1. HIV associated renal disease Dr David Makanjuola Dr Stephen Sampson

2. HISTOPATHOLOGICAL ASPECTS

3. Patterns of glomerular and tubulo-interstitial disease in HIV positive patients Glomerular diseaseN = 127Tubulo-interstitial diseaseN = 9 Focal segmental glomerulosclerosis Membrano-proliferative GN Minimal change disease Membranous glomerulopathy Lupus-like nephritis Amyloidosis Acute post-infectious GN Focal segmental necrotising GN Haemolytic uraemic syndrome IgA nephropathy Immunotactoid glomerulopathy End-stage kidney 88 13 6 5 4 2 1 Interstitial nephritis Drug induced Idiopathic Acute tubular necrosis Malignant lymphoma 5233152331 D’Agati & Appel 1998

4. Normal renal biopsy (PAS stain)

5. Mesangial proliferation and focal sclerosis

6. Florid interstitial nephritis in a patient with HIV

7. Dilated tubules with micro-cyst formation in a patient with HIV

8. Pseudo-crescent formation with collapsing glomerulopathy in a patient with HIV

9. Tubulo-reticular structures on electron microscopy of the glomerulus in a patient with HIVAN

10. CLINICAL ASPECTS

11. Overview of HIV-associated renal disease: Acute renal failure (ARF) – common, with causes broadly similar to those of the non-HIV population, together with some specific to pts with HIV Chronic renal failure (CRF) - largely due to focal glomerulosclerosis (classical HIVAN)/other chronic glomerulopathies

12. Aetiology of ARF in HIV: Pre-renal Acute Tubular Necrosis Allergic interstitial nephritis Rapidly progressive immune-complex-GN Thrombotic Tthrombocytopaenic Purpura (TTP) & Haemolytic Uraemic Syndrome (HUS) Obstructive nephropathy from crystal-induced renal failure Rhabdomyolysis & myoglobinuric renal failure

13. Aetiology of ARF in HIV: Pre-renal –hypovolaemia due to diarrhoea/vomiting/infections –hypotension from sepsis/bleeding/fluid loss Acute Tubular Necrosis due to hypovolaemia, nephrotoxins, sepsis etc is the commonest cause of intrinsic ARF in HIV pts Some of the nephrotoxins implicated: –Pentamidine, –amphotericin B, –foscarnet, –aminoglycosides, –ritonavir, –radio-contrast material

14. ARF in HIV, continued: Acute tubulointerstitial nephritis is usually a complication of drugs such as: –Trimethoprim-sulfamethoxazole –Rifampicin –Foscarnet –Sulfadiazine –ciprofloxacin TTP & HUS more common in HIV-sero+ve & AIDS –Rx with plasmapheresis using FFP –Can occur at any stage of HIV infection & prognosis is poor

15. ARF in HIV, continued: Intra/extra-renal obstruction –Tubular precipitation of sulfadiazine/aciclovir –Urate crystals during chemoRx of AIDS-related lymphoma –Lymphomatous ureteropelvic infiltration/Retro-peritoneal fibrosis Source - UpToDate

16. HIVAN HIVAN is a disease of progressive renal failure with both glomerular & tubulointerstitial components in sero positive patients A description of a new renal syndrome in patients with AIDS 1 st reported in 1984 Rao et al described focal & segmental glomerulosclerosis in 9 pts with AIDS & the nephrotic syndrome in New York city A histological pattern similar to heroin-associated nephropathy was recognised, but a much more rapid deterioration in renal f(x) was noted This HIV-associated focal glomerulosclerosis or “HIVAN” is the commonest HIV nephropathy found in biopsy series

17. HIVAN: Epidemiology Accounts for 60-70% of chronic glomerular lesions in adults with HIV but only 33% of such lesions in children Strong predilection for blacks 12:1 HIVAN usually occurs in pts with low CD4 counts –But can occur in otherwise asymptomatic sero-positive individuals –Has been seen in all groups at risk for AIDS, including perinatally acquired transmission Strongly associated with IV drug use –up to 50% of patients in some case series have a history of intra- venous drug use

18. HIVAN: Clinical features 1. Usually presents with proteinuria, renal failure or the nephrotic syndrome 2. The onset of nephropathy is often abrupt with massive proteinuria and uraemia – these lesions may present as acute renal failure 3. The blood pressure is often normal, even in advanced stages of renal failure

19. HIVAN: Investigations Nephrotic range proteinuria is usually present Serum complement levels normal CD4 counts variable, from normal to low Presence of HIV antibodies Normal kidney, less echogenic than liver Normal sized, but extremely echogenic kidney in pt with HIVAN Renal ultrasound - usually shows echogenic kidneys with preserved or enlarged size of more than 12 cm in spite of severe renal insufficiency

20. HIVAN: Clinical course The progression of renal insufficiency is rapid, especially in nephrotic patients and in blacks, with a median time from presentation to dialysis of 11 weeks Children with HIV-associated glomerulosclerosis have a more protracted clinical course, with a median time from presentation to end-stage renal failure of about 12 months Survival is dictated by the clinical progression of AIDS and is independent of the renal disease

21. HIVAN: Management strategies There are no prospective randomised controlled trials of treatment in HIVAN Some evidence exists for the following however: 1) Zidovudine isolated case reports noting temporary remission of proteinuria or delay in occurrence of renal failure 2) Immunosuppressive agents (steroids/cyclosporin A) Concerns about the use of these agents in an infected population Significant improvements in proteinuria and renal function have been reported with use of high dose steroids in pre-HAART era It is likely that those with significant interstitial inflammation are the most likely to respond to steroid therapy Long-term results of these studies suggest high morbidity from opportunistic infection Cyclosporin used in paediatric patients with biopsy proven HIVAN has achieved remissions; with relapses on discontinuation due to intercurrent infection 3) Highly Active Anti-Retroviral Therapy (HAART) 4) Angiotensin Converting Enzyme Inhibitors (ACEIs)

22. HIVAN: Evidence for HAART Wali et al (1998) 37yr old with Cr 203 -> 770 in 5/52 and biopsy proven HIVAN Initiation of HAART for 13/52 (12/52 dialysis), allowed cessation of haemodialysis Proteinuria dropped from 9.9g/day to 0.7g/day, with Creatinine 132, fourteen weeks after stopping dialysis Viral load fell from 906,000 copies/mL to <500 copies/mL Repeat renal biopsy at time of discontinuation of dialysis revealed substantial improvement in histology

23. HIVAN: Possible mechanisms of benefit of HAART –Suppression of viral replication felt to be a key factor –?viral proteins/cytokines released during active viral replication directly cytopathic to kidneys –Recent evidence (Foster, 2004) suggests ‘non-viral’ actions of HAART may be equally important –Protease inhibitors shown to inhibit reactive O 2 species (ROS) generation and ROS-linked apoptosis of murine mesangial cells independent of HIV gene expression –This anti-apoptotic non-virologic effect of protease inhibitors may be important in humans

24. HIVAN: ACEIs Wei et al (2003) single centre prospective cohort study of the long-term effects of ACEIs on renal survival in HIVAN 44 patients with biopsy proven HIVAN enrolled prior to severe renal insufficiency (Creatinine < 180) during period 5 yrs 28 patients received Fosinopril 10mg/d, 16 followed as controls Median renal survival of treatment group was 479.5 days, with only 1 patient developing ESRF All untreated patients progressed to ESRF, median renal survival was 146.5 days (P < 0.0001)

25. HIVAN: ACEIs RR of renal failure reduced with ACEI (RR = 0.003, P<0.0001) No significant differences between Rx and control groups in age, antiretroviral therapy, CD4 count, initial median Cr, or proteinuria Results suggest ACE inhibition initiated early in natural history of HIVAN may offer long-term benefits on renal survival ?Mechanism – altered glomerular haemodynamics, altered growth factor expression/mesangial matrix production

26. SUMMARY: The spectrum of kidney disease in patients with HIV is broad. 7000 young people contract HIV-1 every day worldwide (UNAIDS); 5- 10% of pts develop nephropathy/ ESRF, HIVAN is assuming increasing importance. Typical clinical features of proteinuria, minimal oedema, normal/enlarged echo-bright kidneys in a sero-positive/at risk patient should prompt consideration of dialysis and renal biopsy. Early, aggressive use of HAART to obtain undetectable viral load may produce recovery of renal excretory function. Despite the advent of HAART, the outlook for patients remains poor. Formal randomised controlled trials are needed to evaluate new therapeutic strategies, in particular the role of & timing of introduction of ACEIs, and the efficacy & patient selection criteria for the use of immunosuppressive agents such as steroids and cyclospotin A.