The prevalence of chronic kidney disease in South Africa - limitations of studies comparing prevalence with sub-Saharan Africa, Africa, and globally.

BACKGROUND: Chronic kidney disease (CKD) is a globally significant non-communicable disorder. CKD prevalence varies between countries and within a country. We compared the prevalence rates of CKD in South Africa with sub-Saharan Africa, Africa, and globally. METHODS: We registered a systematic review with the International Prospective Register of Systematic Reviews for prevalence studies reporting CKD stages III-V from 2013 to 2021. The analysis sought to explain any significant differences in prevalence rates. The R statistical package was used for data analysis. Comparisons included measures of effect size due to the large sample sizes analysed. We also compared sex differences in prevalence rates, common aetiologies, and type of study methodologies employed. RESULTS: Eight studies were analysed, with two from each region. The matched prevalence rates of CKD between the various regions and South Africa showed significant differences, except for one comparison between South Africa and an African study [p = 0.09 (95% CI - 0.04-0.01)]. Both sub-Saharan African studies had a higher prevalence than South Africa. One study in Africa had a higher prevalence, while the other had a lower prevalence, whilst one Global study had a higher prevalence, and the other had a lower prevalence compared to South Africa. The statistical differences analysed using the Cramer's V test were substantially less than 0.1. Thus, differences in comparisons were largely due to differences in sample sizes rather than actual differences. CONCLUSION: Variable prevalence rates between regions included disparities in sample size, definitions of CKD, lack of chronicity testing and heterogeneous laboratory estimations of eGFR. Improved consistency and enhanced methods for diagnosing and comparing CKD prevalence are essential.

Causal and putative pathogenic mutations identified in 39% of children with primary steroid-resistant nephrotic syndrome in South Africa.

There is a paucity of data identifying genetic mutations that account for the high rate of steroid-resistant nephrotic syndrome (SRNS) in a South African paediatric population. The aim was to identify causal mutations in genes implicated in SRNS within a South African paediatric population. We enrolled 118 children with primary nephrotic syndrome (NS), 70 SRNS and 48 steroid-sensitive NS. All children with SRNS underwent kidney biopsy. We first genotyped the NPHS2 gene for the p.V260E variant in all NS cases (n = 118) and controls (n = 219). To further identify additional variants, we performed whole-exome sequencing and interrogated ten genes (NPHS1, NPHS2, WT1, LAMB2, ACTN4, TRPC6, INF2, CD2AP, PLCE1, MYO1E) implicated in SRNS with histopathological features of focal segmental glomerulosclerosis (FSGS) in 56 SRNS cases and 29 controls; we also performed exome sequencing on two patients carrying the NPHS2 p.V260E mutation as positive controls. The overall detection rate of causal and putative pathogenic mutations in children with SRNS was 27/70 (39%): 15 (21%) carried the NPHS2 p.V260E causal mutation in the homozygous state, and 12 (17%) SRNS cases carried a putative pathogenic mutation in the heterozygous state in genes (INF2 (n = 8), CD2AP (n = 3) and TRPC6 (n = 1)) known to have autosomal dominant inheritance mode. NPHS2 p.V260E homozygosity was specifically associated with biopsy-proven FSGS, accounting for 24% of children of Black ethnicity (15 of 63) with steroid-resistant FSGS. No causal or putative pathogenic mutations were identified in NPHS1, WT1, LAMB2, PLCE1, MYO1E and ACTN4. We report four novel variants in INF2, PLCE1, ACTN4 and TRPC6.   Conclusion: We report putative missense variants predicted to be pathogenic in INF2, CD2AP and TRPC6 among steroid-resistant-FSGS children. However, the NPHS2 p.V260E mutation is a prevalent cause of steroid-resistant FSGS among Black South African children occurring in 24% of children with SRNS. Screening all Black African children presenting with NS for NPHS2 p.V260E will provide a precision diagnosis of steroid-resistant FSGS and inform clinical management. What is Known: • Limited data is available on the genetic disparity of SNRS in a South African paediatric setting. • The high rate of steroid resistance in Black South African children with FSGS compared to other racial groups is partially explained by the founder variant NPHS2 p.V260E. What is New: • We report putative missense variants predicted to be pathogenic in INF2, CD2AP and TRPC6 among steroid-resistant FSGS children. • NPHS2 p.V260E mutation remains a prevalent cause of steroid-resistant FSGS among Black South African children, demonstrating precision diagnostic utility.

Gene polymorphisms within regions of complement component C1q in HIV associated preeclampsia.

OBJECTIVE: This study investigates the association of C1q gene (rs292001 and rs294183) polymorphisms in HIV infected and uninfected preeclamptic women of African ancestry. MATERIALS AND METHODS: The study population consisted of 325 pregnant women of African ancestry grouped into 145 normotensive pregnant women (72 HIV uninfected normotensive, 73 HIV infected normotensive) and 180 preeclamptic pregnant women (103 HIV uninfected preeclamptics, 77 HIV infected preeclamptics). Preeclamptic pregnant women were further sub-grouped into 79 early-onset preeclampsia (EOPE) (40 HIV uninfected EOPE, 39 HIV infected EOPE) and 101 late-onset preeclampsia (LOPE) (63 HIV uninfected LOPE, 38 HIV infected LOPE). Genotyping of complement C1q gene polymorphisms (rs292001 and rs294183) was detected using a TaqMan® SNP Genotyping assay from purified DNA. RESULTS: No significant differences in allelic and genotype frequencies of rs292001 and rs294183 between preeclamptic and normotensive women were observed. Likewise, there were no significant differences in allelic and genotype frequencies between HIV infected normotensive vs HIV infected preeclampsia and HIV uninfected normotensive vs HIV uninfected preeclampsia for both SNPs. However, the odds ratio of preeclamptic women having the GA genotype was 1:2. CONCLUSION: We demonstrate that SNPs of the C1q gene (rs292001 and rs294183) are not associated with the pathogenesis of PE development in women of African ancestry. The role ofC1qrs292001 heterozygous GA is highlighted (with and without HIV infection) may affect susceptibility to PE development. Notably, this dysregulation may affect C1q translation and protein output thus influencing the downstream role of the complement system and functional immunology in HIV infection comorbid with PE.

Mycobacterium tuberculosis Intra-Host Evolution Among Drug-Resistant Tuberculosis Patients Failing Treatment.

Background: Understanding Mycobacterium tuberculosis (Mtb) intra-host evolution of drug resistance is important for successful drug-resistant tuberculosis (DR-TB) treatment and control strategies. This study aimed to characterise the acquisition of genetic mutations and low-frequency variants associated with treatment-emergent Mtb drug resistance in longitudinally profiled clinical isolates from patients who experienced DR-TB treatment failure. Patients and Methods: We performed deep Whole Genome Sequencing on 23 clinical isolates obtained longitudinally across nine timepoints from five patients who experienced DR-TB treatment failure enrolled in the CAPRISA 020 InDEX study. The minimum inhibitory concentrations (MICs) were established on the BACTEC™ MGIT 960™ instrument on 15/23 longitudinal clinical isolates for eight anti-TB drugs (rifampicin, isoniazid, ethambutol, levofloxacin, moxifloxacin, linezolid, clofazimine, bedaquiline). Results: In total, 22 resistance associated mutations/variants were detected. We observed four treatment-emergent mutations in two out of the five patients. Emerging resistance to the fluoroquinolones was associated with 16- and 64-fold elevated levofloxacin (2-8 mg/L) and moxifloxacin (1-2 mg/L) MICs, respectively, resulting from the D94G/N and A90V variants in the gyrA gene. We identified two novel mutations associated with elevated bedaquiline MICs (>66-fold): an emerging frameshift variant (D165) on the Rv0678 gene and R409Q variant on the Rv1979c gene present from baseline. Conclusion: Genotypic and phenotypic resistance to the fluoroquinolones and bedaquiline was acquired in two out of five patients who experienced DR-TB treatment failure. Deep sequencing of multiple longitudinal clinical isolates for resistance-associated mutations coupled with phenotypic MIC testing confirmed intra-host Mtb evolution.

Isoniazid resistance-conferring mutations are associated with highly variable phenotypic resistance.

Background: High-dose isoniazid is recommended in the 9-12 months short-course regimen for multidrug-resistant tuberculosis with inhA mutation. However, there is insufficient evidence to support the assumption of genotypic-phenotypic concordance. This study aimed to identify the genetic mutations associated with high-level phenotypic isoniazid resistance. Methods: Clinical isolates from patients with drug-resistant tuberculosis were profiled by whole-genome sequencing and subjected to minimum inhibitory concentration (MIC) testing using MGIT based-method. MICs were performed in concentration ranges based on the mutation present: isolates with no isoniazid resistance-conferring mutations and H37Rv, 0.016-0.256 µg/ml; inhA, 0.256-4.0 µg/ml, katG 1.0-16.0 µg/ml; and inhA + katG, 4.0-64.0 µg/ml. Isolates demonstrating resistance at the upper limit of the concentration range were tested up to the maximum of 64.0 µg/ml. Bootstrap of the mean MICs was performed to increase the robustness of the estimates and an overlap index was used to compare the distributions of the MICs for each mutation profile. Results: A total of 52 clinical isolates were included in this analysis. Bootstrap MIC means for inhA, katG and inhA + katG were 33.64 (95% CI, 9.47, 56.90), 6.79 (4.45, 9.70) and 52.34 (42.750, 61.66) µg/ml, respectively. There was high overlap between inhA and inhA + katG mutations (eta = 0.45) but not with inhA and katG (eta = 0.19). Furthermore, katG showed poor overlap with inhA + katG mutations (eta = 0.09). Unexpectedly, 4/8 (50.0%) of all InhA mutants demonstrated high-level resistance, while 20/24 (83.3%) of katG mutants demonstrated moderate-level resistance. Conclusions: InhA mutations demonstrated unexpectedly high MICs and showed high overlap with inhA + katG. Contrary to the common belief that katG mutants are associated with high-level resistance, this mutation primarily showed moderate-level resistance.

Rapid Molecular Assays for the Diagnosis of Drug-Resistant Tuberculosis.

The recognition that drug-resistant tuberculosis (DR-TB) poses a major threat to global tuberculosis (TB) control efforts has catalysed the development of new and urgently needed TB diagnostics. The full beneficial impact of the subsequent flood of new TB diagnostic tests into the market can only be realised if these diagnostic tests are readily accessible to TB programs and contribute to improved patient outcomes. Although phenotypic drug-susceptibility testing remains the gold standard, an improved understanding of the relationship between mutations and different levels of drug resistance coupled with the advantages of molecular diagnostics could result in rapid molecular diagnostic tests replacing phenotypic drug-susceptibility testing. Successful diagnostics need to diagnose all forms of drug-resistant TB prevalent in each geographic region. Given the finite number and often limited availability of effective drugs for DR-TB, the diagnostic test must be able to detect all clinically important types of resistance to available anti-TB drugs. However, less comprehensive resistance profiling may be sufficient in settings where extensively drug-resistant TB (XDR-TB) and pre-XDR are absent. Rapid molecular diagnostic tests for DR-TB detection suitable for DR-TB endemic settings should be accurate, inexpensive, suitable to be performed on an easily accessible sample, detect prevalent circulating drug-resistant strains, and provide results within a short turnaround time to enable timely treatment initiation. In this review, we appraise the wide range of molecular diagnostics for DR-TB endorsed by the World Health Organisation, discuss the challenges in the development and rollout of rapid molecular DR-TB tests in low- and middle-income countries, and highlight user perspectives and cost-effectiveness factors that influence their utility.

The Effect of miRNA Gene Regulation on HIV Disease.

Over many years, research on HIV/AIDS has advanced with the introduction of HAART. Despite these advancements, significant gaps remain with respect to aspects in HIV life cycle, with specific attention to virus-host interactions. Investigating virus-host interactions may lead to the implementation of novel therapeutic strategies against HIV/AIDS. Notably, host gene silencing can be facilitated by cellular small non-coding RNAs such as microRNAs paving the way for epigenetic anti-viral therapies. Numerous studies have elucidated the importance of microRNAs in HIV pathogenesis. Some microRNAs can either promote viral infection, while others can be detrimental to viral replication. This is accomplished by targeting the HIV-proviral genome or by regulating host genes required for viral replication and immune responses. In this review, we report on 1) the direct association of microRNAs with HIV infection; 2) the indirect association of known human genetic factors with HIV infection; 3) the regulation of human genes by microRNAs in other diseases that can be explored experimentally to determine their effect on HIV-1 infection; and 4) therapeutic interactions of microRNA against HIV infection.

Nephrotic Syndrome in South African Children: Changing Perspectives in the New Millennium.

The epidemiological landscape of nephrotic syndrome (NS) in South Africa has changed drastically in the New Millennium. Although the pattern of disease in the 3 main non-Black racial groups (White, Indian, and Mixed race) mirror that seen in Western countries, Black African children show a pattern of disease that is at variance with these 3 racial groups. The incidence of infectious diseases, particularly hepatitis B virus associated nephropathy has sharply declined to being almost extinct in Black children in the New Millennium whereas HIV-related nephropathy surfaced. However, following the widespread use of anti-retroviral therapy, its incidence has also decreased dramatically. Focal segmental glomerulosclerosis (FSGS), which was once uncommon, has, in the New Millennium, emerged as one of the most challenging forms of NS across all racial groups, particularly in Black children. Although the introduction of calcineurin inhibitors, mycophenolate mofetil and monoclonal antibodies (e.g., rituximab) has improved the outcome of children with FSGS, the reponse in Black children is less than optimal, with those having single gene mutations being universally unresponsive to all forms of immunosuppression.

Prevalence of Primary Hypertension and Risk Factors in Grade XII Learners in KwaZulu-Natal, South Africa.

Hypertension in childhood leads to hypertension in adult life, the strongest risk factor being obesity. This study determined the prevalence of primary hypertension and its risk factors in Grade XII learners in KwaZulu-Natal, South Africa, from March 2016 to June 2017. Weight, height, body mass index (BMI), random finger prick cholesterol and glucose, and spot urine for an albumin : creatinine ratio were measured. An average of three separate blood pressure readings taken was at least 5 minutes apart. Five hundred and sixty-four learners had weight, height, and BMI; 536 had random blood glucose; and 545 had cholesterol and random spot urine albumin : creatinine ratios measured. Prehypertension was detected in 168 (29.7%) and hypertension in 77 (13.7%) of learners. Ninety (15.9%) were overweight and 75 (13,3%) were obese. Hypercholesterolaemia was present in 58 (10.8%) and a high spot random urine albumin : creatinine ratio in 5 (1.0%). None had a high blood glucose level. Both prehypertension and hypertension in all learners showed a significant increase with increasing BMI. Six (1.0%) learners had metabolic syndrome. Female learners in other racial groups (defined as Indian, mixed race, and White learners), overweight, and obese learners showed significantly higher rates of hypercholesterolaemia. We showed overweight and obesity as risk factors for prehypertension and hypertension. This presages the need for an appropriate diet and adequate exercise in a child's school career.