disorders of the kidney in hiv infection

Chapter 29: Disorders of the Kidney in HIV

Infection

Amanda Valliant, MDNephrology FellowFellows’ Curriculum

1.16.2013

Roadmap

• HIV and AKI• Electrolyte Disturbances• Medication Toxicity• Thrombotic Microangiopathy and HIV• HIV-Associated Nephropathy• Immune-Complex Mediated GN• Hepatitis C Co-Infection

HIV and Acute Kidney Injury

Prior to HAART, AKI was typically due to sepsis, volume depletion, medication toxicity

AKI more common in HIV-infected hospitalized patients (6 % versus 2.7% in 2003 study)

Ambulatory HIV patients Single center study—at least 1 episode of AKI in 71 of 754

patients (9.4%) in a 2-year period (2000-2002)

Francescini, et al. Kidney Int 2005; 67:1526

HIV and AKI: Epidemiology

HIV and AKI

• Most common causes similar to the general population (ATN and prerenal states)

• Francescini study (2 year prospective): – Prerenal states include true volume depletion,

cirrhosis, heart failure (39%)– ATN ischemic and nephrotoxic (37%)– Crystalluria with obstruction (5%)– Interstitial Nephritis (5%)

- Inpatient mortality significantly higher among HIV-infected patients with AKI compared to those without AKI (2003, New York, 27% vs 4%)

- Long-term mortality higher among HIV-infected individuals with AKI- National sample of US veterans from 1986-2006 (>17K patients)- Hospitalized patients who survived 90 days after discharge- AKI occurred in 18% (3060 patients)- 334 patients with AKI required dialysis - Average f/u was 5.7 years after discharge, HIV-infected patients

with AKI significantly more likely to die (56% versus 47%)

- ESRD and cardiovascular events also more common among HIV-infected patients with AKI

HIV and AKI: Outcomes

Choi, et al. Kidney Int 2010; 78:478

Electrolyte Disturbances

Electrolyte Disturbances

-Prior to HAART, hyponatremia was the most common electrolyte disturbance in HIV

- Volume depletion was the most common cause- SIADH, idiopathic and related to lung infections and malignancy

-Hyperkalemia is most commonly associated with treatment or prophylaxis for PJP with pentamadine or trimethoprim-sulfamethoxazole

-Electrolyte depletion due to tubular dysfunction associated with a number of agents used to treat HIV or infectious complications

- Tenofovir, foscarnet, amphotericin, pentamidine - Hypophosphatemia, hypomagnesemia, hypocalcemia can be

severe and symptomatic, require aggressive replacement

Ampho B Renal Failure Mechanism

Medication Nephrotoxicity

- Indinavir (Crixivan) and Atazanavir (Reyataz) can cause - Indinavir (Crixivan) and Atazanavir (Reyataz) can cause crystalluria and AKI (protease inhibitors)crystalluria and AKI (protease inhibitors)

- Tenofovir (Truvada—an NRTI) can cause AKI with or without Tenofovir (Truvada—an NRTI) can cause AKI with or without proximal tubular dysfunctionproximal tubular dysfunction

- Fanconi syndrome, with associated risks of osteomalacia, Fanconi syndrome, with associated risks of osteomalacia, occurs most commonly with tenofoviroccurs most commonly with tenofovir

Meta-analysis of 17 studies examining TDF Meta-analysis of 17 studies examining TDF safety safety shows a significantly greater loss of kidney shows a significantly greater loss of kidney function function with TDF (0.7% risk difference with 95% CI with TDF (0.7% risk difference with 95% CI

0.2-1.2)0.2-1.2) Also demonstrated with didanosine (Videx—Also demonstrated with didanosine (Videx—

NRTI)NRTI)

HAART

- Herpes simplex or CMV Treatments- Herpes simplex or CMV TreatmentsAcyclovir – ATN/crystalluriaAcyclovir – ATN/crystalluriaFoscarnet – Nephrogenic DI, electrolyte disturbancesFoscarnet – Nephrogenic DI, electrolyte disturbancesCidofovir – Proximal Tubular DamageCidofovir – Proximal Tubular Damage

- Anti-Pseudomonal Drugs- Anti-Pseudomonal DrugsTrimethoprim-SulfamethoxazoleTrimethoprim-Sulfamethoxazole AIN AINPentamadine Pentamadine nephrotoxic ATN in 25% of patients nephrotoxic ATN in 25% of patients

Other Medications

Trimethoprim crystals in the

urine

Thrombotic Microangiopathy

and HIV

Thrombotic Microangiopathy (TMA) of HIV

-TTP and adult HUS are considered part of a spectrum of disease known as “thrombotic microangiopathies” (TMA) because they have similar clinical and histological characteristics, both result in endothelial cell damage

- Intravascular platelet clumping leads to clinical pentad of MAHA, thrombocytopenia, fever, neurological and renal dysfunction

-TMA is rare in healthy people- Mortality is >95% if untreated- Treatment with plasma exchange dramatically improves prognosis and survival

- TMA has been associated with bacterial toxins, immune complexes, autoimmune disorders, cancer and antineoplastic therapy, organ and marrow transplantation, drugs (IFN, ticlopidine, quinine, simvastatin, rifampicin)

-Association between TMA and HIV first recognized in 1984, both TTP and HUS have been reported in HIV-infected patients (no difference clinically from non- infected patients)

Thrombotic Microangiopathy (TMA) of HIV

-Reports of the prevalence of TMA in HIV-infected patients varies from 1.4% in the pre-HAART era to 7% in patients hospitalized with AIDS

- In the Collaborations in HIV Outcomes Research/US (CHORUS) cohort of 6022 patients, only 17 (0.3%) had TMA (June 1997-May 2003)

- When compared to similar patients without TMA, they had: ● Lower mean CD4 counts (197 vs 439 cells/mm, p = 0.0009) ● Higher mean HIV RNA levels (4.6 vs 3.3 copies/mL, p = 0.0001) ● Greater incidence of AIDS (82% vs 55%, p = 0.025) ● Greater incidence of Mycobacterium avium complex

infection (18% vs 3%, p = 0.018) ● Greater incidence of Hepatitis C (29% vs 11%, p = 0.001) ● Greater incidence of death (41% vs 7%, p < 0.0001)

- In this cohort, 10 of 17 patients were white, 4 hispanic, 3 of African descent

Becker, et al. Clin Inf Dis, 2004; 39: 267-275

Tubular reticular endothelial cell inclusions demonstrated in HIVAN, not collapsing FSGS

Tubular reticular endothelial cell inclusions demonstrated in HIVAN, not collapsing FSGS

HIV-Associated Nephropathy

HIVAN-First described in 1984 in patients with advanced HIV infection

-Collapsing form of focal sclerosing glomerulosclerosis (FSGS)- Associated tubular microcysts and interstitial inflammation- Typically presents with significant proteinuria, rapidly progressive

renal disease- Usually in the setting of NORMAL BLOOD PRESSURES- Normal to enlarged kidneys are typical

-Pathogenesis (hypothesized): - Infection of kidney epithelial cells by HIV and expression in those cells-Transgenic mouse models suggest that HIV genes such as Nef and Vpr are involved- Genetic susceptibility (strongly favors black race)

HIVAN: Epidemiology

- Closely associated with black race, more so than any other cause of ESRD outside of sickle cell disease

- Leading cause of ESRD in young African-American adults

- HAART has decreased the % of HIV-infected patients that have HIVAN

- Due to increasing numbers of HIV-infected patients, the annual incidence of HIVAN is increasing (approximately 900 new cases per year)

-First described in 1984 as a complication of AIDS, but can occur in acute seroconversion or in less advanced disease

HIVAN: Clinical Presentation

- USRDS data: Approx 90% of new ESRD cases due to HIVAN occur in patient of African descent

- Advanced HIV disease (mean CD4 count 127, viral load >30K)

- Nephrotic range proteinuria

- Rapid decline in renal function, usually advanced at time of diagnosis

- Hypertension, edema, hematuria are less common but can occur

Figure 1. The pathology of HIVAN from human kidney biopsy samples. Typical pathologic changes of HIVAN include global glomerular collapse with overlying

epithelial cell crowding and hypertrophy (left panel) as well as tubular microcystic disease (right panel) (images courtesy of Dr Vivette D'Agati).

Kaufman, et al. Advances in CKD, 2002, 17; 1:36-43

HIVAN: Pathology

HIVAN: Differential Diagnosis

- Study of 107 HIV-infected black patients with worsening renal function and >3g of proteinuria biopsy results revealed the following:

- HIVAN (56%)- Classic FSGS (21%)- Membranoproliferative Glomerulonephritis (6%)- Amyloidosis (4%)- Diabetic Nephropathy (4%)- Lupus-like Immune Complex GN (4%)

** Nearly 40% suspected clinically of having HIVAN did not** Biopsy should be done unless there is a contraindication

Atta MG, et al. Am J Med 2005; 118:1288

HIVAN: Treatment- In patients diagnosed with HIVAN not on HAART, this is the initial treatment

- Endorsed by KDIGO Clinical Practice Guidelines for GN- Patients typically have another indication for starting HAART as well- No randomized trials looking at HAART treatment - Median survival higher among patients receiving HAART (18.4 vs 3.9 months) but in this retrospective study the serum creatinine was lower among the HAART group and this was not adjusted for.

- In patients who are proteinuric or hypertensive, therapy with either an ACEI or ARB is indicated; this should be up-titrated rapidly

- Not suggested to routinely treat with glucorticoids although some centers do-Some experts use a trial of steroid in patients with progressive disease who are nearing a need for RRT despite the treatments above-Only small, uncontrolled studies conducted before HAART or early in the HAART era have looked at glucocorticoids in this disease

Immune Complex-Mediated GN

Immune Complex Mediated Glomerulonephritis

- Nearly 40% of HIV-infected patients with proteinuric kidney disease and suspected HIVAN will have another diagnosis at biopsy

- Membranous Nephropathy- Membranoproliferative and mesangial proliferative GN- “Lupus-like” proliferative GN- Rare cases of IgA Nephropathy

- Natural history of these diseases in HIV and response to HAART has not been well studied

- In general, based on small case series reports, patients with non-HIVAN kidney disease tend to have less advanced HIV, slower progression to ESRD, less likely to be black

- “Lupus like” disease tends to be more aggressive and is more likely to be seen in black patients

- In one cohort of 14 patients, 10 progressed to ESRD within one year

- HIVICK: HIV Immune Complex Kidney Disease

- Unique immune complex disease with a characteristic “ball in cup” basement membrane reaction

- First described in a South African biopsy series

- Role of viral antigens in circulating immune complexes and the pathogenic relationship between HIV and the development of HIVICK has not been studied

HIVICK

www.readcube.com

HIVICK: Pathology

Hepatitis Co-Infection with HIV

Hepatitis C Co-Infection

- Associated with the development of both acute and chronic kidney disease in large cohort studies of HIV patients

- Histologic patterns have NOT been studied in large groups

- MPGN is strongly associated with Hepatitis C infection in the general population and is a common diagnosis in co-infection as well

- Classic findings that are clinically associated with cryoglobulinemia and hypocomplementemia may be less common in coinfection

- Treatment of Hepatitis C associated MPGN in the setting of HIV has not been well studied- Plasmapheresis- Corticosteroids- Antiviral therapy for Hepatitis C

ReferencesReferences

- Wyatt CM. - Wyatt CM. www.uptodate.com, “Overview of Kidney Diseases in HIV-Infected, “Overview of Kidney Diseases in HIV-InfectedPatients”Patients”

- Kalyesubula R, Perazella M. Nephrotoxicity of HAART. AIDS Research and - Kalyesubula R, Perazella M. Nephrotoxicity of HAART. AIDS Research and Treatment, 2011.Treatment, 2011.

- Wyatt CM. - Wyatt CM. www.uptodate.com, “HIV-associated nephropathy (HIVAN)”, “HIV-associated nephropathy (HIVAN)”

- Becker, et al. HIV-Associated Thrombotic Microangiopathy in the era of Highly - Becker, et al. HIV-Associated Thrombotic Microangiopathy in the era of Highly Active Antiretroviral Therapy: An Observational Study. Clin Inf Dis, Active Antiretroviral Therapy: An Observational Study. Clin Inf Dis, 2004;39:267-275.2004;39:267-275.

- Greenberg A, Cheung A. - Greenberg A, Cheung A. Primer on Kidney Diseases, 5Primer on Kidney Diseases, 5thth Edition. Edition. Elsevier Elsevier Health Sciences, 2009. Chapter 29: Disorders of the Kidney in HIV Health Sciences, 2009. Chapter 29: Disorders of the Kidney in HIV Infection. Infection.