Expression Of Concern From The K Editors:Apolipoprotein-1 Risk Variants And Associated Kidney Phenotypes in An Adult HⅣ Cohort in Nigeria

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The Editors of Kidney International(K) are releasing this Expression of Concern for 2 articles that were recently published in K.In July 2021, KI published a study on phenotypes associated with APOL1 kidney disease risk variants(RVs)in an adult HIV cohort in Nigeria.' This cross-sectional study examined the association of APOL1 KRVs with albuminuria and estimated glomerular filtration rate (eGFR) in a cohort of HIV-positive adults (N= 2458)on antiretroviral therapy(ART). Three major ethnic groups in northern Nigeria were included. The study reported the prevalence of microalbuminuria and macro-albuminuria in this cohort at 37% and 3%, respectively. The odds of microalbuminuria, and macroalbuminuria. and reduced eGFR with overt proteinuria was higher in individuals with APOLI high-risk genotypes than those carrying low-risk genotypes (adjusted odds ratio = 1.97,3.96, and 5.56, respectively). As pointed out by the accompanying Commentary by Olabisi and Freedman, there was no significant association between APOL1 genotype status and eGFR, and the findings in the study were driven primarily by albuminuria.

On August 26, 2021, concerns were raised in an email to the Editor-in-Chief from the corresponding author regarding a laboratory quality control (QC)exercise initiated due to a higher than expected proportion of study participants having normoalbuminuria(urine albumin-creatinine ratio |uACR]<30 mg/g). These measurements of ACR were obtained in the Nigerian laboratory as screening for eligibility into the randomized control trial(RCT)phase of the study after the participants had been previously identified as having microalbuminuria(ACR 30-300 mg/g)in the published manuscript. In this published cohort, the determinations of ACR have been performed at 2 visits 1 to 2 months apart between September 1, 2018, and November 30, 2019. Out of the 2498 patients enrolled in the study in 2018-2019、275 patients(11%) were screened for eligibility for the RCT in 2021.Of these 275 reassessed patients, 157(57.1%) had regressed to normoalbuminuria(uACR<30 mg/g),1 (0.4%)had progressed to macroalbuminuria (>300 mg/g), and 117(42.5%) were found to have persistent micro-albuminuria. The majority of participants(91.7%)who regressed to normoalbuminuria were in the APOL1 low-risk genotype group.

In view of the high proportion of patients showing regression in microalbuminuria, the authors sought to validate the findings in an independent laboratory, However, during the exercise, the authors were unable to reliably measure albuminuria using the same Nigerian research platform as they did in 2018-2019. Because there were no stored urine samples available from these earlier visits, the published albuminuria results can neither be confirmed nor refuted. This raises concerns of a potential measurement error confounding the outcomes of the study published in KI.

The Journal's Editorial team is unclear whether this potential error was differential or nondifferential(that is, whether albuminuria, the potentially misclassified outcome, is dependent or independent of the APOL1 genotype status). If the proportion of participants misclassified differs between the 2 study groups(a differential bias), the error would be more serious because it may lead to either an overestimation or underestimation of the association between APOLI high-risk status and albuminuria. An in-depth investigation that is relevant to these concerns is currently being conducted. Pending the conclusion of this investigation, KI is publishing this Editorial Expression of Concern to alert the readership of serious concerns regarding the findings of this study.