1 Academic Hospital Rotterdam, Dijkzigt, Department of Internal Medicine, Division of Nephrology, Rotterdam, The Netherlands and 2 Department of Infectious Diseases, Tropical Medicine and AIDS, F4-222, Academic Medical Centre, Amsterdam, The Netherlands
Keywords: ACE-inhibition; anti-retroviral therapy; glomerulosclerose; HIV-1; nephropathy; proteinuria
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Introduction |
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Case 1 |
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Laboratory tests showed a plasma creatinine of 9.17 mg/dl, urea 84.0 mg/dl, and albumin 17 g/l. Two months before the plasma creatinine concentration was 0.84 mg/dl. The urinary sediment revealed four to 10 erythrocytes and four to 10 leukocytes per high power field and urinary protein was 16 g/day. Ultrasound examination showed normal sized kidneys measuring 11 cm with increased echogenicity of the cortex.
HIV-1 antibodies were present and the viral load was 210 000 copies/ml. The CD4-positive lymphocyte count was 30/mm3. Tests for collagen diseases, vasculitis, or hepatitis were all negative. Smear cultures from the skin ulcers were positive for herpes simplex virus. A renal biopsy was performed. Microscopic examination revealed 20 glomeruli, all showing a varying degree of collapse of the capillaries with areas of proliferation of visceral podocytes. In the mesangium there was a slight proliferation of mesangial cells and minimal fibrosis. The tubuli were atrophic with cystic dilatation. In the interstitium some oedema and fibrosis was present with minimal infiltration of mononuclear cells. A diagnosis of HIVAN was made but the patient did not accept the diagnosis of HIV infection and, therefore, refused to take anti-retroviral medication the first 3 months of her admission. In these months she was treated with diuretics and a brief period of ACE-inhibition. Two months after starting HAART, containing lamivudine, stavudine, and nevirapin, the viral load had declined to 1200 copies/ml and the CD4 cell count increased to 280/mm3. This was accompanied by a rapid and stable improvement of renal function (Figure 1, top).
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Case 2 |
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Four weeks after starting HAART the bleeding time was normal and a kidney biopsy was performed. It showed changes typical for HIVAN. All the 11 glomeruli showed significant segmental or global tuft collapse with wrinkling of the basal membrane and epithelial crescents in some of the glomeruli. The mesangial extracellular matrix was increased with variable mesangial cell proliferation. The tubuli were atrophic with cystic dilatation and were embedded in an interstitium with fibrosis and variable infiltration of mononuclear cells. On electron-microscopic examination glomerular endothelial cells showed tubuloreticular inclusions. No significant deposits of immunoglobulins or complement could be detected.
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Case 3 |
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A renal biopsy was performed that contained 34 glomeruli, 13 showing global sclerosis. The other glomeruli showed signs of focal glomerulosclerosis with varying collapse and proliferation of visceral podocytes. The tubuli were atrophic and dilated. The interstitium showed infiltration of predominantly lymphocytes and extensive interstitial fibrosis. Some granular distribution of IgM and complement was seen on immunofluorescence examination. Electron microscopy revealed many tubuloreticular structures in the endothelial cells of the glomerulus. A diagnosis of HIVAN was made and patient was treated with HAART (stavudine, lamivudine, and efavirenz) in conjunction with ACE-inhibition. The viral load dropped to 70 copies/ml and the CD4 cell count increased to 290/mm3. The renal function improved with a decrease in proteinuria (Figure 1).
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Discussion |
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HIV-1 infects renal cells and the kidney may be an important long-term reservoir for the virus [5]. The porte d'entree for HIV-1 is not known as cellular receptors on renal cells like CD4 or the chemokine receptors have not been identified beyond doubt [7].
HIVAN usually occurs in patients with an AIDS-defining diagnosis with high viral loads, suggesting the importance of a high viral burden in the pathogenesis of HIVAN [1,8]. Also, the introduction of HAART has decreased the prevalence of HIVAN. The marked susceptibility of black HIV-1-infected patients and a familial disposition for ESRD indicates a strong genetic predisposition for HIVAN [1].
Based on pathogenic considerations as mentioned above, the optimal treatment for HIVAN would be the lowering of viral load. Since the introduction of HAART, this has now become feasible in most HIV-1-infected patients in western countries. The effect of HAART on renal function in patients with HIVAN is poorly studied, but is probably beneficial [35]. In these reports most patients were already treated with anti-retroviral drugs or were given steroids thereby limiting the interpretation of the data. Monotherapy with a reverse transcriptase inhibitor like AZT was associated with a better renal prognosis especially early in the course of the disease [1].
Besides anti-retroviral drugs, corticosteroids and ACE-inhibition have been employed in the treatment of HIVAN. Corticosteroids may improve renal function although data from prospectively randomized trials are not available [1]. A recently published retrospective cohort study showed that corticosteroids are effective in slowing down the progression of renal dysfunction although most patients became dialysis dependent after 1 year [1]. The effect of corticosteroids may be mediated by diminishing the tubulo-interstitial mononuclear cell infiltrate [9]. Although corticosteroids can be safely used for a short-term period in most HIV patients, they should not be given to patients with severe opportunistic infections like Cases 1 and 2.
ACE-inhibition seems particularly beneficial in the treatment of HIVAN. When given to patients with modest renal insufficiency and proteinuria, ACE-inhibition may markedly slow down further progression of HIVAN [1]. Data from randomized clinical trials are unfortunately not available but the beneficial effects of ACE-inhibition were substantiated in HIV-1 transgenic mice. Captopril given after birth in these mice largely prevented the clinical and histopathological sequences of HIVAN [10]. The effects of ACE-inhibition have been attributed to inhibition of renal fibrosis caused by over expression of transforming growth factor (TGF)-ß and ß fibroblast growth factor (FGF). However, renal TGF-ß expression did not differ between the captopril-treated and control mice [10].
The three patients in this report showed the typical clinical and pathological characteristics of HIVAN. They were black, had high viral loads, and impaired immunity as evidenced by low CD4 lymphocyte counts and serious infections in Cases 1 and 2. None of them were using medication or drugs. All three patients showed a rapid decline in renal function with massive proteinuria. Renal biopsy revealed the typical collapsing glomerulosclerosis with involvement of all renal cell compartments and the presence of reticulotubular structures. Cases 2 and 3 showed rapid improvement of renal function together with diminishing peripheral oedema during treatment with furosemide. This beneficial effect on renal function is probably mediated partly by diminishing the renal oedema as well, as in the renal biopsies no other rapidly reversible factor could be identified. Further improvement occurred with effective lowering of the viral load by giving HAART. The additional role of ACE-inhibition is unclear, although in Case 1 the proteinuria decreased markedly on furosemide and ACE-inhibition without HAART. This patient stopped the use of ACE-inhibition early in the course of treatment but nevertheless showed an excellent and stable improvement of renal function after starting HAART. Corticosteroids were not given because of the co-existence of severe infections and the good response on HAART and ACE-inhibition. In all the patients HAART was continued but the effect on long-range renal function remains to be established.
The rapid progression of renal dysfunction in HIVAN combines usually with an impressive amount of irreversible renal damage. The ultimate recovery of renal function is dependent on the amount of glomerulosclerosis and interstitial fibrosis. The collapsed glomerulus with little or no sclerosis may recover completely [3]. In our cases no follow-up biopsies were performed.
Based on our preliminary data it appears that HAART with ACE-inhibition should be the treatment of choice in HIVAN and that stable and impressive improvement in renal function can be achieved. It should be noted that the clearance of several anti-retroviral drugs is dependent on renal function and, therefore, dosage reductions or interval extensions should be made according to the existing guidelines. The use of corticosteroids can be reserved for patients that do not respond favourably to this therapy and have a dense tubulo-interstitial cell infiltrate. Early recognition and treatment is of paramount importance to minimize irreversible renal damage and optimally preserve renal function. The importance is further stressed by the fact that HIVAN is now the third leading cause of ESRD in blacks in the USA [1].
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Notes |
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References |
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