Renal Disease

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:

• CD4 count <200 cells/µL
• HIV viremia, particularly RNA levels >4,000 copies/mL
• African-American race
• Family history of kidney disease
• Use of nephrotoxins (including medications; see Table 2, below)
• Comorbidities
  • Diabetes mellitus
  • Hypertension
  • Hepatitis C

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 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:

• Serum creatinine (Cr) and calculated estimate of renal function (eGFR); the eGFR usually is provided by the laboratory but may be calculated as follows:

  • 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):

    

• Urinalysis, for proteinuria, hematuria
• Quantitative test for proteinuria (if eGFR <60 mL/min/1.73m² or ≥1+ protein on dipstick):
  • Random urinary protein to urinary Cr ratio (U Pr/U Cr)
  • This estimates 24-hour protein excretion; correlates well with grams per day of proteinuria; for example, a random U Pr/U Cr of 1.0 correlates with 1 g/day of proteinuria (normal is ≤0.2)

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."

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:

• Systemic illness
  • Night sweats, fever, weight lost
  • Shortness of breath, cough, hemoptysis, nasal congestion, rhinorrhea
  • Diarrhea, hematochezia, melena
  • Dysuria, frequency, urgency, polyuria, decreased urine output, discoloration of urine
  • Skin rash or skin lesions
  • Edema, arthralgias, painful swollen joints, myalgias
• Family history of kidney disease, hypertension, diabetes mellitus
• Recent radiographic imaging with IV dyes

Review the patient's medication list (see Table 1).

• Include over-the-counter medications, nonsteroidal antiinflammatory drugs, phosphate-containing enemas

O: Objective

Check blood pressure, temperature, and weight. Compare these with values from previous readings. Perform a physical examination, including evaluations of the following:

• Volume status (blood pressure, pulse, skin turgor, mucous membrane moistness, edema)
• Optic fundi (signs of retinopathy)
• Cardiovascular system (peripheral pulses, bruits), to assess for peripheral vascular disease
• Abdomen (auscultate for unilateral bruit [renal artery stenosis], distention, mass, organomegaly, tenderness)
• Musculoskeletal system (bruises, muscle pain, muscle weakness, swollen joints)
• Skin (rash to help evaluate for drug reaction, vasculitis)
• Rectum (enlarged prostate, if obstruction is suspected)

Review previous laboratory values (e.g., serum Cr, blood urea nitrogen [BUN], electrolytes, urinalysis) to determine whether the kidney disease is acute or chronic.

• Acute kidney injury (AKI) is assumed if there are no previous serum Cr values.

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.

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:

• Nephrotic syndrome or nonnephrotic proteinuria
• Normal blood pressure
• Elevated Cr, often with rapid progression to end-stage renal disease (<6 months)
• Renal ultrasound usually reveals normal size or slightly enlarged echogenic kidneys
• Renal biopsy shows a collapsing FSGS

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," above, and Table 2, below.

P: Plan

Diagnostic Evaluation

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.

• Urinalysis with microscopy and examination of urine sediment (e.g., hematuria, pyuria, casts) can help in identifying etiologies such as nephritic syndrome, ATN, or infection.
• Quantify the proteinuria by obtaining a random urine protein-to-urine creatinine ratio (U Pr/U Cr), if not done already; this correlates well with grams per day of proteinuria, as discussed above.
• Fractional excretion of sodium (FeNa) may be helpful in distinguishing causes of acute kidney injury.
  • 
  • FeNa <1 is highly suggestive of prerenal state
  • FeNa >1 is suggestive of intrinsic renal injury
• Urine culture, if urinary tract infection is suspected

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:

• >3.5 g/day proteinuria
• "Bland" sediment, with no or few red or white blood cells
• Edema
• Hyperlipidemia
• Hypoalbuminemia
• Check serum complements (C3 and C4):
  • Low complements: glomerulonephritis associated with subacute bacterial endocarditis, infection (postinfectious),lupus, membranoproliferative glomerulonephritis, and mixed cryoglobulinemia

Glomerulonephritis:

• Proteinuria
• "Active" sediment, with white and red blood cells; may see red blood cell casts
• Further categorized into those with normal renal function and those with abnormal renal function

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 is 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

• Acute kidney injury
  • Monitor serum electrolytes, BUN and Cr
  • After these normalize, perform routine follow-up
• Acute interstitial nephritis
  • Avoid offending medications
• Chronic kidney disease
  • Follow blood pressure closely
    • If hypertensive, consider an ACEI or ARB as first-line medication, as above
    • Target blood pressure is <130/80 mm Hg
    • If evidence of nephropathy, target blood pressure is <125/75 mm Hg
  • For patients with diabetes, optimize blood glucose control
  • Address other risk factors for cardiovascular disease (see chapter Coronary Heart Disease Risk)
    • Dyslipidemia
    • Cigarette smoking
    • Obesity
    • Physical inactivity
  • Monitor serum electrolytes, BUN, Cr, and hemoglobin
  • Risk of secondary hyperparathyroidism:
    • Serum calcium <9.5 mg/dL
    • Parathyroid hormone level >35 pg/mL
    • Management:
      • Low-phosphate diet
      • Phosphate binders with meals
      • 1,25-dihyroxyvitamin D3 or its analogues
  • Anemia
    • Consider recombinant human erythropoietin and iron supplement (consult with a nephrologist)
    • Target hemoglobin 11-12 g/dL
• Avoid nephrotoxins, if possible
• Adjust medication dosages based on renal function (eGFR); see below

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

• Management
• Education
• Evaluation for renal replacement therapy
  • Peritoneal dialysis
  • Hemodialysis
• Kidney transplant evaluation

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.

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:

• Atazanavir
  • Unboosted atazanavir should not be used.
  • Treatment-naive patients: atazanavir must be boosted by ritonavir.
  • Treatment-experienced patients: atazanavir (boosted or unboosted) is not recommended.
• Lopinavir/ritonavir
  • Once-daily dosing should not be used.
  • In patients with PI resistance, lopinavir/ritonavir levels may be subtherapeutic.
• Maraviroc
  • All patients with elevated lipid levels should initiate TLC. If pharmacologic intervention is indicated, statins (hydroxymethylglutaryl coenzyme A [HMG-CoA] reductase inhibitors) are the first-line treatment for most patients.
• Nevirapine
  • An additional dose (200 mg) should be given after each dialysis session.

Available agents in the integrase inhibitor and fusion inhibitor classes do not appear to require dosage adjustment for patients with CKD.

Patient Education

• Early diagnosis of kidney disease is important. Acute kidney injury usually is reversible but may take time and may require temporary hemodialysis support.
• Advise patients to report all the medications they take, including over-the-counter medications and herbs or supplements.
• Risk factors for kidney disease are uncontrolled HIV infection (viral load above 4,000 copies/mL and CD4 count <200 cells/µL), coexisting conditions (diabetes mellitus, hypertension, hepatitis C), and ethnicity (African-Americans, Hispanic Americans, Asians, Pacific Islanders, and American Indians). Advise patients that it is important to reduce any modifiable risks, including optimizing HIV control and diabetes mellitus and/or hypertension management.
• Advise patients that control of blood pressure is important in slowing the progression of renal disease. Hypertension control can be maximized by both lifestyle modifications (e.g., weight lost, exercise, avoiding excessive alcohol intake) and antihypertensive medications. ACEIs or ARBs are the drugs of choice for patients with hypertension and kidney disease. Target blood pressure is <125/75 mm Hg for patients with proteinuric kidney disease.
• Educate patients that management of chronic kidney disease helps avoid or control complications such as high blood pressure, weak bones (osteodystrophy), anemia, and nerve damage (neuropathy).
• When the kidney disease progresses to end-stage renal disease, several options can be explored. These are dialysis, kidney transplant, or palliative care. There are two modes of dialysis, hemodialysis and peritoneal dialysis. A nephrologist and the patient can decide which option is best. HIV control (suppressed viral load, optimal CD4) is required if kidney transplant is to be considered.

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