Clinical Guide > Comorbidities and Complications > Renal Disease

Renal Disease

Author: Alfredo Tiu, DO
January 2011

Chapter Contents

Background

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

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:

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."

Figure 1. Follow-Up for Patients with Normal Screening Test Results

Figure 1. Follow-Up for Patients with Normal Screening Test Results

S: Subjective

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).

O: Objective

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.

A: Assessment

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.

Table 1. Causes of Renal Failure

PrerenalRenalPostrenal

Abbreviations: ACE = angiotensin-converting enzyme; HUS = hemolytic uremic syndrome; NSAID = nonsteroidal antiinflammatory drug; TTP = thrombotic thrombocytopenic purpura

Laboratory
  • Urine sodium (Na) <30 mEq/L
  • Fractional excretion of Na (FeNa) <1% (see below)
  • Fractional excretion of urea <35%
  • Serum BUN:serum Cr ratio ≥20
  • Urine Na >30 mEq/L
  • FeNa >1% (see below)
  • Fractional excretion of urea >50
  • Serum BUN:serum Cr ratio ≥10

Hematuria

Imaging showing obstruction

Partial Differential Diagnosis
Decreased renal perfusion
  • Volume depletion
  • Effective volume depletion
    • Heart failure
    • Cirrhosis
    • Shock

Vascular disease

  • Renal artery stenosis

Medication induced

  • Prostaglandin inhibition (NSAID)
  • ACE inhibitors and angiotensin receptor blockers

Acute tubular necrosis

Ischemia leading to ATN

  • Prolonged hypotension due to any cause
    • Sepsis syndrome
    • Volume depletion (gastrointestinal bleeding)
  • Atheroembolism and thromboembolism
  • Systemic vasculitis
  • Thrombotic microangiopathy (TTP, HUS)

Endogenous toxins

  • Myoglobin (rhabdomyolysis)
  • Uric acid and calcium-phosphate complexes (tumor lysis syndrome)

Exogenous-induced ATN

  • Aminoglycosides
  • Amphotericin B
  • Foscarnet
  • Ganciclovir
  • Intravenous pentamidine
  • Tenofovir
  • Chemotherapeutic agents (methotrexate, cisplatinum)

Glomerulonephropathy*

  • Many specific types; some associated with HIV (including HIVAN) or associated infections and other conditions

Other intrarenal lesions

  • Acute interstitial nephritis (AIN)
  • Drug induced
  • Infections associated with AIN
    • Bacterial (Streptococcus, Mycobacteria, Legionella, Pneumococcus)
    • Viral (Epstein-Barr, herpes simplex type 1, cytomegalovirus, BK virus)
    • Fungal (histoplasmosis, candidiasis)
    • Other infections (toxoplasmosis, syphilis, schistosomiasis, malaria, leptospirosis)
  • Infectious
    • Granulomatous (mycobacterial disease, coccidioidomycosis, histoplasmosis)
  • Tumors
    • Multiple myeloma
    • Lymphoma
  • Nephrolithiasis
    • Intratubular obstruction
      • Drug-induced crystalluria
        • Antiviral (acyclovir, indinavir, atazanavir)
        • Antibiotic (trimethoprim/sulfamethoxazole)

Prostate hypertrophy

Tumors

Stones or crystal deposition

Kidney disease associated with HIV infection

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.

Table 2. Selective Drugs Causing Acute or Chronic Kidney Injury in HIV-Infected Patients

DrugsAcute Tubular NecrosisAcute Interstitial NephritisOther Associated Abnormalities
Antiretroviral Medications
Abacavir+/-
Atazanavir+Nephrolithiasis
Indinavir+Crystalluria
Tenofovir+Fanconi syndrome (hypokalemia, non-gap metabolic acidosis, hypophosphatemia, glycosuria) May cause a slow increase in Cr
Other Medications
TMP-SMX (Bactrim, Septra)+++Hyperkalemia, crystalluria
Beta-lactams++
Sulfonamides++
Fluoroquinolones+
Aminoglycosides (e.g., streptomycin, gentamycin, amikacin)+++
Rifampin++
INH+Overdose leads to high anion gap metabolic acidosis
Dapsone+/-Papillary necrosis
Amphotericin B+++Hypokalemia, hypernatremia (nephrogenic diabetes insipidus)
Pentamidine+++Crystalluria
Foscarnet+++
Gancyclovir+
Acyclovir+Crystalluria
NSAIDs+Proteinuria, secondary minimal change disease, papillary necrosis

P: Plan

Diagnostic Evaluation

Figure 2. Workup of Abnormal Screening Test Results

Figure 2. Workup of Abnormal Screening Test Results

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

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:

Nephrotic syndrome:

Glomerulonephritis:

Hematuria

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

Red blood cell casts strongly suggest glomerulonephritis, which can progress rapidly.

ATN

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.

AIN

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

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.

Crystalluria and nephrolithiasis

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.

Imaging

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.

Renal biopsy

Biopsy is not always indicated for patients with renal disease, but it can be very helpful in establishing some diagnoses and determining treatment options.

Treatment

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.

Follow-Up

Patients with severe or chronic renal disease should be referred to Nephrology for further evaluation and assistance with the following:

Medication Dosage Adjustment

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.

Table 3. Dosing of Antiretroviral Drugs in Adults with Chronic Kidney Disease and Hemodialysis

DrugStandard DosageDosing in Chronic Kidney Disease and Hemodialysis

Abbreviations: CrCl = creatinine clearance; HD = hemodialysis; Wt = weight

Adapted from McNicholl I, Rodriguez R. Dosing of Antiretroviral Drugs in Adults with Chronic Kidney Disease and Hemodialysis. In: HIV InSite, Coffey S, Volberding P, eds. San Francisco: UCSF Center for HIV Information; October 2009.

Abacavir300 mg PO BIDDosage adjustment for CKD does not appear necessary
Didanosine (enteric-coated capsules)250 mg to 400 mg PO once daily, depending on weightCrCl (mL/min)Weight ≥60 kgWeight <60 kg
≥60400 mg once daily250 mg once daily
30-59200 mg once daily125 mg once daily
10-29125 mg once daily125 mg once daily
<10125 mg once dailyFormulation not suitable
HD125 mg once dailyFormulation not suitable
Embricitabine200 mg PO once dailyCrCl (mL/min)
≥50200 mg once daily
30-49200 mg Q48H
15-29200 mg Q72H
<15200 mg Q96H
HD200 mg Q96H, give dosage after dialysis
Lamivudine150 mg PO BID or 300 mg PO once dailyCrCl (mL/min)
≥50150 mg BID or 300 mg once daily
30-49150 mg once daily
15-29150 mg first dose, then 100 mg once daily
5-14150 mg first dose, then 50 mg once daily
<550 mg first dose, then 25 mg once daily
Stavudine20 mg to 40 mg PO BID, depending on weightCrCl (mL/min)Weight ≥60 kgWeight <60 kg
≥5040 mg BID30 mg BID
26-5020 mg BID15 mg BID
10-2520 mg once daily15 mg once daily
HD20 mg once daily15 mg once daily
Tenofovir300 mg PO once dailyExperience in patients with CrCl <60 mL/min is limited. Preliminary data suggest the following:
CrCl (mL/min)
≥50300 mg once daily
30-49300 mg Q48H
10-29300 mg twice weekly (i.e., Q 3-4 days)
HD300 mg once weekly
Zidovudine300 mg PO BIDCrCl (mL/min)
<15100 mg Q6-8H (or 300 mg once daily)
HD100 mg TID (or 300 mg once daily)
Fixed-Dose Combinations
Atripla (efavirenz/ emtricitabine/ tenofovir)1 tab PO QHSSubstitute component drugs, adjusting dosage of each drug for CrCl
Combivir (zidovudine/lamivudine)1 tab PO BIDSubstitute component drugs, adjusting dosage of each drug for CrCl
Epzicom or Kivexa (abacavir/lamivudine)1 tab PO once dailySubstitute component drugs, adjusting dosage of each drug for CrCl
Trizivir (zidovudine/lamivudine/ abacavir)1 tab PO BIDSubstitute component drugs, adjusting dosage of each drug for CrCl
Truvada (emtricitabine/ tenofovir)1 tab PO once dailyCrCl (mL/min)
≥501 tablet once daily
30-491 tablet Q48H
<30Substitute 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.

Patient Education

References