Shortly after the earliest descriptions of HIV infection were published in 1981, the first observations of focal segmental glomerular sclerosis and renal failure associated with HIV infection were reported.(1-6) This entity is now known as HIV-associated nephropathy (HIVAN), and it remains the most common form of kidney disease among HIV-infected individuals. Kidney disease is now widely recognized as a frequent complication of HIV infection.(7) However, other causes of kidney disease related to antiretroviral therapy (ART), its complications, or comorbid conditions appear to be growing in importance as the natural history of HIV infection evolves and the life expectancy of HIV-infected individuals increases.
Renal disorders are encountered at all stages of HIV infection, and they range from the fluid and electrolyte imbalances commonly seen in hospitalized patients to end-stage renal disease (ESRD). This chapter begins with a review of acute renal failure (ARF) and fluid and electrolyte disorders; the focus of the subsequent discussion is on the epidemiology and prognosis associated with chronic kidney disease (CKD), the pathogenesis and treatment of HIVAN, and the management of ESRD.
| Acute Renal Failure|
| Epidemiology and Etiology of Acute Renal Failure|
Studies of ARF conducted before the advent of ART revealed that HIV infection is associated with an increased incidence of ARF among hospitalized patients. In a study of 449 HIV-infected individuals admitted between 1983 and 1986, ARF, defined as a peak serum creatinine level of ≥2 mg/dL, was reported in 20% of patients.(8) In contrast, studies of ARF during the same period found an incidence rate of 4-5% among hospitalized HIV-uninfected patients.(9) In these series, the two most common causes of ARF among HIV-infected individuals were hypovolemia and acute tubular necrosis (ATN). A study of kidney biopsy specimens from HIV-infected patients with severe ARF, not thought to be associated with prerenal causes or ATN, reported the following distribution of renal lesions: 35% hemolytic uremic syndrome; 26% ATN (either of ischemic-toxic origin or caused by rhabdomyolysis); 17% obstructive renal failure that was either extrinsic, drug induced, or secondary to paraprotein precipitation; 15% HIV-associated nephropathy; 2% acute interstitial nephritis; and 4% various glomerulonephritides.(10)
An increased risk of ARF among HIV-infected individuals also has been reported in the modern era of ART. A study of adult hospitalized patients in New York State in 2003 found ARF in 6% of HIV-infected individuals compared with 2.7% in HIV-uninfected patients. Risk factors for ARF included older age, male gender, diabetes, liver disease, and underlying CKD. The diagnosis of ARF also was associated with an approximate 5-fold increase in mortality (adjusted odds ratio: 5.83; 95% confidence interval [CI]: 5.11-6.65). This study relied on diagnostic codes for ARF reporting and, therefore, likely underestimated the actual incidence of ARF.(11)
In addition, ARF may also be found in ambulatory HIV-infected patients. An observational study of 754 HIV-infected patients between 2000 and 2002 found an ARF incidence of 5.9 per 100 person-years (95% CI: 4.9-7.1). The most common etiology was prerenal azotemia of various causes (38%), whereas ATN secondary to nephrotoxic drugs and ischemic causes accounted for 17% and 22% of cases, respectively. Risk factors for outpatient ARF included male gender, hepatitis C virus (HCV) infection, AIDS-defining illness, a history of taking antiretroviral medications, low CD4 count, and high HIV RNA levels.(12)
| Acute Renal Failure Related to Medications|
Other studies of ARF among HIV-infected individuals also have found that medications commonly used in the treatment of HIV-related infections are important causes of ATN. Aminoglycoside antibiotics, pentamidine, acyclovir, foscarnet, amphotericin, tenofovir, adefovir, and cidofovir have all been associated with ATN in HIV-infected patients.(13)
The dramatic increase in the use of tenofovir since its approval by the U.S. Food and Drug Administration in 2001 has prompted considerable interest in studying the incidence and severity of tenofovir nephrotoxicity. Similar to the renal toxicity seen with the related compounds, adefovir and cidofovir, multiple case reports of ARF, Fanconi syndrome, and nephrogenic diabetes insipidus associated with tenofovir use have been published.(14-17) Fanconi syndrome caused by tenofovir nephrotoxicity is characterized by generalized proximal tubular dysfunction resulting in one or more of the following: bicarbonaturia, glucosuria, phosphaturia, uricosuria, aminoaciduria, and tubular proteinuria. It is hypothesized that this toxicity may be a result of mitochondrial DNA depletion or direct tubular cytotoxicity similar to that associated with the use of adefovir and cidofovir.(18-22) Although these toxicities are rare, episodes of ARF related to tenofovir may be irreversible and lead to ESRD.(17) Therefore, regular monitoring of kidney function and urine studies during tenofovir administration are recommended.(7,23) Further research is needed to determine the clinical significance of small decrements in kidney function detected with long-term use of tenofovir.(24-27)
Agents known to cause acute interstitial nephritis, such as nonsteroidal antiinflammatory drugs (NSAIDs), trimethoprim-sulfamethoxazole, and rifampin, are used frequently in HIV-infected patients. Acute interstitial nephritis associated with ART is less common. In a study of renal biopsy specimens for ARF involving 60 HIV-positive patients, only 2 patients had drug-related interstitial nephritis.(10) There are various case reports of acute interstitial nephritis among patients taking indinavir, ritonavir, abacavir, and atazanavir.(28-30) In most cases of acute interstitial nephritis, an inciting agent cannot be clearly identified. Cessation of the suspected causative drug usually leads to renal recovery, and a short course of steroid therapy can be considered in severe cases of biopsy-proven acute interstitial nephritis.
Obstruction also should be considered in the differential diagnosis of ARF among HIV-infected patients. Sulfadiazine crystal formation causing tubular obstruction and sulfadiazine stones causing ureteral obstruction have been reported among volume-depleted, HIV-infected patients.(31-33) Acyclovir also can cause crystalluria and ARF, and dosage adjustments should be made for patients with preexisting CKD.(34) The protease inhibitor indinavir may cause indinavir crystalluria in 20% and leukocyturia in 25-35% of patients receiving indinavir at the normal dose. Symptomatic urinary tract disease, including renal colic, dysuria, or urgency, with or without evidence of nephrolithiasis, has occurred in 8% of patients taking the drug. Those with symptomatic urinary tract disease usually have indinavir crystalluria detected with urinalysis, and many have radiographic evidence of either stones or renal parenchyma filling defects. Renal failure occurs only in a minority of cases, and tends to be mild to moderate in severity.(35) Indinavir nephrolithiasis can be prevented with ample fluid intake (1.5-2 liters per day).(7) Symptomatic urinary tract disease may resolve with hydration alone, but among some patients, recurrence of symptoms necessitates permanent discontinuation of indinavir. The drug should not be discontinued for asymptomatic crystalluria.(36) Indinavir also may cause acute interstitial nephritis presenting with mild renal insufficiency and pyuria.(28)
| Fluid and Electrolyte Disorders|
| Disorders of Osmolality|
Hyponatremia is a frequent finding among HIV-infected persons, with a reported prevalence of 30-60% in hospitalized patients.(37,38) It is a marker of severe illness that is associated with increased mortality in HIV-infected patients.(39) In a study of 212 HIV-infected patients admitted to a large metropolitan hospital, the mortality rate for the hyponatremic group was higher than that for the normonatremic group (36.5% vs 19.7%; p < .01).(39)
The etiology and management of hyponatremia may differ according to the timing of its presentation. Volume depletion caused by diarrhea or vomiting is the usual cause of hyponatremia present at the time of hospital admission. Clinical management includes replacement of the volume deficit, along with measures to treat the underlying cause of volume depletion. In contrast, the syndrome of inappropriate antidiuretic hormone (SIADH) is the likely culprit among patients who develop hyponatremia during hospitalization.(39) SIADH is associated with common pulmonary and intracranial diseases such as Pneumocystis jiroveci pneumonia, toxoplasmosis, and tuberculosis. The initial treatment of SIADH consists of fluid restriction and treatment of the underlying infection or malignancy. Persistent release of antidiuretic hormone resulting from infections that are slow to respond to treatment also can be managed with demeclocycline at a dosage of 600-1,200 mg per day, which will inhibit the action of antidiuretic hormone on the renal tubule.
| Potassium Disorders|
Both hypokalemia and hyperkalemia are common among HIV-infected patients. Hypokalemia is usually found in the setting of gastrointestinal infections leading to vomiting or diarrhea. Amphotericin B, frequently used to treat fungal infections in patients with AIDS, can cause tubular dysfunction resulting in hypokalemia. As noted, tenofovir has been associated with proximal tubular dysfunction resulting in an electrolyte wasting state, including life-threatening hypokalemia.(14,40,41)
Drug-induced hyperkalemia is common among patients receiving either high-dose trimethoprim-sulfamethoxazole or intravenous pentamidine. In a manner similar to the action of potassium-sparing diuretics such as amiloride, both drugs inhibit distal nephron sodium transport, leading to a decrease in potassium secretion.(42,43) Hyperkalemia and hyponatremia also may be a manifestation of mineralocorticoid deficiency resulting from adrenal insufficiency or the syndrome of hyporeninemic hypoaldosteronism.(44,45) Acute or chronic kidney disease also may contribute to potassium retention. Adrenal causes of hyperkalemia often respond clinically to treatment of the underlying disorder, loop diuretics, or fludrocortisone.(45)
| Acid-Base Disorders|
Acid-base disturbances in HIV-infected patients are commonly caused by infections or drugs. Respiratory alkalosis and respiratory acidosis may occur in opportunistic infections of the lungs or central nervous system. Nonanion gap metabolic acidosis may occur as a result of several different processes, including intestinal losses of bases caused by diarrhea and renal acidosis resulting from adrenal insufficiency, the syndrome of hyporeninemic hypoaldosteronism, or drug toxicity (eg, amphotericin B).(13,44,46)
High anion gap metabolic acidosis in this population results from chronic kidney disease, type A lactic acidosis caused by tissue hypoxia, and type B lactic acidosis.(47) Type B lactic acidosis presents with markedly elevated blood lactate levels, possibly caused by drug-induced mitochondrial dysfunction. Affected patients show no evidence of hypoxemia, tissue hypoperfusion, malignancy, or sepsis. This disorder has been reported with use of nucleoside reverse transcriptase inhibitors such as zidovudine, didanosine, zalcitabine, lamivudine, and stavudine.(48) Although life-threatening acidosis is rare, 5-25% of treated patients may develop mildly elevated lactate levels (2.5-5 mmol/L) without acidosis. The value of screening and the predictive value of small, asymptomatic elevations in lactate are unknown.(48,49) Routine monitoring for hyperlactatemia with lactic acid levels is not recommended, but lactic acid levels should be measured in patients who present with low bicarbonate levels, an elevated anion gap, or abnormal liver enzymes.(50)
| Chronic Kidney Disease|
| Epidemiology of Chronic Kidney Disease|
The Infectious Diseases Society of America has recommended the use of guidelines from the National Kidney Foundation to diagnosis and stage kidney disease. CKD is defined by: 1) evidence of structural or functional kidney damage (abnormal urinalysis, imaging studies, or histology) present for at least 3 months with or without a decreased glomerular filtration rate (GFR); or, 2) decreased kidney function (GFR <60 mL/min per 1.73 m2), with or without evidence of kidney damage. In clinical practice, creatinine-based equations, such as the Cockcroft-Gault equation that calculates creatinine clearance or the Modification of Diet in Renal Disease (MDRD) equation for estimated GFR (eGFR) should be used to estimate renal function, instead of serum creatinine measurement alone.(51)
Several studies conducted in the era of ART have provided prevalence estimates for CKD among various HIV-infected populations. Some of these studies have applied the National Kidney Foundation definition of CKD, whereas others focus on kidney dysfunction or kidney damage exclusively. For example, data on proteinuria are frequently available because it is the most common manifestation of kidney damage and it is widely tested in clinical practice. For this reason, the prevalence of CKD may vary, depending on the operational definition of CKD that is applied in a particular study. The epidemiology of CKD also may differ according to the underlying racial composition, comorbid conditions (eg, diabetes, hypertension), and immunologic or virologic characteristics of the population studied.
| United States|
Microalbuminuria was characterized in a nationally representative sample of 760 HIV-infected individuals in the study of Fat Redistribution and Metabolic Change in HIV Infection (FRAM) and compared with 227 participants of the Coronary Artery Risk Development in Young Adults (CARDIA) study.(52) Microalbuminuria, defined as a urine albumin-to-creatinine ratio of >30 mg/g, was present in 11% of HIV-infected participants and 2% of control participants. The severity of microalbuminuria was predicted by markers of insulin resistance, hypertension, and advanced HIV infection.
An urban, multicenter study of women conducted in the United States found that 32.6% of 2,057 women had CKD, defined as proteinuria concentrations of ≥1+ upon dipstick analysis. In another cohort of HIV-infected women, 7.2% of participants were found to have renal disease at baseline, with 14% of patients subsequently developing renal insufficiency after a mean observation time of 21 months.(53,54) Among the predominantly male HIV-infected population in the U.S. Department of Veterans Affairs (VA) health care system, the prevalence of CKD (defined as an eGFR of <60 mL/min per 1.73 m2) was 8.5% (1,041 of 12,315 patients).(55)
Mocroft et al conducted a cross-sectional study among 4,474 participants of the EuroSIDA study, which recruited patients from 31 European countries, Israel, and Argentina beginning in 2004.(56) Kidney disease was defined as a creatinine-based eGFR measurement of ≤60 mL/min per 1.73 m2, which was confirmed with a second eGFR. The prevalence of CKD was 3.5% using the Cockcroft-Gault formula and 4.7% with the MDRD formula. Factors associated with CKD were older age, lower CD4 count nadir, and cumulative tenofovir or indinavir exposure.
In a single-center, cross-sectional study from South Africa, 615 HIV-infected patients were screened for proteinuria after exclusion of individuals with established CKD or known risk factors for kidney disease.(57) The investigators found macroalbuminuria in 38 patients (6.2%) and microalbuminuria in 7 patients (1.1%). Thirty of these 45 patients underwent kidney biopsy. HIV-associated nephropathy was the most common diagnosis, accounting for 6 of 7 biopsy results (83%) among microalbuminuric patients and 19 of 23 (83%) cases among macroalbuminuric patients.
In a study conducted in western Kenya, the prevalence of CKD was estimated among individuals without known risk factors for kidney disease.(58) Proteinuria, defined as a protein concentration of ≥1+ upon urinalysis, was detected in 23 of 373 patients (6.2%). The prevalence of CKD was 11.5% when using the Cockcroft-Gault equation, but only 2.2% when the MDRD equation was used.
Finally, in a study from Hong Kong, kidney disease screening was performed for 322 Chinese patients with HIV infection. The investigators utilized U.S. National Kidney Foundation criteria to define CKD as an eGFR measurement of <60 mL/min per 1.73 m2, proteinuria for more than 3 months, or both. The overall prevalence of CKD was 16.8%; 5.6% of patients had an eGFR of <60 mL/min per 1.73 m2 and 13.7% had a spot urine protein-to-creatinine ratio of >0.3. Similar to data for other populations, risk factors for CKD included older age, lower CD4 count, and use of indinavir.(59)
In summary, CKD appears to be a common complication of HIV infection in the modern era of ART. The prevalence of CKD ranges from 3.5% to 32.6%, depending on the characteristics of the study population and the criteria used to define CKD. In recognition of the burden of renal disease among HIV-infected persons, the Infectious Diseases Society of America recommends screening for kidney disease using urinalysis and a calculated estimate of renal function upon diagnosis of HIV.(7) Patients who are at high risk of CKD, such as patients of black race, those with CD4 counts of <200 cells/µL or HIV RNA levels of >4,000 copies/mL, and those with diabetes, hypertension, or HCV coinfection, should undergo annual screening.
| Prognosis of Chronic Kidney Disease|
Several studies have found that CKD is associated with increased mortality among HIV-infected individuals. Szczech et al (60) demonstrated an independent association between proteinuria (defined as a urinalysis dipstick reading of ≥2+) or elevated serum creatinine levels (≥1.4 mg/dL) and an increased risk of death attributable to all causes (hazard ratio 2.5; p < .0001) after controlling for predictors of AIDS-related death, including CD4 cell count, HIV RNA level, and the use of ART.
Similarly, in a study of 12,315 HIV-infected veterans in the United States, level of kidney function was found to be a strong predictor of mortality. Compared to patients with an eGFR of ≥60 mL/min per 1.73 m2, patients with an eGFR of 30-59, 15-30, and <15 mL/min per 1.73 m2, and those on dialysis, had adjusted hazard ratios for mortality of 1.39 (95% CI: 1.11-1.75), 2.16 (95% CI: 1.43-3.27), 5.97 (95% CI: 3.19-11.20), and 2.17 (95% CI: 1.51-3.13), respectively. This study also found that patients with CKD were less likely to receive ART in follow-up and commonly received medications in dosages that were inadequately adjusted for their level of kidney function. It was hypothesized that ART prescription practices may be a mechanism for increased mortality in this group.(55)
| HIV-Associated Nephropathy|
A variety of renal abnormalities among HIV-infected patients have been described. These include HIVAN, HIV-related immune complex disease, nephropathy secondary to ART or antibiotics, thrombotic microangiopathy, and diseases related to common comorbidities such as amyloidosis from heroin skin popping or HCV-related membranoproliferative glomerulonephritis.(54)
The evaluation of an HIV-infected patient with suspected glomerular renal disease characterized by significant proteinuria, hematuria, or reduced kidney function should start with exclusion of possible secondary causes of glomerular disease. The history, physical examination, and serologic tests should focus on evidence of malignancy, hepatitis B or C virus infection, or syphilis. However, a kidney biopsy is usually warranted in order to obtain a conclusive diagnosis and to guide the course of therapy.
HIVAN is a unique clinical and histopathologic entity that can be definitively diagnosed only by kidney biopsy. Although the clinical features of HIVAN are well defined, the true prevalence of this disease is not known because, in practice, kidney biopsies are performed relatively infrequently. In kidney biopsy series among HIV-infected individuals, HIVAN is present in approximately 40-60% of specimens.(61,62) In contrast, an autopsy study of organs from HIV-infected persons in Texas found that the overall prevalence of HIVAN was 6.9%.(63) Screening protocols for HIVAN based on biopsies in HIV-infected patients with >1.5 g/day of proteinuria have found an overall prevalence of 3.5%.(64) However, kidney biopsy studies of HIV-infected individuals in South Africa suggest that HIVAN is an important cause of milder forms of kidney disease manifested as microalbuminuria.(57)
Several studies have revealed a striking predilection for HIVAN among African American individuals. Numerous kidney biopsy series have supported the finding that HIVAN predominantly occurs in African Americans.(65-68) A study of more than 2 million U.S. veterans found that African Americans with HIV carried a risk of ESRD that was similar to the risk of diabetes. In contrast, among white persons, the risk of ESRD associated with HIV was not increased. Overall, age- and sex-adjusted rates of ESRD were nearly an order of magnitude higher among HIV-infected black versus white patients.(69) Kidney biopsy studies from France, Brazil, and Thailand have confirmed this remarkable susceptibility to HIVAN among HIV-infected patients of African descent.(70-74)
| Clinical Manifestations|
Patients with HIVAN typically present with significant proteinuria and rapidly progressive renal insufficiency in the setting of poorly controlled HIV infection marked by low CD4 counts and elevated HIV RNA levels.(61,75) It is notable that most patients with HIVAN do not have significant edema or hypertension.(76-78) Abdominal ultrasound usually reveals large, echogenic kidneys. Serologic tests such as antinuclear antibody (ANA) and antineutrophil cytoplasmic antibody (ANCA) assays are of limited utility because false-positive serologies are more common in HIV-infected patients than in HIV-uninfected patients.(79-82)
HIVAN is associated with characteristic glomerular, tubulointerstitial, and ultrastructural lesions. The most consistent findings include collapsing focal segmental glomerular sclerosis, cystic tubular dilatation, interstitial edema, cellular infiltrates, and dilated tubules filled with pale-staining amorphous casts (see Figure
1). Immunofluorescence is nonspecific. Electron microscopy often reveals tubuloreticular inclusions in endothelial cells, and nuclear bodies also are noted frequently.(83,84) The ultrastructural changes are not unique to HIVAN, as they are also seen in idiopathic focal segmental glomerulosclerosis, heroin nephropathy, and as a rare complication of bisphosphonate therapy.(85)
The pathogenesis of HIVAN has been studied intensely over the past 15 years, and the accumulated data in humans and animal models provide substantial evidence that HIVAN is caused by direct HIV infection in renal tissue. Early studies using in situ hybridization to a cDNA nucleic acid probe found the HIV genome in tubular and glomerular epithelial cells in patients with HIVAN. Patients with immune-mediated glomerulonephritis and HIV-infected patients with no renal disease had less cellular involvement.(86) More sensitive polymerase chain reaction (PCR) techniques detected DNA from the HIV genome in all renal cell types except interstitial cells in HIV-infected patients with proteinuria, but the HIV DNA was also present in kidney tissue from HIV-infected patients without renal disease.(87)
The important role of HIV viral products in the pathogenesis of HIVAN has been demonstrated in studies using transgenic mice containing a noninfective HIV construct encoding the envelope glycoproteins gp41 and gp120 but lacking the gag and pol genes. These mice develop a renal syndrome closely resembling HIVAN.(88) This transgenic mouse model was also used to confirm that the renal disease develops from factors intrinsic to the kidney vs systemic factors related to HIV infection.(89) In this study, kidneys were cross-transplanted between normal and transgenic mice. HIVAN then developed in the transgenic kidneys transplanted into the nontransgenic littermates, whereas the normal kidneys remained disease free when transplanted into the transgenic littermates. This study provided evidence that HIVAN is caused by a direct effect of HIV gene expression rather than the systemic effects of HIV infection. This model also demonstrated that the HIV transgene is expressed in renal glomerular and tubular epithelial cells, and that transgene expression in renal epithelial cells was required for the development of the HIVAN phenotype.
Several studies have failed to demonstrate renal expression of CD4 and chemokine coreceptors required for HIV entry into cells.(90,91) Therefore, the mechanism for HIV infection of the kidney remains elusive. However, studies in humans have confirmed the presence of HIV in renal epithelial cells and the ability of HIV to generate full-length mRNA in the kidney.(92) The kidney also appears to be a reservoir for HIV. Despite undetectable viral levels in the serum, a case report described a patient who continued to express HIV in renal epithelial cells as determined by RNA in situ hybridization.(65) Active replication of HIV may occur in renal epithelium despite well-controlled HIV infection, possibly producing HIV strains in the kidney microenvironment that differ from HIV circulating in the blood. This suggests that the kidney may serve as a viral reservoir harboring HIV strains that have evolved under tissue-specific selection pressures.(93)
| Clinical Course and Treatment|
In the Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents, the U.S. Department of Health and Human Services now includes a diagnosis of HIVAN as an indication for ART, regardless of CD4 count.(94) Other treatment options that may influence the course of HIVAN include angiotensin-converting enzyme inhibitors (ACEIs) and corticosteroids administered before dialysis or kidney transplantation.
| Antiretroviral Therapy|
The original case reports of HIVAN described a rapid and inexorable progression to ESRD over a period of weeks to months.(2-4) However, after highly active ART came into use, several dramatic reports of renal recovery among these patients emerged in the medical literature. In one study, a patient with HIVAN and dialysis-dependent renal failure became dialysis free after 15 weeks of ART. Repeat renal biopsy revealed significant histologic recovery from fibrosis with only infrequent glomeruli showing mild collapse and minimal fibrosis.(65) Since then, a growing number of studies has helped establish ART as a first-line treatment for HIVAN.
The effect of ART on kidney disease progression has been characterized primarily by observational studies. A cohort of 53 patients with biopsy-proven HIVAN from the Johns Hopkins renal clinic was found to have better renal survival when treated with ART compared with patients who did not receive ART (adjusted hazard ratio: 0.30; 95% CI: 0.09-0.98).(95) In a retrospective study of 19 patients with a clinical diagnosis of HIVAN, after median follow-up of 16.6 months, the use of protease inhibitors was significantly associated with a slowing of the decline in creatinine clearance.(96)
In the Strategies for Management of Antiretroviral Therapy (SMART) study, 5,472 HIV-infected patients who had a CD4 count of >350 cells/µL were randomly assigned to continuous or episodic use of ART and were followed for a mean period of 16 months. Investigators found that, compared with continuous ART, planned treatment interruptions guided by CD4 counts significantly increased the risk of fatal or nonfatal ESRD (hazard ratio: 4.5; 95% CI: 1.0-20.9) in the treatment interruption arm. Although this study was not statistically powered to detect a difference in renal outcomes, the high incidence of ESRD in the treatment interruption group suggests that continuous therapy with antiretroviral medications is a key factor in preventing and slowing progression of kidney disease.(97)
| Angiotensin-Converting Enzyme Inhibitors|
Both ACEIs and angiotensin II receptor blockade have inhibited the development and progression of HIVAN in animal models.(98-100) Two prospective studies support the use of ACEI for the treatment of HIVAN. In a case-control study of 18 patients with HIVAN prior to the advent of ART, 9 were treated with captopril, and matched with 9 controls.(101) The captopril-treated group had improved renal survival, defined as time to ESRD, compared with controls (mean renal survival: 156 ± 71 days vs 37 ± 5 days; p < .002). In a single-center, prospective cohort study of 44 patients with HIVAN, 28 patients received fosinopril 10 mg/day, and 16 patients who refused treatment were followed as controls over 5.1 years.(102) The median renal survival of treated patients was 16.0 months, with only 1 patient developing ESRD. All untreated patients rapidly progressed to ESRD over a median period of 4.9 months. Despite the limitations of these studies, they suggest that ACEIs may be beneficial in curbing progression of HIVAN, and this class of drugs is a reasonable first choice as an antihypertensive agent for patients with HIVAN.
Evidence supporting the use of steroids for the treatment of HIVAN is also based on observational data.(95,103,104) In a single-center cohort study, 20 patients with HIVAN were prospectively enrolled to receive treatment with corticosteroids. Most patients (17 of 20) manifested improvements in kidney function and significant reductions in 24-hour urinary protein excretion. After steroid therapy, mean rates of protein loss declined from 9.1 ± 1.8 g per day to 3.2 ± 0.6 g per day (p < .005).(105) Another study of steroid therapy employed a control group and found similar results with no increased risk of infection in the steroid group.(104) Although these studies were generally limited by their nonrandomized designs, based on this evidence, steroids are considered second-line therapy for patients with HIVAN. The use of steroids should be considered for patients with a documented rapid deterioration in kidney function despite ART.
| End-Stage Renal Disease|
| Epidemiology of ESRD|
The U.S. Renal Data System (USRDS) reported 4,219 incident cases of ESRD secondary to "AIDS nephropathy" from 2000 to 2004.(70) Among these cases, almost 90% occurred among African Americans. Recent epidemiologic studies have further characterized the marked racial differences in ESRD incidence among HIV-infected individuals. A study from the VA health care system ascertained rates of ESRD among 2 million patients and compared rates between HIV-infected (n = 15,135) and HIV-uninfected groups. Among African Americans, rates of ESRD were similar between individuals with HIV infection and HIV-uninfected individuals with diabetes. In contrast, among white individuals, HIV was not associated with an increased risk of ESRD when compared with patients without HIV or diabetes.(106)
Blacks are the largest and fastest growing racial group with HIV in the United States, and 63% of all persons with HIV infection live in sub-Saharan Africa.(107,108) These reports, in combination with demographic trends in HIV infection, have provided a basis for growing concern that ESRD prevalence may increase dramatically in the future.(109)
| Improved Survival of the HIV-Infected ESRD Patient|
Early studies from the 1980s reported that newly diagnosed patients with ESRD and AIDS were dying an average of 1-3 months after starting hemodialysis.(2) Based on this observation, some nephrologists argued that the use of dialysis for this population should be restricted. However, these early studies predominantly included patients presenting late in the course of their HIV disease with advanced opportunistic infections. With the introduction of ART, survival of HIV patients with ESRD has steadily improved over the past decade.(110) Based on data from a national ESRD registry, by 1999, the 1-year survival rate of HIV-infected patients was equivalent to that of the general population (240 deaths per 1,000 patient-years among HIV-infected individuals compared with 236.4 deaths per 1,000 patient-years in the general population).(111) A study comparing survival patterns in France found similar mortality rates between the French Dialysis in HIV/AIDS cohort and the French Dialysis Outcomes and Practice Patterns Study II.(112) In summary, there is no reason at present to withhold renal replacement therapy from patients solely on the basis of HIV infection.(113)
Management of ESRD among HIV-infected patients poses specific medical and logistical challenges for dialysis care providers. Hemodialysis, peritoneal dialysis, and transplantation are options for these patients, and each modality has advantages and disadvantages. In general, preparation for renal replacement therapy should begin with a referral for kidney transplant evaluation for appropriate patients with well-controlled HIV infection and an eGFR of <25 mL/min per 1.73 m2.(114)
The most common renal replacement modality for HIV-infected patients is hemodialysis. Disadvantages of hemodialysis include risk to patients of infections from temporary catheters and grafts, and risk to dialysis providers of blood and needlestick exposure. Early surgical referral for placement of a native arteriovenous (AV) fistula is also preferred because inferior outcomes for AV grafts appear to be magnified among HIV-infected patients.(115-118) A 1992 study showed that synthetic graft infection rate was 43% among patients with AIDS, 36% among patients with asymptomatic HIV infection, and 15% among patients who were HIV negative (p < .05).(119) Subsequent studies have shown that thrombus-free survival of native AV fistulas among HIV-positive patients is comparable to that reported for HIV-negative patients.(118)
| Peritoneal Dialysis|
Outcomes between hemodialysis and peritoneal dialysis patients are equivalent, and HIV-infected individuals initiating renal replacement therapy should be provided the option of choosing either modality.(120) An advantage of peritoneal dialysis is the reduction of potential exposures to contaminated blood and needles among dialysis personnel. Also, peritoneal dialysis patients generally enjoy greater independence and preservation of residual renal function compared with hemodialysis patients.
Disadvantages of peritoneal dialysis include increased protein losses and the potential for severe peritonitis. The incidence and spectrum of peritonitis has been reported for several small cohorts of HIV-infected patients. The largest study involved 39 HIV-infected patients on peritoneal dialysis, and found a greater overall risk of peritonitis along with a percentage of cases attributable to Pseudomonas species and fungi that was higher than corresponding rates for HIV-negative patients.(121,122) It was not clear from this study whether the greater risk of peritonitis was related to HIV infection or to confounding variables such as low socioeconomic status and drug use. In terms of survival, studies suggest that peritoneal dialysis is equivalent to hemodialysis among HIV-infected patients.(120)
| Infection Control in Dialysis|
Dialysis providers treating HIV-infected ESRD patients must adhere carefully to universal body substance precautions. HIV-infected patients do not require special isolation precautions during hemodialysis, and it is permissible to reuse properly sanitized dialyzers that have been used to treat HIV-infected patients. Routine infection control precautions and routine cleaning with sodium hypochlorite solution of dialysis equipment and of frequently touched surfaces are sufficient measures with regard to treating HIV-infected patients on hemodialysis. Precautions such as isolation of HIV-infected patients from other dialysis patients are unnecessary and could violate medical confidentiality regulations.
Dialysate should be treated as a potentially contaminated body fluid. The size of the HIV particle is much larger than most dialyzer membrane pore sizes; therefore, it is likely that HIV particles do not cross the dialyzer membrane into the dialysate or ultrafiltrate. Despite a small decrease in plasma HIV RNA levels during hemodialysis, one study could not measure HIV RNA in the ultrafiltrate of 10 HIV-infected hemodialysis patients.(123) However, there are few data concerning HIV in dialysate, especially in dialyzers that are being reused.
HIV has been identified in peritoneal dialysate fluid, which should be handled as a contaminated body fluid.(124) Peritoneal dialysis patients should be instructed to pour dialysate into the home toilet, and to dispose of dialysate bags and lines by tying them in plastic bags and disposing of the plastic bags with conventional home garbage.
| Kidney Transplantation|
Accumulating data support kidney transplantation in patients with well-controlled HIV infection. Multiple studies have demonstrated that HIV-infected kidney transplant recipients have patient and graft survival rates that are comparable with those of other high-risk populations.(125-127) However, an unexpected increased risk of acute rejection episodes has been observed in HIV-infected kidney transplant recipients. Roland and colleagues reported a 94% 3-year kidney transplant recipient survival, but 12 of 18 (67%) patients experienced acute rejection episodes. The 3-year cumulative incidence of rejection was 73%.(128) Despite this problem, graft survival has not been compromised and kidney function has been preserved with aggressive immunosuppressive therapy.(129,130) Long-term follow-up data are needed to determine the consequences of acute rejection.
Despite the concern that immunosuppression required to prevent graft rejection might accelerate HIV disease progression, this has not been observed in kidney transplant recipients. In general, CD4 counts and HIV RNA levels have remained stable despite complicated drug interactions and ART dosing alterations with immunosuppressive regimens.(129) In one series, most patients on ART continued to manifest increases in CD4 counts with a median gain of 109 (interquartile range: -75 to 228) cells/µL in the 3-year period posttransplant.(128) In addition, many of the antiretroviral qualities of commonly used immunosuppressive agents have helped convince reluctant HIV clinicians to consider kidney transplantation. Cyclosporine, mycophenolate mofetil, and sirolimus are effective immunosuppressive medications with concomitant antiretroviral activity that may counteract the theoretical risk of HIV disease progression.(131-136)
The National Institutes of Health is sponsoring an ongoing study of kidney and liver transplantation among HIV-infected individuals in 20 transplant centers across the United States. Preliminary results from this trial provide further support that kidney transplantation is a viable option for HIV-infected patients. Inclusion criteria for participants include CD4 count of ≥200 cells/µL for adults, CD4 percentage of ≥30% for children 1-2 years old, and CD4 percentage of ≥20% for children 2-10 years old. For patients taking ART, HIV RNA must be undetectable using an ultrasensitive assay. Other centers are providing solid organ transplantation to HIV-infected patients on a case-by-case basis.(137)
| Medical Management of the HIV-Infected ESRD Patient|
The standard Kidney Disease Outcomes Quality Initiative (KDOQI) recommendations should be followed for treating HIV-infected patients with ESRD.(138) As noted, the use of native AV fistulas is optimal for these patients in reducing the incidence of catheter and graft infections. The goals for dialysis dosage, renal osteodystrophy and anemia management, and vascular access monitoring should be established as outlined in the KDOQI recommendations.
Although many HIV medical providers are accustomed to treating HIV-infected individuals with anemia, those with both CKD and anemia should be treated according to KDOQI guidelines. HIV-infected patients with CKD respond to recombinant human erythropoietin (rHuEPO) in a manner similar to their HIV-uninfected counterparts with CKD. One study compared hemoglobin response to 100 units/kg of rHuEPO administered 3 times a week in groups of HIV-infected patients and HIV-uninfected patients with and without diabetes. All groups had similar responses to intravenous rHuEPO therapy as measured by rise in hematocrit.(139)
Coinfection with HCV is common among HIV-infected ESRD patients, with a prevalence that may be as high as 50%.(55) The optimal therapy for HCV infection in the ESRD patient remains undetermined, as ribavirin is not recommended for use by patients with renal failure. At a minimum, HIV/HCV-coinfected patients should be discouraged from alcohol use and should be vaccinated against hepatitis A and B virus. In the absence of ESRD, HIV-infected patients have an 88% antibody response rate to hepatitis A virus vaccine, but only a 42% response rate to hepatitis B virus vaccine.(140,141)
Recent improvements in survival rates of HIV-infected patients are attributable not only to the availability of ART but also to improved prophylaxis for and treatment of opportunistic infections. Several antiretroviral drugs are excreted primarily through the kidney and must be dose adjusted in the setting of renal insufficiency or hemodialysis (see Table
1). Guidelines for antiretroviral drug dosing for patients with impaired renal function have been issued by the Infectious Diseases Society of America.(7) All nucleoside and nucleotide analogue reverse transcriptase inhibitors, with the exception of abacavir, require dosage adjustment for patients with renal insufficiency. Although there are few data on the pharmacokinetic properties of the nonnucleoside reverse transcriptase inhibitors and protease inhibitors in patients with renal insufficiency, the pharmacokinetic profiles of these drugs suggest a minimal effect of renal function on drug elimination.
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