Does this patient have HIV-related kidney disease?
The classic HIV-related kidney disease is the entity that has been termed “HIV-associated nephropathy” or HIVAN. Affected patients, who are almost exclusively African or African-American, present with reduced kidney function and features of nephrotic syndrome. Most patients with HIVAN have significant HIV-related immunosuppression with low CD4 count and other features of HIV infection or AIDS and have not been treated with antiretroviral therapies (or have been non-adherent with therapy).
HIVAN is a form of focal segmental glomerulosclerosis (FSGS) called “collapsing FSGS” or “collapsing glomerulopathy” usually associated also with extensive tubulointerstitial injury with fibrosis, tubular atrophy, and cystic dilatation of tubules, which are often filled with proteinaceous casts. Tubuloreticular inclusions may be seen by electron microscopy within glomerular endothelial cells. None of these histopathologic features is pathognomonic for HIVAN but collectively they are very highly suggestive of this disorder and should prompt testing for HIV infection in patients with these findings who are not known to be HIV-infected.
Other HIV-related immune complex kidney diseases have also been described, including IgA nephropathy, membranous nephropathy, membranoproliferative glomerulonephritis, and other conditions such as post-infectious glomerulonephritis. These other non-HIVAN glomerular diseases are just as likely to occur in non-African American as in African American patients with HIV infection.
Patients may also present with nephrotoxicity from antiretroviral agents or other therapies used for prevention or treatment of opportunistic infections. In particular, tenofovir disoproxil fumarate (until recently the only formulation of tenofovir and a very widely used nucleotide reverse transcriptase inhibitor) can cause both decrease in glomerular filtration rate (GFR) as well as proximal tubular toxicity with manifestations of Fanconi syndrome, including proteinuria, renal glycosuria, proximal renal tubular acidosis, and renal wasting of potassium, phosphate, and uric acid. (Except where indicated, mentions of tenofovir in this chapter refer to the disoproxil fumarate formulation). The protease inhibitors indinavir and atazanavir can cause nephrolithiasis, and AKI related to urinary drug crystals.
Acute kidney injury may also develop in patients with HIV infection due to concomitant infection, sepsis, hypotension, obstructive uropathy, and thrombotic thrombocytopenic purpura.
Various studies have indicated that there can be direct infection by HIV of mesangial cells, glomerular endothelial cells, podocytes, and renal tubular epithelial cells. Studies in transgenic mice suggest a role for specific HIV genes in the pathogenesis of HIVAN. Individual genetic predisposition is known to be important (see discussion of APOL1 risk variants below), and other host and viral factors may also contribute to disease pathogenesis.
What tests to perform?
The diagnosis of HIVAN can only be made definitively by kidney biopsy. The use of kidney biopsy in HIV-infected patients with typical features of HIVAN (see below) varies markedly and is discussed in more detail later in this section.
Typical laboratory features that are consistent with this diagnosis include the nephrotic syndrome with heavy proteinuria (>3 g per 24 hours), hypoalbuminemia, and edema. The serum creatinine and blood urea nitrogen (BUN) are usually elevated, indicative of reduced GFR. Patients may also have hyperlipidemia. The urinalysis is generally relatively bland with proteinuria but few red cells or white cells and no red cell casts. Hypertension is not a prominent feature. In the absence of highly active antiretroviral therapy (HAART), kidney function often declines relatively rapidly. It is thought that HAART can halt or significantly slow progression of HIVAN and there have even been reports of regression of HIVAN with substantial improvement in kidney function and resolution of nephrotic syndrome.
A comprehensive metabolic panel will detect the elevated serum creatinine and BUN and low albumin level, as well as electrolyte abnormalities that may be related to HIVAN-associated kidney failure; a serum phosphorous level, which is not included in a comprehensive metabolic panel, should also be obtained. A fasting lipid panel may also be obtained. Assessment of urine protein can be accomplished with a 24-hour urine collection (it is best to also measure 24-hour urine creatinine to assess adequacy of the 24-hour urine collection) or a “spot” urine protein-to-creatinine ratio. A complete blood count (CBC) should also be obtained.
It is important to note that none of the equations that are currently used to estimate GFR have been well validated in large numbers of HIV patients, particularly among those with advanced HIV infection. Use of the creatinine-based Chronic Kidney Disease-Epidemiology Collaboration (CKD-EPI) prediction equations, with or without combination with cystatin C are probably adequate for routine clinical practice in stable HIV-infected patients who are not overtly ill, malnourished or suffering from muscle wasting or other major other health problems although there remain problems with accuracy using all estimating equations. Formulas for estimating GFR using cystatin C alone appear to have the greatest variability and lowest accuracy since cystatin C levels are affected by infection and inflammation, and should not be used.
Other laboratory tests that may be useful in excluding alternative diagnoses include tests for hepatitis C virus, hepatitis B virus (HBsAg), syphilis (rapid plasma reagin; RPR), serum complement levels (C3 and C4), and blood cultures.
A urinalysis should be performed to assess for features that might suggest other diseases. Coarse “muddy brown” casts would suggest acute kidney injury (AKI) with ischemic or nephrotoxic injury and acute tubular necrosis (ATN). Many white blood cells would suggest the possibility of an interstitial nephritis or urinary tract infection. Neither ATN nor interstitial nephritis are associated with nephrotic syndrome. Many red blood cells, especially dysmorphic red blood cells, and red cell casts would indicate the presence of an acute glomerulonephritis rather than HIVAN.
A kidney ultrasound should be performed. This will provide for an overall assessment of kidney anatomy and size and rule out urinary tract obstruction as the cause for reduced GFR. The kidneys in patients with HIVAN are often described as being of normal to increased size with markedly increased cortical echogenicity, although the sensitivity and specificity of this increased echogenicity is not clear.
A kidney biopsy is necessary for a definitive diagnosis of HIVAN and for the exclusion of other glomerular diseases that may occur in HIV-infected individuals. The decision whether or not to perform a kidney biopsy is made with consideration of presenting features. In an African-American patient with HIV infection and low CD4 count not on antiretroviral treatment with typical clinical features of nephrotic syndrome, reduced GFR and densely echogenic kidneys who does not have clinical and laboratory features suggestive or indicative of other kidney diseases, many nephrologists would choose to not perform a kidney biopsy. It must be recognized though that this will lead to missed diagnoses of other diseases in occasional patients.
Since HIVAN is almost exclusively a disease of African-Americans, a biopsy is more likely to be indicated in patients of other ethnic or racial backgrounds. Patients with atypical features should also generally have a kidney biopsy performed. These would include hypocomplementemia, presence of hepatitis B or C infection, positive RPR, red blood cell casts in the urine, and so forth.
Overall interpretation of test results (diagnosis, prognosis)
Patients presenting with advanced chronic kidney disease are likely to progress to end stage kidney disease relatively rapidly, often over weeks to months, particularly if not treated with HAART. Histopathologic features may also provide some clues to prognosis, with more extensive glomerular scarring and collapse and more extensive and severe tubulointerstitial changes portending a more rapid course and poorer overall prognosis.
Controversies in diagnostic testing
The primary controversy in the diagnostic approach to patients with suspected HIVAN relates to the decision to perform a kidney biopsy. As noted above this is the only way to make a definitive diagnosis. In the past, the decision to perform a kidney biopsy and make a definitive diagnosis of HIVAN had a potential impact on treatment of the patient’s HIV infection, as HIVAN was considered an indication for initiation of antiretroviral treatment in patients who may otherwise not have been treated. The situation is now different given that the most recent guidelines recommend HAART for all HIV patients regardless of CD4 count. The issue of distinguishing HIVAN from other renal diseases, however, remains, as even patients with nephrotic-range proteinuria and CD4 count <200/mm3 are sometimes found on biopsy to have kidney diseases other than HIVAN. As is true in other settings, the decision to perform a biopsy largely depends on the clinician’s judgement as to whether the biopsy results are likely to change clinical management, depending on the specific clinical features of the case and the alternative diagnoses under consideration.
How should patients with HIV-related kidney disease be managed?
The incidence of HIVAN has changed markedly since the advent of HAART, which first became available in 1995. A cohort study that followed almost 4000 patients between 1989 and 2001 found that use of HAART decreased the risk of HIVAN by 60%. The incidence of HIVAN declined by 50% in the period 1998-2001 compared to previous years. In this study, there were no new cases of HIVAN in patients who had started HAART before developing AIDS.
All patients with HIVAN should be treated with HAART and an angiotensin converting enzyme (ACE) inhibitor or angiotensin receptor blocker, unless specific contraindications to these treatments exist. However, it must be recognized that none of these treatments have been studied in randomized controlled trials in this patient population.
Patients diagnosed with HIVAN should be initiated on HAART, if they were not already being treated, regardless of CD4 count. Although there is no evidence from randomized controlled trials that confirms the efficacy of HAART for treatment of HIVAN, available data suggest a benefit of HAART in patients with HIVAN. There appears also to be an association between HAART use and preservation or improvement of kidney function, and prevention of HIVAN in HIV-infected patients.
Early observational studies conducted in the 1990s with small numbers of patients suggested that therapy with a single antiretroviral agent (most commonly zidovudine) slowed the progression of HIV-associated kidney disease. More recent studies also suggest a benefit of HAART in slowing progression to end-stage renal disease (ESRD), but it is unclear whether this benefit applies to HIV-infected patients with kidney diseases other than HIVAN.
In a cohort of 23 patients, 12 were diagnosed with a variety of renal lesions by biopsy, while the rest received a clinical diagnosis of HIVAN. Among the 10 patients who did not receive therapy, all reached the endpoint of doubling in the serum creatinine, and 8 progressed to ESRD. By contrast, none of the 13 patients who received HAART experienced a doubling of creatinine or required dialysis.
Whereas this small study suggested a benefit of HAART regardless of the etiology of renal disease, a larger study in which all patients were biopsied did not support this conclusion. Of 89 patients, 42 were found to have HIVAN, while 47 had renal lesions other than HIVAN (the most common ones were immune complex glomerulonephritis, membranous glomerulopathy, diabetic nephropathy, membranoproliferative glomerulonephritis, and hypertensive nephrosclerosis). The use of antiretroviral therapy was associated with a slower progression to ESRD in the patients with HIVAN, but no such benefit was observed in the patients whose biopsies showed other renal lesions. Case reports have described regression of histopathological changes of HIVAN and improvement in kidney function, even such that dialysis could be discontinued attributed to HAART. A retrospective study of 36 patients with biopsy-proven HIVAN found improved renal survival in the 26 patients who received antiretroviral therapy compared to the 10 patients who did not.
HIV infection is an independent risk factor for microalbuminuria, the severity of which was found to be inversely related to CD4 cell count. Although a relationship between albuminuria and poor kidney and cardiovascular outcomes has not been specifically defined in the HIV-infected population, it is hypothesized that such a relationship might exist, as is the case in other patient populations. An interest therefore exists in the prevention and treatment of albuminuria in HIV patients as a possible way to reduce cardiovascular risk and future CKD and ESRD in these patients. At this time, however, HAART has not been consistently demonstrated to prevent the development of microalbuminuria or reduce the degree of proteinuria in HIV-infected patients with normal GFR.
Two retrospective studies have examined the use of ACE inhibitors in HIVAN, one using captopril and the other using fosinopril. In both studies the use of ACE inhibitors (with antiretroviral therapy) was associated with marked improvement in renal survival and incidence of ESRD. In one of these studies, ACE inhibitor treatment was also associated with higher patient survival. A single prospective cohort study suggested a benefit of ACE inhibitor treatment on renal survival in patients with biopsy-proven HIVAN.
Unless there is a contraindication to use of an ACE inhibitor, we recommend their use in patients with documented or presumed HIVAN. Although not specifically tested, angiotensin receptor blockers (ARBs) are likely to have similar effect. Both ACE inhibitors and ARBs have been shown to mitigate the development and progression of HIV-related kidney disease in animal models of HIV nephropathy.
Several case reports and small retrospective studies of corticosteroid (typically prednisone) treatment in HIV-infected patients with kidney disease were reported prior to the widespread use of modern HAART. These studies suggested that in some patients declining kidney function could be arrested and that proteinuria and kidney function improved with a delay in the development of dialysis-requiring ESRD compared to untreated patients.
We do not recommend use of corticosteroids routinely in patients with HIVAN but would consider treatment with steroids (prednisone 60 mg daily for 1-3 months tapered over several weeks to months) in selected patients with biopsy-documented HIVAN and the absence of known opportunistic infections in the setting of rapid loss of kidney function despite HAART and ACE inhibitors or angiotensin receptor blockers.
What happens to patients with HIV infections on dialysis?
A recent study estimated that the number of patients who started treatment for ESRD in the U.S. declined from 893 in 2006 to 525 in 2011. Despite the persistently downward trend in HIVAN-ESRD incidence, the prevalence has continued to increase given the improved survival of these patients.
The prevalence of HIV infection among ESRD patients varies widely among populations and is difficult to establish, but available data suggest that it is about 1.5% in the United States and 0.5-0.7% in Europe. In some urban U.S. dialysis centers with a high community prevalence of HIV infection, as many as 20% dialysis patients may have HIV.
The survival of patients HIVAN-ESRD has markedly improved over the past couple of decades. Compared with patients who initiated dialysis in 1989-1992, mortality for those who initiated dialysis in 1999-2000 and 2009-2011 decreased by 40% and 64%, respectively. Despite these promising trends, however, mortality for HIVAN-ESRD patients remains higher compared to patients with ESRD from other causes.
The mortality for HIV-infected dialysis patients with non-HIVAN diagnoses has also improved markedly. Risk factors that have been associated with poorer outcomes include higher viral load, history of opportunistic infections, injection drug use, and hepatitis C infection.
Mortality is not different in HIV-infected patients with ESRD undergoing hemodialysis compared with those on peritoneal dialysis. Both modalities should be considered in HIV-infected patients as they approach ESRD and the need for renal replacement therapies. Home hemodialysis should be considered in appropriately selected patients, similar to patients without HIV infection.
Among patients on hemodialysis, arteriovenous (AV) grafts have a higher risk of thrombosis and infection in HIV-infected patients compared to HIV-negative patients, although it is possible that some of this excess risk is related to past or ongoing injection drug use. Outcomes with AV fistulas, however, have been found to be comparable between the two groups. One study of infections associated with tunneled cuffed hemodialysis catheters found that patients with HIV patients had a five-fold higher risk of infection with a Gram-negative organism compared with HIV-negative controls. Rates of fungal infections were also more common in the HIV group, but this finding did not reach statistical significance. The overall infection rate, however, did not differ between the two groups. Despite their risk for thrombosis and infection, AV grafts are still preferred over tunnelled cuffed hemodialysis catheters.
Whether HIV infection increases the risk of peritonitis in patients on peritoneal dialysis is not clear. While some studies have suggested a higher peritonitis risk, particularly for Pseudomonas and fungal infections, other studies have not found higher peritonitis rates.
Should HIV patients undergo kidney transplantation?
The real incidence and prevalence of ESRD due to HIVAN are unknown because, as discussed above, a kidney biopsy is not performed in many patients. According to data from the United States Renal Data System (USRDS), in the period 2009-2013 there were 2,845 incident ESRD patients with a reported diagnosis of HIVAN (For comparison, this number had been 4,208 in the period 2003-2007). The median age of these patients was 47, compared to a median age of 64 for all incident ESRD patients during this period). In 2013, ESRD was attributed to HIVAN in 0.6% of prevalent patients.
HIV infection was initially considered an absolute contraindication to transplant due to the concern that immunosuppressive therapy would worsen HIV disease and increase the risk for opportunistic infections and neoplasms. Recent experience has shown, however, that renal transplant is a feasible option for appropriately selected HIV-infected patients with ESRD. A meta-analysis of 12 series including a total of more than 200 patients found that rates of infection-related deaths and neoplasia were low, and most patients had CD4 cell counts >200 cells/µL after transplantation.
The largest prospective, multicenter, non-randomized study conducted to date followed 150 HIV-infected kidney transplant recipients for a median period of 1.7 years. All patients initially had CD4 cell counts >200 cells/µL and undetectable HIV RNA, and all except two were receiving HAART. Renal allografts were from both deceased and living donors. Patient survival rates were 94.6% and 88.2% at 1 and 3 years, respectively, and the corresponding graft survival rates were 90.4% and 73.7%. The 1-year overall and graft survival rates in patients with HIVAN were not significantly different from those of patients with ESRD from other etiologies.
During the follow-up period, 38% of patients had infections requiring hospital admission, and nine cases of neoplasms were reported. Even though CD4 cell counts declined (especially in patients receiving antithymocyte globulin induction), there was no evidence that immunosuppression accelerated HIV disease progression or precipitated HIV viremia. A concerning finding of this study was a high rate of allograft rejection, with a cumulative incidence of 31% and 41% at 1 and 3 years, respectively, which is approximately 2-3 fold higher than would have been expected in patients without HIV infection. Rejection rates in this study were significantly higher in patients receiving cyclosporine as compared to those taking tacrolimus.
Prior studies had also observed a higher rate of rejection among HIV-infected recipients than that in HIV-negative recipients. The reasons for this are unclear, but it is believed that subtherapeutic immunosuppression due to pharmacokinetic interactions between immunosuppressants and antiretrovirals may contribute. For example, protease inhibitors inhibit CYP3A enzymes, so patients on HAART frequently require lower doses or less frequent dosing of cyclosporine, tacrolimus or sirolimus, and may have a different total exposure to these drugs even if their trough levels are in the therapeutic range.
Avoiding antiretroviral agents that affect CYP3A enzymes may result in more therapeutic levels of calcineurin inhibitors or sirolimus and reduced rejection rates. In a small retrospective study of liver and kidney transplant recipients treated with raltegravir, an HIV integrase inhibitor that is not a substrate of cytochrome P450 enzymes, rather than a protease inhibitor, therapeutic trough levels of calcineurin inhibitors were achieved without the need for dose reduction.
Although eligibility criteria for transplant in HIV-infected subjects have not been standardized across transplant centers, it is generally agreed that the CD4 cell count should be >200 cells/µL and the HIV viral load should be undetectable on HAART. Although a history of any opportunistic infection was initially considered a contraindication to transplant, some opportunistic infections such as Pneumocystis jiroveci pneumonia, tuberculosis, and esophageal candidiasis have been removed as exclusion criteria since they can be effectively prevented and treated.
Recent registry data indicate that there is a marginally increased risk of graft loss but no increase in risk of death compared to HIV negative controls.
What happens to patients with HIV-related kidney disease?
Despite the favorable trends noted above, HIVAN continues to be an important cause of ESRD among HIV-infected African Americans. It has been shown that blacks are at much higher risk of CKD progression to ESRD than HIV-infected white subjects. Among blacks, HIV infection confers a similar increase in the risk of ESRD as diabetes. In contrast, HIV was not found to increase the risk of ESRD among white patients.
As mentioned above, HIVAN occurs almost exclusively in individuals of African ancestry. Two genetic variants in the APOL1 gene, which only occur in people with recent African ancestry, have been found to be very strongly associated with HIVAN. Case-control studies have shown that the high-risk APOL1 genotypes increase the risk of developing HIVAN by 29-fold in HIV-infected African Americans, and by 89-fold in HIV-infected black South Africans. These are among the strongest effect sizes known for common variants on complex disease. The lifetime risk of developing HIVAN in individuals with one of the high risk APOL1 genotypes who are not treated with HAART has been estimated to be ~50%. These genetic variants, which arose in Africa, became common likely because they conferred a survival benefit by enhancing innate immunity and protecting against certain trypanosomes and possibly other pathogens. These genetic variants also explain a large fraction of the high rates of other non-diabetic kidney diseases in African Americans. The role of ApoL1 in the normal kidney, and the mechanisms by which the risk variants cause renal disease, are not yet understood.
In contrast to HIVAN, immune complex-mediated glomerular diseases and other kidney diseases associated with HIV occur in all racial and ethnic groups.
Are there specific pharmacologic considerations in treating HIV patients?
All of the nucleoside and nucleotide reverse transcriptase inhibitors (NRTIs) other than abacavir are eliminated primarily by the kidneys so reduced dosages are necessary for patients with reduced kidney function. They are also removed by dialysis so they should be administered after dialysis. Abacavir has minimal urinary elimination and is not significantly cleared by dialysis. Most other antiretroviral agents do not need dosing adjustment in patients with reduced kidney function or in relation to dialysis treatments. An additional dose of the non-nucleoside reverse transcriptase inhibitor nevirapine (200 mg) is recommended after hemodialysis treatments.
Tenofovir disoproxil fumarate (TDF) should generally be avoided in patients with impaired kidney function given its potential for glomerular and tubular toxicity. A new formulation of tenofovir, called tenofovir alafenamide (TAF), first became available in the United States in November 2015. Randomized-controlled trials conducted to date suggest that TAF-containing regimens are non-inferior to the corresponding TDF-containing combinations with regard to virological suppression, but have less renal (and bone) toxicity.
Cobicistat, a CYP3A inhibitor used a pharmacokinetic boosting agent in some antiviral combinations, blocks tubular secretion of creatinine, thereby increasing serum creatinine and decreasing eGFR without affecting kidney function and true GFR. A similar effect has been described for the integrase inhibitor dolutegravir.
Some hemodialysis patients on atazanavir have lower than expected blood levels of this drug, so concomitant ritonavir is recommended to boost atazanavir levels.
Dosing recommendations for the NRTIs are generally based on limited pharmacokinetic information but evidence of therapeutic efficacy and avoidance of toxicity is generally lacking.
The oral solution of amprenavir is contraindicated in patients with kidney failure due to the potential for toxicity from its propylene glycol excipient.
How to utilize team care?
Given the complexity of the issues involved in the care of HIV-infected transplant recipients, especially the interactions between immunosuppressants, antiretrovirals, and potentially many other medications, a multidisciplinary approach is particularly important in the care of these patients, with close coordination between infectious disease HIV experts, pharmacists, transplant nephrologists, nurse coordinators, social workers, and primary care physicians.
Are there clinical practice guidelines to inform decision making?
The 2014 updates of the International Antiviral Society-USA Panel recommend starting antiretroviral therapy in all patients with HIV regardless of CD4 cell count. These guidelines also recommend avoiding tenofovir in patients with reduced kidney function, and note an association between renal impairment and use of atazanavir, which can also cause nephrolithiasis.
Recommendations of the HIV Medicine Association of the Infectious Diseases Society of America (IDSA) with regard to the management of CKD in HIV-infected patients include the following:
Monitoring creatinine-based estimated GFR at least twice yearly in stable HIV-infected patients, and whenever antiretroviral therapy is initiated or changed.
Performing a urinalysis or quantitative measure of proteinuria at baseline, at least annually in stable patients, and whenever antiretroviral therapy is initiated or changed.
Referral to a nephrologist when there is a clinically significant decline in eGFR that fails to resolve after nephrotoxic drugs are discontinued, albuminuria >300 mg per day, hematuria with albuminuria or increasing blood pressure, or for advanced CKD management.
Treatment with HAART in all patients with biopsy-proven or clinically suspected HIVAN.
When feasible, tenofovir and other nephrotoxic drugs should be avoided in patients with eGFR <60 mL/min/1.73 m2. If a tenofovir-treated patient experiences a >25% eGFR decline to a level <60 mL/min/1.73 m2, an alternative drug should be substituted for tenofovir, particularly if there is evidence of proximal tubule dysfunction.
HIV-infected patients with suspected or confirmed HIVAN or albuminuria (>30 mg/day in diabetics, >300 mg/day in non-diabetics) should be treated with ACE inhibitors or angiotensin II receptor blockers.
Blood pressure goals of <140/90 and <130/80 are recommended for HIV-infected CKD patients in the absence and presence of albuminuria, respectively.
Patients who have or are approaching ESRD should be evaluated for the possibility of kidney transplantation.
None of these guidelines are based on randomized controlled clinical trials.
Although the available evidence suggests that patients with HIVAN benefit from HAART, it is unclear whether this benefit differs in patients with HIV-associated renal disorders other than HIVAN. This distinction is difficult to make given that not all patients are biopsied and there is no standardized case definition of HIVAN across different studies. Furthermore, other comorbidities that can contribute to renal disease are common among HIV patients (including hepatitis C, diabetes, and hypertension), and renal insufficiency in some patients may be due to toxicity associated with antiretrovirals and other medications.
Considerable debate currently exists on the optimal blood pressure goals in different patient groups with CKD. Some patients may benefit from more stringent targets than those in current guidelines, particularly if they have cardiovascular disease.
What is the evidence?
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