Genomic approaches to the burden of kidney disease in Sub-Saharan Africa: the Human Heredity and Health in Africa (H3Africa) Kidney Disease Research Network

Abstract

In a typical day in Korle-Bu Teaching Hospital, Ghana (and in most teaching and referral hospitals in Sub-Saharan Africa), physicians are often confronted with challenging cases not based on medical diagnosis but on the ability to offer appropriate medical care. Here, we describe a case that typifies the ethical dilemma facing nephrologists in low resource countries. Ama (name changed for privacy), age 15 years, developed edema a few months before presentation. At admission, she had significant pulmonary congestion and was diagnosed with end-stage renal disease (ESRD) documented by an ultrasound demonstrating small kidneys bilaterally. She received urgent in-hospital hemodialysis for pulmonary edema, but her family struggled to raise the US $50 needed for each dialysis session and could not cope with the burden of lifelong therapy with dialysis or kidney transplant. Ama was abandoned by her family and spent her last months hospitalized, receiving dialysis only when her pulmonary edema was severe. Acute dialysis was paid through a small hospital fund; however, this could not support long-term dialysis. Ama died in the hospital 9 months after diagnosis. Sadly, this is often the fate of a large number of individuals in Sub-Saharan Africa who develop ESRD. Even more worrisome is the rising burden of kidney disease throughout Africa without additional health care resources. During a 1-month period in the renal ward at Korle-Bu Teaching Hospital, 29 patients with ESRD were admitted, but only 18 (62.1%) could afford dialysis. The situation is no different across the continent; for example, at university hospitals in Nairobi, Kenya, and Ibadan, Nigeria, fewer than one-half of the patients can afford dialysis. The situation is even worse in Ethiopia, where chronic kidney disease (CKD) and ESRD patients are managed only in private hospitals (Table 1).Table 1Estimates of prevalence of kidney disease in 4 countries participating in H3Africa Kidney Disease Network and world development indicatorsCountryPopulation (million)Medical admissions for CKD per monthbMedical admissions per month were obtained from data collected during March and April 2015 in Korle-Bu Teaching Hospital, Ghana, and the average admission per month on the medical ward over a year in Kenyatta National Hospital, Nairobi, Kenya; and University College Hospital, Ibadan, Nigeria. The proportion of medical admissions for CKD per month was calculated with total number of CKD patients admitted by total admissions on the medical ward. The proportion of ESRD on dialysis per month was calculated from the total number of ESRD admissions within the calendar month who required dialysis and could afford it.ESRD treated with dialysis per monthbMedical admissions per month were obtained from data collected during March and April 2015 in Korle-Bu Teaching Hospital, Ghana, and the average admission per month on the medical ward over a year in Kenyatta National Hospital, Nairobi, Kenya; and University College Hospital, Ibadan, Nigeria. The proportion of medical admissions for CKD per month was calculated with total number of CKD patients admitted by total admissions on the medical ward. The proportion of ESRD on dialysis per month was calculated from the total number of ESRD admissions within the calendar month who required dialysis and could afford it.Estimated prevalence of CKDcThe prevalence data on CKD for each country was obtained from a systematic review by Stanifer et al.2Life expectancy at birth (yr)dAll data on development indicators are from worldbank.org (2014) except health expenditure per capita, which was obtained from http://www.who.int/countries (2013).GNI per capitadAll data on development indicators are from worldbank.org (2014) except health expenditure per capita, which was obtained from http://www.who.int/countries (2013).GDPdAll data on development indicators are from worldbank.org (2014) except health expenditure per capita, which was obtained from http://www.who.int/countries (2013).Health expenditure per capita (% GDP)dAll data on development indicators are from worldbank.org (2014) except health expenditure per capita, which was obtained from http://www.who.int/countries (2013).EthiopiaaNo hospital data available for Addis Ababa University in Ethiopia.97.0–––64$55055.63.8Ghana26.817.2% (42/244)62.1% (18/29)17.0%61$159038.65.4Kenya44.913.9% (25/180)60% (15/25)4%62$129060.94.5Nigeria177.515.2% (32/211)69.2% (18/26)17.6%52$2970568.53.5CKD, chronic kidney disease; ESRD, end-stage renal disease; GNI, gross national income in US dollars; GDP, gross domestic product in billions of US dollars.a No hospital data available for Addis Ababa University in Ethiopia.b Medical admissions per month were obtained from data collected during March and April 2015 in Korle-Bu Teaching Hospital, Ghana, and the average admission per month on the medical ward over a year in Kenyatta National Hospital, Nairobi, Kenya; and University College Hospital, Ibadan, Nigeria. The proportion of medical admissions for CKD per month was calculated with total number of CKD patients admitted by total admissions on the medical ward. The proportion of ESRD on dialysis per month was calculated from the total number of ESRD admissions within the calendar month who required dialysis and could afford it.c The prevalence data on CKD for each country was obtained from a systematic review by Stanifer et al.2Stanifer J.W. Jing B. Tolan S. et al.The epidemiology of chronic kidney disease in sub-Saharan Africa: a systematic review and meta-analysis.Lancet Glob Health. 2014; 2: e174-e181Abstract Full Text Full Text PDF PubMed Scopus (287) Google Scholard All data on development indicators are from worldbank.org (2014) except health expenditure per capita, which was obtained from http://www.who.int/countries (2013). Open table in a new tab CKD, chronic kidney disease; ESRD, end-stage renal disease; GNI, gross national income in US dollars; GDP, gross domestic product in billions of US dollars. Noncommunicable diseases, such as cardiovascular disease, diabetes, hypertension, and respiratory disease, are increasingly common in Africa and contribute substantially to morbidity and mortality.1Alleyne G. Binagwaho A. Haines A. et al.Embedding non-communicable diseases in the post-2015 development agenda.Lancet. 2013; 381: 566-574Abstract Full Text Full Text PDF PubMed Scopus (140) Google Scholar The burden of CKD is often forgotten, despite being a common complication of hypertension, diabetes, and HIV infection. CKD affects an estimated 13.9% (95% confidence interval 12.2–15.7) of adults in Sub-Saharan Africa, but precise estimates are lacking.2Stanifer J.W. Jing B. Tolan S. et al.The epidemiology of chronic kidney disease in sub-Saharan Africa: a systematic review and meta-analysis.Lancet Glob Health. 2014; 2: e174-e181Abstract Full Text Full Text PDF PubMed Scopus (287) Google Scholar If only 5% to 10% of patients with CKD reach ESRD, this will lead to a continent-wide health care burden, which cannot be handled by the current government health care systems. Kidney disease imposes incalculable human suffering and a catastrophic economic burden on the African continent in several respects. The age of onset of ESRD is approximately 20 years younger in African populations compared with that of developed Western countries (40–45 years vs. 63 years). Africa is also experiencing an accelerated increased incidence of hypertension and type 2 diabetes mellitus. Current dialysis treatment or transplant options in Sub-Saharan Africa are severely limited because of inadequate health care resources. Given the limited health expenditure across the continent, none of the 54 countries in Sub-Saharan Africa will be able to afford the medical costs associated with predialysis CKD care or renal replacement therapy.3Naicker S. Burden of end-stage renal disease in sub-Saharan Africa.Clin Nephrol. 2010; 74: S13-S16PubMed Google Scholar, 4Arogundade F.A. Barsoum R.S. CKD prevention in Sub-Saharan Africa: a call for governmental, nongovernmental, and community support.Am J Kidney Dis. 2008; 51: 515-523Abstract Full Text Full Text PDF PubMed Scopus (106) Google Scholar Even more out of reach is the annual cost of dialysis treatment, approximately US $10,000 to $20,000 per person each year in Sub-Saharan Africa. This means that most children and adults will only receive palliative care or limited dialysis treatments of 1 to 2 per week.5Ulasi II Ijoma C.K. The enormity of chronic kidney disease in Nigeria: the situation in a teaching hospital in South-East Nigeria.J Trop Med. 2010; 2010: 501957Crossref PubMed Scopus (102) Google Scholar These distressing facts elevate the urgent need for research to mitigate the incidence and severity of kidney disease for the Sub-Saharan African population. Scientific research in Africa has primarily focused on infectious diseases with recently emerging clinical trial networks and innovations in diagnostic testing. In contrast, noncommunicable diseases, specifically kidney diseases, have not been systematically screened for among general populations in Sub-Saharan countries. Although CKD and the nephrotic syndrome are reportedly common in Africa, little is known about the prevalence of disease or possible genetic contributions to these disorders. The recent discovery of a major genetic risk factor among African Americans highlights the potential genetic contribution to kidney disease especially among those of West African ancestry. Persons who are homozygous or compound heterozygous for the apolipoprotein L1 (APOL1) G1 or G2 alleles have about a 2 to 3 times increased risk of CKD compared with low-risk carriers across the spectrum of kidney diseases including glomerular disease, HIV-associated nephropathy, sickle cell disease, and nondiabetic CKD.6Parsa 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 (530) Google Scholar Persons harboring 1 or 2 copies of the APOL1 risk alleles are also protected against some species of trypanosomal infection (African sleeping sickness), suggesting that selection pressures from an infectious agent lead to a high prevalence of high-risk alleles. The story is more complicated, though, as the trypanosomal infections from Trypanosoma brucei gambiense species in West Africa are not protected by APOL1 high-risk carrier status, unlike Trypanosoma brucei rhodesiense, which is more prevalent in East Africa, where APOL1 high-risk GI and G2 haplotype prevalence is very low (Figure 1). It is unclear whether Sub-Saharan Africans share the same pernicious proclivity seen in African Americans for CKD based on genetic risk and the contribution of environmental factors such as infection, hypertension, diabetes, and cardiovascular disease. The Human Hereditary and Health in Africa (H3Africa) consortium was established in June 2010 to facilitate a contemporary research approach to the study of genomics and environmental determinants of common diseases with the goal of improving the health of Africans.7Rotimi C. Abayomi A. Abimiku A. et al.Research capacity. Enabling the genomic revolution in Africa.Science. 2014; 344: 1346-1348Crossref PubMed Scopus (252) Google Scholar The consortium, funded by both the U.S. National Institutes of Health and Wellcome Trust (United Kingdom), supports studies throughout Sub-Saharan Africa. The H3Africa Kidney Disease Research Network (H3AKDRN) is a collaborative research network involving 10 institutions in 5 African countries with an overall goal to increase the capacity for study of kidney disease, and specifically address genetic risk for kidney disease in Sub-Saharan Africa. Conducting studies in Africa is important because the populations harbor the greatest genetic diversity among mankind and could lead to novel genetic discoveries. Additionally, understanding selection across the continent will provide insights into possible migrations, infectious exposures, or admixture of populations. The design of the H3Africa Kidney Disease Study is a multinational case-control approach with approximately 4000 participants with a specified kidney disease diagnoses who meet the inclusion criteria to be enrolled over 36 months. Approximately 4000 control participants are also being recruited for cross-sectional assessment. Cases will be followed up longitudinally to understand risk factors for progression. The network consists of 2 coordinating centers in Accra, Ghana, and Michigan, USA, 9 clinical sites that enroll participants from university teaching hospitals located in 4 African countries (Ethiopia, Ghana, Kenya, and Nigeria), and 1 bioinformatics core (South Africa). The overall aims are (i) to perform comprehensive phenotyping of 8000 patients and controls and 50 families from 4 African countries (Ethiopia, Ghana, Kenya, and Nigeria); (ii) to train clinical research personnel and genomic investigators for Africa-based genomic research; (iii) to establish genomic research laboratories in West Africa using sustainable, low-capital intensity laboratory technologies; and (iv) to conduct international-level quality genetic and translational research projects in CKD with more detailed methods previously described.8Osafo C. Raji Y.R. Burke D. et al.Human Heredity and Health (H3) in Africa Kidney Disease Research Network: a focus on methods in sub-Saharan Africa.Clin J Am Soc Nephrol. 2015; 10: 2279-2287Crossref PubMed Scopus (35) Google Scholar We are conducting comprehensive baseline evaluation of clinical characteristics, risk factors, treatment, and outcomes of the kidney disease cohorts with specific clinically defined diseases such as hypertension, HIV, diabetes, sickle cell disease, and glomerular disorders. There are a few studies in Africa that have evaluated the genetic components of kidney disease occurrence, but none have studied the genetic components of kidney disease progression.9Ulasi I.I. Tzur S. Wasser W.G. et al.High population frequencies of APOL1 risk variants are associated with increased prevalence of non-diabetic chronic kidney disease in the Igbo people from south-eastern Nigeria.Nephron Clin Pract. 2013; 123: 123-128Crossref PubMed Scopus (0) Google Scholar The identification of the genetic determinants for kidney disease progression phenotype is of great significance in Sub-Saharan Africa because the onset of ESRD portends imminent demise for the majority who progress. Therefore, we will leverage the case-control study for future longitudinal cohort and translational studies of kidney disease. Genotyping will use a new array platform to be developed among the H3Africa Consortium to cover rare variants among those of African ancestry. Genetic analyses will include both unbiased (genome-wide) and hypothesis-driven approaches when studying each specific cause of kidney disease and CKD progression. We will also study the association of APOL1 with subtypes of kidney diseases using a case-control design and the association with CKD progression using a prospective cohort design. An essential component of the activities of the Kidney Disease Network is the development of scientific capacity within the continent to undertake further independent, large-scale research into genetic and environmental factors underlying the substantial kidney disease burden on the continent. Rapid advances and the decreasing costs of sequencing technology have resulted in growing engagement with human health genetics and genomics research on the African continent. Key areas for capacity development include development of research skills, laboratory facilities to enable genetic analysis, and bioinformatics capacity. Development of this infrastructure and expertise will empower African investigators to independently analyze and store clinical, genomic, and transcriptomic data within the continent. These aims are in keeping with the principles underpinning the H3Africa initiative.7Rotimi C. Abayomi A. Abimiku A. et al.Research capacity. Enabling the genomic revolution in Africa.Science. 2014; 344: 1346-1348Crossref PubMed Scopus (252) Google Scholar To date, 5 doctors have completed a 2-year training program on clinical research methods and biostatistics, 5 biomedical scientists are training in laboratory genomics, 1 MPhil student is training in biochemistry, 3 scientists are training in bioinformatics, and 2 research administrators are training in the National Institutes of Health program management. There are social and ethical implications for conducting a study of this magnitude across 4 countries in 9 different cities with many logistical, political, and cultural differences. The pressures on the economies in Sub-Saharan Africa limit patients’ ability to afford chronic dialysis care. Studying kidney disease addresses access to costly therapy such as dialysis or transplantation and highlights the burden of disease to legislative bodies in each country. Additionally, collaboration with local community leaders will also facilitate further change and education. The overall project has significant merit for training clinicians and scientists throughout Africa and advancing scientific questions needed to address the burden of chronic disease across West and East Africa. The international collaborative project provides the infrastructure, network, and support to continue to build and innovate in clinical research. The aim of the H3Africa Kidney Disease Research Network is to leave a footprint on the continent to study kidney disease with the ambitious goals of improving the care of patients and ultimately saving lives. All the authors declared no competing interests. We are grateful to the participants of the H3Africa Kidney Disease Research Network who have agreed to participate in the study and to the research teams that make this study possible. The H3Kidney Disease Research Network and investigators are funded under a cooperative agreement from the National Human Genome Research Institute (1U54HG006939-01). (http://h3africa.org/). This project is also in part funded with federal funds from the National Cancer Institute, National Institutes of Health, under contract HHSN26120080001E. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government. This research was supported in part by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research. We would like to thank the participants, families, and research staff for taking part in the study. Counterfeit and substandard drugs in Sub-Saharan Africa may pose a major hurdle to H3Africa’s initiative to study genetics of kidney disease progressionKidney InternationalVol. 91Issue 1PreviewThe Human Heredity and Health in Africa Kidney Disease Research Network aims to investigate the genetics of renal disease progression.1 Diabetes mellitus and hypertension have emerged as the commonest cause of end-stage renal disease in Sub-Saharan Africa.2 Additionally, obstructive uropathy (observed in malaria), HIV infection, and toxic nephropathies also contribute considerably. Therefore, apposite management of the above conditions is essential before mapping the phenotype of renal-disease progression to the genotype. Full-Text PDF Open Archive