Alternative creatinine-based GFR estimates in United States populations-similar performance, same gaps-is it time to move on?

This study evaluated performance of the European Kidney Function Consortium (EKFC) equation in a US cohort, comparing population-specific (EKFCPS) with race-free (EKFCRF) Q values (median normal creatinine). Both EKFCPS and EKFCRF equations showed less bias than the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) 2021 equation. The percentage of estimated glomerular filtration rate (GFR) within 30% of measured GFR was similar for CKD-EPI 2021 (79.2% [range, 78.5%-79.9%]) and EKFCRF (80.1% [range, 79.4%-80.7%]) equations but improved with the EKFCPS equation (81.1% [range, 80.5%-81.8%]), confirming utility of the EKFC equation in US populations.

Cystatin C should be routinely available for estimating kidney function.

PURPOSE OF REVIEW: In this report, we summarize why the availability of cystatin C is important across a variety of clinical scenarios, the recent literature on when, why and in whom cystatin C testing should be considered, and how nephrologists can take practical steps to incorporate cystatin C testing into their practice. RECENT FINDINGS: Large intra-individual discrepancies between estimated glomerular filtration rate by creatinine (eGFRcr) and estimated glomerular filtration rate by creatinine eGFRcys (known as eGFRdiff) are observed in at least 1 in 4 people. These differences are seen more commonly among more vulnerable individuals: older adults, females, non-White individuals and those living with multiple medical conditions. A large eGFRdiff, where eGFRcys is lower than eGFRcr, is associated with a plethora of adverse outcomes, including medication-associated adverse events, acute kidney injury, cardiovascular disease, kidney failure and all-cause mortality. Among studies that have measured GFR, eGFRcr-cys usually provides the most accurate estimation of kidney function compared to mGFR, including among participants with large discrepancies between eGFRcr and eGFRcys. SUMMARY: Cystatin C improves sensitivity and specificity of chronic kidney disease diagnosis, improves detection of harmful acute and chronic changes in kidney function, improves precision of treatment eligibility and safety, and may reduce healthcare inequalities. Better education, curiosity, and motivation among nephrologists could substantially improve the availability and utilization of cystatin C.

Proteomic insights into the pathophysiology of hypertension-associated albuminuria: Pilot study in a South African cohort.

BACKGROUND: Hypertension is an important public health priority with a high prevalence in Africa. It is also an independent risk factor for kidney outcomes. We aimed to identify potential proteins and pathways involved in hypertension-associated albuminuria by assessing urinary proteomic profiles in black South African participants with combined hypertension and albuminuria compared to those who have neither condition. METHODS: The study included 24 South African cases with both hypertension and albuminuria and 49 control participants who had neither condition. Protein was extracted from urine samples and analysed using ultra-high-performance liquid chromatography coupled with mass spectrometry. Data were generated using data-independent acquisition (DIA) and processed using Spectronaut™ 15. Statistical and functional data annotation were performed on Perseus and Cytoscape to identify and annotate differentially abundant proteins. Machine learning was applied to the dataset using the OmicLearn platform. RESULTS: Overall, a mean of 1,225 and 915 proteins were quantified in the control and case groups, respectively. Three hundred and thirty-two differentially abundant proteins were constructed into a network. Pathways associated with these differentially abundant proteins included the immune system (q-value [false discovery rate] = 1.4 × 10- 45), innate immune system (q = 1.1 × 10- 32), extracellular matrix (ECM) organisation (q = 0.03) and activation of matrix metalloproteinases (q = 0.04). Proteins with high disease scores (76-100% confidence) for both hypertension and chronic kidney disease included angiotensinogen (AGT), albumin (ALB), apolipoprotein L1 (APOL1), and uromodulin (UMOD). A machine learning approach was able to identify a set of 20 proteins, differentiating between cases and controls. CONCLUSIONS: The urinary proteomic data combined with the machine learning approach was able to classify disease status and identify proteins and pathways associated with hypertension-associated albuminuria.

The African Liver Tissue Biorepository Consortium: Capacitating Population-Appropriate Drug Metabolism, Pharmacokinetics, and Pharmacogenetics Research in Drug Discovery and Development.

Pharmaceutical companies subject all new molecular entities to a series of in vitro metabolic characterizations that guide the selection and/or design of compounds predicted to have favorable pharmacokinetic properties in humans. Current drug metabolism research is based on liver tissue predominantly obtained from people of European origin, with limited access to tissue from people of African origin. Given the interindividual and interpopulation genomic variability in genes encoding drug-metabolizing enzymes, efficacy and safety of some drugs are poorly predicted for African populations. To address this gap, we have established the first comprehensive liver tissue biorepository inclusive of people of African origin. The African Liver Tissue Biorepository Consortium currently includes three institutions in South Africa and one in Zimbabwe, with plans to expand to other African countries. The program has collected 67 liver samples as of July 2023. DNA from the donors was genotyped for 120 variants in 46 pharmacogenes and revealed variants that are uniquely found in African populations, including the low-activity, African-specific CYP2C9*5 and *8 variants relevant to the metabolism of diclofenac. Larger liver tissue samples were used to isolate primary human hepatocytes. Viability of the hepatocytes and microsomal fractions was demonstrated by the activity of selected cytochrome P450s. This resource will be used to ensure the safety and efficacy of existing and new drugs in African populations. This will be done by characterizing compounds for properties such as drug clearance, metabolite and enzyme identification, and drug-drug and drug-gene interactions. SIGNIFICANCE STATEMENT: Standard optimization of the drug metabolism of new molecular entities in the pharmaceutical industry uses subcellular fractions such as microsomes and isolated primary hepatocytes, being done mainly with tissue from donors of European origin. Pharmacogenetics research has shown that variants in genes coding for drug-metabolizing enzymes have interindividual and interpopulation differences. We established an African liver tissue biorepository that will be useful in ensuring drug discovery and development research takes into account drug responses in people of African origin.

Disparities in the Prevalence of Osteoporosis and Osteopenia in Men and Women Living in Sub-Saharan Africa, the UK, and the USA.

PURPOSE: To review the rising prevalence of osteopenia and osteoporosis in sub-Saharan Africa and the challenges this poses to governments and healthcare services. Using existing studies, we compare the prevalence of osteopenia and osteoporosis in men and women from sub-Saharan Africa to US and UK cohorts. Context-specific disparities in healthcare are discussed particularly the challenges in diagnosis and treatment of osteoporosis. RECENT FINDINGS: There are few epidemiological data describing the burden of osteoporosis in sub-Saharan Africa. In the studies and cohorts presented here, osteoporosis prevalence varies by sex, country and area of residence, but is generally higher in African populations, than has previously been appreciated. Risk factors contributing to poorer bone health include HIV, malnutrition and "inflammaging." Reprioritization towards care of ageing populations is urgently required. Equitable access to implementable preventative strategies, diagnostic services, treatments and pathways of care for bone health (for example embedded within HIV services) need now to be recognized and addressed by policy makers.

Kidney dysfunction: prevalence and associated risk factors in a community-based study from the North West Province of South Africa.

BACKGROUND: Globally, the World Health Organization ranks chronic kidney disease (CKD) as one of the top 10 causes of mortality. In South Africa, where noncommunicable diseases have become leading causes of mortality, the true population prevalence of CKD is unknown and associated risk factors remain understudied. This study aimed to describe the prevalence of kidney dysfunction and associated risk factors in a community from the North West province of South Africa. METHODS: This cross-sectional study included 1999 participants older than 30 years. Kidney dysfunction was defined as (i) estimated glomerular filtration rate (eGFR) < 90 ml/min/1.73m2, or (ii) urine albuminuria-to-creatinine ratio (uACR) ≥ 3.0 mg/mmol, or a combination (i and ii). Risk factors included age, sex, urban/rural locality, body mass index (BMI), blood pressure (BP), lipid profile, haemoglobin A1c (HbA1C), C-reactive protein (CRP), gamma-glutamyl transferase (GGT), tobacco use, and HIV status. RESULTS: Mean age of participants was 48 (42;56) years, and 655/1999 (33%) had eGFR < 90 ml/min/1.73m2 and/or uACR ≥ 3.0 mg/mmol. Compared to those with normal kidney function, participants with eGFR < 90 ml/min/1.73m2 and/or uACR ≥ 3.0 mg/mmol were older, female, had higher measures of adiposity, systolic, diastolic, and mean arterial blood pressure, serum lipids and C-reactive protein (CRP) (all p ≤ 0.024). In multiple regression analyses eGFR was associated with systolic BP (ß = 0.11) and HIV infection (ß = -0.09), and albuminuria was associated with elevated CRP (ß = 0.12) and HIV infection (ß = 0.11) (all p < 0.026). In both groups (individuals with and without kidney dysfunction respectively), eGFR was associated with age (ß = -0.29, ß = -0.49), male sex (ß = 0.35, ß = 0.28), BMI (ß = -0.12, ß = -0.09), low-density/high-density lipoprotein cholesterol ratio (ß = -0.17, ß = -0.09) and CRP (ß = 0.10, ß = 0.09) (all p < 0.005); and uACR was associated with female sex (ß = 0.10, ß = -0.14), urban locality (ß = -0.11, ß = -0.08), BMI (ß = -0.11, ß-0.11), and systolic BP (ß = 0.27, ß = 0.14) (all p < 0.017). CONCLUSION: In this study from the North West province, South Africa, eGFR < 90 ml/min/1.73m2 and/or uACR ≥ 3.0 mg/mmol was prevalent and associated with modifiable risk factors. The findings may inform screening strategies for kidney disease prevention, focusing on women, obesity, blood pressure control, dyslipidaemia, identifying and treating inflammation, and HIV diagnosis and treatment.

Evaluating chronic kidney disease in rural South Africa: comparing estimated glomerular filtration rate using point-of-care creatinine to iohexol measured GFR.

OBJECTIVES: The prevalence of chronic kidney disease is rising rapidly in low- and middle-income countries. Serum creatinine and estimation of glomerular filtration rate (GFR) are critical diagnostic tools, yet access to centralised laboratory services remains limited in primary care resource-limited settings. The aim of this study was to evaluate point-of-care (POC) technologies for serum creatinine measurement and to compare their performance to a gold standard measurement using iohexol measured GFR (mGFR). METHODS: POC creatinine was measured using iSTAT® and StatSensor® devices in capillary and venous whole blood, and laboratory creatinine was measured using the compensated kinetic Jaffe method in 670 participants from a rural area in South Africa. GFR estimating equations Chronic Kidney Disease Epidemiology Collaboration and Modification of Diet in Renal Disease (CKD-EPI and MDRD) for POC and laboratory creatinine were compared to iohexol mGFR. RESULTS: Calculated GFR for laboratory and POC creatinine measurements overestimated GFR (positive bias of 1.9-34.1 mL/min/1.73 m2). However, all POC devices had less positive bias than the laboratory Jaffe method (1.9-14.7 vs. 34.1 for MDRD, and 8.4-19.9 vs. 28.6 for CKD-EPI). Accuracy within 30% of mGFR ranged from 0.56 to 0.72 for POC devices and from 0.36 to 0.43 for the laboratory Jaffe method. POC devices showed wider imprecision with coefficients of variation ranging from 4.6 to 10.2% compared to 3.5% for the laboratory Jaffe method. CONCLUSIONS: POC estimated GFR (eGFR) showed improved performance over laboratory Jaffe eGFR, however POC devices suffered from imprecision and large bias. The laboratory Jaffe method performed poorly, highlighting the need for laboratories to move to enzymatic methods to measure creatinine.

Human Leukocyte Antigen Typing with Sequence Specific Oligonucleotides for Renal Transplantation in South Africa.

BACKGROUND: Kidney transplants are the only curative therapeutic intervention for end-stage kidney disease (ESKD). The current organ shortage in South Africa makes recipient risk assessments and effective laboratory workup crucial to assist in better organ assignment and increase the likelihood of better transplant outcomes. HLA typing is a step in the pre-transplant workup for performing virtual crossmatches and matching donors and recipients. Sequence Specific Oligonucleotide (SSO) PCR is a relatively fast and inexpensive method for determining genotypic HLA types at a 2- to 4-digit resolution. This study aimed to validate the SSO technique for achieving a 4-digit resolution when determining HLA types to improve virtual crossmatches. METHODS: DNA was extracted from 33 samples. After PCR amplification, the samples were hybridized to oligonu-cleotide probes and the HLA A, B, C, DRB1, DQA1/B1, DRB3, DRB4, DRB5, and DPA1/B1 types were identified. These results were compared to results from external laboratories. RESULTS: The kappa coefficient calculated for the low-resolution comparison suggested a perfect agreement between the two results (p = 0.32). CONCLUSIONS: SSO was successfully validated for HLA typing in the Johannesburg kidney transplant setting. This will improve the specificity of virtual crossmatches on an automated system by matching the resolution of the HLA typing and the HLA antibody testing. Additionally, common HLA types were identified in this donor cohort. Future research into these common HLA types and haplotypes in a South African population will inform the feasibility of reintroducing HLA matching into the pretransplant workup.

Diagnostic accuracy of semiquantitative point of care urine albumin to creatinine ratio and urine dipstick analysis in a primary care resource limited setting in South Africa.

BACKGROUND: The prevalence of chronic kidney disease (CKD) is predicted to rise over the next few decades. In resource-limited settings access to central laboratory services is limited. Point-of-care (POC) urine dipstick testing offers the potential to detect markers of kidney damage (albuminuria) as well as markers of other disease processes. We evaluated the diagnostic accuracy of the semi-quantitative albumin-creatinine ratio (ACR) Sysmex UC-1000 POC urine dipstick system as well as the extent of other abnormal dipstick findings in urine. METHODS: 700 participants from a rural area in South Africa were screened for albuminuria. A spot urine sample was used to measure POC and central laboratory ACR. We determined the sensitivity, specificity, positive predictive value and negative predictive value of the POC ACR, and recorded dipstick parameters. RESULTS: The prevalence of albuminuria was 11.6% (95%CI; 9.3-14.2). Those with albuminuria had higher mean diastolic (82 vs 79 mmHg, p = 0.019) and systolic (133 vs 128 mmHg, p = 0.002) blood pressures and a higher proportion of diabetes mellitus (17.6 vs 4.9%, p < 0.001). The sensitivity of the POC ACR system was 0.79, specificity 0.84, positive predictive value 0.39 and negative predictive value 0.97. The sensitivity improved to 0.80, 0.85, 0.85 and 0.89 in those with elevated blood pressure, diabetes mellitus, HIV positive status, and those 65 years and older, respectively. Abnormalities other than albuminuria were detected in 240 (34.3%) of the samples; 88 (12.6%) were positive for haematuria, 113 (16.1%) for leucocytes, 66 (9.4%) for nitrites and 27 (3.9%) for glycosuria. CONCLUSION: Our study shows that POC ACR has good negative predictive value and could be used to rule out albuminuria when screening for CKD. Additionally, a high proportion of participants had other urine abnormalities detected with dipsticks which may reflect kidney disease or co-morbid untreated genitourinary pathology such as urinary tract infections or endemic schistosomiasis with important implications for CKD.

Contemporary outcomes of the pediatric kidney transplant program in Johannesburg, South Africa, between 2004 and 2017: Better or not-And which way forward?

BACKGROUND: Outcomes for the pediatric kidney transplant program in Johannesburg (1984-2003) were found to be suboptimal. In this study, we compared (a) early (era 1:1984-2003) to contemporary (era 2:2004-2017) outcomes and (b) compared contemporary outcomes between the public and private sector hospitals in our program. METHODS: We conducted a retrospective record review of all pediatric (<18 years) KA transplants performed in our kidney transplant program at Charlotte Maxeke Johannesburg Academic Hospital (CMJAH) and Wits Donald Gordon Medical Centre (WDGMC) from 2004 to 2017. We collected the following data per site: number of recipients, transplants performed, mean follow-up time, and grafts lost; per recipient: age at time of transplant, sex, self-reported population group; transplant history; donor type; etiology of ESKD; recipient and graft survival. Outcomes for era 1 were based on data published on our kidney transplant program, based at CMJAH. RESULTS: At CMJAH (public sector), there was no improvement in recipient and graft survival over time. In the contemporary analysis, 1-, 5-, and 10-year recipient survival, as % (95% CI) was 93 (84-97); 76 (64-84); 59 (44-70) for CMJAH, and 98 (90-99); 95 (86-99); 82 (54-94) for WDGMC (private sector). Similarly, 1-, 5- and 10-year graft survival was 75 (63-84); 55 (42-66); 36 (24-49) for CMJAH, and 96 (87-99); 84 (73-91); 64 (48-76) at WDGMC. CONCLUSION: Contemporary outcomes for the pediatric kidney transplant program at WDGMC are comparable to outcomes achieved in middle- and high-income settings. However, outcomes at CMJAH are suboptimal, reflecting numerous health system, infrastructural and human resource challenges.

Minding the gap-Providing quality transplant care for South African children with acute liver failure.

Pediatric ALF is rare but life-threatening and may require urgent transplantation. In low and middle-income countries, access to transplantation is limited, deceased organ donation rates are low, and data on outcomes scarce. The Wits Donald Gordon Medical Centre, in Johannesburg, is one of only two centers in South Africa that perform pediatric liver transplant. We describe the etiology, clinical presentation, and outcomes of children undergoing liver transplant for ALF at our center over the past 14 years. We performed a retrospective chart review of all children undergoing liver transplantation for ALF from November 2005 to September 2019. Recipient data included demographics, clinical and biochemical characteristics pretransplant, post-operative complications, and survival. We conducted descriptive data analysis and used the Kaplan-Meier method for survival analysis. We performed 182 primary pediatric liver transplants. Of these, 27 (15%) were for ALF, mostly from acute hepatitis A infection (11/27;41%). Just over half of the grafts were from living donors (15/27;56%), and five grafts (5/27;19%) were ABO-incompatible. The most frequent post-transplant complications were biliary leaks (9/27;33%). There were two cases of hepatic artery thrombosis (2/27;7%), one of whom required re-transplantation. Unadjusted patient and graft survival at one and 3 years were the same, at 81% (95% CI 61%-92%) and 78% (95% CI 57%-89%), respectively. At WDGMC, our outcomes for children who undergo liver transplantation for ALF are excellent. We found workable solutions that effectively addressed our pervasive organ shortages without compromising patient outcomes.

Blood stream infections in children in the first year after liver transplantation at Wits Donald Gordon Medical Centre, South Africa.

Children who undergo liver transplantation and subsequently develop BSI are at risk for adverse outcomes. Research from high-income settings contrasts the dearth of information from transplant centers in low- and middle-income countries, such as South Africa. Therefore, this study from Johannesburg aimed to describe the clinical and demographic profile of children undergoing liver transplantation, and determine the incidence and pattern of BSI and associated risk factors for BSI during the first year after liver transplant. Pediatric liver transplants performed from 2005 to 2014 were reviewed. Descriptive analyses summarized donor, recipient, and post-transplant infection characteristics. Association between BSI and sex, cause of liver failure, age, nutritional status, PELD/MELD score, graft type, biliary complications, and acute rejection was determined by Fisher's exact test; and association with length of stay by Cox proportional hazards regression analysis. Survival estimates were determined by the Kaplan-Meier method. Sixty-five children received one transplant and four had repeat transplants, totaling 69 procedures. Twenty-nine BSI occurred in 19/69 (28%) procedures, mostly due to gram-negative organisms, namely Klebsiella species. Risk for BSI was independently associated with biliary atresia (44% BSI in BA compared to 17% in non-BA transplants; P = .014) and post-operative biliary complications (55% BSI in transplants with biliary complications compared to 15% in those without; P = .0013). One-year recipient and graft survival was 78% (CI 67%-86%) and 77% (CI 65%-85%), respectively. In Johannesburg, incident BSI, mostly from gram-negative bacteria, were associated with biliary atresia and post-operative biliary complications in children undergoing liver transplantation.

How to estimate glomerular filtration rate in sub-Saharan Africa: design and methods of the African Research into Kidney Diseases (ARK) study.

BACKGROUND: Chronic kidney disease (CKD) is a substantial cause of morbidity and mortality worldwide with disproportionate effects in sub-Saharan Africa (SSA). The optimal methods to estimate glomerular filtration rate (GFR) and therefore to determine the presence of CKD in SSA are uncertain. We plan to measure iohexol excretion to accurately determine GFR in Malawi, South Africa and Uganda. We will then assess the performance of existing equations to estimate GFR and determine whether a modified equation can better improve estimation of GFR in sub-Saharan Africa. METHODS: The African Research on Kidney Disease (ARK) study is a three-country study embedded within existing cohorts. We seek to enrol 3000 adults > 18 years based on baseline serum creatinine. Study procedures include questionnaires on socio-demographics and established risk factors for kidney disease along with anthropometry, body composition, blood pressure, blood chemistry and urine microscopy and albuminuria. We will measure GFR (mGFR) by plasma clearance of iohexol at 120, 180 and 240 min. We will compare eGFR determined by established equations with mGFR using Bland-Altman plots. We will use regression methods to estimate GFR and compare the newly derived model with existing equations. DISCUSSION: Through the ARK study, we aim to establish the optimal approach to estimate GFR in SSA. The study has the advantage of drawing participants from three countries, which will increase the applicability of the findings across the region. It is also embedded within established cohorts that have longitudinal information and serial measures that can be used to characterize kidney disease over a period of time. This will help to overcome the limitations of previous research, including small numbers, selected population sub-groups, and lack of data on proteinuria. The ARK collaboration provides an opportunity for close working partnerships across different centres, using standardized protocols and measurements, and shared bio-repositories. We plan to build on the collaboration for this study for future work on kidney disease in sub-Saharan Africa, and welcome additional partners from across the continent.

HIV and Solid Organ Transplantation: Where Are we Now.

PURPOSE OF REVIEW: We review the international evolution of HIV and solid organ transplantation over 30 years. We emphasise recent developments in solid organ transplantation from HIV-infected to HIV-uninfected individuals, and their implications. RECENT FINDINGS: In 2017, Johannesburg, South Africa, a life-saving partial liver transplant from an HIV-infected mother to her HIV-uninfected child was performed. This procedure laid the foundation not only for consideration of HIV-infected individuals as living donors, but also for the possibility that HIV-uninfected individuals could receive organs from HIV-infected donors. Recent advances in this field are inclusion of HIV-infected individuals as living organ donors and the possibility of offering HIV-uninfected individuals organs from HIV-infected donors who are well-controlled on combination antiretroviral therapy (cART). The large number of HIV-infected individuals on cART is an unutilised source of otherwise eligible living organ donors. HIV-positive-to-HIV-negative organ transplantation has become a reality, providing possible new therapeutic options to address extreme organ shortages.

Needs must: living donor liver transplantation from an HIV-positive mother to her HIV-negative child in Johannesburg, South Africa.

The world's first living donor liver transplant from an HIV-positive mother to her HIV-negative child, performed by our team in Johannesburg, South Africa (SA) in 2017, was necessitated by disease profile and health system challenges. In our country, we have a major shortage of donor organs, which compels us to consider innovative solutions to save lives. Simultaneously, the transition of the HIV pandemic, from a death sentence to a chronic illness with excellent survival on treatment required us to rethink our policies regarding HIV infection and living donor liver transplantation . Although HIV infection in the donor is internationally considered an absolute contraindication for transplant to an HIV-negative recipient, there have been a very small number of unintentional transplants from HIV-positive deceased donors to HIV-negative recipients. These transplant recipients do well on antiretroviral medication and their graft survival is not compromised. We have had a number of HIV-positive parents in our setting express a desire to be living liver donors for their critically ill children. Declining these parents as living donors has become increasingly unjustifiable given the very small deceased donor pool in SA; and because many of these parents are virally suppressed and would otherwise fulfil our eligibility criteria as living donors. This paper discusses the evolution of HIV and transplantation in SA, highlights some of the primary ethical considerations for us when embarking on this case and considers the new ethical issues that have arisen since we undertook this transplant.

Early survival on maintenance dialysis therapy in South Africa: evaluation of a pre-dialysis education programme.

BACKGROUND: Mortality in the first year of maintenance dialysis is higher than in subsequent years and, within this first year, the risk of death is highest in the first 90 days. Some studies have shown that pre-dialysis education reduces early mortality. Limited data have been published from South Africa regarding early mortality after commencement of maintenance dialysis treatment and the effect of pre-dialysis intervention programmes on these outcomes. The aim of this study was to assess the impact of a pre-dialysis intervention programme on 90- and 365-day outcomes and to determine incident mortality in a population of chronic haemo- and peritoneal dialysis patients in South Africa. METHODS: This study used a retrospective cohort of 269 patients who received a pre-dialysis intervention [Healthy Start (HS)] and a matched group of 269 patients who did not receive the intervention. Both groups subsequently commenced maintenance haemo-/peritoneal dialysis with National Renal Care (NRC). A between-group comparative analysis was conducted to determine whether there were any differences in morbidity and mortality at 90 and 365 days of chronic dialysis treatment. Survival curves for the first 365 days of treatment were calculated using the Kaplan-Meier estimation for the entire population and by age group, gender, race, diabetes, dialysis modality and presence of a central venous catheter (CVC) at start of dialysis treatment. RESULTS: There were no significant differences between the HS and non-HS groups at 90 and 365 days when comparing mortality, cause of death, hospital admission rates and length of stay. Data were then pooled and a Kaplan-Meier analysis showed 90- and 365-day survival of 96.7 and 85.6%, respectively. The peak mortality occurred at 150 days of dialysis treatment, but this was not significant. Older age and the presence of a CVC were associated with an increased risk of death in the first year of treatment. CONCLUSION: The HS Programme made no difference to mortality in the first year of chronic dialysis. Early survival for both HS and non-HS groups was excellent when compared to international data. Increasing age and the presence of a CVC at the start of chronic dialysis were the two factors that impacted significantly on 1-year survival.

Genetic Association and Transferability for Urinary Albumin-Creatinine Ratio as a Marker of Kidney Disease in four Sub-Saharan African Populations and non-continental Individuals of African Ancestry.

BACKGROUND: Genome-wide association studies (GWAS) have predominantly focused on populations of European and Asian ancestry, limiting our understanding of genetic factors influencing kidney disease in Sub-Saharan African (SSA) populations. This study presents the largest GWAS for urinary albumin-to-creatinine ratio (UACR) in SSA individuals, including 8,970 participants living in different African regions and an additional 9,705 non-resident individuals of African ancestry from the UK Biobank and African American cohorts. METHODS: Urine biomarkers and genotype data were obtained from two SSA cohorts (AWI-Gen and ARK), and two non-resident African-ancestry studies (UK Biobank and CKD-Gen Consortium). Association testing and meta-analyses were conducted, with subsequent fine-mapping, conditional analyses, and replication studies. Polygenic scores (PGS) were assessed for transferability across populations. RESULTS: Two genome-wide significant (P<5x10-8) UACR-associated loci were identified, one in the BMP6 region on chromosome 6, in the meta-analysis of resident African individuals, and another in the HBB region on chromosome 11 in the meta-analysis of non-resident SSA individuals, as well as the combined meta-analysis of all studies. Replication of previous significant results confirmed associations in known UACR-associated regions, including THB53, GATM, and ARL15. PGS estimated using previous studies from European ancestry, African ancestry, and multi-ancestry cohorts exhibited limited transferability of PGS across populations, with less than 1% of observed variance explained. CONCLUSION: This study contributes novel insights into the genetic architecture of kidney disease in SSA populations, emphasizing the need for conducting genetic research in diverse cohorts. The identified loci provide a foundation for future investigations into the genetic susceptibility to chronic kidney disease in underrepresented African populations Additionally, there is a need to develop integrated scores using multi-omics data and risk factors specific to the African context to improve the accuracy of predicting disease outcomes. METHODS: Urine biomarkers and genotype data were obtained from two SSA cohorts (AWI-Gen and ARK), and two non-resident African-ancestry studies (UK Biobank and CKD-Gen Consortium). Association testing and meta-analyses were conducted, with subsequent fine-mapping, conditional analyses, and replication studies. Polygenic scores (PGS) were assessed for transferability across populations. RESULTS: Two genome-wide significant (P<5x10-8) UACR-associated loci were identified, one in the BMP6 region on chromosome 6, in the meta-analysis of resident African individuals, and another in the HBB region on chromosome 11 in the meta-analysis of non-resident SSA individuals, as well as the combined meta-analysis of all studies. Replication of previous significant results confirmed associations in known UACR-associated regions, including THB53, GATM, and ARL15. PGS estimated using previous studies from European ancestry, African ancestry, and multi-ancestry cohorts exhibited limited transferability of PGS across populations, with less than 1% of observed variance explained. CONCLUSION: This study contributes novel insights into the genetic architecture of kidney function in SSA populations, emphasizing the need for conducting genetic research in diverse cohorts. The identified loci provide a foundation for future investigations into the genetic susceptibility to chronic kidney disease in underrepresented African populations.

Genetic association and transferability for urinary albumin-creatinine ratio as a marker of kidney disease in four Sub-Saharan African populations and non-continental individuals of African ancestry.

Background: Genome-wide association studies (GWAS) have predominantly focused on populations of European and Asian ancestry, limiting our understanding of genetic factors influencing kidney disease in Sub-Saharan African (SSA) populations. This study presents the largest GWAS for urinary albumin-to-creatinine ratio (UACR) in SSA individuals, including 8,970 participants living in different African regions and an additional 9,705 non-resident individuals of African ancestry from the UK Biobank and African American cohorts. Methods: Urine biomarkers and genotype data were obtained from two SSA cohorts (AWI-Gen and ARK), and two non-resident African-ancestry studies (UK Biobank and CKD-Gen Consortium). Association testing and meta-analyses were conducted, with subsequent fine-mapping, conditional analyses, and replication studies. Polygenic scores (PGS) were assessed for transferability across populations. Results: Two genome-wide significant (P < 5 × 10-8) UACR-associated loci were identified, one in the BMP6 region on chromosome 6, in the meta-analysis of resident African individuals, and another in the HBB region on chromosome 11 in the meta-analysis of non-resident SSA individuals, as well as the combined meta-analysis of all studies. Replication of previous significant results confirmed associations in known UACR-associated regions, including THB53, GATM, and ARL15. PGS estimated using previous studies from European ancestry, African ancestry, and multi-ancestry cohorts exhibited limited transferability of PGS across populations, with less than 1% of observed variance explained. Conclusion: This study contributes novel insights into the genetic architecture of kidney disease in SSA populations, emphasizing the need for conducting genetic research in diverse cohorts. The identified loci provide a foundation for future investigations into the genetic susceptibility to chronic kidney disease in underrepresented African populations Additionally, there is a need to develop integrated scores using multi-omics data and risk factors specific to the African context to improve the accuracy of predicting disease outcomes.

Blood pressure increases are associated with weight gain and not antiretroviral regimen or kidney function: a secondary analysis from the ADVANCE trial in South Africa.

INTRODUCTION: Recent evidence has raised questions about whether newer HIV treatment regimens, including dolutegravir (DTG) and tenofovir alafenamide (TAF), are associated with increases in blood pressure (BP). METHODS: We assessed changes in BP by treatment regimen and evaluated the relative contribution of kidney function and weight gain to these changes among participants in the ADVANCE phase-3 trial clinical trial in South Africa (study dates: January 2017-February 2022). Our primary outcome of interest was a change in systolic BP (SBP) at 96 and 192 weeks, among those not receiving antihypertensive medication. The secondary outcome was treatment-emergent hypertension at these same time points, defined as BP ≥140/90 mmHg on two occasions, or initiation of antihypertensive medication after week 4 among individuals without hypertension at enrolment. We used linear regression to evaluate the relationship between change in estimated glomerular filtration rate (eGFR) and change in SBP; and Poisson regression to evaluate the relationship between change in eGFR and treatment-emergent hypertension at each time point. All models were adjusted for age, sex, treatment group and change in body mass index (BMI). RESULTS: Over 96 weeks, the average changes in SBP were 1.7 mmHg (95% CI: 0.0-3.4), -0.5 mmHg (95% CI: -2.2 to 1.7) and -2.1 mmHg (95% CI: -3.8 to 0.4) in the TAF/emtricitabine (FTC)/DTG, tenofovir disoproxil fumarate (TDF)/FTC/DTG and TDF/FTC/efavirenz (EFV) groups, respectively. This difference was significant for the TAF/FTC/DTG compared to the TDF/FTC/EFV group (p = 0.002). Over 96 weeks, 18.2% (95% CI: 13.4-22.9), 15.4% (95% CI: 11.0-19.9) and 13.3% (95% CI: 8.9-17.6) of participants developed treatment-emergent hypertension, respectively. In adjusted models, there was no significant relationship between change in eGFR and either outcome. Change in BMI was significantly associated with an increase in SBP, while age was associated with an increased risk of treatment-emergent hypertension. Adjustment for BMI also mitigated the unadjusted relationship between HIV treatment regimen and SBP where present. CONCLUSIONS: In the ADVANCE cohort, weight gain and age accounted for increases in BP and risk of treatment-emergent hypertension. HIV treatment programmes may need to integrate the management of obesity and hypertension into routine care. CLINICAL TRIAL NUMBER: NCT03122262.