Rajendra Bhimma
Department of Maternal & Child Health, Nelson R Mandela School of Medicine, University of Kwazulu-Natal, Durban, South Africa

Address for Correspondence: R Bhimma, Department of Paediatrics & Child Health, Nelson R Mandela School of Medicine, University of Kwazulu-Natal, Private Bag 7, Congella, 4013, South Africa. Email: bhimma@ukzn.ac.za

Keywords: Human Immunodeficiency virus, renal disease, children, HIV, HIVAN, HIV nephropathy, AIDS, proteinuria

Introduction
Following the first reports of kidney disease associated with AIDS in 1984 and 1985 in New York, New York, and Miami, Florida, there has now developed several lines of evidence that point to kidney disease as a major complication of human immunodeficiency virus (HIV) infection [1,2,3]. In adults, kidney function is abnormal in over 30% of HIV-infected patients and kidney disease resulting from HIV associated nephropathy (HIVAN) in African Americans aged 20-64 years in the United States is the third leading cause of end-stage kidney disease [4,5,6].

HIV infection is associated with protean manifestations, with the kidney being a common target. A variety of kidney disorders may occur during the course of HIV infection which can be either acute or chronic [7]. Almost 30 million HIV-infected people live in Africa, especially sub-Saharan Africa which is the most affected region in the world [8]. The true prevalence of kidney disorders associated with HIV-infection in Africa is unknown largely due to lack of surveillance and reporting of kidney disease in HIV positive patients. This is particularly so in children since in many paediatric centres renal biopsies are not performed regularly in HIV-infected patients even with persistent proteinuria [9,10,11,12,13,14,15]. In the USA, Strauss et al [10] and others [12,13,14,15] reported a prevalence of childhood HIVAN of approximately 10-15% with over 95% being African American children. They also made the observation that HIVAN in children progressed at a lower rate when compared with adults [10,16]. Black patients have a much higher risk of developing end-stage kidney disease from HIV-1 infections compared with white patients [17].

Clinical Syndromes associated with HIV infection
Renal disease associated with HIV-1 infection can be divided into four major groups: (1) acute tubular dysfunction with fluid and electrolyte abnormalities and/or renal failure caused by infections and nephrotoxic drugs, (2) HIVAN; (3) immune mediated glomerulopathies (IgA nephropathy, lupus-like syndromes, and (4) HIV-associated thrombotic mesangiopathies, including atypical forms of haemolytic uraemic syndrome [18,9,10].

Table 1 shows the common cause of acute and chronic renal failure in patients with HIV1-infection. Early features of renal involvement include proteinuria, urinary casts, fluid and electrolyte disorders and enlarged echogenic kidneys on ultrasound. Nephrotic range proteinuria has been reported with a prevalence of 7% and 13% of HIV-1 infected adults and children respectively [19]. HIV-associated nephrotic syndrome presents with heavy proteinuria, hypoalbuminuria, and normal or low cholesterol in contrast to the typical nephrotic syndrome of childhood, which presents with hypercholesterolemia. Peripheral oedema is often mild or uncommon probably due to the oncotic pressure being maintained by the hypergammaglobulinaemia associated with HIV-1 infection [20]. Hypertension and haematuria (macroscopic or microscopic) is rare, and when present will suggest renal disease other than HIVAN [20]. Other symptoms are non-specific and include fatigue, malaise, anorexia and pruritis. It is important to note that in the majority of cases reported of HIV related renal diseases, particularly HIVAN, diagnoses was made as a result of routine investigation of patients presenting with acute or chronic renal failure. There is a strong racial bias in the development of HIVAN with black patients predominating, forming 85-97% of patients with this diagnosis [21,22,23,24]. In adults it has been reported that black patients have a relative risk of 51.1% for developing end-stage kidney disease from AIDS or an AIDS defining diagnosis compared with white patients [25] HIVAN in other racial groups is usually associated with intravenous heroin misuse [26,27,28], although between 5 and 50% of black adult patients with HIV have also been reported to be using illicit drugs such as heroin [29,21]. In contrast IgA nephropathy is relatively common in men of European decent [30,31,32]. Thus it would appear that non black patients with HIV-infection having renal affectation typically presenting with a glomerulonephritis whilst black patients usually present with proteinuria (usually nephrotic range) associated with HIVAN. Thrombotic microangiopathy associated with HIV is also more common in Caucasians than Blacks and is associated with a worse prognosis than the idiopathic forms of TTP/HUS [33].

Table 1: Common causes of renal failure

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Acute renal failure
      Drug related nephrotoxicity*
      Hemolytic uraemic syndrome
      Acute tubular necrosis (toxic/ischemic)
      Rhabdomyolysis
      Intrarenal and extrarenal obstructive nephropathy (mostly drug induced)†
      HIV associated nephropathy
      Acute interstitial nephritis
      Membranoproliferative glomerulonephritis‡
      Lupus-like glomerulonephritis
      IgA nephropathy

Chronic renal failure
      HIV associated nephropathy
      Membranous glomerulonephritis
      Membranoproliferative glomerulonephritis
      IgA nephropathy

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*For example, amphotericin B, foscarnet. †Related to sulphonamides and indinavir. ‡Usually related to hepatitis C or B

Pathogenesis
Although the ubiquitous presence of HIV DNA has been demonstrated in renal tissue of HIV-infected patients [34], proteinuria is present in less than half of HIV-infected patients and advanced stages of chronic kidney disease are an uncommon complication of HIV-infection [35,30,36,37]. Therefore it would appear that a simple infection of renal cells in itself is not sufficient for the development of nephropathy. Various cytokines, chemokinesis and growth factors have been shown to be increased in renal tissue from patients with HIV infection regardless of the presence of renal disease [38,39,40]. Thus the pathogenesis of HIV-associated renal disease remains elusive and it will appear that there is a complex inter-relationship between host factors (including genetic susceptibility and socio economic status) with effects on renal cell matrix biology, cytokines, growth factors and chemokine responses and infection by HIV-1 of renal cells. Fig.1 shows a model for glomerular and tubular injury induced by HIV-1.

Fig 1. Model for glomerular and tubular cell injury induced by HIV-1



HIV Associated Nephropathy
This is the most common form of chronic kidney disease resulting directly from HIV infection [41]. Macroscopically the kidneys appear oedematous and microscopically there is a combination of glomerular and tubulointerstitial change [42,43]. The characteristic histological finding is the presence of focal collapsing glomerulopathy although in children mesangial hyperplasia is found with almost equal frequency [9,10,11,12,13,14,15]. Although the mechanism responsible for the development of mesangial hyperplasia is not clearly understood, children with mesangial hyperplasia have a slow rate of progression of their renal disease compared to those with FSGS [15]. In patients with FSGS, renal glomeruli show extensive capillary collapse, tubuloreticular inclusions in endothelial cells, and pronounced hypertrophy and hyperplasia of visceral epithelial cells [1,2,42,43] Increasing evidence regarding the pathogenesis of HIVAN suggests that: (1) The characteristic renal enlargement of HIVAN is due to an increased proliferation of renal tubular epithelial cells, (2) expression of HIV-1 genes in renal tubular epithelial cells is associated with multicystic lesions, (3) the renal accumulation of bFGF/FGF-2 being particularly responsible for these changes. Barisoni et al reported that a dysregulated podocyte phenotype was associated with the proliferation of podocytes and development of HIV-collapsing glomerulopathy and other forms of collapsing FSGS. Under these circumstances, podocytes lose markers of all differentiation (e.g. synaptopodin, podocalyxin, Wilm's tumor antigen (WT-I)), and proliferate [44].

Management
The management of HIV related renal diseases involves a multidisciplinary team effort since the outcome of renal disease is affected by the presence of other AIDS-related illnesses e.g. cardiomyopathy, pulmonary disease, encephalopathy. Therefore the treatment of HIV-1 infection should be a priority over the treatment of renal disease as the only reliable predictor of death is the intensity of immunodeficiency whilst the severity of renal diseases does not appear to affect patient survival [21]. Histological diagnoses influence treatment options and prognoses and is therefore recommended whenever feasible [45]. Also the risks related to biopsy are similar in both HIV positive and HIV negative patients.

Antiretroviral Treatment
Antiretroviral treatment (ART) is the mainstay of treatment of HIV related renal disease. Quick suppression of the viral load with highly active antiretroviral therapy (HAART) significantly slows viral replication and prevents resistant mutations. The kidneys are a reservoir for HIV-1 infection and in one study; follow-up renal biopsy demonstrated dramatic improvements in histological findings following HAART [46]. However in some patients despite HAART therapy there may be inexorable progression to ESRD [47] It is possible that HAART may potentially decrease the development of HIV related nephropathy [48,49].

ACE inhibition
Several small observational studies have shown ACE inhibition to improve outcome of patients with HIVAN [50,51,52]. The exact mechanism of action of ACE inhibitors in HIV nephropathy is unknown. The salubrious effects of these agents may be related to hemodynamic effects a reduction in the transglomerular passage of simple proteins and through cytokine modulation with inhibition of transforming growth factor-beta leading to an antiproliferative effect.

Corticosteroids
Several studies have reported improvement in renal function and proteinuria for patients with HIVAN receiving corticosteroid therapy in the pre HAART era [53,54,55,56,57]. However before giving steroids, underlying infection should be actively excluded. Recent data suggests that short courses of steroids together with HAART even in patients with very low CD4 counts (< 200 cells/m2) is relatively safe and does not predispose to severe infection. The optimum duration and intensity of corticosteroid therapy in HIV nephropathy remains to be determined [58,59]. Experts opinion suggests that in patients whose renal function deteriorates despite HAART, prednisone therapy at 1mg/kg of body weight per day (maximum 80mg) should be given for 2 months, followed by a 2-4 month taper. These patients must be free of active infection or illicit drug use.

General Measures
Hypertension accelerates progression to ESRD and in both HIV negative and HIV positive patients with nephropathy, one should aim to control hypertension in accordance to standard guidelines. Non pharmacological therapies such as salt restriction should be encouraged. The use of ACE inhibitors and angiotensin receptor blockers as first line therapy is advocated particularly in patients with proteinuria and hypertension e.g. HIVAN. Calcium channel blockers should be avoided in patients on protease inhibitors as potential interaction includes severe hypotension and possible conduction delays [60]. Dietary protein restriction is unproven and may have potentially harmful consequences in patients who are malnourished.

Dialysis
Following the introduction of HAART, survival rates are comparable to dialysis patients without HIV-infection. The choice of dialysis modality between haemodialysis and peritoneal dialysis does not influence survival in this group of patients [61]. Since HIV has been isolated in peritoneal dialysate fluid, this should be handled with great care as it is potentially infectious [62]. Patients should be instructed to pour dialysate lines and bags by tying them in plastic bags and disposing the plastic bags in conventional home garbage [63].

Transplantation
Transplantation of HIV-infected patients remains a major challenge for the following reasons: (1) immunosuppressive medication may further increase the risk of opportunistic infections resulting in increased morbidity and mortality; (2) immunosuppression may accelerate viral replication leading to disease progression and lastly (3) there is concern that scarce resources are being used in patients who may have a worse prognosis than HIV-negative patients. In most developing countries HIV infected individuals are usually denied access to renal replacement therapy. UNOS (United Nations Organization Sharing) presently does not prohibit HIV-positive recipients from transplantation.

In the pre-HAART era HIV-infected patients were transplanted inadvertently. Alternatively, HIV was acquired pre-or-post transplant. The few patients with unrecognized HIV-infection who received a transplant had variable courses often characterized by rapid progression of HIV infection. In the post-HAART period after 1996, following the dramatic reduction of morbidity and mortality increasing number of patients are recipients of kidney transplants. The safety of immunosuppression in these patients is of particular concern. Some studies have shown a beneficial impact of immunosuppression on HIV-infection [64,65,66]. This may be due to reduction in the pool of activated T cell targets for new infections, decreasing the immune activation characteristic of HIV pathogenesis [67], inhibiting HIV replication [68], and/or interacting synergistically with antiretroviral agents [69,70].

In one study, 1- and 2- year actuarial patient survival was 85% and 82% respectively, and graft survival was 75% and 71% respectively. Plasma HIV-1 RNA remained undetectable, and CD4 counts remained in excess of 400cells/µl with no evidence of AIDS for up to 2 years [71]. These results were comparable to other high-risk populations receiving kidney transplants. However, surprisingly high rates of acute and chronic rejection have been observed among HIV infected kidney transplant recipients, the aetiology of which to date remains elusive [72,73].

Larger controlled studies are required to determine the impact of HIV infection in kidney transplant recipients and presently in developing countries, HIV related ESRD remains a relative contraindication to kidney transplantation.

Screening and Early detection of HIV related renal disease
The HIV Medicine Association of the Infectious Disease Society of America has made the following recommendation with respect to screening and early detection of kidney disease in HIV-1 infected individuals: [74].

1. All patients at the time of HIV diagnosis should be assessed for existing kidney disease with a screening urine analysis for proteinuria and a calculated estimate of renal function.
2. Patients with no evidence of proteinuria at initial evaluation but at high risk of developing kidney disease (i.e. black race, CD4+ cell counts < 200?l or HIV RNA levels >4000 copies/ml, and those with diabetes mellitus, hypertension, or coinfection with Hepatitis C virus) should undergo annual screening. Renal function should be estimated on a yearly basis to assess for changes over time.
3. Patients with persistent proteinuria of grade =1+ by dipsticks analysis or GFR < 60ml/min per 1.73m2 should be referred to a nephrologist.

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Bhimma R. HIV and Renal Disease in Children. HIV in Children[serial online] 2007 [cited 2007 October 15]1;1. Available from:
http://www.hivinchildren.org/Treatment_issues/hiv_renaldisease.asp