Current aspects of renal diseases in HIV infection · Current aspects of renal diseases in HIV...

Current aspects of renal diseases in HIV infection

Eric DAUGASService de NéphrologieHôpital Bichat – Paris

France

1996 = HAART highly active antiretroviral therapy

combination of three antiretroviral agents two RTI + one PI orthree RTIs

Schwartz et al, JASN, 2005

EPIDEMIOLOGYof

renal diseases in HIV infected patients

HIV is a CKD risk factor

Gardner et al. J Acquir Immune Defic Syndr. 2003

10%400Fernando SK, Am J Med Sci 2008

4%

Stage 3-5 CKD

29847Overton E, CROI 2007

29487Gupta SK, Clin Nephrol, 2004

32

Proteinuria%

n

2057 (w)Szczech LA, Kidney Int, 2002

High prevalence of CKD

CKD is associated with uncontrolledHIV

Proteinuria• Viral load• CD4 ≤ 200 mm3

• Afro-american • HCV

Renal failure• CD4 ≤ 200 mm3

• Viral load• Hypertension• Hypoalbuminemia

Szczech LA, Kidney Int, 2002

CKD = 3rd death risk factor in thisstudy

Gardner et al. J Acquir Immune Defic Syndr. 2003

Acute renal failureProspective data from 754 patients between

2000 and 2002

incidence = 5.9 %/year#100 x Population générale

Risk factors• <200 T4/mm3

• Detectable viral load• AIDS• HCV

Franceschini et al. Kidney Int, 2005

Modifications of renal diseasesprofile in HAART era

New profile of kidney diseases in HAART era

• Improved control of HIV• Control of HIV-related renal diseases• Prolonged life with a continuous

exposure to HIV and to therapies• Immune reconstitution

pre-HAART era

Pro

porti

on %

Time1996

HIV-related Directly due to HIV (group 1) •HIVAN•TMA•Immune complexe GNRelated to immune deficiency (group 2)Infiltrative interstitial nephritis (Lymphomas, DILS…)•Infectious interstitial nephritis•Infectious GN•Amyloidosis?

Related to HAART (group 3)Direct nephrotoxicityIndirectly: IRIS

Unrelated to HIV context (group 4)Diabetic nephropathy,Vascular nephropathyHCV-related…

HAART era

HIVAN: HIV-Associated Nephropathy

Kimmel, Barisoni and Kopp; Ann Intern Med; 2003

Beneficial effect of Zidovudine on HIVAN course in pre-HAART era

• Cook P.P, J Am Soc Nephrol 1990• Michel C., Nephron 1992• Ifudu O., Am J Nephrol 1995• Kimmel P.L, Am J Kidney Dis 1996

HIVAN and HAART

Wali et al; Lancet 1998

Dialysis

Proteinuria10 g/d

Creatinine132 µmol/L

Proteinuria#1g/d

HIVAN and HAART

Winston et al; NEJM 2001


Proteinuria17 g/d


Protenuria1.5 g/d

HIVAN/HAART in African American

Lucas et al, AIDS, 2004

NRT a

lone

No A

RT

HAART

Schwartz et al, JASN, 2005

HIVAN/HAART in African American

HIVAN / HAART in Paris

HIVAN on histology

126 patients in pre-HAART eraMean creatinine 496µmol/L

versus33 patients HAARTMean creatinine 592µmol/L

Laradi et al, JASN 1998 and Burckle et al; Am Soc Nephrol; 2002

0102030405060708090

100

0,5 1 3

follow-up (year)

ren

al s

urv

ival

rat

e

1984-1996 1996-2000

Guidelines for HIVAN treatment

Gupta SK et al. Clin Infect Dis 2005

Immune glomerulonephritis

• Caucasians• Numerous nosologic entities

• IgA nephritis: 8% prevalence in Beaufilset al NDT 1995Eluted immune complex including IgAanti-HIV: Kimmel et al, NEJM 1992Treatment with HAART????

Thrombotic microangiopathy

Decreased incidence in HAART era

Gervasoni et al, Clin Infect Dis, 2002Becker et al, Clin Infect Dis, 2004

Direct and indirect effect of HIV containment by HAART

Renal toxicity of HAART

Indinavir

Renal and urological disorders related to crystalluria

Daudon M et al Lancet. 1997 May 3;349(9061):1294-5

Indinavir (Crixivan°)•Clinical manifestations

Renal colic /Flank pain / Dysuria/ Gross hematuriaUrolithiasis / radiolucent calculiRenal parenchymal defect / Papillary necrosis

Crystalluria / Leukocyturia / Microhematuria / Mild proteinuriaAcute renal failure / Chronic renal failureHypertension

•Histological findingsTubulointerstitial nephritis with indinavir crystals in tubules

Discontinuation in 33% of patients

Recommendations of the HIV MedicineAssociation of the Infectious DiseasesSociety of America

• Patients receiving indinavir should drink at least 1.5 L of water daily to prevent stone formation.

• Periodic monitoring of renal function and pyuria should be performed during the first 6 months of indinavir therapy and biannually thereafter,

• although routine screening for crystalluria is not warranted unless there is a suspicion of nephrolithiasis.

• Indinavir need not be withheld from patients with reduced renal function.

• In patients who develop indinavir nephrolithiasis, it would be reasonable to restart indinavir therapy once rehydration is achieved.

• Patients who develop indinavir-induced hypertension, pyuria, rhabdomyolysis, or renal insufficiency (acute or chronic) should permanently discontinue use of this drug.

Gupta SK et al. Clin Infect Dis 2005 Jun 1;40(11):1559-85.

AKIRitonavir (Norvir®)

Urolithiasis, renal colic Nelfinavir(Viracept®)

Cristalluria, renal colic, AKI and CKD Indinavir(Crixivan®)

Interstitial nephritis, urolithiasisAtazanavir(Reyataz®)

Renal toxicity of antiproteases

Daugas E et al., Kidney International, 2005 Izzedine H et al. AIDS, 2007

Nucleotide reverse transcriptase inhibitors: tenofovir

Dose dependent nephrotoxicityExacerbated by

advanced HIV disease, reduced GFR, no dosage adaptation to

reduced GFRconcurrent ritonavir or ddi, other nephrotoxic

5 to 12 months after starting tenofovir

Tenofovir (Viread° Truvada°)

•Proximal and distal tubular cells dysfunction•Total or partial Fanconi’s syndrome

Earlier manifestations: Glucosuria and hypophosphatemiaNephrogenic diabetes insipidus

•Acute renal failure •One case including nephritic syndrome

Total or (rarely) partial reversibility several months after discontinuation

Discontinuation

Verhelst et al Am J Kidney Dis 2002

Rare in patient without prior kidneydisease

Gallant JE et al; JAMA. 2004 Jul 14;292(2):191-201.

http://www.natap.org/

Recommendations of the HIV MedicineAssociation of the Infectious DiseasesSociety of America

Patients receiving tenofovir

• who have a GFR <90 mL/min per 1.73 m2, • patients receiving other medications eliminated via renal

secretion (e.g., adefovir, acyclovir, ganciclovir, or cidofovir), • patients with other comorbid diseases (e.g., diabetes or

hypertension), • or patients receiving ritonavir-boosted protease inhibitor

regimensshould be monitored at least biannually for measurements of renal

function, serum phosphorus, and urine analysis for proteinuriaand glycosuria.

• Dosage adaptation to reduced GFR.

Gupta SK et al. Clin Infect Dis 2005 Jun 1;40(11):1559-85.

Renal IRIS

Differential diagnosis of HAART renal toxicity

Immune restoration inflammatorysyndrome (IRIS)

Patient with severe immune deficiency

Silent spread of infectious agent

HAART initiation

Immune restoration

“Paradoxical” inflammatory response

IRISUp to 1/3 of patients coinfected with Mycobacterium

tuberculosis, MAC or Cryptococcus neoformans

Time between HAART and IRIS: #6-7 weeks

Risk factors• male gender• long duration and deep immunodeficiency• first introduction of HAART• short delay between treatment of opportunistic

infection and HAART• marked increase of CD4 T cell count and reduction of

HIV RNA level

Shelburne SA et al ; AIDS, 2005;19:399

IRIS: infectious agents and clinicalmanifestations

• Wide spectrum of pathogens• General manifestations• Visceral manifestations (hepatitis,

pneumonitis, encephalitis, lymphadenopathies, splenomegaly..)

• Life threatening in most severe cases• Management: continuation of HAART and

antiinfectious treatment, addition of antiinflammatory therapy: steroid therapy

Hirsch HH et al, Clin Infect Dis 2004;38:1159-

Healthy with normal renal

f ti


f tiHealthy


f ti


f tiOutcome

6NA365Steroid therapy (1 mg/kg/day) duration (months)

Granulomatous interstitial nephritis


Liver biopsy: extensive

granulomatous inflammation

Interstitial nephritis


Kidney biopsy

None

Erythematous skin lesions,

lymphadenopathy, splenomegaly,

cholestasis

Fever, weight loss, severe cholestasis

Fever, abdominal lymphadenopathies, salpingitis, ascitis

Worsening of pulmonary infiltrate

Others IRIS-related symptoms

700346252143 433Creatinine level (µmol/l)

494<200162373104RNA viral load (copies/ml)

3261482999782CD4-cell count (/mm3)

1512070460Time from HAART to IRIS (days)

45-90 43015Time from OI treatment to HAART (days)

TB TB MAC TB TB Infectious agent

177,504<750,000169,85056,7321,247,786Initial RNA viral load (copies/ml)

8837112669Initial CD4-cell count (/mm3)

Salliot et alIzzedine et alDaugas et alDaugas et alJehle et alReferences

Case report

51-year-old Chinese manNo previous medical history

Disseminated tuberculosis revealed HIV-1CD4 cell 80/mm3 RNA viral load 177,504 copies/ml GFR 92 mL/min/ 1.73 m2 (creatinine: 62 µmol/L)

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Antituberculosis therapy

HAART includingtenofovir

Time(months)

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RNA viral load(copies/ml)

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Acute renal failurewith tubulointerstitial nephropathy syndrome

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Tenofovir toxicity?IRIS?

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Tenofovir toxicity?IRIS?

Renal biopsy

J Vérine, Hôpital Saint-Louis, Paris

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Prednisone

However HAART is beneficial

The Strategies for Management of Antiretroviral Therapy (SMART) trial

5472 patients, HIV, >350 CD4+/mm3

Open randomized controlled trial

• Continuous HAART« viral suppression group »

• Episodic HAARTif CD4<250/mm3 until > 350/mm3

« drug conservation group »

SMART study group, NEJM, 2006

After a mean followup of 16 months…


After 16 months (instead of 6 years) enrollmentwas stopped because of a safety risk in the drugconservation group


Conclusion

Main treatment strategy for CKDis HAART

HAART at all stages including stage 5

HAART as early as possible

Choi et al, Kidney Int, 2007

HIV: yet a more severe renal threatthan diabetes in black patients in HAART era

Thank you

Current aspects of renal diseases in HIV infection · Current aspects of renal diseases in HIV...

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