HIV associated renal disease

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HIV associated renal disease
Dr David Makanjuola Dr Stephen Sampson
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HISTOPATHOLOGICAL ASPECTS
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Patterns of glomerular and tubulo-interstitial
disease in HIV positive patients
Glomerular disease N 127 Tubulo-interstitial disease N 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 4 2 1 1 1 1 1 Interstitial nephritis Drug induced Idiopathic Acute tubular necrosis Malignant lymphoma 5 2 3 3 1
DAgati Appel 1998
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Normal renal biopsy (PAS stain)
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Mesangial proliferation and focal sclerosis
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Florid interstitial nephritis in a patient with
HIV
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Dilated tubules with micro-cyst formation in a
patient with HIV
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Pseudo-crescent formation with collapsing
glomerulopathy in a patient with HIV
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Tubulo-reticular structures on electron
microscopy of the glomerulus in a patient with
HIVAN
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CLINICAL ASPECTS
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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

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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

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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

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ARF in HIV, continued

• TTP HUS more common in HIV-serove AIDS
• Rx with plasmapheresis using FFP
• Can occur at any stage of HIV infection
  prognosis is poor

• Acute tubulointerstitial nephritis is usually a
  complication of drugs such as
• Trimethoprim-sulfamethoxazole
• Rifampicin
• Foscarnet
• Sulfadiazine
• ciprofloxacin

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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-peri
  toneal fibrosis

Source - UpToDate
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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 1st 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

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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 121
• 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

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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

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HIVAN Investigations

• Nephrotic range proteinuria is usually present
• Serum complement levels normal
• CD4 counts variable, from normal to low
• Presence of HIV antibodies

• Renal ultrasound - usually shows echogenic
  kidneys with preserved or enlarged size of more
  than 12 cm in spite of severe renal insufficiency

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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

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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)
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HIVAN Evidence for HAART

• Wali et al (1998)
• 37yr old with Cr 203 -gt 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 lt500
  copies/mL
• Repeat renal biopsy at time of discontinuation of
  dialysis revealed substantial improvement in
  histology

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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 O2
  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

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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 lt
  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 lt 0.0001)

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HIVAN ACEIs

• RR of renal failure reduced with ACEI (RR
  0.003, Plt0.0001)
• 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

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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.