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Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection

Management of Medication Toxicity or Intolerance

Nephrotoxic Effects

(Last updated: March 1, 2016; last reviewed: March 1, 2016)

Table 12i. Antiretroviral-Therapy-Associated Adverse Effects and Management Recommendations—Nephrotoxic Effects
Adverse Effects Associated ARVs Onset/Clinical Manifestations Estimated Frequency Risk Factors Prevention/ Monitoring Management
Urolithiasis/ Nephrolithiasis ATV, IDV

Although DRV causes crystalluria, it is not associated with increased nephrolithiasis risk.
  • Weeks to months after starting therapy
Clinical Findings:
  • Crystalluria, hematuria, pyuria, flank pain, sometimes increased creatinine
ATV-related nephrolithiasis occurs in <10%. In adults, elevated urine pH (>5.7)

Unknown in children
  • Maintain adequate hydration.
  • Obtain urinalysis at least every 6–12 months.
Provide adequate hydration and pain control; consider using alternative ARV.
Renal Dysfunction TDF Onset:
  • Variable; in adults, weeks to months after initiation of therapy.
  • Hypophosphatemia appears at a median of 18 months.
  • Glucosuria may have onset after a year of therapy.
More Common:
  • Increased serum creatinine, proteinuria, normoglycemic glucosuria. Hypophosphatemia, usually asymptomatic; may present with bone and muscle pain, weakness.
Less Common:
  • Renal failure, acute tubular necrosis, Fanconi syndrome, proximal renal tubulopathy, interstitial nephritis, nephrogenic diabetes insipidus with polyuria
  • Approximately 2% with increased serum creatinine 
  • Approximately 0.5% with severe renal complications
  • Approximately 4% with hypophosphatemia or proximal tubulopathy; higher with prolonged TDF therapy, in advanced HIV infection or concomitant use of ddI
Risk May Be Increased in Children:
  • Aged >6 years
  • Black race, Hispanic/Latino ethnicity
  • Advanced HIV infection
  • Concurrent use of ddI or PIs (especially LPV/r), and preexisting renal dysfunction
  • Risk increases with longer duration of TDF treatment.
Monitor urine protein and glucose or urinalysis, and serum creatinine at 3- to 6-month intervals. For patients taking TDF, some panelists add serum phosphate to the list of routine labs to monitor.

In the presence of persistent proteinuria or glucosuria, or for symptoms of bone pain or muscle pain or weakness, also measure serum phosphate.

Because toxicity risk increases with duration of TDF treatment, frequency of monitoring should not decrease with time. While unproven, routine monitoring intervals of every 3–6 months might be considered. Abnormal values should be confirmed by repeat testing, and frequency of monitoring can be increased if abnormalities are found and TDF is continued.
If TDF is the likely cause, consider using alternative ARV.
Elevation in Serum Creatinine DTG, COBI, RPV Onset:
  • Within a month of starting treatment
  • Asymptomatic. These drugs decrease renal tubular secretion of creatinine, leading to an increase in measured serum creatinine without a true change in GFR.

Need to distinguish between true change in GFR and other causes. True change might be associated with other medical conditions, continuing rise of serum creatinine with time, and albuminuria.
N/A Monitor serum creatinine. Assess for renal dysfunction if serum creatinine increases by >0.4 mg/dL or increases are ongoing with time. No need to change therapy.

Reassure patient about the benign nature of the laboratory abnormality.
Key to Acronyms: ARV = antiretroviral; ATV = atazanavir; COBI = cobicistat; ddI = didanosine; DRV = darunavir; DTG = dolutegravir; GFR = glomerular filtration rate; IDV = indinavir; LPV/r = boosted lopinavir/ritonavir; PI = protease inhibitor; RPV = rilpivirine; TDF = tenofovir disoproxil fumarate


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