HIV associated nephropathy

Oleg Rubin, MDApril 30, 2003

Outline

• Epidemiology• Definition of HIVAN• Overview of renal disease in HIV• Pathology and pathogenesis• Clinical presentation• Treatment• Conclusions

Epidemiology of HIV in the US• Currently there are 800,000 to 900,000 HIV

positive people in the US with approximately 40,000 new infections each year.

• By race, more than half of new HIV infections occur among blacks, though they only represent 13% of population

• Better treatments have led to an increasing number of people living with AIDS despite slowed progression from HIV to AIDS.(HIV/AIDS Update)

US AIDS Prevalence

Recent Progress in HIVAN, M. Ross et al, J Am Soc Nephrol

Epidemiology of End Stage Renal Disease in the US

• Incident rate per million population has been increasing steadily since 1980, showing 3-5% increase per year since 1995. Overall changes in prevalent rates reflect slow growth in the number of new patients and no significant improvement in the mortality rate.

• Diabetes is the most common cause of ESRD, followed by hypertension. (USRDS)

Epidemiology of End Stage Renal Disease due to HIV.

• USRDS listed roughly 900 patients entering ESRD with the diagnosis of AIDS related nephropathy in 2000, 90% are of African descent.

• Currently in the US, AIDS related nephropathy is the most common cause of renal failure among HIV patients, and is the third most common cause of ESRD in African Americans aged 20-64 years (Cosgrove et al, 2002)

ESRD from AIDS Nephropathy

Recent Progress in HIVAN, M. Ross et al, J Am Soc Nephrol

There is a noticeable geographic variation in the incidence of AIDS nephropathy. The highest rates areseen in the Gulf Coast and East Coast states. The greatest predominance of the disease is in patients age 20-65 and in blacks.

(USRDS data, 2002)

Definition of HIVAN.

• Nephrotic Range Proteinuria• Bland urine sediment• Rapidly progressing renal failure• Absence of edema and hypertension• Large echogenic kidneys on ultrasound• Collapsing focal segmental glomerulosclerosis

with microcystic tubular dilatation an interstitial infiltrates and fibrosis

Renal Disease in HIV

• The term HIV associated nephropathy has been used in different ways, including describing all HIV related glomerular disease, ESRD in patients with HIV infection, as well as biopsy proven FSGS.

• USRDS in reporting numbers of patients with HIV nephropathy used information reported on the Medical Evidence form, biopsy is not required.

Spectrum of Renal Disease in HIV

• Glomerular SyndromesFocal and Segmental Glomerulosclerosis (HIVAN)Immune Complex Glomerulonephritis( IgA

nephropathy, Membranous glomerulonephritis and Membranoproliferative glomerulonephritis)

Thrombotic MicroangiopathyAmyloid

• Acute Renal Failure Syndromes• Fluid/Electrolytes and Acid Base disorders

Types of Glomerular Lesions in HIV before HAART

• “The types of Renal Disease in AIDS”, Rao et al, NEJM 1987

• 750 patients admitted to two hospitals in NYC with AIDS, 78(10.4%) needed renal evaluation, 55(70%) had nephrotic syndrome with or without azotemia or azotemia with nonnephrotic range proteinuria

• All patients were black, only 6 were women. • Renal histology showed FSGS in 27

patients(49%), mesangial changes in 3(5%), in the remaining 25(45%) no tissue was available

Types of Renal Lesions before HAART

• “Renal Pathology and Premortem clinical presentation of Caucasian patients with AIDS: An autopsy study from the era prior to antiretroviral therapy” Hailemariam et al, Swiss Med Weekly 2001

• Autopsy study of 239 patients who died from AIDS between 1981 and 1989. No patient received antiretroviral therapy. 195 patients were male, 228 were Caucasian.

• 11% of patients had renal insufficiency

Swiss Study Results.The most frequent histological diagnosis wasscarring related to vascular lesions. Only 4patients had FSGS, and only one patient had collapsing FSGS. This patient was of African origin.

HIV-Associated Renal Disease in the HAART Era

• Observation on HIV-Associated Renal Disease in the Era of HAART, Cosgrove et al, Am J Med Sci 2002

• Retrospective study of 23 patients referred to Nephrology clinic between 1996 and 2001.

• Inclusion criteria were either renal insufficiency, proteinuria over 1g/day or both

• 13 received HAART either prior to referral (10) or after evaluation in the Renal Clinic (3) and 10 did not.

• 12 patients were biopsied, remaining 11 had clinical diagnosis of HIVAN based on nephrotic proteinuria, bland sediment and negative serology.

Cosgrove et al StudyRenal Lesion HAART no HAART

Indinavir Nephropathy 3

Idiopathic FSGS 1 2

Arterionephrosclerosis with AIN

1

Chronic Interstitial Nephritis 1

Amyloidosis 1

Membranous GN 1

Membranoproliferative GN 1

Immunotactoid GN with AIN 1

HIVAN (clinical diagnosis) 2 9

Cosgrove et al study- discussion• Despite the high number of African Americans

(74%), a number of lesions were noted.• Only 2 of 10 patients receiving HAART (20%)

had clinical diagnosis consistent with HIVAN, but 9 of 13 patients (70%) not receiving HAART were thought to have HIVAN

• In the absence of biopsy it is possible that either idiopathic or other HIV related glomerulopathy associated with bland sediment and nephrotic range proteinuria were present in these cases.

» Cosgrove et al, Am J Med Sci, 2002

HIV RELATED Renal Disease in the HAART Era

• HIV associated nephropathy: Is it going to Disappear? Marques and Rioja, Nephron 2000

• Review or results of renal biopsies obtained over period of 14 years (1985-1998) at the referral hospital for HIV care.

• 13% were White, 28% Black and 58% of mixed race• Renal biopsies were done when proteinuria of >1g/24h

was found (19 patients)• HIVAN was diagnosed in 8 patients (0.5%)• There was progressive decrease in the incidence of

HIVAN with the introduction of antiretroviral therapy.

Marquez and Rioja, ResultsPeriod Patients Renal Biopsies HIVAN (n/%)

1985-1989 398 6 5/1.2%

1990-1994 754 7 3/0.4%

1995-1998 962 6 0/0

The incidence of HIVAN was higher during the period 1985-1989 when antiretroviral therapy was not available than during subsequent years with the introduction of AZT/ddI in 1987 and protease inhibitors in 1997.

Pathology of HIVAN-Glomerular Changes

• Hyperproliferation of renal epithelial cells• Focal sclerosis of the glomerular tufts• Glomerular capillary collapse• Mesangial expansion may be seen early-

unclear if it represents precursor lesion or separate process

Pathology of HIVAN: Tubulointerstitial changes

• Marked degree of interstitial fibrosis occurs with the focal mononuclear cell infiltrates.

• Cystic tubular degeneration is widespread, with dilated tubular lumens filled with proteinaceous eosinophilic material

Normal Glomerulus

Early HIVAN

Tubular changes of HIVAN

Pathogenesis of HIVAN

• Direct Infection of Renal Epithelial Cells• Toxicity of Viral Proteins• Aberrant Immune response• Genetic and Environmental factors

R. Schrier, Atlas of Nephrology, 2001

HIVAN is a late, not early manifestation of HIV Infection

Winston et al, Kidney International, 1999• HIVAN can be an initial presentation of HIV infection,

leading to an assumption that it can present at an early stage of HIV.

• Winston et al studied 20 seropositive patients with proteinuria and azotemia. HIVAN was the most common diagnosis in this group (50%).

• Mean CD4 count in the patients with HIVAN was 60 (range 0-200)

• Authors also reviewed 6 studies reporting CD4 counts in patients with the diagnosis of HIVAN (1984-1997), majority of the patients had CD4 counts less than 200.

HIVAN is a late manifestation of HIV infection

• Although this group of patients had advanced HIV infection at the time of diagnosis, it is unclear if early detection of proteinuria would lead to recognition of renal disease at an earlier stage of HIV.

• Interestingly, in this predominantly black group of patients diagnoses other than HIVAN were present in 50% of cases.

• Patients with HIVAN could not be distinguished from patients with other glomerular lesions based on proteinuria, degree of azotemia or CD4 count.

Clinical Course of HIVAN- Incidence of Proteinuria in Asymptomatic HIV Infected Patients

• At the time of presentation of HIVAN advanced renal failure is frequently present. Little is known about early manifestations of HIV related renal disease, including the prevalence of asymptomatic proteinuria.

• S. Crowley et al prospectively studied the prevalence of asymptomatic proteinuria in the ambulatory VA population, and attempted to correlate its presence with the status of HIV infection.

Incidence of Proteinuria in Asymptomatic HIV Infected Patients

• 67 HIV+ patients participated in the study.• 49 were included in the final analysis, 7 subjects

demonstrated persistent proteinuria >1+ on a dipstick, (14% prevalence).

• Previously reported prevalence of proteinuria in the pre-HIV era among veterans with the history of IVDU was only 2.7% (1975)

• Study did not show difference in the viral load between the 2 groups, the difference in the CD4 count was present (180 in the proteinuria group vs. 280), but was not statistically significant.

Predictors of Proteinuria and Renal Failure among women with HIV Infection

Szczech et al, Kidney International 2002

• Prospective cohort of 2059 women• Estimate the association between clinical

variables on presence of proteinuria on initial evaluation and risk factors of progression to renal failure

• Study follow up 54 month

Predictors of Proteinuria and Renal Failure among women with HIV Infection

Szczech et al, Kidney International 2002• Prevalence of proteinuria was 32% during initial

evaluation• Predictors of proteinuria were increased viral load,

CD4 count <200, black race and presence of hepatitis C

• 2.1% of patients experienced a doubling of creatinine during the study follow up

• Factors associated with renal failure in women with proteinuria were CD4 count <200, detectable viral load, increasing systolic blood pressure and decreasing albumin.

Treatment Modalities

• Nonspecific therapies:– Avoidance of uncontrolled hypertension– Avoidance of volume depletion– Avoidance of nephrotoxic agents

• Specific therapies:– ACE inhibitors– Antiretroviral therapy– Corticosteroids

ACE Inhibitors in treatment of HIVAN

• Captopril and Renal Survival in Patients with HIV Nephropathy, Kimmel et al, Am J. Kidney Dis, 1996

• Nonrandomised, case control study• 18 patients with biopsy proven HIVAN• 9 patients were treated with Captopril 3 times a day, starting

at a dose of 6.25 mg and titrating to 25 mg as tolerated• Controls were matched as much as possible to the case

study patients for level of serum creatinine and age at the time of the renal biopsy, race and gender.

• Response to therapy was monitored by urinary protein to creatinine ratio and serum creatinine with the primary end point being entry in to ESRD program.

Kimmel et al, Results• 7 African American men and 2 women were in the

Captopril group, 8 men and 1 woman were in control group• There was no difference in the initial mean serum creatinine

level and CD4 count, age or antiretroviral treatment.• Mean urinary protein over creatinine level was lower in the

case patients vs. control patients (5.3 vs 9.6) at the time of the biopsy.

• All patients in the control group progressed to ESRD• 6 patients in the study group progressed to ESRD, 1

committed suicide.• Mean renal survival time was 156 vs 37. days in the

Captopril treated group vs. control.

Kimmel et al, discussion

• Results suggest that course of HIVAN may be prolonged by treatment with Captopril

• Both patients with the longest renal survival had Captopril initiated when serum creatinine was less than 1.6

• Nonrandomized design and small study sample were the most significant problems with this study.

Effect of ACE Inhibition in HIVAN,Godfrey Burns et al, J Am Soc Nephrol, 1997• Nonrandomized, prospective study• Between 1993 and 1995 all patients seen in the AIDS clinic were

screened for proteinuria, positive results were followed by 24 hr urinary protein excretion

• Patients with excretion >500 mg were referred to renal clinic• 11 patients with nonnephrotic range proteinuria, Cr<2, biopsy

consistent with HIVAN, normal blood pressure and serum K, no prior renal disease, IVDU or sickle cell disease were enrolled

• 9 patients with nephrotic range proteinuria were included as well• All patients were offered treatment with Fosinopril 10 mg daily, of

the 11 patients with non nephrotic proteinuria 7 accepted treatment, and of the 9 patients with nephrotic proteinuria 5 accepted treatment

• Patients who declined treatment served as controls

Effects of ACEI in HIVAN, results

00.5

11.5

22.5

33.5

44.5

5

0 4 8 12 16 20 24

FosinoprilControls

Mean Serum Creatinine of patients with non-nephrotic range proteinuria

0123456789

0 4 8 12 16 20 24

FosinoprilControls

Mean protein excretion of patientswith non-nephrotic range proteinuria

0

1

2

3

4

5

6

7

8

9

10

0 4 8 12

FosinoprilControls

0

2

4

6

8

10

12

0 4 8 12

FosinoprilControls

Mean serum creatinine in patientswith nephrotic range proteinuria

Mean 24 hr protein excretion in patientswith nephrotic range proteinuria

Effect of ACEI in HIVAN, results

Effects of ACEI in HIVAN, Conclusions

• In the treatment group of patients with non nephrotic range proteinuria both serum Cr and 24 hour protein excretion stabilized over 24 weeks, the group of patients that did not receive treatment showed progression to advanced renal insufficiency

• The group of patients with nephrotic range proteinuria treatment with ACEI stabilized serum Cr over the 12 week period

• Despite the study limitations, this study suggests that early use of ACEI can stabilize renal function and 24 hour protein excretion in patients with HIVAN at least in short term

Antiretroviral Therapy• Several case reports, case series and nonrandomized trials

suggest a benefit in reducing the progression of renal disease on monotherapy with AZT, protease inhibitors and HAART (Hedayati, 2003)

• In retrospective analysis of 11 patients with biopsy proven HIVAN, 4 patients treated with AZT progressed more slowly to ESRD (Michel, Nephron 1992). In another study, monotherapy with AZT was compared to HIV positive controls with nephrotic syndrome. All controls initiated renal replacement therapy within 6 month, none of the patients on AZT developed ESRD. (Ifudu, Am. J. Nephrol, 1995)

Observation on HIV-Associated Renal Disease in the Era of HAART, Cosgrove et al, Am J. Med Sci,

2002• Retrospective study of HIV positive patients referred to

Renal Clinic with either renal insufficiency or proteinuria from 1996 through 2000.

• Number of renal lesions were noted on the biopsies as described earlier, with the clinical diagnosis of HIVAN being made in 20% in the HAART group versus 70% of cases in control group

• The average time of follow up was 626 days for HAART group vs. 315 days for non-HAART group.

Cosgrove et al, results

0123456789

FirstVisit

FinalVisit

FirstVisit

FinalVisit

All patientsHIVAN only

HAART No HAART

S. Creatinine

Cosgrove et al.

• Study results show that the renal disease runs more stable course in the patients on HAART. Viral load was lower and CD4 count higher in the treatment group, both at the beginning of the study period and at the end. Level of proteinuria was significantly higher in non-HAART group.

• The incidence of HIVAN was lower in the HAART group

Protease inhibitors are associated with the slowed progression of HIV related Renal Diseases, Szczech

et al, Clinical Nephrology, 2002• Retrospective study of patients with biopsy proven HIVAN or

nephrotic range proteinuria felt to be due to HIVAN or other HIV-related renal lesion.

• Clinical course was reviewed through hospital medical records. Patients were followed until the development of ESRD or death.

• 19 patients were identified between 1993 and 1998, age ranged from 22- 53, 11 patients were male and 8 female. 84% of study group were African-American. 7 patients reached ESRD during the study follow-up (19 months), all were African-American.

• The creatinine clearance of cohort fell at an overall rate of 2.56 ml/min/month, use of protease inhibitors and prednisone (n=3) was associated with diminished rate of loss of renal function

Protease inhibitors are associated with the slowed progression of HIV related Renal Diseases, Szczech

et al, Clinical Nephrology, 2002

Group Received Did Not Receive

p-value

Protease Inhibitor

0.08 4.3 0.04

Prednisone -5.57 3.32 0.003

ACE Inhibitor 0.08 3.03 0.31

Reverse Transcriptase Inhibitor

2.33 3.48 0.67

Prednisone in the Treatment of HIVAN

• A short term decrease in proteinuria and decline in progression of renal dysfunction has been demonstrated in case series with the use of steroids

• No randomized trials of the use of corticosteroids exist to this date.

• No studies other than case reports exist of use of corticosteroids after the initiation of renal replacement therapy

Prednisone Improves Renal Function and Proteinuria in HIVAN

Smith et al, Am J of Med Sci, 1996• Prospective cohort study of 20 consecutive HIV+ patients

with azotemia (Cr>2) and/or proteinuria >2g/day.• Renal biopsy was performed in 17 patients, in the

remaining three the diagnosis was clinical.• All patients received PPD, CXR, eye exam, serum

Cryptococcal antigen and blood cultures for MAC• Patients were than given Prednisone at 60 mg/d for a

median period of 4 weeks, dose was than tapered over 2 to 26 weeks period.

• Primary end points were consisted of changes in serum creatinine, 24 hour protein excretion, new or recurrent OI and steroid side effects.

Prednisone Improves Renal Function and Proteinuria in HIVAN

Smith et al, Am J of Med Sci, 1996• 2 patients did not respond to therapy and progressed to ESRD in 4

and 5 weeks after initiation of Prednisone.• 17 patients who were started on Prednisone due to azotemia showed

median decline in serum creatinine from 8.1 to 3.0 (p<0.001)• Median time from initiation of therapy to nadir of serum creatinine

was 5 weeks.• Four patients with the average serum Cr of 13.3 required temporary

hemodialysis before renal function improved to a mean Cr of 2.7• Nine patients developed worsening azotemia after Prednisone was

discontinued. Five patients were retreated and promptly responded.• Overall, in the 19 azotemic patients the median time to death, ESRD

of loss to follow up was 32 weeks.

Prednisone Improves Renal Function and Proteinuria in HIVAN

Smith et al, Am J of Med Sci, 1996

19 patients withHIVAN, Cr>2

17 respondersSerum Cr 8.1-3.0 after 5 wks

2 nonrespondersESRD in 4 and 5 weeks

8 pt with stable renal functionMedian f/u 17wks3 died, 1 lost to f/u4 alive at 8-25 wks

9 relapsed to pre-treatment Serum Cr at median time of 20 wks

5 retreatedCr 8.2 to 3.9 4 not retreated

1 with declining renal function 2 with steble renal function 2 relapsed

Prednisone Improves Renal Function and Proteinuria in HIVAN

Smith et al, Am J of Med Sci, 1996• Short term course of moderate dose of

corticosteroids improves renal function in patients with HIVAN.

• This study did not identify any factors that could predict favorable response.

• Six patients developed opportunistic infections during Prednisone therapy, CMV retinitis (3), disseminated MAC (2), candidemia (1) and pulmonary MAC (1)

• Limitations of the study are lack of control group, nonrandomized design and small sample size.

Cohort study of the treatment of severe HIVAN with corticosteroids,

Eustace et al, Kidney International, 2000• Retrospective cohort study of patients with biopsy

proven HIVAN and progressive azotemia who were eligible for corticosteroid treatment and had no clinical or histological evidence of alternative diagnosis (1994-1997)

• Selected patients received 60 mg of Prednisone daily for 1 month followed by several month taper.

• 21 eligible patients were identified, 13 received corticosteroid treatment (the choice of who received therapy was based on individual physician preference).

Cohort study of the treatment of severe HIVAN with corticosteroids,

Eustace et al, Kidney International, 2000• At three month of follow up the degree of

azotemia had progressed in six of eight non-corticosteroid treated patients, but only in 2 of 13 treated patients.

• Three patients in non-corticosteroid treated group progressed to ESRD by three month, in the remaining five the mean change in serum creatinine was 1.46.

• Among corticosteroid treated group, no patients progressed to ESRD, mean change in serum Cr was -2.2 at three month

Cohort study of the treatment of severe HIVAN with corticosteroids,

Eustace et al, Kidney International, 2000

A: Long term follow-up of the steroid treated group (N=13)B: Long term follow-up of the non-steroid treated group (N=8)

Cohort study of the treatment of severe HIVAN with corticosteroids,

Eustace et al, Kidney International, 2000• There were 18 infections in the corticosteroid treated

group and 8 in the non-corticosteroid treated group, however after adjustment for the duration of the follow-up, the incidence of infectious complications was not statistically significant.

• Limitations of the study are small sample size, retrospective and nonrandomized design

• Study suggests that limited use of corticosteroids in the patients with severe azotemia who are not requiring renal replacement therapy may result in temporary improvement in renal function and delay onset of ESRD.

Conclusions• Patients presenting with HIVAN usually have advanced

renal and HIV disease• It is unclear if screening asymptomatic HIV positive

patients for proteinuria would lead to early recognition of HIVAN or precursor lesion.

• The data from nonrandomized trials suggests that early intervention with ACE inhibitors and HAART may stabilize renal disease and until more data is available screening should be considered.

• Group of patients particularly at risk are those with CD4 count <200

Conclusions• Renal disease of HIV may present with several

distinct glomerular lesions, of which classic HIVAN (collapsing FSGS), while being the most common lesion in blacks, has clinical presentation that may be similar to other glomerular syndromes.

• Renal biopsy is the only way to definitively diagnose HIVAN

• Tissue diagnosis is essential if specific therapy is being considered, or if there are no other indications to initiate HAART

Conclusions HIV positive patients presenting with proteinuria and/or

azotemia should be started on ACE inhibitor Dose should be titrated as patient tolerates In patients with proteinuria with or without azotemia

HAART should be strongly considered. Patient with progressive renal failure despite ACE

inhibitors and HAART, no active infection and biopsy proven HIVAN may be given a trial of Prednisone at 60 mg/d

In patients failing to respond in 4-5 weeks, dose should be tapered quickly.