Human immunodeficiency virus–associated kidney disorders

1. How do you begin the evaluation of kidney disease in the setting of human immunodeficiency virus (HIV) infection?

The differential diagnosis of kidney disease in the setting of HIV infection covers a wide spectrum of kidney disorders including acid-base and electrolyte abnormalities, glomerular disease, acute kidney injury (AKI), and chronic kidney disease (CKD). There is no difference in the initial basic approach in the evaluation of a patient with HIV compared to that of a patient who does not have HIV. If patients with HIV develop kidney disease, the specific site of involvement (e.g., glomerular, interstitial, or vascular) should be identified. Treatment options are dependent on proper identification and classification of the various HIV-associated kidney diseases.

2. How is kidney disease first detected in patients with HIV?

Standard recommendations for screening HIV patients have been established and require a measurement of kidney function (creatinine and glomerular filtration rate [GFR] calculation), urine dipstick with microscopy, and a urine protein to creatinine ratio at the time of initial evaluation. This is repeated annually, or more often, depending on whether the patient has risk factors for kidney disease, such as exposure to nephrotoxic drugs or co-morbidities including hypertension, diabetes, or concurrent hepatitis C (HCV) or B (HBV). It is not necessary to measure the GFR by 24-hour urine collections; it can be accurately estimated glomerular filtration rate (eGFR) from the creatinine level using conventional estimating formulas.

The standard National Kidney Foundation and Kidney Disease: Improving Global Outcomes (KDIGO) definitions for CKD should be applied to patients with HIV as well as the Acute Kidney Injury Network definition of AKI.

3. How accurate is creatinine for detecting kidney disease in patients with HIV?

It is now clear that the serum creatinine has significant limitations in many HIV patients as a result of:

1.

The dependence of creatinine on gender, age, and underlying nutritional status. Patients with active HIV who are not receiving combination anti-retroviral therapy (cART) may have marked reductions in muscle mass as a result of malnutrition, and will have lower baseline serum creatinine levels than in the general population. It would not be unusual for a patient with advanced, untreated HIV to have a seemingly normal serum creatinine level of 0.9 mg/dL and yet have a significant reduction in eGFR.
2.

Interference of HIV therapy with the laboratory measurement of creatinine. Some cART drugs interferes with the tubular secretion of creatinine. Since creatinine is both filtered and secreted, impairment of tubular secretion will increase the serum creatinine even without a change in the GFR. This will cause the eGFR to fall and may lead to an erroneous diagnosis and inappropriate work-up for acute or chronic kidney injury. This process is similar to the spurious elevations of creatinine seen with cimetidine and trimethoprim. Specifically in cART, the integrase strand inhibitors characteristically impede the secretion of creatinine, and it is expected that the creatinine will be higher in these patient by 0.5 mg/dL. Cobicistat, used as a booster for the other cART medications, has also been shown to have the same effect on creatinine secretion. The absence of other markers of kidney injury—that is, abnormal urinary sediment, a normal blood urea nitrogen, and stable clinical course—all support a benign drug-induced elevation of creatinine.

4. How is proteinuria used as a marker for HIV kidney disease?

In addition to an impaired GFR as a sign of kidney disease in patients with HIV, often a patient with HIV will first present with only proteinuria and even microalbuminuria. Proteinuria represents one of the pathognomonic hallmarks of HIV-induced glomerular disease, but also could represent early onset of cART-related kidney tubular injury. All patients with HIV should have a dipstick urinalysis performed for detection of proteinuria. The finding of proteinuria is an accurate and significant predictor of increased morbidity and mortality in patients with HIV. If the dipstick test result is positive, then a spot urine test for protein/creatinine ratio should be done to estimate the degree of proteinuria with a ratio >300 mg/g being a key cut-off level that requires further investigation.

Studies have shown that microalbuminuria may be an important indicator of the presence of kidney disease in patients with HIV, which is similar to the use of microalbuminuria in patients with diabetes. However, current guidelines do require the measurement of microalbuminuria in this population.

5. What are the common causes of AKI in HIV patients?

Approximately 5% to 10% of hospitalized patients with HIV will experience AKI, with a mortality risk that is five times higher than the general AKI population without HIV. The most important approach in the assessment of AKI in a patient with HIV requires answers to the following questions:

•

Is the patient receiving cART?
•

What is the viral control of HIV?

The approach to AKI will be different based on the answers to these questions. If a patient is not receiving cART and has uncontrolled HIV viremia, the most common causes of kidney injury are related to systemic infection and volume depletion leading to prerenal azotemia and possible acute tubular necrosis (ATN). Uncontrolled infectious diarrhea with fever and large insensible fluid losses is a common presenting scenario in a patient with HIV who is cART naïve. Patients with HIV frequently develop sepsis from pneumonia and other opportunistic infections complicated by hypotension, which may also lead to ATN. In patients with infection who are cART-naïve, multiple antibiotics are often used to cover bacterial, viral, fungal, and atypical infectious agents. Many of these antibiotics can result in AKI, as noted in Table 36.1 .

Table 36.1.

Antibiotics Can Result in Acute Kidney Injury

ANTIBIOTIC	KIDNEY SYNDROME(S)
Amphotericin	ATN, type I kidney tubular acidosis
Trimethoprim-sulfamethoxazole	Crystal-induced ATN, allergic interstitial nephritis
Penicillin/cephalosporin agents	Allergic interstitial nephritis
Aminoglycosides	ATN
Foscarnet	ATN
Pentamidine	ATN
Vancomycin	ATN
Ciprofloxacin	Crystal-induced ATN, allergic interstitial nephritis
Acyclovir	Crystal-induced ATN, allergic interstitial nephritis
Azole class antifungals	Potentiate NRTI and calcineurin-induced nephrotoxicity

ATN , Acute tubular necrosis; NRTI , nucleaside reverse transcriptase inhibitors.

If the patient is receiving cART therapy with a controlled viral load, then the development of AKI may be secondary to drug-induced tubular dysfunction. Patients on cART have been shown to have a significantly higher risk of AKI, particularly in the setting of volume depletion. It is essential that all physicians treating patients with HIV be familiar with the potential nephrotoxicity of cART.

6. How does cart cause kidney disease?

cART involves multiple classes of agents, including protease inhibitors (PI), reverse transcriptase inhibitors, integrase strand inhibitors, and entry blockers. Distinct syndromes are associated with certain classes of cART that must be kept in mind during the evaluation of each patient ( Table 36.2 ). PI can be associated with three main kidney side effects:

1.

They can crystallize in the urinary tract and form either macroscopic stones, resulting in urinary obstruction (hydronephrosis), or they may crystallize inside the tubules, causing microtubular obstruction and ATN (no hydronephrosis).
2.

They may lead to acute interstitial nephritis.
3.

They inhibit the cytochrome P450 system, which may lead to nephrotoxicity from other drugs, especially in transplant patients on calcineurin inhibitors (CNI). In the presence of PIs, CNIs may need only once-a-week dosing due to impaired P450 metabolism.

Table 36.2.

Kidney Syndromes Associated With HAART

cART CLASS	REPRESENTATIVE DRUGS	KIDNEY SYNDROME(S)
Protease inhibitors	Indinavir, atazanavir, nelfinavir, saquinavir, ritonovir, amprenavir	Urolithiasis: obstructive uropathy, ATN Interstitial nephritis CKD
Nucleoside reverse transcriptase inhibitors	Stavudine, zidovudine, didanosine, lamivudine	Mitochondrial cytopathy: hepatic steatosis, lactic acidosis, rhabdomyolysis, acute tubular necrosis
Nucleotide reverse transcriptase inhibitors	Tenofovir, adefovir	Fanconi syndrome, ATN, CKD
Integrase strand inhibitors	Raltegravir, Dolutegravir	—