genotyping.28Chen T.K. Katz R. Estrella M.M. et al.Association between APOL1 genotypes and risk of cardiovascular disease in MESA (Multi-Ethnic study of atherosclerosis).J Am Heart Assoc. 2017; 6: e007199Google Scholar The Multi-Ethnic Study of Atherosclerosis found no association between APOL1 RRVs and subclinical CVD. Although there was a higher risk of incident heart failure in the APOL1 high-risk genotype group, no evidence of association was seen with incident myocardial infarction, coronary heart disease, or stroke. There was also no association between APOL1 genotype and blood pressure or eGFR. The mean baseline SBP and DBP were similar in the 1533 APOL1 low-genetic-risk participants (average blood pressure 132/74 mm Hg) and 213 APOL1 high-genetic-risk participants (average baseline blood pressure 131/75 mm Hg). This primary prevention study is important because baseline blood pressure readings were unlikely to be confounded by disease. APOL1 genotypes were also assessed in 2010 African-American Reasons for Geographic and Racial Differences in Stroke (REGARDS) study participants. In an analysis assessing lipoprotein subfraction measurements and associations with clinical CVD, the risk of ESRD was significantly higher in those with 2 APOL1 RRVs than in those with 0 or 1.29Gutierrez O.M. Judd S.E. Irvin M.R. et al.APOL1 nephropathy risk variants are associated with altered high-density lipoprotein profiles in African Americans.Nephrol Dial Transplant. 2016; 31: 602-608Crossref PubMed Scopus (18) Google Scholar There were no significant difference in blood pressure based on the number of APOL1 RRVs; 73% of patients with 2 APOL1 RRVs had hypertension at baseline compared with 76% with 0 and 77% with 1 APOL1 RRV. The effect translated to a 1 to 2 mm Hg difference in SBP between groups. Finally, relationships between APOL1 and hypertension were assessed in patients with type 2 diabetes mellitus. The importance of these reports lies in their ability to test APOL1 association with hypertension without the potential for confounding by APOL1 association with diabetic kidney disease. Among 717 African American-Diabetes Heart Study (AA-DHS) participants, the proportions of participants with 0, 1, or 2 APOL1 RRVs was similar to that in the general population.24Freedman B.I. Langefeld C.D. Lu L. et al.APOL1 associations with nephropathy, atherosclerosis, and all-cause mortality in African Americans with type 2 diabetes.Kidney Int. 2015; 87: 176-181Abstract Full Text Full Text PDF PubMed Scopus (59) Google Scholar Adjusting for demographic and renal disease risk factors in this diabetes-affected cohort, APOL1 RRVs were not significantly associated with albuminuria or eGFR. There was also no difference in the percentage of individuals with hypertension based on APOL1 genotype. The proportion of AA-DHS participants with hypertension was 83.3%, 84.2%, and 80.7% for 0, 1, and 2 APOL1 RRVs, respectively, (intergroup P value = 0.72). There was also no association between APOL1 genotype and hypertension in the AA-DHS Memory in Diabetes cohort.25Freedman B.I. Gadegbeku C.A. Bryan R.N. et al.APOL1 renal-risk variants associate with reduced cerebral white matter lesion volume and increased gray matter volume.Kidney Int. 2016; 90: 440-449Abstract Full Text Full Text PDF PubMed Scopus (11) Google Scholar Discovery of the powerful association between APOL1 and CKD in populations with recent African ancestry demonstrates that nondiabetic nephropathy with low-level proteinuria is frequently an inherited disorder in this population and produces secondarily elevated blood pressure. A multitude of studies in populations with people of different ages and those with various kidney and systemic diseases and in population-based cohorts support this conclusion. It remains important to recognize that intensive blood pressure control, including with high-dose RAAS blockade, does not slow the progression of or prevent declines in eGFR in hypertensive individuals with CKD and subnephrotic proteinuria. The effects of APOL1 RRV proteins on kidney cells need to be blocked to cure APOL1-associated kidney diseases, as intensive blood pressure control has not produced favorable effects.
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