Author: Alfredo Tiu, DO
The prevalence of renal complications among patients with HIV infection has increased as more patients with HIV are living longer as a result of effective antiretroviral therapy (ART) and opportunistic infection prophylaxis. More widespread access to and earlier initiation of ART has decreased the incidence of HIV-associated nephropathy (HIVAN), but other causes of renal disease persist, and in some cases are increasing in prevalence. These may be infections and other conditions related to HIV infection, other comorbidities (e.g., hypertension, diabetes), or medication adverse effects, including those caused by some antiretroviral (ARV) medications (see "Kidney disease associated with HIV infection" and Table 2, below).
Risk factors for renal disease in HIV-infected patients include the following:
Renal disease in HIV-infected individuals can occur as a primary disease, as a secondary disease in the setting of other systemic illness, or as an adverse effect of medications. In the United States, the most common causes of end-stage renal disease in the general population are diabetes mellitus and hypertension. HIV-infected patients are at a fourfold higher risk of developing diabetes mellitus and a threefold higher risk of developing hypertension compared with seronegative individuals. Chronic hepatitis C, seen in 30-40% of HIV-infected individuals in the United States, is associated with several types of chronic kidney disease, including progressive secondary glomerulonephropathy, membranoproliferative glomerulonephropathy, and mixed cryoglobulinemia.
Note that ART should be given to HIV-infected individuals with renal disease, according to usual criteria for ART initiation; however, some ARVs must be avoided and some should be given at modified dosages according to the degree of renal dysfunction (see Table 3). Additionally, for patients with HIVAN, ART is the primary treatment.
Screening for kidney disease in HIV-infected persons is an important aspect of primary care, as patients typically have no symptoms until very late. High-risk patients (see list of risk factors, above) should be identified and monitored. Early identification of patients with renal dysfunction allows early intervention targeted at reversing the process of renal injury or slowing down its progression. Current guidelines of the U.S. Department of Health and Human Services (DHHS) and the Infectious Diseases Society of America recommend screening at entry to care, with subsequent screening as indicated by the patient's risk factors.
Screening consists of three tests:
eGFR by the Modification of Diet in Renal Disease (MDRD) equation:
GFR (mL/min/1.73 m2) = 186 x [serum Cr (mg/dL)]-1.154 x [age (years)]-0.203 x [0.742 if female] x [1.212 if African-American]
Normal GFR: ≥90 mL/min/1.73 m2
Chronic kidney disease (CKD): GFR <60 mL/min/1.73 m2
An online eGFR calculator is available at the National Kidney Disease Education Program website.
The creatinine clearance (CrCl) can be used as a surrogate for eGFR but is considered to be less accurate. Note that CrCl is used in determining medication dosages.
CrCl (Cockroft-Gault equation):
Suggested follow up for patients with normal screening test results is shown in Figure 1; suggested follow up of abnormal screening test results is shown in "Diagnostic Evaluation."
As noted above, patients usually have no symptoms until late in the course of kidney disease and are diagnosed on the basis of laboratory abnormalities.
In symptomatic patients, presenting signs or symptoms are nonspecific. Patients with renal failure may present with fatigue, weakness, anorexia, nausea, pruritus, vomiting, edema, diminished urine output, discolored urine, altered mental status, and seizures. Those with renal disease associated with systemic illnesses may present with fever, arthralgias, respiratory symptoms, flank pain, abdominal pain, and diarrhea.
For patients with renal disease suspected on the basis of laboratory abnormalities (e.g., elevated serum Cr [azotemia], electrolyte disturbances, acid-base disorders, proteinuria, hematuria, and anemia), and for symptomatic patients with known kidney disease, ask about the risk factors and symptoms described above, and about the following:
Review the patient's medication list (see Table 1).
Check blood pressure, temperature, and weight. Compare these with values from previous readings. Perform a physical examination, including evaluations of the following:
Review previous laboratory values (e.g., serum Cr, blood urea nitrogen [BUN], electrolytes, urinalysis) to determine whether the kidney disease is acute or chronic.
The presence of an abnormal GFR (≤60 mL/min for at least 3 months) suggests chronic kidney disease (CKD).
Review the CD4 cell count and HIV viral load.
Once the duration of the elevated serum Cr is assessed, a differential diagnosis can be made.
The causes of renal failure are classified traditionally based on the area of the renal anatomy where the injury occurred: prerenal, renal, and postrenal (obstructive uropathy). Acute tubular necrosis (ATN) is the most common cause of acute kidney injury.
Imaging showing obstruction
|Partial Differential Diagnosis|
| Decreased renal perfusion |
Acute tubular necrosis
Ischemia leading to ATN
Other intrarenal lesions
Stones or crystal deposition
A discussion of glomerulonephropathy is beyond the scope of this chapter, but HIV and associated comorbidities (e.g., infections such as hepatitis C, hepatitis B, and cytomegalovirus, along with malignancies, heroin use, nephrotoxic medications, diabetes mellitus, and hypertension) are among the many causes of glomerulonephropathy. The condition most closely associated with HIV is HIVAN. This is a collapsing focal segmental glomerulosclerosis (FSGS) that usually occurs in persons of African heritage, and particularly those with a low CD4 count or high HIV RNA level. The clinical presentation includes the following:
In addition, several conditions may be caused by ARV medications. Tenofovir may cause, though rarely, AKI with type 2 renal tubular acidosis (RTA) and Fanconi syndrome. Alternatively, it may cause a gradual increase in serum Cr; this perhaps is seen more commonly in persons on ritonavir-boosted PIs. Patients who take tenofovir should have renal function monitored every 3-6 months. Indinavir can cause crystalluria, nephrolithiasis, and acute interstitial nephritis, and atazanavir can cause nephrolithiasis.
Some other medications commonly used in the treatment of patients with HIV infection and associated conditions may cause acute or chronic kidney injury. See "Table 1. Causes of Renal Failure," above, and Table 2, below.
|Drugs||Acute Tubular Necrosis||Acute Interstitial Nephritis||Other Associated Abnormalities|
|Tenofovir||+||Fanconi syndrome (hypokalemia, non-gap metabolic acidosis, hypophosphatemia, glycosuria) May cause a slow increase in Cr|
|TMP-SMX (Bactrim, Septra)||+++||Hyperkalemia, crystalluria|
|Aminoglycosides (e.g., streptomycin, gentamycin, amikacin)||+++|
|INH||+||Overdose leads to high anion gap metabolic acidosis|
|Amphotericin B||+++||Hypokalemia, hypernatremia (nephrogenic diabetes insipidus)|
|NSAIDs||+||Proteinuria, secondary minimal change disease, papillary necrosis|
Determine whether the renal disease is acute or chronic, as above (see "O: Objective").
Perform a targeted laboratory evaluation, depending on results of initial tests, history, and physical examination.
Further workup will depend on the findings and the suspected cause.
Proteinuria can be present in patients with primary renal disease, and also in those with hypertension, diabetes mellitus, vascular disease, collagen vascular disease, malignancy, or certain infections. Proteinuria is not always pathologic and may be caused by transient conditions such as pregnancy, strenuous exercise, fever, seizure, or congestive heart failure; in some cases, it may be benign. However, proteinuria should be evaluated if it persists. If present with hematuria, proteinuria is highly suspicious for a glomerular disease.
The major classifications of persons with proteinuria are as follows:
For asymptomatic isolated microscopic hematuria, obtain a follow-up urinalysis. If hematuria is persistent, obtain a renal ultrasound. If the result is normal, the eGFR is normal, and there are no other urine abnormalities, conduct routine follow-up with urinalysis and serum Cr testing. Refer patients aged ≥40 with persistent hematuria to a urologist for formal evaluation. Consider checking urine cytology, though that test is not sensitive enough to rule out genitourinary malignancy.
Red blood cell casts strongly suggest glomerulonephritis, which can progress rapidly.
ATN is the most common cause of AKI. A history of certain medication exposures, recent IV contrast, and concurrent illness may provide important clues to ATN. Laboratory findings that are consistent with ATN include increasing serum Cr and a characteristic urine sediment that shows "muddy brown" casts, which are casts that contain densely packed tubular cells.
During AIN, the classic triad of AKI, fever, and rash are not always present. Laboratory findings suggestive of AIN in the setting of AKI include sterile pyuria and eosinophiluria.
Sterile pyuria also may occur in malignancy (e.g., renal, bladder), and in genitourinary tuberculosis. If tuberculosis is suspected, further testing usually requires three first-void urine specimens sent for acid-fast bacilli culture.
Usual causes of nephrolithiasis should be considered in patients with hematuria, particularly if symptoms consistent with nephrolithiasis are present. Other causes in persons with HIV infection include some medications, including the ARVs indinavir and (rarely) atazanavir; see Table 2 above.
Obtain radiographic imaging (see below) as part of the initial evaluation, and send the passed renal calculus, if available, for analysis in order to provide more specific recommendations for management. If there is suspicion that the condition is caused by a medication, order specific chemical analysis (e.g., for atazanavir).
In patients with multiple renal stones, active renal stone formation, and recurrent kidney stones, a metabolic evaluation should be done. This includes a serum intact parathyroid hormone measurement and 24-hour urine collection for Cr, sodium, calcium, oxalate, uric acid, and citrate.
Radiographic imaging of the kidneys is important in the evaluation of renal disease. The size and echogenicity of the kidneys may help differentiate acute and chronic kidney disease. Small and echogenic kidneys are consistent with CKD, though HIV, diabetes, and some other chronic conditions are associated with normal size or large kidneys. Imaging also helps identify obstruction (though the absence of hydronephrosis does not completely rule that out), malignancy, and other conditions.
Both spiral computed tomography (CT) scan and renal ultrasound are acceptable radiographic imaging studies for nephrolithiasis. The advantage of spiral CT scan is its ability to localize stones and assess their size without the use of contrast. Gallium renal scan may be helpful in AIN.
Biopsy is not always indicated for patients with renal disease, but it can be very helpful in establishing some diagnoses and determining treatment options.
Patients with proteinuria will benefit from angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin receptor blockers (ARBs). Follow the serum potassium and Cr during treatment with an ACEI or ARB (check 1 week after initiation, then periodically). Follow the JNC VII (Joint National Committee on Prevention, Detection, Evaluation and Treatment of Blood Pressure) guidelines for blood pressure control. For patients with hypertension and proteinuria, the target blood pressure is <125/80 mm Hg.
The cornerstone of HIVAN management is fully suppressive ART, and this should be quickly initiated or optimized in all patients, if possible. An ACEI or ARB also should be used to treat proteinuria. A trial of corticosteroids can be considered for patients with deteriorating kidney function while on effective ART plus an ACEI or ARB; consult with a specialist.
For ATN and AIN, discontinue the offending medications and provide supportive care, which may include gentle volume repletion, replacement of bicarbonate deficit, and management of electrolyte abnormalities (e.g., hyperkalemia); consult with a renal specialist.
Other modalities of treatment such as steroids or immunomodulators may be needed, depending on the specific glomerular disease diagnosed by renal biopsy.
Uncomplicated nephrolithiasis can be managed with hydration and pain control. Oral fluid intake should be titrated to produce ≥2 liters of urine output per day. Recommendations for dietary modifications should be based on the 24-hour urine metabolic evaluation. A low-calcium diet usually is not helpful for patients with normal serum calcium and may be detrimental to patients with oxalate renal stones. If the crystalluria is caused by medications, discontinue the offending medications, if possible (in the case of ARVs, make substitutions to maintain optimal virologic suppression).
Patients with complicated nephrolithiasis or pyelonephritis require urgent urologic evaluation.
Patients with severe or chronic renal disease should be referred to Nephrology for further evaluation and assistance with the following:
Dosages of many medications, including most nucleoside analogues (NRTIs), must be adjusted for patients with CKD, and for those on hemodialysis; see Table 3, below.
|Drug||Standard Dosage||Dosing in Chronic Kidney Disease and Hemodialysis|
|Abacavir||300 mg PO BID||Dosage adjustment for CKD does not appear necessary|
|Didanosine (enteric-coated capsules)||250 mg to 400 mg PO once daily, depending on weight||CrCl (mL/min)||Weight ≥60 kg||Weight <60 kg|
|≥60||400 mg once daily||250 mg once daily|
|30-59||200 mg once daily||125 mg once daily|
|10-29||125 mg once daily||125 mg once daily|
|<10||125 mg once daily||Formulation not suitable|
|HD||125 mg once daily||Formulation not suitable|
|Embricitabine||200 mg PO once daily||CrCl (mL/min)|
|≥50||200 mg once daily|
|30-49||200 mg Q48H|
|15-29||200 mg Q72H|
|<15||200 mg Q96H|
|HD||200 mg Q96H, give dosage after dialysis|
|Lamivudine||150 mg PO BID or 300 mg PO once daily||CrCl (mL/min)|
|≥50||150 mg BID or 300 mg once daily|
|30-49||150 mg once daily|
|15-29||150 mg first dose, then 100 mg once daily|
|5-14||150 mg first dose, then 50 mg once daily|
|<5||50 mg first dose, then 25 mg once daily|
|Stavudine||20 mg to 40 mg PO BID, depending on weight||CrCl (mL/min)||Weight ≥60 kg||Weight <60 kg|
|≥50||40 mg BID||30 mg BID|
|26-50||20 mg BID||15 mg BID|
|10-25||20 mg once daily||15 mg once daily|
|HD||20 mg once daily||15 mg once daily|
|Tenofovir||300 mg PO once daily||Experience in patients with CrCl <60 mL/min is limited. Preliminary data suggest the following:|
|≥50||300 mg once daily|
|30-49||300 mg Q48H|
|10-29||300 mg twice weekly (i.e., Q 3-4 days)|
|HD||300 mg once weekly|
|Zidovudine||300 mg PO BID||CrCl (mL/min)|
|<15||100 mg Q6-8H (or 300 mg once daily)|
|HD||100 mg TID (or 300 mg once daily)|
|Atripla (efavirenz/ emtricitabine/ tenofovir)||1 tab PO QHS||Substitute component drugs, adjusting dosage of each drug for CrCl|
|Combivir (zidovudine/lamivudine)||1 tab PO BID||Substitute component drugs, adjusting dosage of each drug for CrCl|
|Epzicom or Kivexa (abacavir/lamivudine)||1 tab PO once daily||Substitute component drugs, adjusting dosage of each drug for CrCl|
|Trizivir (zidovudine/lamivudine/ abacavir)||1 tab PO BID||Substitute component drugs, adjusting dosage of each drug for CrCl|
|Truvada (emtricitabine/ tenofovir)||1 tab PO once daily||CrCl (mL/min)|
|≥50||1 tablet once daily|
|30-49||1 tablet Q48H|
|<30||Substitute component drugs, adjusting dosage of each drug for CrCl|
Protease inhibitors (PIs) and nonnucleoside reverse transcriptase inhibitors (NNRTIs) do not appear to require dosage adjustment in persons with CKD. Some PIs and NNRTIs, however, do require changes in dosing strategy for patients on hemodialysis. (It should be noted that most PIs have not been studied in the setting of hemodialysis.) The CCR5 antagonist maraviroc should not be used for certain patients with CKD. Available recommendations for hemodialysis patients include the folowing:
Available agents in the integrase inhibitor and fusion inhibitor classes do not appear to require dosage adjustment for patients with CKD.