Kidney Disease Guideline

Kidney Disease Guideline

Introduction

Medical Care Criteria Committee, September 2012

KEY RECOMMENDATIONS
Introduction
  • Clinicians should:
    • Inform and educate patients with HIV about the associations between HIV and kidney disease (B3)
    • Routinely assess kidney function in patients with HIV (A3)
    • Counsel patients with HIV-associated nephropathy about the increased urgency of initiating ART (A2)
    • Assess whether dose adjustments or discontinuation of renally cleared ART medications are necessary when a patient’s glomerular filtration rate reaches ≤50 mL/min (A3)

Kidney disease in the setting of HIV can pose a significant challenge to patients and clinicians by increasing the risk for AIDS-defining illness, hospitalization, and death [Gardner et al. 2003a; Gardner et al. 2003b; Szczech et al. 2004]. The importance of routine screening, even for patients not receiving antiretroviral therapy (ART) [Winston et al. 2008], is underscored by the following:

  • Risk for HIV-associated nephropathy, a kidney disease that is caused directly by HIV infection
  • Use of potentially nephrotoxic agents, such as some ART medications, as well as nonsteroidal anti-inflammatory drugs (NSAIDs)
  • Increased prevalence of recognized causes of kidney disease in people with HIV as compared with people who do not have HIV, including diabetes [Pullinger et al. 20105], hypertension [Pullinger et al. 20105], and liver disease [Ibrahim et al. 2010]
KEY POINT
  • Black patients with HIV and chronic kidney disease (CKD) have a significantly higher risk for end-stage renal disease (ESRD) compared with White patients with HIV and CKD [Choi et al. 2007].
References

Choi AI, Rodriguez RA, Bacchetti P, et al. Racial differences in end-stage renal disease rates in HIV infection versus diabetes. J Am Soc Nephrol 2007;18:2968-2974. [PubMed]

Gardner LI, Holmberg SD, Williamson JM, et al. Development of proteinuria or elevated serum creatinine and mortality in HIV-infected women. J Acquir Immune Defic Syndr 2003a;32:203-209. [PubMed]

Gardner LI, Klein RS, Szczech LA, et al. Rates and risk factors for condition-specific hospitalizations in HIV-infected and uninfected women. J Acquir Immune Defic Syndr 2003b;34:320-330. [PubMed]

Ibrahim F, Naftalin C, Cheserem E, et al. Immunodeficiency and renal impairment are risk factors for HIV-associated acute renal failure. AIDS 2010;24:2239-2244. [PubMed]

Pullinger CR, Aouizerat BE, Gay C, et al. Metabolic abnormalities and coronary heart disease risk in human immunodeficiency virus-infected adults. Metab Syndr Relat Disord 2010;8:279-286. [PubMed]

Szczech LA, Hoover DR, Feldman JG, et al. Association between renal disease and outcomes among HIV-infected women receiving or not receiving antiretroviral therapy. Clin Infect Dis 2004;39:1199-1206. [PubMed]

Winston J, Deray G, Hawkins T, et al. Kidney disease in patients with HIV infection and AIDS. Clin Infect Dis 2008;47:1449-1457. [PubMed]

Patient Education

Medical Care Criteria Committee, September 2012

RECOMMENDATION
Patient Education
  • Clinicians should educate patients about the following: (B3)
    • The association between HIV and kidney disease
    • The role of ART in preventing HIVAN
    • Importance of routine monitoring appointments to assess for other causes of kidney disease

Patient education about preserving kidney function, even for those who are asymptomatic for kidney disease, should emphasize the importance of ART to prevent HIVAN [Lescure et al. 2012; Wearne et al. 2012.], as well as the importance of keeping routine monitoring appointments to assess for other causes of kidney disease, including medication-related nephrotoxicity, hypertension, and diabetes.

References

Lescure FX, Flateau C, Pacanowski J, et al. HIV-associated kidney glomerular diseases: Changes with time and HAART. Nephrol Dial Transplant 2012;27:2349-2355. [PubMed]

Wearne N, Swanepoel CR, Boulle A, et al. The spectrum of renal histologies seen in HIV with outcomes, prognostic indicators and clinical correlations. Nephrol Dial Transplant 2012. In press. [PubMed]

 

Renal Syndrome and Risk Factors

Medical Care Criteria Committee, September 2012

Acute Renal Failure

Acute renal failure (ARF), also known as acute kidney injury, is characterized by a rapid loss of kidney function [Schrier et al. 2004], including the capacity to excrete waste and maintain fluid balance. In patients with HIV, immunodeficiency may be the greatest risk factor for ARF [Ibrahim et al. 2010]. However, many of the common risk factors for ARF are similar in people with and without HIV, such as older age, diabetes, and exposure to nephrotoxic agents. Many agents used to treat opportunistic infections, as well as certain antiretroviral medications used in the primary treatment of HIV, have nephrotoxic potential [Gupta et al. 2005]. ARF in patients with HIV in ambulatory care settings is most frequently due to pre-renal azotemia or acute tubular necrosis, possibly caused by exposure to nephrotoxic agents [Gupta et al. 2005]. Unlike CKD, race has not been clearly established as a risk factor for ARF.

Kidney Disease Prevalence and Complications provides information about the reported prevalence of ARF among HIV-infected patients.

Chronic Kidney Disease

CKD is defined as either proteinuria, a marker of kidney damage, or glomerular filtration rate (GFR) <60 mL/min for ≥3 months. Hypertension and diabetes are important causes of CKD in HIV. In one cross-sectional analysis, 55% of patients with HIV and CKD had hypertension and 20% had diabetes [Wyatt et al. 2007].

There is a higher prevalence of both HIV and CKD among blacks compared with whites. CKD in the setting of HIV is more likely to progress to ESRD in black patients. Genetic factors unique to individuals of African descent, and not to whites, are associated with focal segmental glomerulosclerosis and non-diabetic ESRD [Kao et al. 2008; Kopp et al. 2008; Nelson et al. 2010; Behar et al. 2010; Genovese et al. 2010]. An allele that confers protection against infection by Trypanosoma brucei, a parasite commonly found in Africa, has been linked to greater susceptibility to non-diabetic kidney disease among blacks [Genovese et al. 2010]. The presence of this allele among blacks in the United States may contribute to the higher incidence of advanced kidney disease in this population [Genovese et al. 2010].

Other known risk factors include hepatitis C virus (HCV) co-infection, family history, increased viral load levels (>4000 copies/mL), reduced CD4 cell count (<350 cells/mm3), and older age, although GFR does naturally decline with age [Gupta et al. 2005]. It is estimated that as many as 40% of individuals older than 70 years meet criteria for CKD based on GFR levels <60 mL/min. These cases may be misclassified because the distinction between physiologic aging and CKD at or near a GFR of 60 mL/min is unclear. CKD risk factors, including arteriosclerosis, hypertension, and diabetes, increase with age, and development and/or progression of kidney disease may occur when these risk factors increase in elderly patients.

References

Behar DM, Rosset S, Tzur S, et al. African ancestry allelic variation at the MYH9 gene contributes to increased susceptibility to non-diabetic end-stage kidney disease in Hispanic Americans. Hum Mol Genet 2010;19:1816-1827. [PubMed]

Genovese G, Tonna SJ, Knob AU, et al. A risk allele for focal segmental glomerulosclerosis in African Americans is located within a region containing APOL1 and MYH9. Kidney Int 2010;78:698-704. [PubMed]

Gupta SK, Eustace JA, Winston JA, et al. Guidelines for the management of chronic kidney disease in HIV-infected patients: Recommendations of the HIV Medicine Association of the Infectious Diseases Society of America. Clin Infect Dis 2005;40:1559-1585. [PubMed]

Ibrahim F, Naftalin C, Cheserem E, et al. Immunodeficiency and renal impairment are risk factors for HIV-associated acute renal failure. AIDS 2010;24:2239-2244. [PubMed]

Kao WH, Klag MJ, Meoni LA, et al. MYH9 is associated with nondiabetic end-stage renal disease in African Americans. Nat Genet 2008;40:1185-1192. [PubMed]

Kopp JB, Smith MW, Nelson GW, et al. MYH9 is a major-effect risk gene for focal segmental glomerulosclerosis. Nat Genet 2008;40:1175-1184. [PubMed]

Nelson GW, Freedman BI, Bowden DW, et al. Dense mapping of MYH9 localizes the strongest kidney disease associations to the region of introns 13 to 15. Hum Mol Genet 2010;19:1805-1815. [PubMed]

Schrier RW, Wang W, Poole B, et al. Acute renal failure: Definitions, diagnosis, pathogenesis, and therapy. J Clin Invest 2004;114:5-14. [PubMed]

Wyatt CM, Winston JA, Malvestutto CD, et al. Chronic kidney disease in HIV infection: An urban epidemic. AIDS 2007;21:2101-2113. [PubMed]

Kidney Disease Prevalence and Complications

Medical Care Criteria Committee, September 2012

Acute Renal Failure: Prevalence and Complications

HIV-infected patients in ambulatory care (2005) [Franceschini et al. 2005]:

  • Among 754 HIV-infected patients in ambulatory care, 10% experienced at least one episode of ARF over 2 years
  • More than half of the ARF episodes were attributed to underlying infections, 76% of which were AIDS-defining illnesses
  • Complications of drug therapy accounted for nearly one-third of ARF cases; conventional antibiotics and antifungal agents were the primary agents that caused the complications
  • Liver disease accounted for approximately 10% of cases, and HCV co-infection and lower CD4 cell counts were identified as independent risk factors

Hospital discharges in New York State (2006) [Wyatt et al. 2006]:

  • In an analysis of administrative data from more than 2 million hospital discharges in New York State, HIV infection was associated with a 2.8-fold increase in documented ARF
  • ARF was associated with a nearly 6-fold increase in in-hospital mortality

Chronic Kidney Disease Prevalence

EuroSIDA:

  • A total of 3.5% of patients with HIV-1 infection had a GFR <60 mL/min
  • The low prevalence might be explained by: 1) the predominantly white study population, in whom risk for kidney disease is lower than in blacks; and 2) lack of information about proteinuria

HERS:

  • Kidney disease was present in 7.2% of HIV-infected women at baseline and developed in an additional 14% over a mean follow-up period of 21 months [Gardner et al. 2003]
  • This study defined kidney disease as serum creatinine >1.4 mg/dL or urine dipstick >2+ protein on any research visit; such criteria omitted patients with a low GFR and a serum creatinine <1.4 mg/dL and likely underestimated CKD prevalence

National Sample of U.S. Veterans Affairs Patients: 

  • A total of 7.1% of HIV-infected individuals had a GFR <60 mL/min [Choi et al. 2007], whereas an analysis of HIV-infected patients in an urban AIDS center found 15.5% had low GFR or proteinuria [Wyatt et al. 2007]

Fat Redistribution and Metabolic Change in HIV Infection (FRAM): Microalbuminuria, which is predictive of kidney disease in diabetic patients, was detected in 11% of HIV-infected participants

References

Choi AI, Rodriguez RA, Bacchetti P, et al. Racial differences in end-stage renal disease rates in HIV infection versus diabetes. J Am Soc Nephrol 2007;18:2968-2974. [PubMed]

Franceschini N, Napravnik S, Eron JJ Jr, et al. Incidence and etiology of acute renal failure among ambulatory HIV-infected patients. Kidney Int 2005;67:1526-1531. [PubMed]

Gardner LI, Holmberg SD, Williamson JM, et al. Development of proteinuria or elevated serum creatinine and mortality in HIV-infected women. J Acquir Immune Defic Syndr 2003;32:203-209. [PubMed]

Wyatt CM, Arons RR, Klotman PE, et al. Acute renal failure in hospitalized patients with HIV: Risk factors and impact on in-hospital mortality. AIDS 2006;20:561-565. [PubMed]

Wyatt CM, Winston JA, Malvestutto CD, et al. Chronic kidney disease in HIV infection: An urban epidemic. AIDS 2007;21:2101-2113. [PubMed]

Routine Screening

Medical Care Criteria Committee, September 2012

RECOMMENDATIONS
Routine Screening
  • Clinicians should routinely assess kidney function in all patients with HIV. A renal assessment should include:
    • Glomerular filtration rate estimated from serum creatinine (baseline and at least every 6 months) (A2)
    • Blood urea nitrogen (baseline and at least every 6 months) (A3)
    • Urinalysis, total protein, and albumin (baseline and at least annually) (A3)
    • For patients with diabetes and no known proteinuria: calculation of urine albumin-to-creatinine ratio to detect microalbuminuria, at baseline and at least annually (A1)
Patients Taking Tenofovir
  • For patients receiving a tenofovir-containing regimen, clinicians should estimate glomerular filtration rate at initiation of therapy, 1 month after initiation of therapy, and at least every 4 months thereafter.

Routine tests for kidney disease screening in patients with HIV should be performed according to the recommendations above.

Glomerular Filtration Rate

A glomerular filtration rate (GFR) of <60 mL/min meets criteria for CKD; this threshold is supported by epidemiologic data linking low GFR to an increased frequency of hospitalization, cardiovascular events, or death [Hemmelgarn et al. 2010]. GFR can be calculated in the clinical setting using one of the following three equations:

Any of these equations may be used to follow trends in creatinine as part of determining GFR. If creatinine is rising, GFR will be falling by any of these equations; if creatinine is stable, then GFR is stable by any of these equations.

These equations remain the most highly validated formulas for screening and ongoing assessment of kidney disease; however, they have not been validated in large numbers of patients with HIV infection.

Important limitations to calculating GFR:

  • Unlike the CKD-EPI, the MDRD and Cockcroft-Gault have not been validated in people with normal kidney function and do not accurately estimate GFR in the normal range; therefore, when GFR is >60 mL/min, small but possibly meaningful changes in GFR that may indicate early kidney disease cannot be reliably measured with the MDRD and Cockcroft-Gault equations.
  • All of these equations have diminished accuracy in patients with extremes of body weight, such as body builders, amputees, and frail individuals; for these patients, a 24-hour creatinine clearance may be a better test because serum creatinine within the normal range may not correlate with a normal GFR.
KEY POINTS
  • The MDRD or CKD-EPI, not the Cockcroft-Gault, equations are used by clinical laboratories when reporting estimated GFR from serum creatinine; however, drug manufacturers’ recommended dose adjustments for kidney function are based on the Cockcroft-Gault equation, not the MDRD.
  • The CKD-EPI equation has begun to replace the MDRD equation when clinical laboratories report GFR. Unlike the other equations, the CKD-EPI equation has been validated in individuals with normal kidney function of >60 mL/min, although this has not been studied in the setting of HIV infection.

Other markers that reliably measure GFR are needed. Cystatin C, a member of the cysteine protease family, may be more closely correlated with changes in GFR. Evidence suggests that a proposed equation combining creatinine and cystatin C performs better than creatinine alone [Inker et al. 2012]. However, no standardized measurement is currently available.

Urine Protein Excretion

The most sensitive indicator of kidney damage is an elevated urinary protein excretion, measured qualitatively using urine dipstick or quantitatively using a spot urine protein-to-creatinine ratio or a 24-hour urine collection. A protein-to-creatinine ratio is measured from a random sample of urine, as opposed to the timed collection (e.g., a 24-hour calculation).

For patients with ≥1+ by urinary dipstick, urinary protein excretion should be quantified using the protein-to-creatinine ratio from a random sample of urine or a 24-hour urine collection. Patients with heavy proteinuria and apparently normal GFR may have worse clinical outcomes than those with moderately reduced GFR and normal proteinuria [Go et al. 2004].

The laboratory may report urinary protein and creatinine concentrations (both in milligrams per deciliter) and provide the ratio, or the laboratory may report milligrams of protein per gram of creatinine. With these results, kidney function can be assessed as follows:

  • 150 to <200 mg protein/gram creatinine: the upper limit of normal (ratio, 0.15 to <0.2) and approximately 150 to 200 mg protein excretion per 24 hours
  • 200 to <1500 mg protein/gram creatinine: mild proteinuria (ratio, 0.2 to <1.5) that is generally asymptomatic but may indicate tubulointerstitial disease or a focal glomerular abnormality
  • 1500 to ≤2000 mg protein/gram creatinine: moderate proteinuria (ratio, 1.5 to ≤0.2) suggesting glomerular disease
  • >2000 mg protein/gram creatinine: nephrotic-range proteinuria with glomerular disease
KEY POINT
  • Microscopic hematuria and mild proteinuria (urinary protein excretion <1500 mg/day) are generally asymptomatic. They have little clinical impact alone but can indicate an early stage of a serious disease, such as acute or chronic glomerular disease. A kidney biopsy is often deferred in such circumstances until the renal disease progresses, as manifested by increasing proteinuria, decreasing GFR, or the development of hypertension.

Microalbuminuria Screening in Diabetic Patients

The standard dipstick is not sufficient for urinary screening in individuals with diabetes because the dipstick will not detect microalbuminuria, which predicts the subsequent development of clinically important kidney disease in patients with diabetes. In diabetic patients without gross proteinuria, the albumin-to-creatinine ratio should be used annually to detect microalbuminuria, according to American Diabetes Association Guidelines [2012]. A urinary albumin excretion between 30 and 299 µg/mg creatinine indicates microalbuminuria. Isolated microalbuminuria in patients without diabetes has not been clearly linked to the subsequent development of kidney failure, and screening for microalbuminuria in all patients is not currently recommended.

References

American Diabetes Association. Standards of Medical Care in Diabetes—2012. Diabetes Care 2012;35(Suppl 1):S11-S63. Available at: http://care.diabetesjournals.org/content/35/Supplement_1/S11.full

Go AS, Chertow GM, Fan D, et al. Chronic kidney disease and the risks of death, cardiovascular events, and hospitalization. N Engl J Med 2004;351:1296-1305. [PubMed]

Hemmelgarn BR, Manns BJ, Lloyd A, et al. Relation between kidney function, proteinuria, and adverse outcomes. JAMA 2010;303:423-429. [PubMed]

Inker LA, Schmid CH, Tighiouart H, et al. Estimating glomerular filtration rate from serum creatinine and cystatin C. N Engl J Med 2012;367:20-29. [PubMed]

Diagnosis and Evaluation

Medical Care Criteria Committee, September 2012

RECOMMENDATIONS
Diagnostic Evaluation
  • All patients with borderline glomerular filtration rate, regardless of age, should undergo the following diagnostic evaluation of kidney function: (A2)
    • Urinalysis to screen for cells and cellular casts
    • Quantification of urinary protein excretion
    • Renal sonogram
    • Careful physical examination
Referral to Nephrologist
  • Primary care clinicians should refer patients to a nephrologist when: (A2)
HIV-Associated Nephropathy
  • In circumstances when a kidney biopsy is not performed for a patient with HIV and kidney dysfunction, because of contraindication, clinician judgment, or patient preference, the following diagnostic criteria for HIV-associated nephropathy are reasonable: (B3)
    • No other explainable cause(s) of kidney disease and
    • Proteinuria of >2000 mg and
    • Normal to large echogenic kidneys on sonogram and
    • Black race
  • For patients with empirically diagnosed HIV-associated nephropathy whose kidney disease worsens after initiation of ART, a biopsy should be performed to determine the underlying cause. (A3)

Although most aspects of the diagnosis and evaluation of kidney disease can be performed by the primary care clinician, consultation with a nephrologist, including patient referral, may benefit the patient’s care during any stage of his/her disease.

Diagnosis of CKD is often delayed because it may be asymptomatic. CKD is often detectable only by laboratory testing. The distinction between CKD and ARF frequently requires a careful physical examination and review of the patient’s medical record, including prior laboratory tests, as well as follow-up visits and repeat laboratory testing.

CKD is categorized in five stages (see Table 1). Patients with normal GFRs but have evidence of kidney damage are classified as having stage 1 or 2 CKD.

Table 1: Stages of Chronic Kidney Disease [a]
Stage Description [b] GFR (mL/min) [c]
1 Kidney damage with normal or increased GFR ≥90
2 Kidney damage with mildly decreased GFR 60-89
3 Moderately decreased GFR 30-59
4 Severely decreased GFR 15-29
5 Kidney failure <15
(or dialysis)
  1. Adapted from K/DOQI Clinical Practice Guidelines for Chronic Kidney Disease: Evaluation, Classification, and Stratification [2002] by permission of Elsevier.
  2. CKD is defined as either kidney damage or GFR <60 mL/min for ≥3 months. Kidney damage is defined as pathologic abnormalities or markers of damage, including abnormalities in urine tests or imaging studies.
  3. GFR can be calculated in the clinical setting using one of the following equations/calculators:
    1. Chronic Kidney Disease Epidemiology Consortium (CKD-EPI) calculator 
    2. Modification of diet in renal disease (MDRD) calculator
    3. Cockcroft-Gault. A Cockcroft-Gault calculator 
Click to enlarge

Once the presence of kidney disease has been confirmed, the history and physical examination will likely provide important information about the duration of disease and predisposing risk factors, such as hypertension, diabetes, liver disease, or exposure to potential nephrotoxins. In addition, urinalysis to detect red cells, white cells, and cellular casts can provide information about the cause of kidney disease.

Steps for screening and initial management of kidney disease are provided in Figure 1.

KEY POINT
As CKD progresses, more pronounced signs or symptoms may appear, including increased blood pressure, anemia, or edema (mild to severe). All forms of CKD have the potential to progress to ESRD.

Renal Sonogram: A renal sonogram provides information about kidney size and structure and can demonstrate obstructive uropathy or small, echogenic kidneys diagnostic of chronic disease. The test is readily available, noninvasive, and inexpensive and should be performed in all patients with ARF or CKD.

Kidney biopsy: The indications for performing a kidney biopsy in patients with HIV are difficult to generalize and should not be different for those in patients without HIV. Biopsies have the greatest clinical utility in patients with acute glomerulonephritis or unexplained CKD, especially in the setting of heavy proteinuria (defined as 24-hour urinary protein excretion of >2000 mg or protein-to-creatinine ratio >2000 mg/g creatinine) or in patients with relatively rapid decreases in GFR, because they are at high risk for progression to ESRD.

Most nephrologists would treat a proteinuric patient (e.g., 24-hour urinary protein excretion of >300 mg/g or protein-to-creatinine ratio of >200 mg/g creatinine) with an angiotensin-converting enzyme ACE) inhibitor or angiotensin receptor blocker (ARB), regardless of whether or not a biopsy is obtained (see Management of Comorbidities).

HIV-Associated Nephropathy

The first reports of AIDS-related kidney disease appeared in the mid-1980s and described immunosuppressed patients with nephrotic-range proteinuria who progressed to renal failure and required dialysis within several weeks after presentation [Rao et al. 1984]. These were cases of what is now recognized as HIV-associated nephropathy (HIVAN), a kidney disease with a pathogenesis that is directly related to the expression of HIV mRNA or DNA in glomerular and tubule epithelial cells, leading to renal damage through pro-inflammatory cytokines [Bruggeman et al. 2000; Ross et al. 2006]. HIVAN is a combined glomerular and tubule disorder, with collapsing glomerulopathy, focal glomerulosclerosis, microcystic tubule damage, varying degrees of interstitial inflammation, and tubular atrophy [Rao et al. 1984; Humphreys 1995; D’Agati and Appel 1997]. The disease has been described in black patients at much higher rates than other racial populations and occurs primarily in patients with advanced HIV disease. A genetic polymorphism on chromosome 22 may explain this racial predilection.

In the era of ART, HIVAN has become more indolent, which makes it difficult to distinguish from other forms of kidney disease with clinical assessment alone. HIVAN is a pathologic entity that is distinct from other kidney diseases. Black race, high viral load level, low CD4 cell count, and heavy proteinuria (24-hour urinary protein excretion of >2000 mg or protein-to-creatinine ratio >2000 mg/g creatinine) predict the presence of HIVAN. However, no guidelines currently exist for diagnosing HIVAN in the absence of biopsy. According to biopsy studies, the predictive value of clinical signs alone are not very specific [Szczech et al. 2004; Estrella et al. 2006].

References

Bruggeman LA, Ross MD, Tanji N, et al. Renal epithelium is a previously unrecognized site of HIV-1 infection. J Am Soc Nephrol 2000;11:2079-2087. [PubMed]

D’Agati V, Appel GB. HIV infection and the kidney. J Am Soc Nephrol 1997;8:138-152. [PubMed]

Estrella M, Fine DM, Gallant JE, et al. HIV type 1 RA level as a clinical indicator of renal pathology in HIV-infected patients. Clin Infect Dis 2006;43:377-380. [PubMed]

Humphreys MH. HIV-associated glomerulosclerosis. Kidney Int 1995;48:311-320. [PubMed]

National Kidney Foundation. K/DOQI clinical practice guidelines for chronic kidney disease: Evaluation, classification, and stratification. Am J Kidney Dis 2002;39(2 Suppl 1):S1-S266. [PubMed]

Rao TK, Filippone EJ, Nicastri AD, et al. Associated focal and segmental glomerulosclerosis in the acquired immunodeficiency syndrome. N Engl J Med 1984;310:669-673. [PubMed]

Ross MJ, Fan C, Ross MD, et al. HIV-1 infection initiates an inflammatory cascade in human renal tubular epithelial cells. J Acquir Immune Defic Syndr 2006;42:1-11. [PubMed]

Szczech LA, Gupta SK, Habash R, et al. The clinical epidemiology and course of the spectrum of renal diseases associated with HIV infection. Kidney Int 2004; 66:1145-1152. [PubMed]

Management

Medical Care Criteria Committee, September 2012

RECOMMENDATIONS
Treatment
  • Patients with low-grade proteinuria and/or slightly decreased glomerular filtration rate should receive ART if not already receiving it, an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker, and careful monitoring of kidney function.
  • Clinicians should consult with a nephrologist when managing patients who are approaching end-stage renal disease due to stage 4 to 5 chronic kidney disease (see Table 1. Stages of Chronic Kidney Disease) and require special interventions for hyperparathyroidism, anemia, hemodialysis vascular access, peritoneal dialysis, and/or kidney transplant options. (A2)
Use of ART to Prevent Progression
  • Clinicians should educate patients with HIV-associated nephropathy about the increased urgency of initiating ART. (A2)
Management of Comorbidities
  • Clinicians should treat hyperglycemia, dyslipidemia, anemia, and hypertension in patients with HIV and kidney disease according to standard guidelines for patients who do not have HIV. (A1)
  • Normotensive patients with HIV and kidney disease should receive angiotensin-converting enzyme inhibitors or angiotensin receptor blockers according to standard guidelines for patients who do not have HIV. (A1)
Referral to a Nephrologist

Clinicians should refer patients with HIV who have kidney disease to a nephrologist when:

  • Considering management with steroids, immunosuppression, hemodialysis, or transplantation (A3)
  • A diagnosis of membranoproliferative glomerulonephritis has been made in a patient who also has hepatitis C infection. (A3)

Use of ART to Prevent Progression

The incidence and spectrum of kidney diseases in patients HIV have been dramatically altered by ART. The risk for ESRD has been reduced, survival on dialysis among patients with HIV approaches survival for patients without HIV, and kidney transplantation is a viable option [NIH 2007; Ahuja et al. 2002; Schwartz et al. 2005; Lucas et al. 2004]. One multicenter study demonstrated a 3-year survival rate of 83% among patients with HIV [Roland et al. 2008]. Survival on dialysis is expected to continue to improve with newer antiretroviral drug therapies [Ahuja et al. 2002].

Several case reports provide evidence that ART reverses the structural and functional abnormalities associated with HIVAN [Wali et al. 1998; Wintson et al. 2001; Scheurer 2004]. Patients with HIVAN who are receiving effective ART have a slower decrease in GFR [Szchzech et al. 2004; Cosgrove et al. 2002; Atta et al. 2006] and experience fewer incidents of fulminant renal failure [Lucas et al. 2004]. ART is responsible for at least a 30% reduction in new ESRD cases from HIVAN [Schwartz et al. 2005].

ART-naïve patients should be educated about the increased importance of initiating ART in the presence of HIVAN, and patients with low-grade proteinuria and/or slightly decreased GFR should initiate ART if not already receiving it. However, initiation of ART may not have a beneficial effect on the natural history of other forms of CKD, such as IgA nephropathy and diabetes, which could be mistaken for HIVAN when a biopsy is not obtained. If kidney disease worsens after initiating ART, a biopsy should be performed to determine the underlying cause.

Management of Comorbidities

For most patients, the most effective approach to CKD treatment is effective medical management of two major risk factors: diabetes and hypertension.

Patients with HIV with low-grade proteinuria and/or slightly decreased GFR should receive ART if not already receiving it, an ACE inhibitor or ARB, and careful monitoring of kidney function. Patients with HIV who have kidney disease and hyperglycemia, dyslipidemia, anemia, or hypertension should receive management and treatment according to standard guidelines [National Kidney Foundation 2002, 2003, 2004, 2006] for patients without HIV. Guidelines for treating hypertension in patients with HIV with kidney disease, including antihypertensive therapy for normotensive patients with proteinuria, are the same as those for patients without HIV. Standard ACE inhibitor or ARB therapy should also be considered for normotensive patients with HIVAN [Gupta et al. 2005].

Referral to a Nephrologist

Consultation with a nephrologist can be useful at any stage of a patient’s kidney disease to guide clinical examination and interpret findings. Referral to a nephrologist is recommended when treatment for a patient’s kidney disease becomes complex, such as when steroids, immunosuppression, hemodialysis, transplantation, or treatment for membranoproliferative glomerulonephritis (MPGN) may be required.

Steroids and immunosuppression: Steroids have been used in HIVAN because they can reduce urinary protein excretion and/or improve GFR in other kidney diseases, such as idiopathic focal segmental glomerulosclerosis and interstitial nephritis. In nonrandomized trials, kidney function can stabilize or improve in steroid-treated patients [Eustace et al. 2000].

Hemodialysis and transplantation: Proper planning for hemodialysis, peritoneal dialysis, or kidney transplantation should be managed by a nephrologist, well in advance of uremic symptoms. In patients who are likely to begin hemodialysis, an arteriovenous fistula should be created months before an anticipated start date. Dose adjustments for ART in patients on hemodialysis have been well established [AIDSinfo 2014].

Successful results have been demonstrated in renal transplant patients on ART. The rates of both acute rejection and infection among patients with HIV were comparable to transplant recipients who do not have HIV [Gruber et al. 2008; Locke et al. 2009]. More recently, prospective data from the Solid Organ Transplantation in HIV: Multi-Site Study demonstrated excellent patient and graft survival, despite an increased rate of acute rejection in kidney transplant recipients with HIV [Stock et al. 2010]. Clinicians should be aware of the potential for significant drug-drug interactions between ART and immunosuppressive agents.

Membranoproliferative glomerulonephritis in patients with HIV/HCV co-infection: HIV/HCV co-infection increases the risk for CKD [Wyatt et al. 2008; Fischer et al. 2010]. Antibodies to HCV can induce immune complex glomerular disease and MPGN. However, relatively few cases of MPGN have been reported in patients with HIV, suggesting other associations between HCV and CKD.

The decision to initiate anti-HCV therapy for HCV and MPGN is often simplified by the fact that therapy is indicated for the liver disease, irrespective of cryoglobulinemia, and a kidney biopsy is not necessary to confirm the clinical suspicion of MPGN. A more difficult decision arises when anti-HCV therapy is ineffective and the kidney disease remains active. In this setting, a kidney biopsy should be obtained to confirm the diagnosis. If MPGN is present, the patient should be referred to a nephrologist for treatment.

References

Ahuja TS, Grady J, Khan S. Changing trends in the survival of dialysis patients with human immunodeficiency virus in the United States. J Am Soc Nephrol 2002;13:1889-1893. [PubMed]

AIDSinfo Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents. 2014 May 1. https://aidsinfo.nih.gov/guidelines/html/1/adult-and-adolescent-arv-guidelines/44/arv-dosing-for-renal-or-hepatic-insufficiency

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HIV Medication Adjustments

Medical Care Criteria Committee, September 2012

RECOMMENDATIONS
ARV Dose Adjustment
  • Clinicians should determine whether dose adjustments are required for certain antiretroviral agents or whether patients should avoid use of certain agents when glomerular filtration rate reaches ≤50 mL/min; recommendations for such considerations are provided in the text. (A3)
Tenofovir

For taking ART regimens that include tenofovir, clinicians should:

  • Estimate glomerular filtration rate at initiation of therapy, 1 month after initiation of therapy, and at least every 4 months thereafter (B2)
  • Adjust tenofovir dosing when glomerular filtration rate approaches 50 mL/min or discontinue tenofovir according to clinical status (A2)
  • Withhold tenofovir until all potential causes have been determined in patients who develop acute renal failure (B2)
NSAIDS
  • Clinicians should assess for use of nonsteroidal anti-inflammatory drugs (NSAIDs) in patients with HIV who have  declining renal function. Decisions about the use of such agents for these patients should be individualized and patients should be educated about the importance of using these drugs with caution. (B2)

When GFR approaches levels that suggest the need for ART dose adjustments, the decision to make adjustments should be based on trends in serum creatinine levels over time and on clinical judgment. Dose modification of antiretroviral agents may be necessary when GFR is chronically reduced. Nucleoside/nucleotide agents that are cleared renally (i.e., zidovudine, stavudine, didanosine, lamivudine, emtricitabine, and tenofovir) require dose modification when GFR is reduced. Combination pills that contain these nucleosides/nucleotides should not be used in patients with reduced GFR because the individual components require separate dosing regimens. See AIDS info.gov for ART dosing recommendations in patients with renal or hepatic insufficiency).

Tenofovir

Tenofovir-associated kidney disease is characterized either by a decrease in GFR or by tubule dysfunction, such as Fanconi syndrome (tubular injury with hypophosphatemia, euglycemic glycosuria, tubule proteinuria, uric acid wasting, and aminoaciduria). For prescribing information, see the FDA label.

For patients receiving a tenofovir-containing ART regimen, GFR should be assessed at initiation of therapy, 1 month after initiation of therapy, and at least every 4 months thereafter. Product labeling recommends routine monitoring of serum phosphate levels, but there is little evidence to suggest that serum phosphate is a sensitive or specific marker of tubule dysfunction, nor is it a more sensitive indicator for tenofovir-associated renal dysfunction than measuring GFR (serum creatinine) alone. There are insufficient data to support tenofovir dose adjustment or discontinuation based on low serum phosphate alone. However, the combination of reduced GFR and hypophosphatemia is highly suggestive of tenofovir-associated renal dysfunction, and tenofovir should be dose-adjusted according to GFR or discontinued according to clinical status. Concomitant use of nephrotoxic agents should be avoided in these circumstances.

As an initial regimen, tenofovir is relatively contraindicated in patients with preexisting kidney disease and GFR levels near 50 to 60 mL/min. Tenofovir should be dose-adjusted when GFR approaches 50 mL/min. Both the renal and nonrenal safety profiles, as well as the efficacy, of alternative regimens play an important role in the decision to switch regimens. The decision to continue treatment in patients with gradually decreasing GFR and CKD, such as in patients with hypertension or diabetes, is more complex and should be individualized. The underlying cause of kidney disease should be considered, as should the likelihood that kidney function may stabilize or improve after stopping tenofovir. When patients develop ARF while receiving tenofovir, the drug should be withheld until all potential causes have been determined.

NSAIDs

Use of NSAIDs, which is common among patients with HIV who have pain syndromes, may exacerbate kidney disease. NSAID use should be assessed, and these agents should be used with caution, in the setting of declining renal function.

All Recommendations

Medical Care Criteria Committee, September 2012

ALL RECOMMENDATIONS: KIDNEY DISEASE GUIDELINE
Introduction
  • Clinicians should:
    • Inform and educate patients with HIV about the associations between HIV and kidney disease (B3)
    • Routinely assess kidney function in patients with HIV (A3)
    • Counsel patients with HIV-associated nephropathy about the increased urgency of initiating ART (A2)
    • Assess whether dose adjustments or discontinuation of renally cleared ART medications are necessary when a patient’s glomerular filtration rate reaches ≤50 mL/min (A3)
Patient Education
  • Clinicians should educate patients about the following: (B3)
    • The association between HIV and kidney disease
    • The role of ART in preventing HIVAN
    • Importance of routine monitoring appointments to assess for other causes of kidney disease
Routine Screening
  • Clinicians should routinely assess kidney function in all patients with HIV. A renal assessment should include:
    • Glomerular filtration rate estimated from serum creatinine (baseline and at least every 6 months) (A2)
    • Blood urea nitrogen (baseline and at least every 6 months) (A3)
    • Urinalysis, total protein, and albumin (baseline and at least annually) (A3)
    • For patients with diabetes and no known proteinuria: calculation of urine albumin-to-creatinine ratio to detect microalbuminuria, at baseline and at least annually (A1)
Patients Taking Tenofovir
  • For patients receiving a tenofovir-containing regimen, clinicians should estimate glomerular filtration rate at initiation of therapy, 1 month after initiation of therapy, and at least every 4 months thereafter.
Diagnostic Evaluation
  • All patients with borderline glomerular filtration rate, regardless of age, should undergo the following diagnostic evaluation of kidney function: (A2)
    • Urinalysis to screen for cells and cellular casts
    • Quantification of urinary protein excretion
    • Renal sonogram
    • Careful physical examination
Referral to Nephrologist
  • Primary care clinicians should refer patients to a nephrologist when: (A2)
HIV-Associated Nephropathy
  • In circumstances when a kidney biopsy is not performed for a patient with HIV and kidney dysfunction, because of contraindication, clinician judgment, or patient preference, the following diagnostic criteria for HIV-associated nephropathy are reasonable: (B3)
    • No other explainable cause(s) of kidney disease and
    • Proteinuria of >2000 mg and
    • Normal to large echogenic kidneys on sonogram and
    • Black race
  • For patients with empirically diagnosed HIV-associated nephropathy whose kidney disease worsens after initiation of ART, a biopsy should be performed to determine the underlying cause. (A3)
Treatment
  • Patients with low-grade proteinuria and/or slightly decreased glomerular filtration rate should receive ART if not already receiving it, an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker, and careful monitoring of kidney function.
  • Clinicians should consult with a nephrologist when managing patients who are approaching end-stage renal disease due to stage 4 to 5 chronic kidney disease (see Table 1. Stages of Chronic Kidney Disease) and require special interventions for hyperparathyroidism, anemia, hemodialysis vascular access, peritoneal dialysis, and/or kidney transplant options. (A2)
Use of ART to Prevent Progression
  • Clinicians should educate patients with HIV-associated nephropathy about the increased urgency of initiating ART. (A2)
Management of Comorbidities
  • Clinicians should treat hyperglycemia, dyslipidemia, anemia, and hypertension in patients with HIV and kidney disease according to standard guidelines for patients who do not have HIV. (A1)
  • Normotensive patients with HIV and kidney disease should receive angiotensin-converting enzyme inhibitors or angiotensin receptor blockers according to standard guidelines for patients who do not have HIV. (A1)
Referral to a Nephrologist

Clinicians should refer patients with HIV who have kidney disease to a nephrologist when:

  • Considering management with steroids, immunosuppression, hemodialysis, or transplantation (A3)
  • A diagnosis of membranoproliferative glomerulonephritis has been made in a patient who also has hepatitis C infection. (A3)
ARV Dose Adjustment
  • Clinicians should determine whether dose adjustments are required for certain antiretroviral agents or whether patients should avoid use of certain agents when glomerular filtration rate reaches ≤50 mL/min; recommendations for such considerations are provided in the text. (A3)
Tenofovir

For taking ART regimens that include tenofovir, clinicians should:

  • Estimate glomerular filtration rate at initiation of therapy, 1 month after initiation of therapy, and at least every 4 months thereafter (B2)
  • Adjust tenofovir dosing when glomerular filtration rate approaches 50 mL/min or discontinue tenofovir according to clinical status (A2)
  • Withhold tenofovir until all potential causes have been determined in patients who develop acute renal failure (B2)
NSAIDS
  • Clinicians should assess for use of nonsteroidal anti-inflammatory drugs (NSAIDs) in patients with HIV who have  declining renal function. Decisions about the use of such agents for these patients should be individualized and patients should be educated about the importance of using these drugs with caution. (B2)