Bihl, G

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CLINICALGeoffrey Bihl, ME BCh, MM,d, FCP (SA)7j'gerberg Academic Hospital, 1jJgerberg, W CapeHIV-RELATED RENAL DISEASE - A CLINICALAND PRACTICAL APPROACH IN THE SOUTHAFRICAN CONTEXTEPIDEMIOLOGYThe clinical determinants of HIVAN are heterogeneous,although commonly described risk factors for itsdevelopment include black ethnic group, male gender,injected drug use, a low CD4 count and a high viral load.Although the exact pathogenesis is not completelyunderstood, two distinct features appear to be ofimportance:• molecular mechanisms related to geneticpredisposition, and• HIV itself.RISK FACTORS FOR HIVANPATHOGENESISPatients who are homozygous for a deletion mutation inthe CCR5 co-receptor appear to be protected from HIVinfection." It has been demonstrated that HIV-1 mRNA isexpressed in human renal epithelium and this transgenicIn South Africa the majority of patients with HIVAN areblack, although this may simply reflect the high prevalenceof HIV in this population group in general. However, in astudy from Cape Town Bates et 0/.' described 5 patients ofmixed race in a cohort of 22 biopsy-proven HIVAN cases.Interestingly, patients with family members with renaldisease appear to have a higher risk of developing HIVAN.It is possible that an inherited susceptibility to renal failureis present in many blacks with HIV infection whosubsequently develop nephropathy.'In the USA over 85% of cases of HIVAN occur in African-Americans, and it is the third leading cause of end-stagerenal disease (ESRD) in blacks aged 20 - 64 years.'patients with HIV and renal disease have limited or noaccess to antiretroviral and renal replacement therapy(including dialysis). Although such therapies are notcurative, they may slow disease progression and evenprolong survival.'----------- FEBRUARY 2003THE SOUTHERN AFRICAN JOURNAL OF HIV MEDICINEHuman immunodeficiency virus-related renal diseasesoccur in up to lOO/a of patients infected with HIV. Themajority of such patients are black and the commonestpathology seen is HIV-associated nephropathy [HIVAN).This is a clinicopathological entity characterised byproteinuria and rapidly developing renal failure andhistologically by a collapsing variant of focal andsegmental glomerulosclerosis with acute tubularnecrosis and mild interstitial inflammation. It mayprogress rapidly to end-stage renal disease (within 6months). HIVAN appears to be the commonest cause ofrenal disease in HIV-infected patients in South Africa,although the exact prevalence is unknown. The diseaseaffects predominantly black males, although it has beendescribed in patients of mixed race. Current thoughtswith regard to pathogenesis revolve around the role ofHIV in the renal epithelium and the effects of cytokines,including transforming growth factor-beta and basicfibroblast growth factor, on renal structures. Treatmentmodalities available locally include corticosteroids,angiotensin-converting enzyme (ACE) inhibitors andwhere possible antiretroviral agents. The demographicsof the HIV/AIDS epidemic indicate that the risk pool forHIVAN will continue to rise, and with it the prevalence ofrenal failure.Data from the USA suggest that 10% of HIV-infectedpatients will develop HIV renal disease at some stage oftheir infection (although usually late in the course of thedisease). From these data it is estimated that in the SouthAfrican context 650 000 people may well suffer from HIVrenal disease - frightening figures indeed. Furthermore,South Africa is part of the developing world, so mostOf the South African population of 47 million an estimated6.5 million people are infected by HIV, although theprevalence is not universally agreed upon.'Renal manifestations are an important component of HIVdisease, and renal disease contributes significantly tomorbidity and mortality in patients with HIV.HHR.UARY 2003 -----------expression results in cellular proliferation and is likely toplay a key role in the pathogenesis of HIVAN.' The presenceof HIV-l mRNA further suggests localised replication ofHIV-l in the kidney and the existence of a renal viralreservoir.' Furthermore, upregulation of transforminggrowth factor-beta (TGF-~) may cause loss of nephronstructure and sclerosis.'PATHOLOGYAlthough the classic pathological feature of HIVAN is thecollapsing form of focal and segmental glomerulosclerosis,the affected glomeruli contain hypertrophied visceralepithelial cells, large cytoplasmic vacuoles and numerousprotein resorption droplets. Such distortion results in anincrease in kidney size by up to 250/0. Glomerularendothelial cells classically contain tubuloreticularinclusions, the interstitium is oedematous with T-cellinfiltration, and Bowman's capsule can be dilated."Importantly, a spectrum of other histological lesions areassociated with HIV infections. Lesions such asmesangiocapillary glomerulonephritis (GN), post-infectiousGN, membranous GN, amyloid AA, and IgA nephropathymake up to one-third of the diagnoses in renal biopsyseries, including those in South African patients""'"CLINICAL PRESENTATION AND RISK FACTORS FORHIVANAlthough HIVAN may be the presenting manifestation ofAIDS, it usually occurs after a prolonged period of viralinfection often associated with high levels of HIVviraemia." Cases have been described in which HIVAN hasoccurred before HIV antibody seroconversionHPatients typically present with nephrotic range proteinuriaand unrelenting progression to renal failure. Peripheraloedema and hypertension are uncommon, althoughpatients with malignant hypertension have beendescribed." Besides proteinuria urinalysis is bland,although in the uncommon proliferative GNs found in HIVthe sediment may contain red blood cell casts.Unfortunately the correlation between clinical presentationand underlying HIV renal pathology is poor and truediagnosis is only possible on biopsy.FACTORS PREDISPOSING TO PROGRESSIONStrong associations exist between increasing HIV RNA leveland decreasing CD4 Iymphocyte count and the presence ofproteinuria and occurrence of renal failure. Furthermorethe presence of coinfection with hepatitis C increases thechance of progression."EVALUATION OF HIV-INFECTED PATIENTS WITHRENAL DYSFUNCTIONEven among patients with normal kidney function, thepresence of proteinuria indicates early glomerular disease.Although no clinical practice guidelines exist for theevaluation of HIV-infected patients with renal dysfunction,considering the high incidence of HIVAN in such patients, itwould be appropriate to perform a simple urinalysis at theirinitial visit. Annual follow-up examinations of individualsin high-risk groups (see above) may be justified. Proteinuriashould be quantified with a protein/creatine ratioperformed on a spot urine sample, serological tests forcoinfection with hepatitis Band C and syphilis should bedone, and CD4 and HIV RNA levels should be measured iffacilities are available. Renal biopsy is warranted andindicated in patients with significant proteinuria(> 0.5 g/24 h) or progression of renal failure, and when adefinitive histological diagnosis will alter therapy.ACUTE RENAL FAILURE IN HIVAcute renal failure is well described in patients with HIV,and possible causes are listed in Table I. Underlyingglomerular disease and disturbances in renal tubularfunction predispose these patients to haemodynamic andnephrotoxic insults. Prerenal azotaemia is the commonestcause, although direct damage to the renal tubules fromnephrotoxic medications occurs frequently in hospitalisedpatients. Tubulointerstitial nephritis as a result of allergicreactions to medications is also well described. Importantly,crystalluria and nephrolithiasis occur in relation to drugsused to treat HIV directly and those used to treat associatedinfections.TABLE I. ACUTE RENAL FAILURE IN HIV - POSSIBLE CAUSESGlomerular diseases• H~AN• Membranoproliferative glomerulonephritisAcute tubular necrosis• Hypotension and sepsis• Antibiotics: Aminoglycosides; amphotericin B• Antivirals: Pentamidine; foscarnet; cidofovir; acyclovirHaemolytic uraemic syndromeAcute interstitial nephritis• Trimethoprim-sulphamethoxazole• Non-steroidal anti-inftammatory drugs (NSAIOs)• Rifampicin and isoniazid IINH)Renal obstruction [crystalluria and nephrolithiasis}• Sulfadiazine; indinavir; acyclovirHIV-positive patients presenting with acute renal failurehave a similar outcome to those who are not infected, soHIV should NOT be an exclusion criterion when deciding onacute renal failure therapy in such patients.THE SOUTHERN AFRICAN JOURNAL Of HIV MEDICINETREATMENTIn the South African context there are few options for themajority of patients with HIV and renal disease, particularlyHIVAN. Although there are no randomised clinical trials,angiotensin-converting enzyme (ACE) inhibitors haveshown promise in the therapy of HIV and kidney diseaseand are available in this country. Interestingly, ACEinhibitors appear to mediate their effect in HIVAN viamechanisms other than altered renal haemodynamics. Byinhibiting the angiotensin-II-mediated rise in TGF-~(present in the kidneys of patients with HIVAN), ACEinhibitors may slow the formation of sclerosis in the kidneyand thus slow the progression of renal failure."The proteinuria-decreasing effects of ACE inhibitors havelong been recognised, and it seems logical to prescribe anACE inhibitor for patients with HIVAN.Logic would seem to dictate that corticosteroids should notbe used in a patient with HIV. However, their use isdefinitely advocated in HIV patients with nephropathies towhich they are known to respond, e.g. minimal-change GNand aggressive interstitial nephritis related to concomitantdrug use. Their place in direct therapy is more controversial.Observational studies have shown improved survival insome patients, although relapses are common and whenthey are used for prolonged periods there is a risk ofinfection."" They should therefore be used judiciously,while closely monitoring clinical response, and ideally withthe backing of a histological diagnosis. Common sensewould suggest the addition of preventive antibiotics suchas INH and trimethoprim-sulphamethoxazole (Bactrim),although these drugs cause renal problems in their ownrightAntiretroviral therapy has been shown to slow theprogression of HIVAN, whether it consists of monotherapywith zidovudine, protease inhibitors or highly activeantiretroviral therapy (HAARn.''''''' Patients who receivedHAART have been found to maintain stable renal function,whereas patients who did not required dialysis or died withadvanced renal failure. Monotherapy for HIV could induceresistance and is not recommended, although with thepossibility that HAARTwill become more readily available inSouth Africa, the treatment of HIVAN should be optimised.Many of these drugs are renally cleared, so caution isrequired when prescribing them to patients already in renalfailure. Furthermore, little information is available onHAART medications and their clearance by dialysis.Stavudine and nevirapine accumulate in renal failure andare cleared by haemodialysis, whereas Saquinavir is poorlyremoved and adjustment of the dose is needed.HIV patients are excluded from State-funded long-termdialysis programmes in South Africa, and although thisraises ethical issues, the grounds for such a ruling may notbe unfounded, particularly with regard to a resource asscarce as dialysis. Patients who do receive dialysis have apoor prognosis, with SQO,b mortality within the first year,although this may improve if they receive HAART."Infection and thrombosis are more common than inpatients without HIV infection, and the risk an HIV-positivepatient poses to staff and other patients should not beforgotten. Peritoneal dialysis has similar problems in theway of infection, and the fact that virus replicates inperitoneal dialysis fluid may worsen the patient's systemicviral load.CONClUSIONAs therapy for HIV becomes more readily available in SouthAfrica it is to be hoped that the prevalence of HIVAN andrenal disease related to this epidemic will decrease.Currently available therapy is far from adequate, andwithout HAART many patients will die of the renal illness.REFERENCES1. News. Lonctr 2002; 359: 2095.2 Winston JA, Burns GC, Klotman PE. Trearmtnr of Hrv-a.ssocia~ nephropathy.SmJin Nephro/200l; 20: 293-298.mRUAR 2003-----------3. Monahan M. Tanji N. K10tman PE. HrJ-associGted nephropathy: an urban ~jdM1ic.Semin Nephro12001; 21: 394-402.4. 8at~ W, 5cifu I... Wa'e,e A Hili renal aiS('iiSf at Tygerberg Hospital, Western Cope.South African Renal SocietY Congros, Bloemfonrein, Juty 2002 (Abstract).5. Frmlman 21, Souae JM. Stone SM, Pt9ram S. Familial c!uster:ng 0: end-stage ren;;ajsease in blacks with HIV·assOOareo rephropatny. Am) K.idn~Vis 1999; 34: 254-258.6. Lenner T. The roe of COlS chemok ne ligands and ;;nobodies to COlS corettptorsin pr~t'nting HIV infection. Trends !mmur.ol 2002; 23: 347-351.7. xnwaru: 8, Dca A, Snoed. H, Ross MD_ Human immunooeficiency virus-l indu~loss of contact inhibition in podocyt~ JAmSocNephra/2001; 12: 1677-1684.8. Marras 0, Bruggeman LA Gao F, Tanji N, Mansukhani MM. Rep!ication andcompartrnentalization of HIV-1 in kidn~ epithelium of patients witn HIV-associated nephropathy. Not Med 2002; 8: 522-526.9. Yamamoto T, Noble NA, Miller DE. Increased INelS of trOinsforming growth factor-btta in HIV-assocIated nephropathy. K.idneylnt 1999; 55: 579-592.10. O'Agati V, Appel GB. Renal pathology of human immunodeficiency virus inmtion.Semin Nephro11998; 18: 406-421.I}- Twahir M, Halkeu J, Ouffield M. A five years retrospective study of renal biopsydiagnosis in HIV positive patients in Groote Schuur hospital. South African RenalSociety Congress, Cape Town, February 2oo2lAbstract 17, p. 32).12. WaH RI<, Orachenberg Cl, Papadimiuiou Jc. HIV-l-assoeiated nephropathy andresponse to highly-active anorwoy'ral therapy_ [ana! 1998; 352: 783-784.13. Winston lA, K10tman ME, Kfotrnan PE. HIV-associated nephropathy is a late, notmly, m"nif&ation of HIV-1 infection. Kidney/nt 1999; 55: 1036-1040.14. Levin Ml, Pal61a F, Shah S. HfV-associarell nephropathy occiJrr:ng before HIVantibody s«oconvet5ion. Am JKidney Dis 2001; 37: E39.15. EooJardo G, AJ~nso M,luis RJ. Maigr.ant hypertension in Hrv patients. Nephrol DialTransplant 2002; 17: suppJ 1,83.16. Szezech L~ GOinge SJ, van aer Hors! C. BartJeu lA. PrelfcrotS of proteinuriG andrer.al fai;ure among ....omen with HN infection. Kianey Inr 2002; 61: 195-202.17. Border WA, Nob.e N. Maximizing herr.odynamic-inaependeN effects of angiotensin11 artagonists in fibrotic dise:a~ Sfflrin NephroJ 2001; 21: 563-572.18. laradi A. Maee A, BeGufils H. HIV-associat~ nephropathy: outCOJTe and progrosisr"ctors. Groupe d' Etudes Nephrolog'ques d'lI~ de FrcUlce. JAm Soc Nephroll99B;9: 2327-2335.19. Smith MC, Austen JL Car~ JT, Emancipator SN. Prronisone improves renal functionand proteinuria in human immunodeficiency virus-associated nephropathy. Am JMed 1996; 101: 41-48.20. Szczech lA, Edwards U, Sanders Ll., van der Hors! C. Protease inhibitors areassociated with a slowed progression of HIV-related renal diseases. Clin N~phrol2002; 57: 336-341.21. Cosgrove CJ, Abu-A1fa AK, Perazella MA ObseNations on HN-associated renaldisease in the erOi of highly active antiretroviral therapy. Am J Med Sei 2002; 323:102-106.22. Ahuja is, Grcdy J, Khan S. Changing uerds in the surviva of d;alysis patients withhuman immunodeficiency virus in the United Stat~ JAm 50c NephroI2002; 13:1889~ 1893.TH£ SOUTHfR MRICA JOURNAL OF HI MfOICIN£

HIV-related renal disease- A clinical and practical approach in the South African context

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HIV-related renal disease- A clinical and practical approach in the South African context

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