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The kidney is the target for a wide variety of chemical agents, including heavy metals, haloalkenes, analgesics and antibiotics. The functional and metabolic characteristics of the proximal tubule (PT) predispose it as the primary site for xenobiotic damage. The aim of this study was to isolate and characterise human and rat PT cells in suspension and primary culture for use as defined models to investigate drug-induced PT cell damage in vitro . A second aim was to compare the response of human and rat systems to known nephrotoxins. Human and rat PT cells (90&'37 viable) were isolated from kidney cortex by collagenase digestion followed by isopycnic Percoll density centrifugation. This resulted in the formation of two distinct bands of cell at densities 1.040g/ml (A) and 1.060g/ml (B) for both preparations. Characterisation of human cells in terms of morphology, marker enzymes, retention of active transport systems and responsiveness to parathyroid hormone indicated that &'62 95&'37 of the cells in band B were proximal tubular. Each transport system demonstrated Michaelis-Menten kinetics; kinetic parameters suggested that a higher proportion of PT cells from the S1-S2 segment of the nephron were present in human isolates. Human isolated cells also contained levels of glutathione and cytochrome P450, in particular ethoxyresorufin-O-deethylase activity, a marker for the P4501A family, similar to the intact kidney. Both human and rat cells were successfully cultured in serum-supplemented medium (10&'37 v/v) with human cells reaching confluence by 3-4 days and rat by 5-6. Maximal attachment was seen when cells from both preparations were inoculated onto collagen coated plates with an additional layer of fibronectin. Only human cells were able to reach confluence on porous membranes and demonstated an enhanced morphology when compared to normal cultured cells. Cultured cells from both preparations retained an epithelial morphology and showed minimal secondary cell contamination as shown by light microscopy and in the case of human cultures additionally through immunohistochemical staining. Immunohistochemical staining also demonstrated that human cells in culture were depositing components of the extracellular matrix. The maintenance of PT cell function, throughout the time in culture, was shown following maintenance of active transport systems, in particular the glucose carrier system and on porous membranes the organic anion system. Only rat cells maintained the organic cation system in primary culture. In addition human cells maintained the preferential response to parathyroid hormone. Except for the transport of organic cations, the other carrier systems and responsiveness to hormones were evident at both sub-confluent and confluent stages of cell culture.

Division of Nephrology Department of Internal Medicine School of Clinical Medicine Faculty of Health Sciences University of Witwatersrand 7th June, 2017 / Objective Renal transplantation is the ideal therapeutic option for patients that reach end-stage renal failure. However, patients require long term immunosuppression following surgical transplantation to prevent graft rejection [1,2,4]. Mycophenolate mofetil (MMF) had proven to be an effective immunosuppressant in transplant patients[8,9,10], although it is associated with an increase in gastrointestinal adverse effects, which may result in dose adjustment or termination of use [22]. There is a paucity of data regarding gastrointestinal side effects of MMF in South Africa. This study attempts to describe the incidence of gastrointestinal complications, incidence of dose adjustment and discontinuation of MMF due to side effects, to compare the incidence of GI complications between those that had prior gastrointestinal ailments and those that had no prior gastrointestinal ailments and finally to determine possible risk factors (age, gender, ethnicity, donor type, pre-transplant GI diagnosis, pre-transplant diabetes and combination of MMF with tacrolimus) of gastrointestinal adverse effects. Method Data was collected retrospectively from the file records of the renal transplant unit at CMJAH (Charlotte Maxeke Johannesburg Academic Hospital) on adult patients who had received kidney transplants between 1998 and 2010 and who had received MMF as part of the immunosuppressive regimen for at least the one year post-transplant. Relevant data was captured in an anonymous fashion on a collection sheet. Descriptive analysis of the data was carried out. Time-to-event data were analysed by Kaplan-Meier survival analysis. The assessment of the effect of prior gastrointestinal ailments, as well as risk factors, was carried out by Cox Proportional Hazards regression to estimate the Hazard Ratios. Results A total of 188 patients were included in the study group, which comprised 65.4% males and 32.4% females (2.1% missing data). The mean age at transplant was 38.1 years. The patients were predominantly black (69.1%). Donors were predominantly deceased donors. Of the 24.5% of donors who were living donors, 76.1% were related living donors, while the rest were non-related living donors. The majority of patients (82%) were induced with MMF dose of 2 grams per day. After 5 years, 13.8% of patients discontinued MMF while 86.2% of the patients were still on MMF. 48.1% had a dose adjustment due to gastrointestinal side effects. 61% of patients had had a diarrhoeal adverse event by 5 years. 21.8% of the patients had gastrointestinal side effects other than diarrhoea by 5 years. The combination of tacrolimus and MMF was found to be a significant risk factor for diarrhoeal adverse events (Hazard Ratio 1.82; 95% CI 1.21-2.73). Having a living donor graft reduced the chance of non-diarrhoeal gastrointestinal adverse event (Hazard Ratio 0.33; 95% CI 0.13-0.84, p<0.02). A trend towards significance was seen in living donors having less diarrhoeal events although it did not reach statistical significance (Hazard Ratio 1.32; 95% CI 0.87-2.00, p=0.20). Conclusion As far as the authors are aware, this is the first local study on MMF and GIT adverse effect. We found the combination of MMF and tacrolimus is associated with increased risk of having diarrhoeal adverse events, which is consistent with international data[34,35]. Living donor graft is associated with a lower risk of developing non-diarrhoeal gastrointestinal events. Although non-significant, data suggest the same trend favoring living donor graft with regards to diarrhoeal events. / MT2017

MMed (Paediatrics), Faculty of Health Sciences,University of the Witwatersrand / IgA (Immunoglobulin A) nephropathy is reported as the most common form of primary glomerulonephropathy worldwide. Despite this there is limited research on IgA nephropathy in African children. This study reviewed IgA and Henoch-Schonlein Purpura (HSP) nephropathies, as it is believed that they are variants of the same pathological process. This study hypothesized that IgA and HSP nephropathies occur in South African black children and that disease progression is worse in this population group and compares them to their international counterparts. Methods: The study was a retrospective review of the records of children that presented to the paediatric renal clinics at two academic hospitals in Johannesburg. It reviewed the epidemiology and progression in South African children. These results were then compared to appropriate international reviews. There were a total of 1835 paediatric renal biopsies between 1985 and 2008. Of these 51 were confirmed to be IgA nephropathy (3%) of which one was excluded. Children were reviewed as a whole and then divided into a HSP and an IgA nephropathy group. Results: The average age at presentation was 9.5 years old. There was a male predominance with a male to female ratio of 2.2:1. Racial differences were noted, and when reviewed in the light of the demographics of the area, there was a higher “prevalence” in Caucasian and Indian patients. The most common presenting symptom in the study population was haematuria. Nephrotic range proteinuria occurred in more than half of all patients. Presentation in acute renal iii dysfunction was uncommon. Predictors of a poor prognosis were found to be nephrotic range proteinuria, and a lower GFR at presentation. The study hypothesis that black African children with IgA or HSP nephropathy have a poorer prognosis than other children with similar presentations, was disproved.

Dissertation in fufillment of the degree of MSc(Med), Faculty of Health Sciences, University of the Witwatersrand / Introduction: Measurement of small solute clearance is the objective means of quantifying dose of peritoneal dialysis (PD) and various organisations have issued guidelines on target values. Assessment of PD adequacy involves other factors such as blood pressure control, anaemia management, mineral metabolism, nutritional status and ultrafiltration. Membrane transport characteristic is important for PD prescription on an individual patient basis and is related to patient outcome. In this study the adequacy of PD, using small solute clearance measurement as well as other factors, and membrane characteristics have been assessed and classification of patients using our own reference values is reported for the first time. Nutritional status has been studied and the use of simple tools such as the subjective global assessment has been validated for use in our patients. Materials and Methods: A cross sectional study involving 80 adult continuous ambulatory peritoneal dialysis (CAPD) patients. Peritoneal equilibration test (PET) was performed to assess the membrane characteristics; 24 hour dialysate fluid and urine samples were collected and used for the measurement of solute clearance, while nutritional status was assessed using the subjective global assessment (SGA) instrument, anthropometric measurements and serum albumin estimation. Results: The mean age was 38 ± 12.43 years, 42.3% were females and 86% were blacks. Mean duration on CAPD was 19.8 ± 20.67 months. The mean of 4 hour D/P creatinine was 0.74 ± 0.13 and based on this, 18% were high transporters, 33.8% high average, 36.9% low average and 12% low transporters. Mean kt/v urea was 1.72± 0.32, and the recommended level of 1.7 was achieved by 62.8% of the patients. Mean haemoglobin was 10.99 ± 2.14 g/dl and the recommended target value of 11-12g/dl was reached by 55.8% of the patients. The mean BMI vi was 24.76 ± 3.50, mean Mid Upper Arm Circumference (MUAC) was 28.53±3.89 cm and mean serum albumin was 37.10 ± 7.6 g/l. Based on SGA scores, 42% of our patients were well nourished, 50% moderately undernourished while 8% were severely malnourished. We noted significant correlations between SGA score and BMI and MUAC while there was none with serum albumin level. The mean serum calcium and phosphate levels were within normal though the mean PTH level was higher. Conclusion: The D/P creatinine at 4 hours was higher than those reported in the literature, though the distribution of the transport types was similar. The recommended targets of kt/v and haemoglobin were achieved by the majority of our patients. Mineral metabolism parameters were within normal range. Malnutrition is common and SGA is a reliable method for nutritional assessment in our patients.

A research report submitted to the Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, in partial fulfilment of the requirements for the degree of Master of Medicine in the branch of Internal Medicine.Johannesburg, 2013 / Chronic Kidney disease (CKD) is emerging as a global threat to health. In sub-Saharan Africa, most patients do not receive renal replacement therapy due to lack of funds. Measures to retard the progression of CKD are important. METHOD: A retrospective review of 122 patients attending a renal clinic, over a two a year period was performed. Patients with CKD from hypertension, diabetes mellitus, tubulo-interstitial disease were inluded. Patients with CKD due to viruses, malignancies and autoimmune RESULTS: Diabetes mellitus and hypertensiion were the leading causes of CKD. BP control improved, though 765 were on ≥3 anti-hypertensives. Serum creatinine doubled in 8.2% of patients. BP, acidosis and anaemia were independent risk factors for progression of CKD. The two year renal survival rate was 82%. CONCLUSION: Renal function progressed in few patients, which would be related to low levels of proteinuria, good BP control and us of RAS blockers

Tin Sik Cheng. / Thesis (M.Phil.)--Chinese University of Hong Kong, 1990. / Bibliography: leaves 83-86. / Acknowledgement --- p.i / Abstract --- p.ii / Chapter Chapter 1 --- Introduction --- p.1 / Chapter Chapter 2 --- Methodology --- p.13 / Chapter Chapter 3 --- Determination of the purity of inulin --- p.19 / Chapter Chapter 4 --- Determination of the optimal lysine concentration --- p.25 / Chapter Chapter 5 --- Protective role of lysine --- p.40 / Chapter Chapter 6 --- An enzyme study --- p.52 / Chapter Chapter 7 --- A plasma protein study --- p.71 / Chapter Chapter 8 --- Epilogue --- p.79 / References --- p.83

by Choi Kim Ming, Arthur. / Thesis (M.Sc.)--Chinese University of Hong Kong, 1998. / Includes bibliographical references (leaves 85-91). / Abstract also in Chinese. / ACKNOWLEDGEMENTS --- p.i / CONTENTS --- p.ii / LIST OF FIGURES --- p.v / LIST OF TABLES --- p.vi / SUMMARY --- p.viii / Chapter 1. --- Introduction --- p.1 / Chapter 2. --- Brief Review on Nephrolithiasis --- p.5 / Chapter 2.1 --- Mechanism of nephrolithiasis --- p.5 / Chapter 2.2 --- Biochemical states leading to nephrolithiasis --- p.8 / Chapter 2.3 --- Inhibitors of nephrolithiasis --- p.10 / Chapter 3. --- Biochemistry of Citrate --- p.13 / Chapter 3.1 --- Basic aspects --- p.13 / Chapter 3.2 --- The role of kidney in citrate metabolism --- p.14 / Chapter 3.3 --- The role of kidney in citrate excretion --- p.17 / Chapter 3.4 --- Altered urinary citrate excretion --- p.18 / Chapter 4. --- Hypocitraturia as a Risk Factor of Nephrolithiasis --- p.21 / Chapter 4.1 --- Experimental and clinical evidence on the role of citrate as a stone inhibitor --- p.21 / Chapter 4.2 --- Mechanism of the inhibitory activity of citrate against nephrolithiasis --- p.22 / Chapter 4.3 --- Clinical conditions associated with hypocitraturiain nephrolithiasis --- p.22 / Chapter 5. --- Analytical Methods for Urinary Citrate Assays --- p.27 / Chapter 5.1 --- Enzyme-spectrophotometric methods --- p.27 / Chapter 5.2 --- High performance ion chromatography --- p.30 / Chapter 5.3 --- Capillary electrophoresis and indirect ultraviolet absorbance detection --- p.31 / Chapter 5.4 --- Comparison on the analytical methods --- p.32 / Chapter 6. --- Quantitation of Urinary Citrate --- p.35 / Chapter 6.1 --- Principle of the assay --- p.35 / Chapter 6.2 --- Instrumentation --- p.35 / Chapter 6.3 --- Preparation of reagents and standards --- p.37 / Chapter 6.4 --- Specimen collection & storage --- p.41 / Chapter 6.5 --- Sample preparation --- p.42 / Chapter 6.6 --- Assay protocol for urinary citrate --- p.43 / Chapter 6.7 --- Factors affecting the assay performance --- p.45 / Chapter 6.8 --- Evaluation of urine citrate assay --- p.45 / Chapter 7. --- Results of Evaluation of the Urine Citrate Assay --- p.50 / Chapter 7.1 --- Calibration --- p.50 / Chapter 7.2 --- Imprecision --- p.50 / Chapter 7.3 --- Linearity --- p.53 / Chapter 7.4 --- Recovery --- p.53 / Chapter 7.5 --- Detection limit --- p.53 / Chapter 7.6 --- Carryover --- p.58 / Chapter 7.7 --- Interference studies --- p.58 / Chapter 7.8 --- Correlation study --- p.60 / Chapter 7.9 --- Discussion on the methodology --- p.63 / Chapter 8. --- Study in Control Subjects --- p.65 / Chapter 8.1 --- Subjects --- p.65 / Chapter 8.2 --- Method of evaluation --- p.65 / Chapter 8.3 --- Results of the control subjects --- p.67 / Chapter 8.4 --- Discussion --- p.67 / Chapter 9. --- Study in Chinese patients with Nephrolithiasis --- p.72 / Chapter 9.1 --- Subjects --- p.72 / Chapter 9.2 --- Method of the patients study --- p.72 / Chapter 9.3 --- Results of the patients study --- p.72 / Chapter 9.4 --- Discussion --- p.77 / Chapter 10. --- General Discussion and Suggestions for Further Studies --- p.80 / Chapter 11. --- Conclusion --- p.84 / Chapter 12. --- References --- p.85

Thesis (M.D.)—Boston University