3. Electronic Theses and Dissertations (ETDs) - All submissions
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Item The pivotal role of a kidney stone clinic in the management and prevention of recurrent calcium oxalate nephrolithiasis(2020) Meyers, Anthony MNephrolithiasis occurs in 12 to 15% of males and 5 to 6% of females with frequent recurrence in about 50% of them. The prevalence of stone disease is unknown in the South African black population and is of low frequency. The commonest type of nephrolithiasis in the South African population is calcium oxalate stones. This thesis involved the study of the epidemiology, causes, pathogenesis and management of kidney stones in patients with recurrent calcium oxalate stones. Dedicated stone clinics indicate that there is a 30% lower mortality rate accompanied by an increase in patient satisfaction, improved recruitment of staff and improved morale. Patients and methods Seven previously published studies, which form the basis for this Doctor of Medicine degree, were analysed; six in-vivo and one laboratory study. Three of the studies, analysed the urinary metabolites in a large number of black and white male and female normal controls. Stone risk factors were studied in a total of five papers, also in a large number of patients of comparative cohorts with nephrolithiasis. Standard work-up protocols included dietary, anthropomorphic, serological, 24-hour urinary excretion of mineral and electrolyte measurements. Special crystallographic techniques were used in the paper presenting the role of cystine in calcium oxalate stone formation. The metastable limits of urine were measured using various quantities of cystine in pooled urine, in spun and filtered as well as ultra-filtered specimens. In addition, particle numbers, diameter and volume were measured. Promotion of calcium oxalate formation was measured in the specimens using various concentrations of cystine. Hypocitraturia was present in ~50% of white stone patients; black controls excreted much less citrate than whites, 50% of whom fell into the hypocitraturic range. Therefore, two separate controls for blacks and whites were formulated and validated viii by statistical evidence and accepted as “good laboratory practice”. Oxalate excretion in controls and stone formers, whether of black or white ethnicity, male or female, was similar. Both black normal controls and stone formers excreted less calcium than their white counterparts. No blacks had calcium phosphate calculi; 20% of the whites did. The role of calcium phosphate excretion was not assessed in the work-up protocols. However, in a “post-hoc” exercise, useful data on urinary metabolites, which included analysis differentiating between the ethnic groups as well as controls versus stone formers, was extrapolated from the relevant published papers. The presence of hyperurcosuria with hyperoxaluria or hypercalciuria was present in whites only. However, due to the invariable presence of hypernatrituria, hypercalciuria cannot be accepted as truly non-dietary from these and most other reported studies. The in vitro laboratory experiment demonstrated the ability of cystine to promote calcium oxalate stones and was an entirely original postulate at the time of publication. The urinary metastable limit did not change with the varying cystine levels, while particle diameter and volume increased significantly and proportionately in a dose responsive manner. The highest dose of cystine increased the calcium oxalate level by 52%. The results were confirmed in 14C-oxalate experiments as well as scanning electron microscopy, neither of which revealed any cystine crystals. Thus, adding cystine to undiluted urine results in marked calcium oxalate precipitation. This study also demonstrated many of the latest and advanced techniques in the study of crystal formation science known at the time. Two of the papers dealt with medical management of nephrolithiasis. The first clearly demonstrated the outstanding efficacy of potassium citrate in the successful long-term prevention of recurrent stones in these patients. Likewise, the use of indapamide clearly outperformed hydrochlorothiazide therapy in patients with hypercalciuria. Significantly superior efficacy and safety parameters were found with indapamide which is clearly the drug of choice. Conclusions Hypocitraturia was present in ~50% of white stone formers and considered to be pathogenic. The presence of hypocitraturia in the South African black population, together with their low prevalence of nephrolithiasis warrants further research. A dedicated renal stone clinic is advocated; such an institution would provide high quality care of patients, coupled with a high research output; all of which strongly supports the creation of a dedicated Kidney Stone InstituteItem Genetics of hypertension-attributed chronic kidney disease in black South Africans(2018) Nqebelele, Nolubabalo UnatiBackground: Chronic kidney disease (CKD) is recognised as a global public health problem. Variants in apolipoprotein L1 (APOL1) gene were shown to associate with higher rates of nondiabetic kidney disease in African American patients compared with white patients. Frequencies of these variants differ substantially in African populations, with the highest frequency reported in west African populations, with complete absence in east African populations, suggesting that the contribution of these variants to kidney disease might also differ. As not all individuals at high genetic risk (presence of two APOL1 risk variants) develop kidney disease, it is possible that there are modifying factors which act as ‘second hits’ (other genes or environmental factors) interacting with APOL1 to initiate kidney disease. Aims: The aim of this thesis was to determine the association of the APOL1 variants with hypertension-attributed CKD in black South Africans. A further aim was to determine the associations of potential ‘second hits’, such as polyomavirus infections and polymorphisms in other genes, with hypertension-attributed CKD. Furthermore, we aimed to test the interactions of these ‘second hits’ with APOL1 risk variants. Methods: This was a cross-sectional study conducted in the Divisions of Nephrology at Charlotte Maxeke Johannesburg Academic Hospital and Chris Hani Baragwanath Academic Hospital, following approval from the Human Research Ethics Committee of the University of the Witwatersrand (Clearance certificate no M141192). Black patients with hypertension-attributed CKD, together with their first-degree relatives and healthy controls were included in the study after providing written informed consent. Blood samples were genotyped for polymorphisms in the APOL1, uromodulin, podocin, bone morphogenic protein 4 (BMP4) and serologically defined colon cancer antigen 8 genes, together with measurement of urinary uromodulin levels and quantification of polyomaviruses in urine. Results: Carriage of two APOL1 risk alleles (vs. zero or one risk allele) was not associated with hypertension-attributed CKD (OR 0.849; 95% CI [0.255 - 2.831]; p = 0.790). Absence of JCV DNA was strongly associated with hypertension-attributed kidney disease (OR 15.27; 95% CI [3.52 to 66.31]; p <0.001), with even higher odds ratio of 43-fold after correcting for age, sex, socioeconomic status and the number of APOL1 risk alleles. There was no significant interaction observed between the absence of JC virus and the presence of one or two APOL1 risk alleles. There was a trend for an increased risk of kidney disease in those who had two APOL1 risk variants and were major allele homozygotes at rs16854341 (podocin gene) (4.78 (95% CI [0.87 - 26.31]; p = 0.072) and at rs8014363 (BMP4 gene) (5.16 (95% CI [0.92 - 29.87]; p = 0.062. For each 1-standard deviation increase in urinary uromodulin level, the multivariable-adjusted odds ratio for CKD was 0.6 (95% CI [0.48 to 0.81]; p <0.01). Conclusion: Our study provides evidence that APOL1 risk variants are present in black South Africans, though their frequency does not differ between patients with hypertension-attributed CKD, their first degree relatives and healthy black South Africans. We showed a very strong association between the absence of JC viruria and hypertension-attributed CKD. In the presence of two APOL1 risk variants, major allele homozygotes in the podocin and BMP4 genes had a trend towards an increased risk of kidney disease. Further research with larger sample size and CKD of various etiologies and different stages of CKD are warranted.Item Biochemical and genetic markers of mineral bone disease in South African patients with chronic kidney disease(2017) Waziri, BalaBackground Abnormalities of mineral bone disease have been consistently associated with adverse clinical outcomes in patients with chronic kidney disease (CKD). The consequences of these changes have also been shown to differ across races. However, in Africa the impact of derangements of CKD -mineral and bone disorder (CKD-MBD) on patients with CKD is largely unknown. In addition, studies from the USA have reported racial variations in markers of CKD and it remains unclear whether genetic factors may explain this discrepancy in the levels of biochemical markers of CKD-MBD across ethnic groups. Therefore, this study has been conducted to determine the existence of racial differences in the levels of fibroblast growth factor 23(FGF23) and traditional markers of mineral bone metabolism in a heterogeneous African CKD population, and to provide important insights into the pattern and genetic variability of CKD-MBD in sub-Saharan Africa. Methods This was a cross sectional multicenter study carried out from April 2015 to May 2016, involving two hundred and ninety three CKD patients from three renal units in Johannesburg, South Africa. The retrospective arm of this study involved two hundred and thirteen patients undergoing maintenance haemodialysis (MHD) from two dialysis centers in Johannesburg between January 2009 and March 2016. The first part of this study described the pattern of CKD-MBD in MHD patients using traditional markers of CKD-MBD. The second part of the study looked into the spectrum of CKD-MBD and racial variations in markers of CKD-MBD in pre dialysis and dialysis patients. This was followed by the genetic aspect of the study that examined the influence of vitamin D receptor polymorphisms on biochemical markers of mineral bone disorders. Lastly, the study also evaluated the association between markers of CKD-MBD and mortality in MHD patients. Results The prevalence of hyperparathyroidism (iPTH>150 pg/mL), hyperphosphataemia, hypocalcaemia and 25-hydroxyvitamin D deficiency (<30 ng/mL) was 73.4%, 57.0%, 20.3% and 80.7 % respectively in our MHD patients. The combination of markers of bone turnover (iPTH>150 pg/mL and total alkaline phosphatase > 112 U/L) suggestive of high turnover bone disease, was present in 47.3 % of the study population. The odds ratios for developing secondary hyperparathyroidism with hypocalcaemia and hyperphosphataemia were 5.32 (95% CI 1.10 - 25.9, P =0.03) and 3.06 (95 % CI 1.15 - 8.10, P =0.02) respectively. The 293 CKD patients (208 blacks, 85 whites) had an overall mean age of 51.1±13.6 years, and black patients were significantly younger than the white patients (48.4 ±.13.6 versus 57.1±15.5 years; p<0.001). In comparison to whites, blacks had higher median iPTH (498 [37-1084] versus 274[131-595] pg/ml; P=0.03), alkaline phosphatase (122[89-192] versus 103[74-144] U/L; P=0.03) and mean 25- hydroxyvitamin D (26.8±12.7 versus 22.7 ±12.2 ng/ml, P=0.01) levels, while their median FGF23 (100 [34-639] versus 233[80-1370] pg/ml; P=0.002) and mean serum phosphate (1.3±0.5 versus 1.5±0.5, P =0.001) levels were significantly lower. With the exception of vitamin D receptor (VDR) Taq I polymorphism, the distribution of the VDR polymorphisms differs significantly between blacks and whites. In hemodialysis patients, the BsmI Bb genotype was significantly associated with moderate secondary hyperparathyroidism (OR, 3.88; 95 CI 1.13-13.25, P=0.03) and severe hyperparathyroidism (OR, 2.54; 95 CI 1.08-5.96, P=0.03). Patients with high total alkaline phosphatase (TAP) had significantly higher risk of death compared to patients with TAP <112 U/L (hazard ratio, 2.50; 95% CI 1.24–5.01, P = 0.01). Similarly, serum calcium >2.75 mmol/L was associated with increased risk of death compared to patients within levels of 2.10–2.37 mmol/L (HR 6.34, 95% CI 1.40–28.76; P = 0.02). The HR for death in white patients compared to black patients was 6.88; 95% CI 1.82–25.88; P = 0.004. Conclusions Secondary hyperparathyroidism and 25–hydroxyvitamin D deficiency were common in our haemodialysis patients. The study also highlighted the existence of racial differences in the circulating markers of mineral bone disorders in our African CKD population. In addition, the study showed that both moderate and severe secondary hyperparathyroidism are predicted by the BsmI Bb genotype, and the over expression of this genotype in black patients may partly explain the ethnic variations in the severity of secondary hyperparathyroidism in the CKD population. High levels of serum alkaline phosphatase, hypercalcaemia, and white race are associated with increased risk of death in MHD patients.Item Biomarkers in acute kidney injury due to contrast induced nephropathy(2016) Banda, JustorBackground: Despite preventive guidelines, iatrogenic contrast-induced nephropathy (CIN) ranks third as a cause of hospital acquired acute kidney injury (AKI), and impacts significantly on morbidity and mortality and is associated with high hospital costs. In Sub-Saharan Africa, the rates and risk factors for CIN remain unexplored. Despite the positive association of genetic polymorphisms in the TNFα and IL10 genes with CIN in Asian populations, the CIN genetic susceptibility in other races is unknown. Serum creatinine is a sub-optimal biomarker for the early diagnosis of CIN resulting in delayed interventions. This study investigated rates, risk factors and outcomes of CIN, the influence of genetic susceptibility to CIN in the black population and lastly, the accuracy of novel biomarkers in the early diagnosis of CIN and prognosticating patient outcomes. Methods: This was a prospective case-controlled study conducted at Charlotte Maxeke Johannesburg Academic Hospital, in South Africa from January 1, 2014 to December 30, 2015.Hospitalized patients undergoing enhanced computed tomography and angiography were consecutively recruited to the study and followed up for development of CIN. CIN was defined as an increase in serum creatinine >25% or an absolute increase of >44 μmol/l from baseline at 48-72 hours after exposure to contrast media. In the second part of the study, a nested case-controlled cohort that included 30 CIN patients and 60 controls (those undergoing contrast administrations and not meeting CIN criteria) were ethnically matched for gender, and age in a case: control ratio of 1:2 at all-time intervals. Sera for neutrophil gelatinaseassociated lipocalin-2 (NGAL), cystatin C, beta-2 microglobulin (β2M), interleukin 18 (IL18), IL10, and tumor necrosis factor alpha (TNFα) were collected at four time points: baseline (pre-contrast), 24 hours, 48 hours and ≥5-7 days after contrast administration and their concentrations were determined using luminex assays and an enzyme linked immunosorbent assay for β2M as per manufacturer’s instructions. The areas under receiver operating characteristic curves (AUROC) were generated to determine accuracy of novel biomarkers to diagnose CIN and CIN mortality. Genomic DNA was extracted from peripheral blood samples of 208 black South Africans using the Maxwell DNA purification kit (Promega AS1010, USA) and their genotypes for - 308(rs1800629) and -857(rs1799724) in the TNFα gene and -592(rs1800872), - 819(rs1800871), -1082 (rs1800896) and +1582(rs1554286) in the IL10 gene were determined by restriction fragment length polymorphism (RFLP). Results: We recruited 371 hospitalized patients (mean age 49.3±15.9); the rates of CIN were4.6% and 16.4% respectively, using an absolute or relative increase in serum creatinine from baseline. Anaemia was an independent predictor for the development of CIN (RR 1.71, 95% 1.01-2.87; p=0.04). The median serum albumin was 34 g/l (IQR: 29-39.5) vs. 38 g/l (IQR: 31-42), p=0.01 in the CIN and control groups respectively.Mortality was significantly increased in the CIN group (22.4% vs. 6.8%; p<0.001), and CIN together with anaemia predicted mortality with a 2-fold (p=0.01) and a 3-fold (RR p=0.003) riskrespectively. The median cystatin C at 24 hours (p<0.001) and β2M(at all-time points)levels were significantly higher in the CIN group compared to controls. The median cystatin C at 24 hours and β2Mlevels at 48 hours were 856.59 ng/ml (IQR 620.75-1002.96) vs. 617.42 ng/ml (IQR 533.11-805.20); p<0.001 and 5.3 μg/ml (IQR 3.8-6.9) vs. 3.3 μg/ml (IQR 2.7-4.5); p<0.001 with AUROCs of 0.75 and 0.78 respectively for early CIN discrimination.Pre-contrast IL18 (p <0.001), β2M (p=0.04) and TNFα (p<0.001) levels were significantly higher in the nonsurviving group and their AUROC were 0.83, 0.82 and 0.94 for CIN+ mortality. Baseline NGAL was a better marker for excluding patients at higher risk of developing CIN with negative predictive and positive predictive values of 0.81 and 0.50 respectively. The frequency of TNFα -308 AA genotype was significantly increased in the CIN group compared to controls (13.3% vs.1.82%, p=0.016) and the presence of the TNFα-308 AA (high producer) vs. GA genotypes was associated with a 9-fold CIN risk (9.24, 95% CI, 1.88-45, p=0.006). The IL10-1082 AA-allele (low producer) was significantly higher in the non-surviving CIN+ patients compared to controls (p=0.01). Conclusions:CIN occurred at a relatively high rate in our study and predicted poorer clinical outcomes. The presence of CIN and anaemia positively predicted mortality. Caution should be exercised in patients with anaemia and hypoalbuminaemia undergoing contrast studies. Serumcystatin C was the best novel biomarker for the early diagnosis of CIN and while baseline NGAL is superior as a biomarker for excluding patients at higher risk for CIN. IL18, β2M and TNFα are the best novel biomarkers for predicting the prognosis of patients with CIN. Increased frequency of the TNFα-308 AA genotype is a predisposing factor for CIN development. The low producer IL10-1082 AA genotype decreases survival in patient with CIN.Item A review of patterns of renal disease at Chris Hani Baragwanath Academic Hospital from1982 to 2011(2014) Vermeulen, AldaThis study reports a review of biopsy-confirmed renal pathology from Soweto Gauteng. A retrospective analysis was conducted of 1848 adult native renal biopsy reports from Chris Hani Baragwanath Academic Hospital from 1 January 1982 to 31 December 2011. The mean age of all patients biopsied was 33.5 ± 12.6 years and the majority of patients (96.4%) were black. The most frequent histological findings were secondary glomerular diseases (SGNs) (49.3%) and primary glomerular diseases (PGNs) (39.7%). SGNs increased, while PGNs decreased over time (p<0.001). The main contributors to SGN were lupus nephritis (31.0%) and HIV associated nephropathy (HIVAN) (13.3%) while for PGN it was focal segmental glomerulosclerosis (FSGS) (29.6%). HIV positive biopsies constituted 19.7% of all biopsies with a dominant diagnosis of HIVAN (32.7%). Changing patterns of renal disease are evident in the data. The increased SGNs likely reflect the influence of renal pathology secondary to HIV and lupus nephritis.