Betjes, M.G.H. (Michiel)

Verhagen, D.W.

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Case ReportStable improvement of renal function after initiation of highly activeanti-retroviral therapy in patients with HIV-1-associated nephropathyMichiel G. H. Betjes1 and Dominique W. M. Verhagen21Academic Hospital Rotterdam, Dijkzigt, Department of Internal Medicine, Division of Nephrology, Rotterdam,The Netherlands and 2Department of Infectious Diseases, Tropical Medicine and AIDS, F4-222, Academic MedicalCentre, Amsterdam, The NetherlandsKeywords: ACE-inhibition; anti-retroviral therapy;glomerulosclerose; HIV-1; nephropathy; proteinuriaIntroductionInfection with human immunodeficiency virus type 1(HIV-1) is associated with a variety of well-knownrenal diseases like IgA nephropathy, membranousnephropathy, and haemolytic uraemic syndrome [1].HIV-associated nephropathy (HIVAN) is now beingrecognized as a distinct clinico-pathological entity thatpresents with proteinuria in the nephrotic range andimpairment of renal function [1]. Untreated, HIVANcaries a poor prognosis and invariably leads to end-stage renal failure within months. The most strikingfinding on renal biopsy is collapsing focal glomerulo-sclerosis, but all renal compartments are essentiallyaffected [1]. HIVAN is predominantly seen in blackpatients and has become a major cause for end-stagerenal disease (ESRD) in this patient group. Treatmentof HIVAN has included the use of steroids, ACE-inhibition and anti-retroviral drugs but the optimaltreatment is not known [1]. Corticosteroids and ACE-inhibition probably slow down the progression toESRD especially in cases with mild to moderate renalimpairment. An animal model of mice transgenic foran HIV-1 gene construct suggested a direct pathogeniceffect of HIV on renal cells [2]. Aggressive reductionof the viral load by a combination of anti-retroviraldrugs, also known as highly active anti-retroviraltherapy (HAART), is now considered standard ther-apy for HIV-1 infection. Anecdotal data suggest thatmarked improvement of renal function may occurafter starting HAART [3]. Preliminary reports showeda better renal survival for patients with HIVANtreated with HAART [4,5]. Prospective randomizedclinical trials comparing different treatment regimesfor HIVAN have not been performed. Based onpresent data, HAART combined with ACE-inhibitionmay be the optimal treatment for HIVAN. In thisreport we describe three patients with HIVAN, whopresented with rapidly progressive renal insufficiencyand were not treated previously for their HIV-1infection. Marked and prolonged improvement ofrenal function was established after starting HAARTand ACE-inhibition.Case 1A 30-year-old black female patient was admitted witha 1-week history of general malaise, increase in weight,and peripheral oedema. Her weight was 72.7 kg andher blood pressure was 120u60 mmHg. There weresigns of oedema periorbitally and at the lower legs.Multiple ulcera were present on the buttocks.Laboratory tests showed a plasma creatinine of9.17 mgudl, urea 84.0 mgudl, and albumin 17 gul. Twomonths before the plasma creatinine concentrationwas 0.84 mgudl. The urinary sediment revealed fourto 10 erythrocytes and four to 10 leukocytes per highpower field and urinary protein was 16 guday. Ultra-sound examination showed normal sized kidneysmeasuring 11 cm with increased echogenicity of thecortex.HIV-1 antibodies were present and the viral loadwas 210 000 copiesuml. The CD4-positive lymphocytecount was 30umm3. Tests for collagen diseases,vasculitis, or hepatitis were all negative. Smear culturesfrom the skin ulcers were positive for herpes simplexvirus. A renal biopsy was performed. Microscopicexamination revealed 20 glomeruli, all showing avarying degree of collapse of the capillaries withareas of proliferation of visceral podocytes. In themesangium there was a slight proliferation ofmesangial cells and minimal fibrosis. The tubuli wereCorrespondence and offprint requests to: Michiel G. H. Betjes, MD,PhD, Academic Hospital Rotterdam, Dijkzigt, Department ofInternal Medicine, Division of Nephrology, Dr Molewater plein40, NL-3015 GD Rotterdam, The Netherlands.Email: betjes@inw1.azr.nlNephrol Dial Transplant (2002) 17: 1836–1839# 2002 European Renal Association–European Dialysis and Transplant Associationatrophic with cystic dilatation. In the interstitiumsome oedema and fibrosis was present with minimalinfiltration of mononuclear cells. A diagnosis ofHIVAN was made but the patient did not accept thediagnosis of HIV infection and, therefore, refused totake anti-retroviral medication the first 3 months ofher admission. In these months she was treated withdiuretics and a brief period of ACE-inhibition. Twomonths after starting HAART, containing lamivudine,stavudine, and nevirapin, the viral load had declinedto 1200 copiesuml and the CD4 cell count increased to280umm3. This was accompanied by a rapid and stableimprovement of renal function (Figure 1, top).Shortly after admission her clinical course wasfurther complicated by a Pneumocystis carinii pneu-monia infection, a pneumonia and bacteraemia causedby Streptococcus pneumonia and a Candida albicansesophagitis, for which she was treated successfully.Eighteenmonths afterpresentation shehadgained20 kgin weight with stable plasma creatinine concentrations.Case 2A 32-year-old male black patient presented withcomplaints of general malaise and a short history ofprogressive oedema of the lower legs. His bloodpressure was 140u70 mmHg, weight 69 kg, and height172 cm. There were signs of bilateral pleural effusionand on the lower legs peripheral oedema extendingto the knees was found. Laboratory investigationsshowed a plasma creatinine of 11.3 mgudl, urea94.4 mgudl, and albumin 16 gul. Two weeks before hisplasma creatinine was 6.8 mgudl. Additional labor-atory tests revealed a normal urinary sediment onmicroscopy with a urinary protein excretion of13 gu24 h. Tests for collagen diseases, vasculitis, orhepatitis were negative. Antibodies to HIV-1 werepresent. His CD4 lymphocyte count was below thelower level of detection and the viral load 40 000 viralcopiesuml. Ultrasonography showed large and swollenkidneys. A percutaneous kidney biopsy could notbe performed because of a prolonged bleeding timethat could not be corrected. He was treated withfurosemide, enalapril, and HAART consisting ofretonavir, saquinavir, lamivudine, and stavudine(Figure 1). His renal function improved markedlyand the viral load dropped below 50 copiesuml.Four weeks after starting HAART the bleedingtime was normal and a kidney biopsy was performed.It showed changes typical for HIVAN. All the 11glomeruli showed significant segmental or global tuftcollapse with wrinkling of the basal membrane andepithelial crescents in some of the glomeruli. Themesangial extracellular matrix was increased withvariable mesangial cell proliferation. The tubuli wereatrophic with cystic dilatation and were embeddedin an interstitium with fibrosis and variable infiltrationof mononuclear cells. On electron-microscopic exam-ination glomerular endothelial cells showed tubulo-reticular inclusions. No significant deposits ofimmunoglobulins or complement could be detected.Case 3A 40-year-old female black patient was seen at theoutpatient clinic of the gastroenterology departmentbecause of weight loss. She used no medication ordrugs. Pneumonia of the middle lobe was diagnosedwhich was treated with antibiotics orally. Additionalinvestigations revealed a positive HIV-1 serology witha lowered CD4-positive lymphocyte count of 160umm3and a viral load of 124 000 copiesuml. She was referredto the outpatient clinic of the department of infectiousdiseases. Her blood pressure was 130u85 mmHg and nosigns of oedema were present; plasma creatinine was0.89 mgudl. Shortly thereafter, she developed a severeherpes zoster infection ophthalmicus, which wastreated appropriately. Anti-retroviral therapy couldnot be started because of problems with the healthinsurance. During follow-up, renal function deterior-ated. The urinary sediment revealed four to 10erythrocytes and four to 10 leukocytes per highpower field and urinary protein was 17.2 guday.Serology tests were negative for hepatitis C andpositive for hepatitis B surface and core antibody.Ultrasonography showed kidneys measuring 11 cmwith a hyperechogenic cortex.A renal biopsy was performed that contained 34glomeruli, 13 showing global sclerosis. The otherFig. 1. Plasma creatinine concentrations (j) and proteinuria (s)in time (days) of patients described in Case 1 (top), Case 2 (middle),and Case 3 (bottom). The black bars indicate the period of treatmentwith HAART and the dashed bars the period of treatment withACE-inhibition.1837HIV-1-associated nephropathy and HAARTglomeruli showed signs of focal glomerulosclerosiswith varying collapse and proliferation of visceralpodocytes. The tubuli were atrophic and dilated. Theinterstitium showed infiltration of predominantlylymphocytes and extensive interstitial fibrosis. Somegranular distribution of IgM and complement wasseen on immunofluorescence examination. Electronmicroscopy revealed many tubuloreticular structuresin the endothelial cells of the glomerulus. A diagnosisof HIVAN was made and patient was treated withHAART (stavudine, lamivudine, and efavirenz) inconjunction with ACE-inhibition. The viral loaddropped to 70 copiesuml and the CD4 cell countincreased to 290umm3. The renal function improvedwith a decrease in proteinuria (Figure 1).DiscussionThe pathogenesis of HIVAN most probably involvesa direct cytotoxic effect of HIV on renal cells. Hetero-zygote HIV-1 transgenic mice develop a nephroticsyndrome that closely resembles the human situation[2]. Crossover renal transplantation experiments sug-gested that intrarenal expression of HIV genes isessential in the pathogenesis [2]. The cytopathic effecton podocytes leads to dedifferentiation, proliferation,and loss of contact inhibition thereby causing collaps-ing glomerulosclerosis and heavy proteinuria [6]. Themesangial extracellular matrix may be thickened withincreased numbers of mesangial cells. The tubuli arealways affected and show dedifferentiation, atrophy,and increased apoptosis leading to cystic dilatation.In the interstitium, extensive fibrosis may be observedwith varying infiltration by mononuclear cells [1].Electron microscopic examination of the glomerularendothelial cells frequently reveals tubuloreticularstructures, a feature that is shared with systemic lupuserythematosus (SLE) nephritis. Their presence couldbe caused by the action of interferon-alpha [1].HIV-1 infects renal cells and the kidney may be animportant long-term reservoir for the virus [5]. Theporte d’entree for HIV-1 is not known as cellularreceptors on renal cells like CD4 or the chemokinereceptors have not been identified beyond doubt [7].HIVAN usually occurs in patients with an AIDS-defining diagnosis with high viral loads, suggesting theimportance of a high viral burden in the pathogenesisof HIVAN [1,8]. Also, the introduction of HAARThas decreased the prevalence of HIVAN. The markedsusceptibility of black HIV-1-infected patients and afamilial disposition for ESRD indicates a stronggenetic predisposition for HIVAN [1].Based on pathogenic considerations as mentionedabove, the optimal treatment for HIVAN would bethe lowering of viral load. Since the introduction ofHAART, this has now become feasible in mostHIV-1-infected patients in western countries. Theeffect of HAART on renal function in patients withHIVAN is poorly studied, but is probably beneficial[3–5]. In these reports most patients were alreadytreated with anti-retroviral drugs or were given steroidsthereby limiting the interpretation of the data.Monotherapy with a reverse transcriptase inhibitorlike AZT was associated with a better renal prognosisespecially early in the course of the disease [1].Besides anti-retroviral drugs, corticosteroids andACE-inhibition have been employed in the treatmentof HIVAN. Corticosteroids may improve renal func-tion although data from prospectively randomizedtrials are not available [1]. A recently publishedretrospective cohort study showed that corticosteroidsare effective in slowing down the progression of renaldysfunction although most patients became dialysisdependent after 1 year [1]. The effect of corticosteroidsmay be mediated by diminishing the tubulo-interstitialmononuclear cell infiltrate [9]. Although cortico-steroids can be safely used for a short-term periodin most HIV patients, they should not be givento patients with severe opportunistic infections likeCases 1 and 2.ACE-inhibition seems particularly beneficial in thetreatment of HIVAN. When given to patients withmodest renal insufficiency and proteinuria, ACE-inhibition may markedly slow down further progres-sion of HIVAN [1]. Data from randomized clinicaltrials are unfortunately not available but the beneficialeffects of ACE-inhibition were substantiated inHIV-1 transgenic mice. Captopril given after birth inthese mice largely prevented the clinical and histo-pathological sequences of HIVAN [10]. The effects ofACE-inhibition have been attributed to inhibition ofrenal fibrosis caused by over expression of transforminggrowth factor (TGF)-b and b fibroblast growth factor(FGF). However, renal TGF-b expression did not differbetween the captopril-treated and control mice [10].The three patients in this report showed the typicalclinical and pathological characteristics of HIVAN.They were black, had high viral loads, and impairedimmunity as evidenced by low CD4 lymphocyte countsand serious infections in Cases 1 and 2. None of themwere using medication or drugs. All three patientsshowed a rapid decline in renal function with massiveproteinuria. Renal biopsy revealed the typical collaps-ing glomerulosclerosis with involvement of all renalcell compartments and the presence of reticulotubularstructures. Cases 2 and 3 showed rapid improvementof renal function together with diminishing peripheraloedema during treatment with furosemide. Thisbeneficial effect on renal function is probably mediatedpartly by diminishing the renal oedema as well, as inthe renal biopsies no other rapidly reversible factorcould be identified. Further improvement occurredwith effective lowering of the viral load by givingHAART. The additional role of ACE-inhibition isunclear, although in Case 1 the proteinuria decreasedmarkedly on furosemide and ACE-inhibition withoutHAART. This patient stopped the use of ACE-inhibition early in the course of treatment but never-theless showed an excellent and stable improvement ofrenal function after starting HAART. Corticosteroidswere not given because of the co-existence of severe1838 M. G. H. Betjes and D. W. M. Verhageninfections and the good response on HAART andACE-inhibition. In all the patients HAART was con-tinued but the effect on long-range renal functionremains to be established.The rapid progression of renal dysfunction inHIVAN combines usually with an impressive amountof irreversible renal damage. The ultimate recoveryof renal function is dependent on the amount ofglomerulosclerosis and interstitial fibrosis. The col-lapsed glomerulus with little or no sclerosis mayrecover completely [3]. In our cases no follow-upbiopsies were performed.Based on our preliminary data it appears thatHAART with ACE-inhibition should be the treatmentof choice in HIVAN and that stable and impressiveimprovement in renal function can be achieved. Itshould be noted that the clearance of several anti-retroviral drugs is dependent on renal function and,therefore, dosage reductions or interval extensionsshould be made according to the existing guidelines.The use of corticosteroids can be reserved for patientsthat do not respond favourably to this therapy andhave a dense tubulo-interstitial cell infiltrate. Earlyrecognition and treatment is of paramount importanceto minimize irreversible renal damage and optimallypreserve renal function. The importance is furtherstressed by the fact that HIVAN is now the thirdleading cause of ESRD in blacks in the USA [1].References1. Kimmel P. The nephropathies of HIV infection: pathogenesisand treatment. Curr Opin Nephrol Hypertens 2000; 9: 117–1222. Bruggeman LA, Dikman S, Meng C, Quaggin SE, Coffman TM,Klotman PE. Nephropathy in human immunodeficiency virus-1transgenic mice is due to renal transgene expression. J Clin Invest1997; 100: 84–923. Wali RK, Drachenberg CI, Papadimitriou JC, Keay S,Ramos E. HIV-1 associated nephropathy and response tohighly-active antiretroviral therapy. Lancet 1998; 352: 783–7844. Szcech LA, van der Horst C, Bartlett JA, Heald AE, Svetkey LP.Protease inhibitors are associated with a slowed progression ofHIV-associated nephropathy. J Am Soc Nephrol 1999; 10: A05955. Winston JA, Bruggeman LA, Ross MD et al. Nephropathy andestablishment of a renal reservoir of HIV type 1 during primaryinfection. N Eng J Med 2001; 344: 1979–19846. Schwartz EJ, Cara A, Snoeck H et al. Human immunodeficiencyvirus-1 induces loss of contact inhibition in podocytes. J Am SocNephrol 2001; 12: 1677–16847. Eitner F, Cui F, Hudkins KL, Stokes MB, Segerer S, Mack M.Chemokine receptor CCR5 and CXCR4 expression and HIV-1detection in HIV-associated kidney disease. J Am Soc Nephrol2000; 11: 856–8678. Winston JA, Klotman ME, Klotman PE. HIV-associatednephropathy is a late, not early manifestation of HIV-1infection. Kidney Int 1999; 55: 1036–10409. Briggs WA, Tanawattanacharoen S, Choi MJ, Scheel PJ,Nadasdy T, Racusen L. Clinicopathologic correlates of pre-dnisone treatment of human immunodeficiency virus-associatednephropathy. Am J Kidney Dis 1996; 28: 618–62110. Bird JF, Durham SK, Giancarli MR et al. Captopril preventsnephropathy in HIV-transgenic mice. J Am Soc Nephrol 1998;9: 1441–1447Received for publication: 14.3.02Accepted in revised form: 3.6.021839HIV-1-associated nephropathy and HAART

Stable improvement of renal function after initiation of highly active anti-retroviral therapy in patients with HIV-1-associated nephropathy

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Stable improvement of renal function after initiation of highly active anti-retroviral therapy in patients with HIV-1-associated nephropathy

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