The spectrum of HIV related nephropathy in KwaZulu-Natal : a pathogenetic appraisal and impact of HAART.
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Date
2012
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Abstract
Sub-Saharan Africa bears 70% of the global HIV burden with KwaZulu-Natal (KZN) identified as
the epicenter of this pandemic. HIV related nephropathy (HIVRN) exceeds any other causes of
kidney diseases responsible for end stage renal disease, and has been increasingly recognized as a
significant cause of morbidity and mortality. There is nonetheless a general lack of surveillance
and reporting for HIVRN exists in this geographical region. Consequentially, the aim of this study
was to outline the histopathogical spectrum of HIVRN within KZN. Moreover, from a pathology
standpoint, it is important to address whether HIVRN was a direct consequence of viral infection
of the renal parenchyma or is it a secondary consequence of systemic infection. Additionally, an
evaluation of the efficacy of Highly Active Anti-Retroviral Therapy (HAART) in combination
with angiotensin converting enzyme inhibitors (ACE-I) was performed via a genetic appraisal of
localized replication of HIV-1 in the kidney, ultrastructural review and immunocytochemical
expression of a podocyte maturity and proliferation marker pre and post-HAART.
Blood and renal biopsies were obtained from 30 children with HIV related nephropathy pre-
HAART, followed-up clinically for a period of 1 year. This cohort formed the post-HAART
group. Clinical and demographic data were collated and histopathology, RT-PCR, sequencing,
immunocytochemistry and transmission electron microscopy was performed.
The commonest histopathological form of HIVRN in children (n = 30) in KZN was classical focal
segmental glomerular sclerosis (FSGS) presented in 13(43.33%); mesangial hypercellularity
10(30%); mesangial, HIV associated nephropathy 3(11%) and minimal change disease 2(6.67%).
Post-HAART (n = 9) the predominant pathology was mesangial hypercellularity 5(55.56%); FSGS
3(33.33%) and sclerosing glomerulopathy 1(11.11%). This study also provides data on the
efficacy of HAART combined with ACE-I. The immunostaining pattern of synaptopodin, Ki67
and p24 within the glomerulus expressed as a mean field area percentage was significantly downregulated
in the pre-HAART compared to the post-HAART group respectively (1.14 vs. 4.47%, p
= 0.0068; 1.01 vs.4.68, p < 0.001; 4.5% vs 1.4%, p = 0.0035). The ultrastructural assessment of all
biopsies conformed to their pathological appraisal however, features consistent with viral insult
were observed. Latent HIV reservoirs were observed within the podocyte cytoplasm but was
absent in mesangial or endothelial cells. Real-Time polymerase chain reaction assays provided
evidence of HIV-1 within the kidney. Sequence analysis of the C2-C5 region of HIV-1 env
revealed viral diversity between renal tissue to blood.
In contrast to a collapsing type of FSGS that occurs in adults, the spectrum of paediatric
nephropathy in treatment-naive children within KwaZulu-Natal was FSGS with mesangial
hypercellularity. Additionally, our study demonstrates podocyte phenotype dysregulation pre-
HAART and reconstitution post therapy. Evidence of ultrastructural viral reservoirs within
epithelial cells is supported by a genetic appraisal confirming the ubiquitous presence of HIV DNA
in renal tissue. Moreover, sequence analysis showed viral evolution and compartmentalization
between renal viral reservoirs to blood. Finally, the interplay of viral genes and host response,
influenced by genetic background, may contribute to the variable manifestations of HIV-1
infection in the kidney in our paediatric population.
Description
Thesis (Ph.D.)-University of KwaZulu-Natal, Durban, 2012.
Keywords
Highly active antiretroviral therapy., HIV-positive children--KwaZulu-Natal., Kidneys--Diseases--Pathophysiology., Theses--Optics and imaging.