PROBLEMS OF HIV NEPHROPATHY IN CHILDREN

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PROBLEMS OF HIV NEPHROPATHY IN CHILDREN

• McCulloch M, Kala U, Nourse P, Gajjar P, Sinclair
  P, Faller G, Petersen KL, Goetsch S, Sinclair
  Smith C, Bates W.
• Red Cross Childrens Tygerberg Hospitals, Cape
  Town and
• Baragwanath Hospital, Johannesburg
• South Africa

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CASE 1presented in 1998

• 6 month old boy with diarrhoeal disease
• Subsequently diagnosed HIV disease
• Presented at 2 years with chronic impetigo and
  resultant post-streptococcal glomerulonephritis
• LIP and Cardiomyopathy
• Hepatomegaly 12cm Splenomegaly 5cm

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CASE 1

• Developed nephrotic syndrome at 5 years of age
• Urine dstix 4 protein 1 blood
• Serum albumin 21mmol/l
• Serum creatinine within normal limits
• Renal biopsy
  
• Focal Segmental Glomerulosclerosis (FSGS)

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CASE 1

• Therapy
• No anti-viral agents available
• Responded intermittently to steroids given for
  lung pathology
• Long term use of steroids
• Captopril
• Response Good initially but proteinuria
  continued
• Demised 3 years later from lung related problems

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HIV infectionWhat is the size of the problem?

• Sub-Saharan Africa
• Total 26 million people HIV Lancet June 2005
• Total number of children 2.1 million
• Total number of children in world HIV
• 2.3 million
• Total number of children lt 14yrs in South Africa
  HIV
• 250 000 Dec 2005
• Total number of children on HAART
• 15 000 March 2006
• Personal communication Prof Brian Eley

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HIV renal disease

• HIV associated renal disease, including HIV-assoc
  nephropathy (HIVAN), is not yet well documented
  among children
• especially from Africa

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• Currently 40 60 paediatric admissions to
  hospital may be HIV related
• With the growing availability of anti-
  retroviral therapy(HAART) in SA, this information
  has become more important for appropriate
  management

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HIV Renal Disease

• Acute tubular dysfunction with
• electrolyte abnormalities /or
• renal failure caused by infections and
  nephrotoxic drugs
• HIV glomerulopathies related to immunological
  abnormalities and HIV-assoc immune complex
  disease (HIVICK)
• HIV-assoc thrombotic microangiopathies
• HIV-assoc Nephropathy(HIVAN)
• Rao TKS 1987 NEJM

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What is HIVAN ?

• HIV nephropathy (HIVAN) is a well known entity in
  adults first documented in 1984
• High incidence in adults with a CD4 lt 200 late
  stage of disease
• Both Glomerular Tubular dysfunction
• Presents with
• Proteinuria severe nephrotic syndrome
• Rapid development of renal insufficiency leading
  to end stage renal disease
• Zilleruelo Strauss Ped Clinics of North America
  1995

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WHAT ABOUT HIVAN IN CHILDREN ?

• Mean age of presentation after prolonged viral
  infection
• 4.9yrs /- 2.6 yrs
• Untreated HIVAN results in renal failure in 40
  children better survival than adults
• 155 children with AIDS 6.5 yr follow-up
• 12 were found to have proteinuria
• 5 had focal glomerulosclerosis
• All 5 had severe renal failure within 1 year and
  died NEJM 1989 321(10) 625-30

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HIVAN in Children Rao et al NEJM 1984

• Most distinctive type is glomerulosclerosis seen
  in 50 of kids
  BUT spectrum of lesions seen
  
• 
  Zilleruelo Strauss, Pediatr Clin North Am 1995
• Clinically ranges from mild to moderate
  proteinuria, haematuria, renal tubular acidosis
  and end stage renal disease
• Miami experience 14 of HIV-positive /AIDS
  children had persistent abnormal proteinuria
  Strauss et al, Ped Nephrol 1993

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HOW DO YOU DIAGNOSE CHILDHOOD HIVAN ? Rao PE Ped
Neph 2004

• Persistent proteinuria
• albustix gt 1 or
• urinary protein creatinine clearance gt 0.1 for
  more than 2 months
• in absence of infection episodes
• Abnormalities in microscopic exam of urinary
  sediment including urine microcysts
• Enlarged echogenic kidneys by renal U/S in _at_
  least 2 studies - 2 months apart
• Black race clinical history consistent with
  HIVAN

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WHAT DOES THE HISTOLOGY SHOW ?

• Glomerular pathology
• Collapsing form of Focal Segmental
  Glomerulosclerosis(FSGS) commonest
• with microcystic tubuloreticular inclusions in
  glomerular peritubular endothelial cells
• Other pathology
• Mesangial hyperplasia
• Minimal change disease
• Lupus nephritis
• Haemolytic Uraemic syndrome
• Interstitial findings
• Dilated tubules filled with proteinaceous
  material

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RENAL BIOPSY FINDINGS

• Proviral DNA detected by PCR in glomeruli,
  tubules and interstitium in patients with HIVAN
  but also in HIV patients with other
  glomerulopathies
• Combination of both apoptosis prolifer-ation
  cause loss of nephron architecture
• Cytokines growth factors especially
  Transforming Growth Factor B cause development of
  sclerosis

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ELECTRON MICROSCOPY

• Tubuloreticular inclusion bodies in endothelial
  cells of glomerular capillaries
• HIV-1 mRNA expressed in human renal epithelium,
  suggesting localised replication and existence of
  renal viral reservoir
• Associated with accumulation of basic fibroblast
  growth factor
• Kidney Int 63(2003)p.2242-2253

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New areas of researchRay P Ped Neph (2004)
191075-1092

• HIV infection
• Affects growth differentiation of glomerular
  tubular epithelial cells
• Enhances renal recruitment of infiltrating
  mononuclear cells cytokines
• Up-regulation of renal heparan sulfate
  proteoglycans
• Increases recruitment of heparin-binding growth
  factors (FGF-2), chemokines, HIV-infected cells
  viral proteins(gp120, TAT)
• These changes enhances infectivity induces
  injury proliferation of intrinsic renal cells

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Racial disparity in HIVAN

• Predominantly seen in African Americans
• Duffy antigen chemokine receptor (DARC) potential
  candidate gene involved in HIVAN
  Liu et al 1999 KI 551491-1500
• High prevalence of DARC promoter polymorphism in
  black race
• Enhances renal recruitment of HIV infected cells
  triggers development of HIVAN
• Genetic alterations in podocytes (mutations in
  CD2AP) incr susceptibility to HIV infection Kim
  et al Science 2003

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WHAT IS THE COURSE OF HIVAN ?

• If untreated in Adults, is uniformly fatal and
  there is a rapid progression to ESRD in 1-4
  months.
• Children rapid progression does not occur
• Treatable condition
• ACEI provide long term renal survival
• 87.5 survived cf 21.4 in control group
• Kidney Int.2003 Oct 64(4)
• HAART reduced the risk of HIVAN by 60
• AIDS.2004 Feb 18(3)

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HIV Related Nephropathy A South African
PerspectiveJan 2003 Dec 2004

• Gerntholz TE, Goetsch SJW, Katz I
• Kidney International (2006) 69, 1885-1891
• HIV positive group(99 patients)
• Classic HIVAN 27
• HIV immune complex kidney disease(HIVICK) 21
• Other membranous, post-infectious, mesangial
  hyperplasia, immunoglobulin A nephropathy
• HIV negative group(48 patients)
• NO collapsing focal segmental glomerulosclerosis
  or non-specific immune complex disease
• Membranous 19
• Minimal change disease 17
• Membranoproliferative disease 13

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HIVICKGerntholz et al KI (2006) 69, 1885-1891

• Glomerular changes mainly mesangial
• Immune deposits
• Eosinophilic sub-epithelial deposits
• Basement membrane reaction resulting in ball in
  cup pattern
• Some marked crescents
• Immunofluorescence confirm immune deposits
  -varying staining for IgG,M and A
• Interstitium some inflammation, fibrosis and
  tubular atrophy
• Marked overlap with other groups

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HIVICK clinical

• Clinically similar to HIVAN but
• Less proteinuria
• Better creatinine
• Better albumin
• In spite of slightly worse CD4 counts

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Paediatric Renal Biopsies
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Paediatric Renal Biopsies
Johannesburg group
Cape Town Group
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Case 2presented 2005

• Recurrent lower respiratory tract infections /
  Pulmonary TB
• Presented at 9mths
• Oedema of face, hands and feet
• Urine 4 protein 3 blood
• Blood
• Urea 11.2mmol/l Creat 72umol/l
• Total protein 74g/l Albumin 13g/l
• Ultrasound
• Large echogenic kidneys
• Left 8.4cm Right 9.1cm(both gtgt97th centile)
• No focal pathology

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Case Study Baby EM

• HIV
• PCR positive
• CD4 of lymphocyte 7.1
• Absolute CD4 218cells/muL
• Clinical stage III
• Urine ProteinCreatinine ratio
• 2.49g/mmol(N lt 0.02)
• Started Enalapril and increased the dosage as
  tolerated

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Therapeutic Interventions
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Clinical status on HAART

• Clinically well and thriving
• Urine NAD
• Bloods
• Urea 2.9mmol/l(11.2) Creat 20umol/l(72)
• Total protein 82g/l(74) Albumin 39g/l(13)
• HIV disease
• CD4 23.2(7.1) Absolute CD4 1347(218)
• U/S
• Significant decrease in renal size
• LK 7.0cm(cf 8.4cm) RK 7.1cm(cf 9.1cm)
• Kidneys remain slightly echogenic

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HIV and Transplantation

• Previously absolute contra-indication and
  potential waste of valuable resource
• Now possible
• Maintenance of HAART
• HIV viral load undetectable for gt 3 mths
• CD4 gt 200cells/muL
• Kumar et al Kidney International 2005
• Protease inhibitors require marked reduction in
  CNI doses
• Izzedine et al Kidney International 2004

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HIV and Transplantation

• Possibility exists not children yet?
• Concern re Increased rejection
• Graft survival equal to non-HIV
• Qiu et al Transplantation 2006
• Hepatitis C recurrence occurred rapidly post
  transplantation in HIV patient
• Stock et al Transplantation 2003
• Standard immunosuppression possible
• Adults do better following transplantation than
  on dialysis

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Nephrotoxicity of HAART DrugsWyatt Klotman
Expert Opin 2006

• Range of nephrotoxic effects
• Crystal induced obstruction
• Lactic acidosis
• Tubular toxicity
• Tenofovir tubular damage Fanconis, Renal
  Insufficiency Nephrogenic DI
• Hussain et al Ped Neph 2006
• Interstitial nephritis
• Electrolyte abnormalities

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HIV Renal Disease

• HIV renal disease presents in many forms
• HIVAN HIVICK
• HAART revolutionised management if detected early
  enough screening?
• HAART drugs have side effects and drug
  interactions

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The future

• Transplantation possible provided HIV disease
  under control on HAART
• Black patients appear to have a genetic
  predisposition to HIV infection
• Major problem remains in Sub-Saharan Africa with
  limited resources

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