June Fabian

Infection and glomerulonephritis

Glomerular injury, occurring either as primary glomerular disease or as part of a systemic disease process, is usually a result of immune-mediated mechanisms. The morphologic reaction pattern has a diverse spectrum of appearance, ranging from normal by light microscopy in minimal change disease to crescentic forms of glomerulonephritis, with conspicuous disruption of the normal glomerular morphology. The mechanisms of glomerular immune deposit formation include trapping of circulating antigen–antibody complexes and the in situ formation of immune complexes within the glomerulus. While the majority of postinfectious immune-complex-mediated glomerulonephritides are believed to result from the deposition of circulating antigen–antibody complexes, preformed outside of the kidney and secondarily deposited in the kidney, the notion of forming in situ antigen–antibody complexes to either planted antigens or to integral structural components of the glomerulus, through “cross-reacting” autoimmune reactions, is gaining popularity in a variety of forms of glomerulonephritides. Patients with HIV infection may develop a spectrum of renal pathology, the glomerular manifestations of which include both antigen–antibody complex and nonimmune-complex-mediated pathogenetic mechanisms. Similarly, patients with Streptococcal infections, Hepatitis B virus, or Hepatitis C virus infection may develop a spectrum of glomerulonephritides, which are predominantly immune-complex-mediated. Therapy for glomerular diseases due to HIV, hepatitis B, or C virus infections remains a challenge.

Symptomatic hyperlactataemia in adults on antiretroviral therapy: a single-centre experience.

OBJECTIVE There are limited data on symptomatic hyperlactataemia caused by antiretroviral therapy (ART) in resource-limited settings. We assessed individuals who developed symptomatic hyperlactataemia on ART in an outpatient clinic in South Africa. DESIGN A retrospective record review was performed on patients attending the clinic from January 2004 to December 2005. RESULTS Thirty-five patients, all on stavudine-containing regimens, developed symptomatic hyperlactataemia. The incidence in this population was 20.5 cases per 1 000 person-years of ART with an associated mortality of 21%. The major risk factor was being female (risk ratio (RR) 3.27). Significant clinical symptoms preceding symptomatic hyperlactataemia include nonspecific gastrointestinal symptoms, weight loss, and development of symptomatic neuropathy. CONCLUSIONS The incidence of symptomatic hyperlactataemia in our population was high. Simple clinical measures, such as neuropathy symptoms and monitoring of weight, may alert the clinician to impending symptomatic hyperlactataemia. Early diagnosis expedites safe outpatient care and switching of ART regimens without interruption, in many cases.

The clinical and histological response of HIV-associated kidney disease to antiretroviral therapy in South Africans

BACKGROUND Little is known about the progression of kidney disease in HIV-infected patients in developing countries in the era of antiretroviral therapy (ART). METHODS HIV-infected patients were screened for kidney disease. Kidney biopsies were performed before and after initiation of ART to assess the clinical and histological response to treatment. Data were collected from all participants in accordance with the study protocol. The mean follow-up was 2.4 patient years on ART. RESULTS There was a rapid immunological and renal response to ART. The renal response was reflected by a significant rise in the estimated glomerular filtration rate (eGFR) and rapid regression of proteinuria. The histological patterns were highly variable, ranging from non-specific lesions such as mesangial hyperplasia and interstitial nephritis to HIV-immune complex disease (HIV-ICD) with or without features of HIV-associated nephropathy (HIVAN). In the follow-up biopsies, the histological response to treatment was variable with a combination of no change, progression or regression of lesions. CONCLUSIONS This study demonstrated a spectrum of renal histological lesions in HIV-associated kidney disease. Initiation of ART produced a rapid and sustained clinical renal response in all participants, irrespective of the histology. Follow-up biopsies showed an inconsistent histological response of lesions to treatment. In lesions that regressed, there appeared to be a discrete lag in histological response when compared with the rapid clinical response.

Uniquely South African: time to consider offering HIV-positive donor kidneys to HIV-infected renal failure patients?

Kidney transplantation has been established as the most effective form of renal replacement therapy from a cost and quality of life perspective in the developed world.

Kidney disease in the setting of HIV infection: conclusions from a Kidney Disease: Improving Global Outcomes (KDIGO) Controversies Conference

HIV-positive individuals are at increased risk for kidney disease, including HIV-associated nephropathy, noncollapsing focal segmental glomerulosclerosis, immune-complex kidney disease, and comorbid kidney disease, as well as kidney injury resulting from prolonged exposure to antiretroviral therapy or from opportunistic infections. Clinical guidelines for kidney disease prevention and treatment in HIV-positive individuals are largely extrapolated from studies in the general population, and do not fully incorporate existing knowledge of the unique HIV-related pathways and genetic factors that contribute to the risk of kidney disease in this population. We convened an international panel of experts in nephrology, renal pathology, and infectious diseases to define the pathology of kidney disease in the setting of HIV infection; describe the role of genetics in the natural history, diagnosis, and treatment of kidney disease in HIV-positive individuals; characterize the renal risk-benefit of antiretroviral therapy for HIV treatment and prevention; and define best practices for the prevention and management of kidney disease in HIV-positive individuals.

Morbidity and mortality of black HIV-positive patients with end-stage kidney disease receiving chronic haemodialysis in South Africa

INTRODUCTION There are few published data from South Africa (SA) on the outcomes of black HIV-positive patients receiving chronic haemodialysis. METHODS This retrospective study compared the incidences of vascular and infectious morbidity and mortality in black HIV-positive patients with those in a group of HIV-negative patients matched for ethnicity, age and gender. All the patients were receiving chronic haemodialysis in the medically insured healthcare sector of SA. RESULTS The incidence of tuberculosis and hospital admission rates for vascular access-related infections were significantly higher in the HIV-positive group than the HIV-negative group. The HIV-positive group had significantly lower albumin (p<0.05) and haemoglobin levels (p<0.01), but this did not impact on mortality. Survival in both groups was excellent. In the HIV-positive group, viral suppression rates were suboptimal with <50% of patients on antiretroviral therapy completely virally suppressed. CONCLUSION This study has shown that black HIV-positive patients receiving chronic haemodialysis in a healthcare-funded environment in SA have excellent overall survival in spite of higher hospital admission rates and higher infectious morbidity compared with HIV-negative patients.

HIV-positive kidney transplants for HIV-positive individuals: Attitudes and concerns of South African patients and health care workers

To the Editor: In South Africa, an estimated 30% of the cadaveric donor pool is HIV-infected; in consequence, these organs are discarded. An undersupply of donor organs combined with limited resources tends to exclude HIV-positive patients from renal replacement programmes. We evaluated the acceptance of using HIV-positive donor kidneys for transplantation into HIV-infected recipients, and found that the vast majority (90% of health care workers and 80% of patients, N=20 and 80, respectively) found this approach acceptable for expanding the organ donor pool, which indicates broad patient and health care worker support for using HIV-infected donor kidneys.

Favourable outcomes for the first 10 years of kidney and pancreas transplantation at Wits Donald Gordon Medical Centre, Johannesburg, South Africa

BACKGROUND It is important for centres participating in transplantation in South Africa (SA) to audit their outcomes. Wits Donald Gordon Medical Centre (WDGMC), Johannesburg, SA, opened a transplant unit in 2004. The first 10 years of kidney and pancreas transplantation were reviewed to determine outcomes in respect of recipient and graft survival. METHODS A retrospective review was conducted of all kidney-alone and simultaneous kidney-pancreas (SKP) transplants performed at WDGMC from 1 January 2004 to 31 December 2013, with follow-up to 31 December 2014 to ensure at least 1 year of survival data. Information was accessed using the transplant registers and clinical records in the transplant clinic at WDGMC. The Kaplan-Meier method was used to estimate 1-, 5- and 10-year recipient and graft survival rates for primary (first graft) kidney-alone and SKP transplants. RESULTS The overall 10-year recipient and graft survival rates were 80.4% and 66.8%, respectively, for kidney-alone transplantation. In the kidney-alone group, children tended towards better recipient and graft survival compared with adults, but this was not statistically significant. In adults, recipient survival was significantly better for living than deceased donor type. Recipient and graft survival were significantly lower in black Africans than in the white (largest proportion in the sample) reference group. For SKP transplants, the 10-year recipient survival rate was 84.7%, while kidney and pancreas graft survival rates were 73.1% and 43.2%, respectively. CONCLUSION Outcomes of the first 10 years of kidney and pancreas transplantation at WDGMC compare favourably with local and international survival data.

A Ten Year Retrospective Review of Infections in the First 12 Months Post Paediatric Liver and Liver-Kidney Transplantation at a Single Centre in Johannesburg, South Africa

Introduction Two paediatric liver transplant centres exist in South Africa, one in Johannesburg and the other in Cape Town. The programme in Johannesburg at Wits Donald Gordon Medical Centre (WDGMC) began in 2005 and is now the largest volume paediatric liver transplant unit in the country. WDGMC also hosts the only live donor paediatric liver transplant programme in sub-Saharan Africa. This research determined the incidence and profile of infectious events in the first year after transplantation. Materials and Methods This retrospective record review included paediatric liver and liver/kidney transplants from 2005-2015. The paediatric population was defined as any recipient <18 years of age on the day of transplant. Only laboratory confirmed infections were included. Ethics approval was obtained from the University’s Institutional Review Board. Information was sourced from clinical records and pathology reports. Statistical analysis was carried out using SAS version 9.4 with a 5% significance level. Results and Discussion There were 69 transplants in 65 patients.Most were female (42/69;61%), median age was 49 months (IQR 27-152) and biliary atresia was the most common indication for transplant (42%).A total of 253 infections occurred, mainly in the first three months after transplant. The most common site was bloodstream, followed by the abdomen and urinary tract. Bacterial infections occurred most commonly (193/253;76.3%). Of these, gram negative organisms predominated (120/193; 62.2%) and klebsiella species (50/120; 41.7%) was most frequently identified. In the gram positive group (72/193; 37.3%), enterococcus faecium predominated (25/72; 34.7%). Drug resistance was higher in the gram negative group (75.0%; 36/48) when compared to the gram positives (22.9% (11/48). Prevalence of viral infection was 16.6% (42/253) and fungal was 7.1% (18/253). Candida parapsilosis was the most commonly identified fungus. TB prophylaxis is not routinely administered and there was only one case of mycobacterial infection. This is the first study of its kind from sub-Saharan Africa. Gram negative infections were the most common, mirroring findings from the USA and Israel. What differed was that candida parapsilosis, not albicans, was the most frequently identified fungus and the most common primary site of infection was not the abdomen, but rather the bloodstream. Risk factors that may predispose to infection are severe malnutrition at the time of transplant and delayed referrals of young children with advanced disease. Conclusion Our findings suggest that standard TB prophylaxis may not be warranted, even in a country with high TB infection rates. This research has resulted in an urgent policy review in the transplant unit which has prioritised the nutritional status of children pre-transplant and implemented stringent infection control measures to prevent bloodstream infections. Study data were collected and managed using REDCap1 electronic data capture tools hosted at University of the Witwatersrand. This research was supported by Wits Donald Gordon Medical Centre, Johannesburg, South Africa. Data capture performed by the medical student group, Chanceplant from the University of the Witwatersrand. Figure. No caption available. Figure. No caption available.

An overview of tenofovir and renal disease for the HIV-treating clinician

Tenofovir disoproxil fumarate (TDF, commonly termed ‘tenofovir’) is the antiretroviral most commonly implicated in antiretroviral-induced nephrotoxicity. As patients on successful antiretroviral therapy (ART) age, their risk for developing renal disease may increase in part because of ART itself, but more importantly, because of HIV-associated and non-HIV-associated comorbidity. Therefore, clinicians need an approach to managing renal disease in people on TDF. TDF as a cause of acute kidney injury (AKI) or chronic kidney disease (CKD) is uncommon, and clinicians should actively exclude other causes (Box 1). In TDF-associated AKI, TDF should be interrupted in all cases, and replaced, or ART interrupted altogether. Tenofovir disoproxil fumarate toxicity can present as AKI or CKD, and as a full or partial Fanconi’s syndrome. TDF has a small but definite negative impact on kidney function (up to a 10% decrease in glomerular filtration rate [GFR]). This occurs because of altered tubular function in those exposed to TDF for treatment and as pre-exposure prophylaxis. Renal function should be assessed using creatinine-based estimated GFR at the time of initiation of TDF, if ART is changed, at 1–3 months, and then ideally every 6–12 months if stable. Specific tests of tubular function are not routinely recommended; in the case of clinical concern, a spot protein or albumin: creatinine ratio is preferable, but in resource-limited settings, urine dipstick can be used. More frequent monitoring may be required in those with established CKD (estimated glomerular filtration rate [eGFR] < 50 mL/min/1.73 m2) or risk factors for kidney disease. The most common risk factors are comorbid hypertension, diabetes, HIV-associated kidney disease, hepatitis B or C co-infection, and TDF in combination with a ritonavir-boosted protease inhibitor. Management of these comorbid conditions must be prioritised in this group. If baseline screening eGFR is < 50 mL/min/1.73 m2, abacavir (the preferred option), and dose-adjusted TDF (useful if concomitant hepatitis B), zidovudine or stavudine (d4T) remain alternatives to full-dose TDF. If there is a rapid decline in kidney function (eGFR drops by more than 25% and decreases to < 50 mL/min/1.73 m2 from of baseline function), or there is new onset or worsening of proteinuria or albuminuria, clinicians should review ART and other potentially nephrotoxic medications and comorbidity and conduct further testing if indicated. If kidney function does not improve after addressing reversible causes of renal failure, then referral to a nephrologist is appropriate. In the case of severe CKD, timeous referral for planning for renal replacement therapy is recommended. Tenofovir alafenamide, a prodrug of tenofovir, appears to have less renal toxicity and is likely to replace TDF in future.