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Rates of kidney disease among populations of African ancestry are two-to-three fold higher than other populations in large part due to apolipoprotein 1 (APOL1) risk alleles. Exciting new developments have illuminated genotype-to-phenotype mechanisms and identified several new therapeutic agents; the efficacy of one was recently reported in New England Journal of Medicine as a Phase IIa trial. The highest absolute numbers of affected persons live in West Africa and the Caribbean. Unless nephrologists and researchers insist on their inclusion in the therapeutic investigative programs, persons living in these regions will not have access to promising medications for decades. We make the case for precise estimation of APOL1 nephropathy in the Jamaican population, in order to build rationale for developing clinical trial sites in this country. In collaboration with two nephrologists practicing in high-volume adult and pediatric centers, we will sequence existing kidney biopsies to estimate prevalence of high-risk APOL1 genotype and project numbers of potential ‘eligible’ patients. We will also scope and build capacity for hosting Phase II and III studies of new therapeutics, with ultimate goal of accelerating access to new therapeutics for APOL1 nephropathy in low-resource settings.
There is a disproportionate prevalence of end-stage kidney disease (ESKD) among persons of recent African Ancestry compared to other racial or ethnic groups. Recent African ancestry, defined as being able to trace one’s family history back to the African continent within the last 400 years, confers 11 to 17-fold higher risk for development of hypertensive and proteinuric kidney disease due to genotypic variance in apolipoprotein 1 (APOL1). This genotypic variance explains the vast racial disparity in end-stage kidney disease in the US, where although African Americans comprise 10% of the adult population they comprise 30% of the dialysis population. Culminating in 2010, dogged investigation revealed that these APOL1 risk variants are associated with a wide spectrum of kidney disease including1,2. Focal Segmental Glomerulosclerosis and HIV associated nephropathy. Studies estimate that 13% of African Americans have two APOL1 risk alleles;4 in certain ethnic groups in Nigeria the population prevalence exceeds 25%.9
There is only one genomic investigation of the frequency of APOL1 risk alleles for persons living in the Caribbean (Figure 2), and this study revealed widely divergent estimates. However, in the Caribbean Renal Registry 70% of the patients were labeled as having ESKD attributed to hypertension. We believe that this mostly likely represents APOL1 mediated kidney disease in Caribbean populations, especially as the historic population migration patterns point to a likely high prevalence of persons two APOL1 risk alleles.6,7 Thus the Caribbean region will host among the highest absolute numbers of people with APOL1 nephropathy.
Currently there are 3 active (Phase I-II) clinical trials investigating medications to treat APOL1 nephropathy. Recently, Egbuna et al. detailed results of a Phase 2a clinical trial of a small molecule drug Inaxaplin for proteinuric disease in patients with the high risk genotype and APOL1. The analysis found an 44% reduction in proteinuria after 13 weeks of treatment.8,9 Notably this study enrolled participants from France, the United States, and the United Kingdom. We aim to change the paradigm of drug development in nephrology by building rationale for ethical inclusion of persons living in areas with the highest prevalence and absolute numbers of likely affected persons in treatment programs aimed at APOL1 nephropathy.
To assess the frequency of APOL1 gene high risk alleles using DNA extraction from kidney tissue, among biopsies with sufficient tissue performed over 10 years in two of Jamaica’s leading tertiary care centers. Plan to obtain 200 Biopsy samples (100 with FSGS diagnosis, 50 with membranous nephropathy, and 50 with Lupus Nephritis)
Design and Methods:
A descriptive, retrospective study will be conducted of native kidney biopsy specimens received by the Department of Pathology, UWI, between July 1, 2013 to June 30, 2023, in the Department of Pathology, UWI. The Department of Pathology, UWI, is the only institution in the island which offers a nephropathology service and therefore the samples would be representative of the Jamaican population.
The medical renal biopsy pathology reports and medical records will be reviewed sequentially and all native kidney biopsies retrieved. Clinical data such as age, sex, clinical diagnosis, indication for biopsy (proteinuria, worsening kidney function, urine albumin creatinine ratio or urine protein creatinine ratio, comorbidities e.g., hypertension and diabetes, creatinine and estimated glomerular filtration rate at the time of biopsy) will be obtained. The light and immunofluorescence microscopic findings will be recorded. If electron microscopic evaluation was performed, this data will also be included.
Paraffin-fixed formalin embedded tissue blocks of the medical renal biopsies are stored in the Department of Pathology, UWI. Two hundred (200) tissue blocks from the study set will be selected randomly for electron microscopy and APOL-1 gene studies at Stanford University. The three main biopsy diagnoses will be Focal Segmental Glomerulosclerosis, Membranous Nephropathy, and Lupus Nephritis. The investigators performing the APOL-1 testing will be blinded to the biopsy findings and clinical data. Genomic DNA will be extracted from paraffin embedded blocks in Department of Pathology at Stanford University. Cases with sufficient DNA extracted will be deidentified and sent to Genewiz (GENEWIZ, South San Francisco, CA, USA) for APOL-1 gene analysis.
Based on review of pathology reports so far, we have identified 63 patients with a FSGS diagnosis, 25 patients with a membranous nephropathy diagnosis, and 103 patients with a Lupus diagnosis. There a 9 path samples with unclear diagnoses. There are 73.5% females, and 26.5% males. The average age of patient’s biopsied was 33. Once blocks are confirmed to have enough tissue for genotyping will be able to get more clinical information from the charts and ultimately have preliminary data while we wait for genotyping results.
Preliminary conclusions will be available at the time of conference. We hypothesize that we will see a rate of the APOL1 HR genotype greater than 13% percent in this Jamaican population with kidney disease and biopsy results. We hope to use the final results to build the rationale for clinical trials in Jamaica among patients with APOL1 nephropathy and proteinuria.