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• W2044148002 abstract "Lipkowitz et al. extend the African American Study of Kidney Disease and Hypertension to the level of genetic epidemiology, in a case–control study design. Analysis of genotypes at the APOL1 kidney disease risk region supports a paradigm shift in which genetic risk is proximate to both kidney disease and hypertension. The findings mandate urgency in clarifying mechanisms whereby APOL1 region risk variants interact with environmental triggers to cause progressive kidney disease accompanied by dangerous hypertension. Lipkowitz et al. extend the African American Study of Kidney Disease and Hypertension to the level of genetic epidemiology, in a case–control study design. Analysis of genotypes at the APOL1 kidney disease risk region supports a paradigm shift in which genetic risk is proximate to both kidney disease and hypertension. The findings mandate urgency in clarifying mechanisms whereby APOL1 region risk variants interact with environmental triggers to cause progressive kidney disease accompanied by dangerous hypertension. Nephrologists in North America have long observed that African Americans with hypertension-associated kidney disease display a poor kidney-protective response to medications that effectively lower arterial blood pressure and a more rapid pattern of kidney disease progression compared with their non-African counterparts. The chicken-and-egg conundrum of hypertension as a cause of nondiabetic, secondary kidney disease or a consequence of primary kidney disease was effectively addressed by the findings of the African American Study of Kidney Disease and Hypertension (AASK) trial and cohort follow-up studies.1.Appel L.J. Wright 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 African-ancestry participants in this landmark comparative therapeutic intervention trial, receiving antihypertensive agents, including angiotensin-converting enzyme inhibitors, appeared not to accrue the benefit expected from effective control of systemic arterial blood pressure, in terms of progression to end points indicative of chronic kidney disease.1.Appel L.J. Wright 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 (A subgroup of subjects with urine protein-to-creatinine-excretion ratios greater than 0.22g may have shown relative benefit from angiotensin-converting enzyme inhibitor therapy.) Although not directly comparable, observational studies in population groups without sufficient representation of people of recent African ancestry supported the conventional wisdom of a kidney-protective benefit from antihypertensive therapy, even in nondiabetic kidney disease.2.Klag M.J. Whelton P.K. Randall B.L. et al.Blood pressure and end-stage renal disease in men.N Engl J Med. 1996; 334: 13-18Crossref PubMed Scopus (1435) Google Scholar In contrast, the AASK studies strongly suggest that an underlying factor(s) other than hypertension per se might be responsible for chronic kidney disease risk with hypertension as an accompaniment, at least among African Americans. The epidemiologic inference is further strengthened by the strikingly different histopathology in the kidneys of African- versus non-African-ancestry people clinically labeled with ‘hypertensive nephrosclerosis.’3.Marcantoni C. Ma L.J. Federspiel C. et al.Hypertensive nephrosclerosis in African Americans versus Caucasians.Kidney Int. 2002; 62: 172-180Abstract Full Text Full Text PDF PubMed Scopus (115) Google Scholar The foregoing would not be expected if a single disease entity were present. Lipkowitz and colleagues4.Lipkowitz 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 (this issue) now provide elegant further resolution at the molecular epidemiologic level, by relating the AASK findings to the rapidly evolving story of powerful kidney disease risk variants at a chromosome 22q genomic region containing the genes MYH9 and APOL1. Although some questions remain about the former, the finding of an association of two DNA sequence risk variants (designated as the G1 and G2 alleles) at the APOL1 gene with certain major forms of nondiabetic kidney disease has transformed our understanding of population ancestry disparities in kidney disease risk.5.Genovese 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 (1412) Google Scholar, 6.Tzur 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, 7.Rosset S. Tzur S. Behar D.M. et al.The population genetics of chronic kidney disease: insights from the MYH9-APOL1 locus.Nat Rev Nephrol. 2011; 7: 313-326Crossref PubMed Scopus (54) Google Scholar Evolutionary adaptive pressures related to a past survival advantage in the face of a potentially lethal pathogen (Trypanosoma brucei rhodesiense) have resulted in the rise to high frequency of these two APOL1 alleles in the parental populations of people from many regions of sub-Saharan Africa. Unfortunately, these same alleles are strongly associated with kidney disease. Thus, for example, the overall risk of developing nondiabetic end-stage kidney disease not attributable to known mendelian genetic or anatomic kidney disease may be increased more than threefold in the presence of two risk alleles.7.Rosset S. Tzur S. Behar D.M. et al.The population genetics of chronic kidney disease: insights from the MYH9-APOL1 locus.Nat Rev Nephrol. 2011; 7: 313-326Crossref PubMed Scopus (54) Google Scholar Furthermore, even the presence of one G1 risk allele may accelerate the onset of end-stage kidney disease.8.Kanji Z. Powe C.E. Wenger J.B. et al.Genetic variation in APOL1 associates with younger age at hemodialysis initiation.J Am Soc Nephrol. 2011; 22: 2091-2097Crossref PubMed Scopus (87) Google Scholar, 9.Kopp 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 (592) Google Scholar, 10.Tzur S. Rosset S. Skorecki K. et al.APOL1 Allelic Variants are associated with Lower Age of Dialysis Initiation, and thereby Increased Dialysis Vintage in African and Hispanic Americans with Non-diabetic End Stage Kidney Disease.Nephrol Dial Transplant. 2012; 27: 1498-1505Crossref PubMed Scopus (76) Google Scholar Among the etiologic entities that contribute the highest odds ratios (ORs) are HIV-associated nephropathy (OR, 29; 95% confidence interval (CI), 13–68) and primary non-monogenic focal segmental glomerulosclerosis (OR, 17; 95% CI, 11–26),9.Kopp 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 (592) Google Scholar both diseases generally characterized by marked glomerular-range proteinuria. Clearly the vast majority of progressive nondiabetic chronic kidney disease in African Americans does not fit either of these latter two classical etiologic presentations, and is often accompanied by hypertension with no proteinuria or only low-grade proteinuria. In these cases, the default diagnosis had been ‘hypertensive nephrosclerosis,’ comprising more than 35% of the etiologic category in the US Renal Data System end-stage kidney disease registry for African Americans.11US Renal Data System 2012 USRDS Annual Data Report: Atlas of End-Stage Renal Disease in the United States. National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA2012http://www.usrds.org/2012/pdf/v2_condensed_ref_tables_12.pdfGoogle Scholar A major conceptual transformation with important further practical implications is now clearly in order in light of Lipkowitz et al.’s insightful and informative population genetic and case–control addition to the AASK trials. Lipkowitz et al.4.Lipkowitz 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 report the G1 and G2 allelic state (as well as genotypes of several other sites in the region and at informative genome-wide ancestry markers) in 675 AASK cases and 618 non-nephropathic controls. The cases were African Americans recruited throughout the United States, between the ages of 18 and 70 years with diastolic blood pressure higher than 95mmHg and a measured iothalamate glomerular filtration rate between 20 and 65ml/min/1.78m2, indicative of chronic kidney disease. Since non-nephropathic controls were not part of the AASK cohort, these African-American subjects were recruited at Wake Forest School of Medicine and fulfilled the enrollment criteria of serum creatinine concentrations less than 1.5mg/dl in men and less than 1.3mg/dl in women. Case–control analysis showed a highly significant association of the G1 genotype and the AASK label of ‘hypertensive nephropathy’ under a recessive inheritance model. While ORs are higher in HIV-associated nephropathy and focal segmental glomerulosclerosis as noted above, the finding of an OR of 2.57 (95% CI, 1.85–3.55), with P=1.4–8 despite the relatively small sample size, can be considered a vindication of the currently much maligned ‘common disease, common variant’ formulation. The clinical phenotype of hypertension with chronic kidney disease affects millions worldwide, and the associated G1 allele frequencies are well into the ‘common’ range in the population of interest (51% of African Americans carry at least one risk allele7.Rosset S. Tzur S. Behar D.M. et al.The population genetics of chronic kidney disease: insights from the MYH9-APOL1 locus.Nat Rev Nephrol. 2011; 7: 313-326Crossref PubMed Scopus (54) Google Scholar). The association of APOL1 G1 was stronger still with more advanced kidney disease at AASK baseline (urine protein-to-creatinine-excretion ratio >0.6g/g) (OR, 6.29; 95% CI, 3.92–10.11; P=2.6–14), and with serum creatinine greater than 3mg/dl during follow-up (OR, 4.61; 95% CI, 3.14–6.76; P=5.6–15). As in previous studies, associations with the lower-frequency G2 risk allele were more difficult to prove—perhaps for statistical or possibly biological reasons.8.Kanji Z. Powe C.E. Wenger J.B. et al.Genetic variation in APOL1 associates with younger age at hemodialysis initiation.J Am Soc Nephrol. 2011; 22: 2091-2097Crossref PubMed Scopus (87) Google Scholar,9.Kopp 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 (592) Google Scholar Lipkowitz et al.4.Lipkowitz 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 took full advantage of the treatment arms of the original AASK intervention trial, which used a two-by-three factorial design to examine the effects of medication class (calcium blocker, angiotensin-converting enzyme inhibitor, and beta-blocker), and of intensity of blood pressure control (‘usual,’ mean arterial pressure <102–107mmHg, versus ‘low,’ mean arterial pressure <92). Importantly, there was no observable influence of APOL1 genotype on achieved blood pressure in the usual- and low-intensity arms. Disappointingly perhaps, multiple analyses, including a general linear model, did not demonstrate a significant interaction of age- and sex-adjusted medication-class group, nor of intensity of blood pressure control arm, with the APOL1 allelic state, under a recessive model. In other words, in contrast to conclusions from recent kidney graft survival studies,12.Reeves-Daniel A.M. DePalma J.A. Bleyer A.J. et al.The APOL1 gene and allograft survival after kidney transplantation.Am J Transplant. 2011; 11: 1025-1030Crossref PubMed Scopus (245) Google Scholar African-ancestry people with no APOL1 risk variants cannot yet be approached with treatment paradigms that seem to apply to non-African-ancestry counterparts. Although the relative benefit reported for angiotensin-converting enzyme inhibitors in the original non-genotyped AASK trial and cohort studies for proteinuric subjects (protein-to-creatinine ratio >0.22g/g) was not replicated in the current study, it may be premature to dismiss a role for APOL1 genotyping in guiding antihypertensive medication choice and usage in African-ancestry populations. It should also be kept in mind that in the AASK trial, patients with low levels of proteinuria who were randomly assigned to the low blood pressure group, experienced worse outcomes compared to the usual blood pressure group.13.Tobe S.W. Poirier L. Tremblay G. et al.Challenges and scientific considerations in hypertension management reflected in the 2012 recommendations of the Canadian Hypertension Education Program Open Medicine.. 2012; 6: e127-133Google Scholar The study by Lipkowitz et al.4.Lipkowitz 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 also made a valiant attempt to address the crucial question of whether or not hypertension, in the absence of clinically overt kidney disease, may also be associated with the APOL1 kidney disease risk region. The investigators were able to question 409 of the 618 controls, and among these, 171 (41.7%) recalled having been told of hypertension by their health-care professionals or reported using antihypertensive medication. In particular, comparison of subsets of controls phenotyped in this manner for hypertension status showed no relation to APOL1 genotype. This provides a tentative suggestion that hypertension in the absence of chronic kidney disease in African Americans may not be related to a clinical entity of subclinical APOL1 associated kidney disease. However, an important caveat is the possibility that in the absence of kidney biopsy, large numbers of people might exist with subclinical forms of APOL1-associated primary kidney disease with hypertension as a first clinical manifestation. Since it is unlikely that kidney biopsies would be performed, an appropriate clinical study should be designed to address this question. This new study should include large numbers of participants with careful and objective determination of blood pressure status, no other evidence of kidney disease at enrollment, and long-term follow-up with tailored examination of the benefit of the antihypertensive therapy conditioned to APOL1 genotype in the African-ancestry population. Perhaps the most appropriate venue for such a study is the African continent, where appreciation of hypertension accompanied by life-threatening complications is growing, and progressive chronic kidney disease without recourse to kidney replacement therapy is the rule (Figure 1). Keeping in mind the need to effectively treat hypertension to prevent nonrenal complications as well, in such a setting it becomes mandatory to have a comprehensive understanding of the possible kidney origin of hypertension (including APOL1 risk allele nephropathy), and the relationship between preferred modalities of treatment for hypertension and preservation of kidney integrity. Moreover, the genetic epidemiology should be more straightforward in the absence of the variable degree of non-sub-Saharan African admixture seen in other study venues. For example, recently released guidelines of the British Hypertension Society provide very clear directives that categorize African-ancestry subjects together as a homogeneous group in terms of recommendation of calcium blockers as the preferred initial antihypertensive modality (http://www.nice.org.uk/nicemedia/live/13561/56015/56015.pdf). In this regard, it will be important to know whether APOL1 genotype should be an additional guiding factor in making the antihypertensive choice that is most appropriate for a given person. So too, at the level of clinical trial design, the genetic epidemiology component that Lipkowitz et al. have so importantly added in the aftermath of the AASK trial and cohort study should now become part and parcel of future clinical trials in this and other areas. It is likely that clinical trials that do not incorporate the technical capacity, and meet the regulatory standards for DNA analysis, will fall short of being able to reach meaningful conclusions. In the case of observational epidemiology, this has been amply proven by the recent mendelian randomization that dissociated the causative relationship between high-density lipoprotein levels and coronary disease risk.14.Voight B.F. Peloso G.M. Orho-Melander M. et al.Plasma HDL cholesterol and risk of myocardial infarction: a mendelian randomisation study.Lancet. 2012; 380: 572-580Abstract Full Text Full Text PDF PubMed Scopus (1655) Google Scholar With appropriately designed, prospective, interventional trials, stratification by categories delineated with the tools of population genetics will likely become the standard approach unifying conventional and genetic epidemiology. Another interesting feature of the study by Lipkowitz et al.4.Lipkowitz 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 is the strong association of APOL1 G1 risk allelic state with kidney disease that is distinctly not characterized by high-grade proteinuria. This raises the question of the other genetic or environmental factors that determine whether the patient with two parental risk alleles at APOL1 will develop no disease throughout his or her lifetime, non-proteinuric chronic kidney disease accompanied by hypertension, or one of the high-grade proteinuria glomerulopathies. This question brings us back to the urgent need to understand the biology of APOL1 risk allele-associated kidney injury. As the authors point out, this may be the only comprehensive and definitive means of developing effective preventive and therapeutic interventions that preserve kidney function, if blood pressure control—as important as it is for prevention of other potentially catastrophic cardiovascular complications—proves simply not to offer kidney protection in the at-risk African-ancestry population. The authors gratefully acknowledge the contribution of Shay Tzur in adapting Figure 1 (left), the contour map of allele frequency distributions of identified APOL1 risk variants in Africa." @default.
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• W2044148002 title "Hypertension-misattributed kidney disease in African Americans" @default.
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