Nicola Wearne

The spectrum of renal histologies seen in HIV with outcomes, prognostic indicators and clinical correlations

BACKGROUND Two hundred and twenty-one HIV-positive renal biopsies were analysed from Groote Schuur Hospital to determine outcomes and prognostic indicators based on histology and clinical features. METHODS The histology findings were compared with patient demographics, clinical and renal parameters, mortality, CD4 count and date of commencing combined anti-retroviral therapy (cART). Follow-up was between 1 and 3.5 years. RESULTS We found a spectrum of renal histologies in HIV-positive patients of which HIV-associated nephropathy (HIVAN) was the most common histology. cART reduced the mortality in those with any feature of HIVAN by 57% [adjusted hazard ratio (AHR) 0.43, 95% confidence interval (CI) 0.22-0.85]. Of those patients with HIVAN who died, 79% died of renal failure as registered on their death certificate. Proteinuria and microcysts were shown to be poor prognostic indicators (AHR 1.36: 1.09-1.70 and 2.04: 1.24-3.37). In patients with HIVAN alone followed for up to 2 years on cART, estimated glomerular filtration rate remained stable and there was a trend towards decreased proteinuria. cART improved survival in patients with isolated immune complex disease. CONCLUSIONS As mortality is improved in patients with any feature of HIVAN or isolated immune complex disease, cART should be initiated once any of these histological features are established. We believe the spectrum of disease that constitutes HIVAN needs to be more specifically defined. The ultimate outcome may be determined by the histological subtype.

The acute, the chronic and the news of HIV-related renal disease in Africa.

The burden of renal disease in human immunodeficiency virus (HIV) and AIDS patients living in Africa is adversely influenced by inadequate socio-economic and health care infrastructures. Acute kidney injury in HIV-positive patients, mainly as a result of acute tubular necrosis, may arise from a combination of hemodynamic, immunological, and toxic insult. A variety of histopathological forms of chronic kidney disease is also seen in HIV patients; HIV-associated nephropathy (HIVAN) and immune complex disease may require different treatment strategies, which at present are unknown. The role of host and viral genetics is still to be defined, especially in relation to the different viral clades found in various parts of the world and within Africa. The arrival and availability of highly active antiretroviral therapy in Africa has given impetus to research into the outcome of the renal diseases that are found in those with HIV. It has also generated a new look into policies governing dialysis and transplantation in this group where previously there were none.

Ambulatory blood pressure profiles in a subset of HIV-positive patients pre and post antiretroviral therapy : cardiovascular topic

Summary Objectives Human immunodeficiency virus (HIV) and antiretroviral therapy (ART) are associated with renal disease and increased cardiovascular risk. The relationship between HIV and ambulatory blood pressure (ABP) non-dipping status, a risk factor for cardiovascular events and target-organ damage, has never been assessed in South Africa. Study objectives were to establish the prevalence of chronic kidney disease, and assess the ABP profile in asymptomatic HIV-positive clinic out-patients. Methods This was a prospective cohort study. Office blood pressure (BP), urinary microalbumin–creatinine ratio, urine dipsticks, serum creatinine and estimated glomerular filtration rate (eGFR) were measured at baseline and six months after ART initiation. A subset of HIV-positive subjects and an HIV-negative control group underwent 24-hour ABP monitoring. Results No patient had an eGFR < 60 ml/min, three patients (4.7%) had microalbuminuria and one had macroalbuminuria. Mean office systolic BP was 111 ± 14 mmHg at baseline and increased by 5 mmHg to 116 ± 14 mmHg (p = 0.05) at six months. This increase was not confirmed by ABP monitoring. In the HIV-positive and -negative patients, the prevalences of non-dipping were 80 and 52.9%, respectively (p = 0.05, odds ratio = 3.56, 95% CI: 0.96–13.13). No relationship between dipping status and ART usage was found. Conclusion The prevalence of chronic kidney disease (CKD) was lower than anticipated. HIV infection was associated with an ambulatory non-dipping status, which suggests an underlying dysregulation of the cardiovascular system. In the short term, ART does not seem to improve loss of circadian rhythm.

The Evolution of Our Knowledge of HIV-Associated Kidney Disease in Africa

Human immunodeficiency virus (HIV) infection started in Africa circa 1930. South Africa has the highest prevalence rate in the world. Although reports of HIV-associated nephropathy (HIVAN) appeared in the early 1980s, the earliest report from sub-Saharan Africa (SSA) came in 1994. Geographical, socioeconomic, political, and ethical factors have worked in concert to shape the character of HIV disease as it is seen in SSA. Political leaders within SSA have, through their actions, significantly contributed to the incidence of HIV infection. Black females, who often face cultural suppression and disadvantage, have a higher prevalence of HIV than males. Too few studies and outcomes data have bedeviled the statistics in SSA in relation to HIVAN prevalence and its management. Much of what is written is approximation and anecdotal. The largest reliable biopsy series comes from the University of Cape Town, where a workable classification of HIVAN has been developed to enable standardization of terminology. Histologic and clinical prognostic indicators with outcomes have been evaluated using this classification. Patients with HIV who present with acute kidney injury appear to have mainly acute tubular necrosis due to sepsis, dehydration, and nephrotoxic drugs. Since the rollout of combination antiretroviral therapy, the extent of HIV infection and kidney disease continues to be modified and possibly retarded.

HIV-associated renal disease - an overview.

The cause of the human immunodeficiency virus (HIV) epidemic in South Africa (SA) was worsened by the denial by key political players that HIV causes acquired immunodeficiency syndrome (AIDS). South Africa continues to have the highest rate of HIV world-wide, which has had a huge impact on the development of both chronic kidney disease and acute kidney injury. Fortunately, there is now an effective antiretroviral therapy (ART) roll-out program. SA is also dealing with a collision of epidemics of HIV, tuberculosis, and non-communicable disease, particularly hypertension and diabetes. This has been evidenced by recent data seen in the reinstated SA renal registry. There is also an unacceptably high rate of tuberculosis in regions of SA, this has led to high rates of granulomatous interstitial nephritis (GIN) and case reports of TB-GIN immune reconstitution inflammatory syndrome (IRIS). HIV-associated nephropathy (HIVAN) remains common in SA and responds well to ART. The definitive diagnosis requires a renal biopsy, which is often not possible in many regions of sub-Saharan Africa. Unfortunately, there is still a high rate of HIVAN in SA due to late presentation and lack of effective screening for renal disease in HIV-positive patients. Transplantation for HIV-positive donors to positive recipients offers a unique and encouraging way forward for these patients.

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.

High prevalence of “non-dipping” blood pressure and vascular stiffness in HIV-infected South Africans on antiretrovirals

Background HIV-infected individuals are at increased risk of tissue inflammation and accelerated vascular aging (‘inflamm-aging’). Abnormal diurnal blood pressure (BP) rhythms such as non-dipping may contribute to an increased risk of cardiovascular and cerebrovascular events in HIV infected individuals. However, little data exists on ambulatory blood pressure (ABP) and measures of vascular stiffness in the black African HIV infected population. Methods This is a cross-sectional analysis of otherwise well, HIV infected outpatients on ART for >5 years. Study assessments included: 24hr ABP monitoring, pulse wave velocity (PWV) and central aortic systolic pressure (CASP) using a AtCor Medical Sphygmocor device, fasting lipogram, oral glucose tolerance test, high-sensitivity C-reactive protein (hsCRP) and anthropometric data. Patients completed a questionnaire of autonomic symptoms. CD4+ counts and viral loads were obtained from the National Laboratory results system. Results Sixty seven black participants were included in the analysis of whom 91% (n = 61) were female with a mean age of 42.2 ± 8.6 years. The median duration on ART was 7.5 years (IQR = 6–10), 84% were virally supressed and the median CD4 count was 529.5cells/mm3 (IQR = 372.0–686.5). The majority (67%) were classified as overweight and 76% had an increased waist circumference, yet only 88% of participants were normotensive. A hsCRP level in the high cardiovascular risk category was found in 68% of participants. The prevalence of non-dipping BP was 65%. Interestingly, there was no association on multivariable analysis between dipping status and traditional risk factors for non-dipping BP, such as: obesity, autonomic dysfunction and older age. Conclusion This relatively young cross-sectional sample of predominantly normotensive, but overweight black women on effective ART >5 years showed: a high prevalence of non-dipping BP, inflammation and vascular stiffness. Causality cannot be inferred but cardiovascular risk reduction should be emphasized in these patients.

Continuous ambulatory peritoneal dialysis: perspectives on patient selection in low- to middle-income countries

Chronic kidney disease is a major public health problem that continues to show an unrelenting global increase in prevalence. The prevalence of chronic kidney disease has been predicted to grow the fastest in low- to middle-income countries (LMICs). There is evidence that people living in LMICs have the highest need for renal replacement therapy (RRT) despite the lowest access to various modalities of treatment. As continuous ambulatory peritoneal dialysis (CAPD) does not require advanced technologies, much infrastructure, or need for dialysis staff support, it should be an ideal form of RRT in LMICs, particularly for those living in remote areas. However, CAPD is scarcely available in many LMICs, and even where available, there are several hurdles to be confronted regarding patient selection for this modality. High cost of CAPD due to unavailability of fluids, low patient education and motivation, low remuneration for nephrologists, lack of expertise/experience for catheter insertion and management of complications, presence of associated comorbid diseases, and various socio-demographic factors contribute significantly toward reduced patient selection for CAPD. Cost of CAPD fluids seems to be a major constraint given that many countries do not have the capacity to manufacture fluids but instead rely heavily on fluids imported from developed countries. There is need to invest in fluid manufacturing (either nationally or regionally) in LMICs to improve uptake of patients treated with CAPD. Workforce training and retraining will be necessary to ensure that there is coordination of CAPD programs and increase the use of protocols designed to improve CAPD outcomes such as insertion of catheters, treatment of peritonitis, and treatment of complications associated with CAPD. Training of nephrology workforce in CAPD will increase workforce experience and make CAPD a more acceptable RRT modality with improved outcomes.

Invited Commentary Should We Be Rationing Dialysis in South Africa in the 21 st Century?PointCounterpoint

South Africa faces a quadruple burden of disease, with human immunodeficiency (HIV) infection and tuberculosis, maternal and child health, injury and violence, and non-communicable disease constituting ‘colliding’ epidemics (1). Since 2009, non-communicable diseases (NCD) collectively have overtaken infectious diseases as the leading cause of mortality, accounting for 55.5% of all deaths in South Africa in 2015 (1,2). Kidney disease accounts for an ever-increasing number of these NCD deaths (3). The increase in chronic kidney disease in South Africa has placed an enormous strain on a health system already buckling under the pressure of the HIV/tuberculosis epidemic (4). South Africa has offered limited access to dialysis and kidney transplantation to its citizens since the 1960s, but initially, no clear policy guided the selection of patients for renal replacement treatment. The implicit rationing of dialysis resulted in unacceptable inequities (5), which triggered a response from nephrologists in the Western Cape and ultimately a formal adoption by the provincial government of a priority-setting policy that was acceptable, and could be defended morally, ethically, and legally (6). The South African economy has been buffeted by a combination of the global recession and political uncertainties; the national economy is growing at about 1.1% per annum, while the end-stage kidney disease (ESKD) burden is increasing at an estimated 7% per annum; this discrepancy further compromises the ability of the country to meet the renal replacement needs of ESKD patients (4).

Outcomes and Challenges of a PD-First Program, a South-African Perspective

Background: South Africa (SA) currently performs the most peritoneal dialysis (PD) in Africa. Yet outcome data on PD programs on the continent are limited. With the escalating need for renal replacement, PD remains a life-saving modality especially as hemodialysis is limited in the public sector. This study aims to evaluate and report the outcomes of a PD-First program performed in a resource-limited setting and identify factors linked to poor outcomes. Methods: This observational cohort study was performed at Groote Schuur Hospital, analyzing all PD patients retrospectively from January 2008 to June 2014 and thereafter prospectively until June 2015. Variables included demographics, adequacy, modality, fluid status, cardiovascular disease, and diabetes. The influence of these variables on peritonitis rate, technique survival, and patient survival was assessed. Results: In total, 230 patients were initiated on PD, 31 of whom excluded as they were on PD for < 90 days. The mean age was 39.7 ± 10.4 years (standard deviation [SD]), 49.8% were male, 63.8% were mixed ancestry and 9.8 % were diabetic at dialysis initiation. The average length of time on PD was 17 months (interquartile range [IQR] 8 – 32). The peritonitis rate was 0.87 (confidence interval [CI] 7.8 – 9.7) events per patient year. The 1-, 2- and 5-year patient and technique survival was 91.3%, 79.6%, 50.2% and 85.0%, 75.2%, 45.0%, respectively. Diabetes subdistribution hazard ratio (SHR) 3.16 (95% CI 1.34 – 7.45, p = 0.009) strongly predicted an increased cumulative incidence for death when accounting for competing risks. African ethnicity SHR 2.16 (95% CI 1.26 – 3.71, p = 0.005) was a strong predictor of increased cumulative incidence for technique failure. Conclusions: In our PD-First program the results are encouraging, despite the lack of home visits due to safety, resource limitations, and a high disease burden. Technique failure in the African race needs further evaluation. Peritoneal dialysis remains a viable, life-saving alternative in an African setting.