hivan.docx

7/29/2019 hivan.docx

1/9

Renal disease is a relatively common complication in patients with human immunodeficiency

virus (HIV) disease.[1]

HIV nephropathy can result from direct kidney infection with HIV or from

the adverse effects of antiretroviral drugs (see the image below).[2, 3]

Further, patients with HIVdisease are at risk for developing prerenal azotemia due to volume depletion resulting from salt

wasting, poor nutrition, nausea, or vomiting.

Types of electrolyte abnormalities observed with some of thedrugs used to treat opportunistic infections in patients with human immunodeficiency virus(HIV). ARF stands for acute renal failure.

HIV-associated nephropathy (HIVAN), formerly known as AIDS-associated nephropathy, ischaracterized by the following findings:

Nephrotic range proteinuria Azotemia Normal to large kidneys on ultrasound images Normal pressure Focal segmental glomerulosclerosis (FSGS) on renal biopsy findings

Although FSGS is the predominant glomerular lesion in HIVAN, other reported glomerular

lesions in patients with HIV include IgA nephropathy, cryoglobulinemia, amyloidosis, and alupuslike immune complex glomerulopathy.

In the preantiretroviral therapy era, HIVAN was characterized by rapid progression to renal

failure and end-stage renal disease (ESRD) leading to the need for dialysis. Highly active

antiretroviral therapy (HAART) has changed the natural course of this disease, increasing theimportance of prompt diagnosis and proper care. Baseline estimated glomerular filtration should

be obtained and renal function monitored during HAART.[4]

Physicians must consider HIVAN in

patients who develop proteinuria.

For other discussions on management of HIV infection, seeHIV Disease,Pediatric HIV

Infection, andAntiretroviral Therapy for HIV Infection.

For patient education information, see theImmune System CenterandSexually Transmitted

Diseases Center, as well asHIV/AIDSandRapid Oral HIV Test.

Epidemiology
http://emedicine.medscape.com/article/211316-overviewhttp://emedicine.medscape.com/article/211316-overviewhttp://emedicine.medscape.com/article/211316-overviewhttp://emedicine.medscape.com/article/965086-overviewhttp://emedicine.medscape.com/article/965086-overviewhttp://emedicine.medscape.com/article/965086-overviewhttp://emedicine.medscape.com/article/965086-overviewhttp://emedicine.medscape.com/article/1533218-overviewhttp://emedicine.medscape.com/article/1533218-overviewhttp://emedicine.medscape.com/article/1533218-overviewhttp://www.emedicinehealth.com/collections/SU300.asphttp://www.emedicinehealth.com/collections/SU300.asphttp://www.emedicinehealth.com/collections/SU300.asphttp://www.emedicinehealth.com/collections/SU305.asphttp://www.emedicinehealth.com/collections/SU305.asphttp://www.emedicinehealth.com/collections/SU305.asphttp://www.emedicinehealth.com/collections/SU305.asphttp://www.emedicinehealth.com/Articles/15476-1.asphttp://www.emedicinehealth.com/Articles/15476-1.asphttp://www.emedicinehealth.com/Articles/15476-1.asphttp://www.emedicinehealth.com/Articles/47944-1.asphttp://www.emedicinehealth.com/Articles/47944-1.asphttp://www.emedicinehealth.com/Articles/47944-1.asphttp://refimgshow%284%29/http://www.emedicinehealth.com/Articles/47944-1.asphttp://www.emedicinehealth.com/Articles/15476-1.asphttp://www.emedicinehealth.com/collections/SU305.asphttp://www.emedicinehealth.com/collections/SU305.asphttp://www.emedicinehealth.com/collections/SU300.asphttp://emedicine.medscape.com/article/1533218-overviewhttp://emedicine.medscape.com/article/965086-overviewhttp://emedicine.medscape.com/article/965086-overviewhttp://emedicine.medscape.com/article/211316-overview


2/9

According to the US Renal Data System (USRDS), HIV-associated nephropathy (HIVAN)

accounts for approximately 1% of new end-stage renal disease (ESRD) cases in the United

States. HIVAN is observed in patients regardless of the route by which HIV was contracted.

HIVAN is observed predominantly among African Americans and is the third leading cause of

ESRD among blacks aged 20-64 years.

[5, 6]

Most patients with HIVAN are young black men, andapproximately 50% of patients with HIVAN are intravenous drug abusers.[7, 8]

Overall, HIVAN

is observed more often in men than in women, with a male-to-female ratio of 10:1. The mean age

of persons with HIVAN is 33 years. HIVAN may occur in children.[9]

Pathophysiology

Experiments using transgenic mice have provided perhaps the strongest evidence for a direct roleby HIV type 1 (HIV-1) in the development of HIV-associated nephropathy (HIVAN).

Researchers created transgenic mice by inserting HIV DNA constructs into the mice's genomes.

The mice developed proteinuria and had a histologic picture similar to that observed in patients

with HIVAN.

A genetic or environmental cofactor that has not yet been identified is required for patients todevelop this disease. This unidentified factor might explain the predilection for HIVAN among

black persons.[5]

The cellular target in the development of HIVAN is probably the renal glomerular and tubular

epithelium. Using in situ hybridization and polymerase chain reaction assays to detect HIV-1

DNA and messenger ribonucleic acid (mRNA), investigators have shown that renal glomerular

and tubular epithelial cells are productively infected by HIV-1 in patients with HIVAN; thisargues strongly for localized replication of HIV-1 in the kidney and for the existence of a renal

viral reservoir.

Further, circularized viral DNA, a marker of recent nuclear import of full-length, reverse-

transcribed RNA, has been detected in kidney biopsy samples from patients with HIVAN,

suggesting active replication in renal tissue.[10]

However, the mechanisms of virus-induced renalinjury remain undetermined.

Peculiar histopathologic features of HIVAN are the enhanced proliferation and the loss of

differentiation markers of glomerular epithelial cells. In one study, HIV-1 infection was shown

to kill renal tubular epithelial cells in vitro by triggering an apoptotic pathway involving caspase

activation and Fas up-regulation, suggesting that apoptosis of nonlymphoid cells can be directly

induced by HIV-1. The net and long-standing glomerular and tubular epithelial cell damage leadsto proteinuria, glomerulosclerosis, and tubulointerstitial scarring.

The role of cytokines has not been established, and although their presence is not essential forthe development of HIVAN, cytokines may modify the progression of infection or a patient's

susceptibility to infection. The levels of cytokines are increased in renal biopsy samples frompatients with HIVAN.


3/9

In one study, mesangial and tubular cell production of interleukin-6 and tumor necrosis factor

alpha was shown to be a potent stimulus for HIV-1 expression in HIV-1infected monocytes.[11]

Viral replication in response to cytokines may play an important role in the pathogenesis ofHIVAN.

Genetics

The reason behind the increased predilection among black persons for the development of HIV-

associated nephropathy is not clear.[5]

In general, black persons have a higher incidence of other

renal diseases (eg, diabetic nephropathy, lupus); therefore, they may have an underlying geneticpredisposition to severe renal disease, regardless of the etiology. The type of host response to the

HIV infection itself may be what determines whether or not nephropathy develops in a specific

individual.

Kopp et al studied genetic variants predisposing to idiopathic and HIV-1associated focal

segmental glomerulosclerosis (FSGS), and they concluded that genetic variation at the MYH9

locus substantially explains the increased burden of FSGS and hypertensive kidney diseaseamong African Americans. They carried out admixture-mapping linkage-disequilibrium genome

scanning on 190 African American individuals with FSGS and 222 controls and identified a

chromosome-22 region centered on MYH9, a functional candidate gene expressed in kidneypodocytes.

[12]

Prognosis

In one study, the rate of progression from the initial presentation to ESRD was 2.5 months in the

pre-HAART (highly active antiretroviral therapy) era. With the introduction of HAART in 1996-

1997, the traditional natural history of rapid progression of HIV-associated nephropathy

(HIVAN) has been slowed significantly. HAART has been shown to retard the progression ofrenal disease in persons with HIVAN, and treatment with angiotensin-converting enzyme

inhibitors may be beneficial.

Among patients with HIV infection and end-stage renal disease receiving hemodialysis, survival

has improved significantly compared with the uniformly dismal outcomes in the 1980s.[13]

Clinical Presentation

Patients with HIV-associated nephropathy (HIVAN) typically present with anephrotic syndrome

consisting of nephrotic-range proteinuria (>3.5 g/d), azotemia, hypoalbuminemia, andhyperlipidemia. Edema is uncommon in HIVAN, yet many authors think that this is a

characteristic of HIVAN. The salt-losing propensity and high oncotic pressure contributed bymarked hypergammaglobulinemia in these patients have been suggested as possible explanations

for this puzzling observation.

CD4+ T-cell count
http://emedicine.medscape.com/article/244631-overviewhttp://emedicine.medscape.com/article/244631-overviewhttp://emedicine.medscape.com/article/244631-overviewhttp://emedicine.medscape.com/article/244631-overview


4/9

The CD4+

T-cell count in patients with HIVAN is usually depressed below 200 cells/L, but

HIVAN has been reported in patients with higher CD4 counts. The prognosis for renal survival is

worse in patients with AIDS, especially if their CD4 count is less than 50 cells/L.

Ultrasound and CT scan

Patients with HIVAN are not typically hypertensive, even in the face of renal insufficiency, and

their kidneys are usually normal to large in size and highly echogenic on ultrasonograms, as well

as on CT scans. This may result from prominent interstitial expansion by cellular infiltrate and

markedly dilated tubules containing voluminous casts.

Urinalysis

Routine urinalysis may occasionally reveal findings of nonnephrotic proteinuria in patients beingevaluated for other medical conditions. The urinalysis reveals microhematuria, leukocytes,

hyaline casts, and oval fat bodies, but no cellular casts. Serum complement levels are normal.

SIADH

Electrolyte abnormalities, such as hyponatremia and hyperkalemia, may be observed in patientswith HIVAN and may reflect an increase in total body water (from nephrotic syndrome or

syndrome of inappropriate secretion of antidiuretic hormone [SIADH]) or from hyporeninemic

hypoaldosteronism, respectively.

SIADH may result from concomitant pulmonary infection or from persistent nausea from

medications or gastrointestinal disease. Hyporeninemic hypoaldosteronism, a cause of type IVrenal tubular acidosis manifesting as hyperkalemia with normal anion gap metabolic acidosis, is

much more common when renal insufficiency is present.

Renal Biopsy

The decision to obtain a biopsy sample is somewhat controversial in the general medical

community. Even if a patient presents with the classic clinical features of HIV-associatedneuropathy (HIVAN), clinical consideration is predictive of the biopsy diagnosis in only 55-60%

of patients.

Therefore, to distinguish HIVAN from other forms of renal disease (eg, immune complex

glomerulonephritis, immunoglobulin-A nephropathy), patients who are seropositive for HIV

require a renal biopsy. The typical practice is to obtain a renal biopsy specimen if the patient's

daily protein excretion is greater than 1 g.

Histology

Findings from light microscopy of kidney biopsy tissue are diagnostic in most cases. The most

common histologic light microscopy finding is a collapsing form of focal segmental


5/9

glomerulosclerosis.[14]

The glomerular capillary tuft is collapsed (see the first image below) and

may be segmentally or globally sclerosed. Visceral epithelial cells are hypertrophied and form a

characteristic pseudocrescent in the Bowman space. Tubulointerstitial scarring, atrophy, andmarked dilatation of the tubules (microcystic dilatations) are usually present (see the second

image below).

Light microscopy with trichrome staining showing the collapse ofthe glomerular tuft, with segmental glomerular and interstitial sclerosis (bluish staining). The

renal tubules are dilated and filled with proteinaceous material.Light microscopy showing prominent microcystic dilatation of renal tubules filled with

proteinaceous material; this finding is characteristic of human immunodeficiency virus (HIV)

associated nephropathy, although it may also be observed in chronic glomerulonephritis.

Immunofluorescent microscopy helps to identify positive staining for albumin andimmunoglobulin G in epithelial cells and for immunoglobulin M, C3, and, occasionally, A in

mesangial or sclerotic areas.

Electron microscopy reveals wrinkling of the basement membranes, epithelial cell proliferation,and focal foot process effacement. Tubuloreticular structures in the glomerular endothelial cells

(consisting of ribonucleoprotein and membrane, the synthesis of which is stimulated by alpha

interferon) is highly predictive of HIVAN (see the image below).
http://refimgshow%282%29/http://refimgshow%281%29/http://refimgshow%282%29/http://refimgshow%281%29/


6/9

Electron microscopy showing a segment of the glomerularbasement membrane; foot process effacement (black arrow) and prominent tubuloreticular

inclusions (red arrow) are present.

Antiretroviral Drugs and Renal Function

Most HIV medications are well tolerated, even in the presence of renal insufficiency. The

(potential) toxicity of the nucleoside reverse transcriptase inhibitors (ie, zidovudine,[15]

didanosine, zalcitabine, stavudine, lamivudine, abacavir, emtricitabine) uniformly manifests as

type-B lactic acidosis. However, didanosine may cause electrolyte abnormalities, such as

hypokalemia, hyponatremia, hypermagnesemia, and hyperuricemia, and stavudine may cause

hyperuricemia.

Tenofovir is a nucleotide reverse transcriptase inhibitor (NRTI) with known renal toxicity andhypophosphatemia, and therefore, dose adjustment is indicated when creatinine clearance is less

than 50 mL/min. Except for nevirapine, which may cause lactic acidosis, the nonnucleoside

reverse transcriptase inhibitors (ie, nevirapine, delavirdine, efavirenz, etravirine) have noreported significant renal toxicity.

As a class, the protease inhibitors (PIs) (ie, saquinavir, ritonavir, indinavir, nelfinavir,

amprenavir, fosamprenavir, lopinavir, atazanavir, tipranavir, darunavir) may precipitatenephrolithiasis. A classic form of this is indinavir crystalluria, which occurs independently of

renal function; however, the stones resolve after cessation of indinavir therapy. A study by

Rockwood et al found that the rate of kidney stones was 7.3 per 1000 patient-years in patientsreceiving ritonavir-boosted atazanavir compared with 1.9 per 1000 patient years in patients

receiving other commonly used antivirals.[16]

Enfuvirtide (Fuzeon) is the first of a newer class of fusion inhibitors that targets the gp41 protein

on the surface of HIV and stops the virus from entering cells. Enfuvirtide has no known renal

effects for creatinine clearance of greater than 35 mL/min.

Maraviroc (Selzentry), approved in August 2007, is also a fusion inhibitor. It blocks the CCR5

coreceptor on CD4+ cells, preventing the virus from entering. Maraviroc does not require dose

adjustment for creatinine clearance greater than 50 mL/min.

Raltegravir (Isentress) is the first of a newer class of integrase strand transfer inhibitors. It doesnot require dose adjustment in patients with abnormal renal function.
http://refimgshow%283%29/


7/9

Dose adjustment should be made in patients receiving nucleoside reverse transcriptase inhibitors

(NRTI) when the glomerular filtration rate falls below 50 mL/min. Patients receiving

nonnucleoside reverse transcriptase inhibitors (NNRTIs) may also receive a dose adjustmentwhen the glomerular filtration rate falls below 50 mL/min. No dose adjustment is required for

patients taking protease inhibitors.

Some drugs used to treat opportunistic infections in HIV disease may also cause nephrotoxicity

or electrolyte abnormalities (see the image below).

Types of electrolyte abnormalities observed with some of thedrugs used to treat opportunistic infections in patients with human immunodeficiency virus(HIV). ARF stands for acute renal failure.

Pharmacologic Therapy

Although there are no guiding clinical studies, some experts recommend consideration of therapy

in all patients with HIV-associated nephritis (HIVAN). Initiation or adjustment of antiretroviral

therapy may be indicated. SeeAntiretroviral Therapy for HIV Infectionfor specific information,including recommendations for dosage adjustments for renal insufficiency.

Angiotensin-converting enzyme (ACE) inhibitors and corticosteroids have been studied for use

in HIVAN. Some reports on pediatric populations suggest that cyclosporine can be effective in

reducing proteinuria in persons with HIVAN. The usefulness of cyclosporine therapy forHIVAN warrants further study. Researchers are pursuing several promising therapeutic

strategies. Patients who progress to end-stage renal disease (ESRD) require dialysis and

consideration of renal transplantation in carefully selected cases.

Angiotensin-Converting Enzyme Inhibitors

In patients with advanced renal insufficiency, captopril was noted to improve renal survival for a

mean length of 37-156 days.[17]

In a subsequent prospective follow-up of 44 patients, the medianlength of renal survival for patients who received fosinopril was 479.5 days, with only 1 patient

developing ESRD. All untreated control subjects progressed to ESRD, with a median length of

renal survival of 146.5 days.[18]

The exact mechanism of action of ACE inhibitors in HIVAN is unknown, but it may be related

to a hemodynamic effect, a reduction in the transglomerular passage of serum proteins, and an
http://emedicine.medscape.com/article/1533218-overviewhttp://emedicine.medscape.com/article/1533218-overviewhttp://emedicine.medscape.com/article/1533218-overviewhttp://refimgshow%284%29/http://emedicine.medscape.com/article/1533218-overview


8/9

antiproliferative effect mediated in part by the inhibition of transforming growth factor beta. Use

ACE inhibitors if patients do not have hyperkalemia.

Corticosteroids

A number of case reports have suggested that corticosteroids offer some short-term benefit inHIVAN.

[19]In one report, results from a pretreatment and posttreatment kidney biopsy suggested

that an improvement in renal function was associated with a reduced number of lymphocytes and

macrophages infiltrating the interstitium.

In another report, of 20 patients who were treated with prednisone, 60 mg/day for 2-11 weeks,

followed by a slow taper,[20]

8 patients required maintenance dialysis, 11 died from

complications, and 7 were alive and no longer had ESRD after a follow-up of 44 weeks.

Experimental therapeutic strategies

Animal research shows promising results for retarding renal disease progression in HIVAN. Inone study, the use of a cyclin-dependent kinase inhibitor decreased visceral epithelial cell

proliferation in HIV-infected mice.[21]

In another study, blocking nuclear factor kappa beta (a cell signaling pathway) in mice resulted

in increased lifespan and kidney and lean body mass preservation.[22]

These benefits wereassociated with a reduction in the number of CD45

+cells infiltrating the kidneys, amelioration of

the renal architecture, and a reduction in the level of circulating inflammatory cytokines. Further

studies are needed to determine the role of these inhibitors on human HIVAN.

End-Stage Renal Disease

The care of patients with HIV-associated nephropathy (HIVAN) who progress to end-stage renaldisease (ESRD) remains a clinical challenge. Physicians must anticipate progressive renal

disease in patients with HIVAN and plan the placement of an arteriovenous fistula in a timely

manner for future use in hemodialysis. In current practice, hemodialysis is the accepted modality

of ESRD therapy in these patients.

A study by Ifudu et al showed that during a 68-month observation period, 17 (50%) of 34patients with HIV infection and ESRD died, compared with 65 (50%) of 131 patients with ESRD

alone.[23]

Mean survival was equivalent between patients with both HIV infection and ESRD and

those with ESRD alone (47.4 mo and 50.2 mo, respectively).

Because of increased susceptibility to infections, peritoneal dialysis has not been widely

advocated. Similarly, immunosuppression after kidney transplantation is thought to pose a

substantive risk of opportunistic infections in patients with HIVAN.[24]

Consequently, kidneytransplantation in these patients is performed with caution in compliant, stable patients with no

prior opportunistic infections who have an undetectable viral load and a CD4+

T-cell count of

more than 300 cells/L.


9/9

Anecdotal reports drawn from small samples of this selected group of patients with HIVAN

suggest no extra risk of opportunistic infections. Until larger studies are performed, however,

transplantation in persons with HIVAN should be focused on stable patients.

In one study, 1- and 2-year actuarial patient survival was 85% and 82%, respectively, and graft

survival was 75% and 71%, respectively. Plasma HIV-1 RNA remained undetectable, and CD4counts remained in excess of 400 cells/L with no evidence of AIDS for up to 2 years. These

results were comparable to other high-risk populations receiving kidney transplantation.

In a prospective study of kidney transplantation in 150 HIV-infected patients, Stock et al

reported 1- and 3-year graft survival rates of 90.4% and 73.7%, respectively. The rejection rate

was higher than expected, however, with 1- and 3-year estimates of 31% and 41%, respectively.Living-donor transplants were protective. Before transplantation, all patients had CD4 counts of

at least 200/L and undetectable plasma HIV-1 RNA levels while being treated with a stable

antiretroviral regimen, and HIV remained well controlled after transplantation.[25]

In an analysis of the United Network for Organ Sharing (UNOS) database, Locke et al evaluated39,501 patients undergoing renal transplantation between January 1, 2004, and June 30, 2006

and found no difference in patient survival among HIV-positive patients versus HIV-negativepatients (95.4% vs 96.2%, respectively).

[13]However, death-censored 1-year graft survival was

significantly lower among HIV-positive patients (87.9% vs 94.6%).

Locke et al concluded that with proper donor selection and transplant recipient management,

including the avoidance of prolonged cold ischemic time, use of living donors, and determination

of optimal immunosuppression dosing before transplant, long-term graft survival comparable tothat in HIV-negative patients can be achieved.

Documents

hivan.docx