A PowerPoint presentation for the pediatric residents and pediatric nephrology fellows

1. S L I D E 0
Nephrotoxins and drug interactions
Ibrahim Sandokji

2. S L I D E 1
15 y/o male presents with back pain and malaise. He took
ibuprofen and naproxen last week. No fever. Normal urine
output. Normal BPs. No edema. Serum creatinine 3.6
mg/dL.
The most likely finding on urinalysis would be:
a) 1+ heme, 1+ LE, >100 WBC/hpf
b) Bland urine with trace protein
c) Dysmorphic RBCs, RBC casts, heavy protein
d) Muddy brown casts, debris

3. S L I D E 2
ABP Content Specifications
• Nephrotoxins and drug interactions:
– Know common nephrotoxins, their mechanisms of
nephrotoxicity, and their clinical manifestations
– Know the natural history of kidney injury caused by
common nephrotoxins
– Recognize drugs that potentiate nephrotoxicity
– Know the management of different types of
nephrotoxicity
• Nephrotoxic Injury Negated by Just-in-time Action (NINJA)

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Kidney Vulnerability
• Final pathways for xenobiotics excretion (particularly, hydrophilic
drugs)
• Proximal tubular cells possess specific secretory pathways -> high
concentrations during transcellular transport -> cytotoxicity
• Large amount of energy consumption. Alterations of blood supply -
> profound cellular damage
• Large amount of oxygen requirement -> high susceptibility to
oxidative stress
• Several medications alter renal hemodynamics -> ischemic damage
• Some drugs are highly concentrated in the tubular lumen and can
crystallize -> obstructive nephropathy

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Natural History of Nephrotoxic-induced AKI
• Usually non-oliguric AKI
• Typically dose-dependent (except AIN which is
idiosyncratic) and more likely to occur with
nephrotoxin combinations
• Urinalysis is often bland
• Might see WBCs & possibly eosinophils in the
urine
• Recovery after removing offending agent(s)

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Acyclovir
• Nephrotoxicity can be seen in 17–35% of children receiving IV
acyclovir. (Rao 2015)
Mechanism of toxicity:
• Rapidly excreted in the urine (both filtered and secreted)
• Crystallization in tubular lumen -> obstructive nephropathy
• Direct tubular toxicity
• Transported by shared organic acid transporters with certain beta-
lactam antibiotics (particularly ceftriaxone) -> increase
nephrotoxicity risk

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Acyclovir
• Prevention of nephrotoxicity:
– Optimize hydration
– Administer over 1–2 hours
– Adjust dose if decreased renal function
– Avoid concurrent nephrotoxic medication exposure

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Amphotericin B
• AKI occurs in 49–65% of adult receiving amphotericin B
Mechanism of toxicity:
• Direct distal tubular toxicity: affect ergosterol in the epithelial cell
membrane -> forms pores in the epithelial cell membrane
• Renal vasoconstriction
• Increased tubular membrane permeability lead to hypokalemia,
hyponatremia, acidosis & hypomagnesemia
• Risk factors:
– Cumulative dose
– Treatment duration
– Dosing schedule
– Dehydration
– Concomitant diuretics or other nephrotoxic drugs
– Impaired glomerular filtration at baseline

10. S L I D E 9
Amphotericin B
• Lipid formulations of amphotericin B (liposomal, lipid complex,
colloidal dispersion):
• A European multicenter prospective open-label study with 134
adults and 204 children with fever and neutropenia compared the
use of liposomal and conventional amphotericin B:
– Similar efficacy, defined as resolution of fever in 3 consecutive days &
recovery of neutrophils
– Nephrotoxicity (doubling of baseline creatinine) occurred in 3% of
liposomal amphotericin, compared to 23% of conventional
amphotericin B group (P<0.01)
– Time to develop nephrotoxicity was longer in liposomal amphotericin
than amphotericin B (P<0.01) and severe hypokalaemia was observed
less frequently in liposomal amphotericin (P<0.01)
Prentice 1997

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Aminoglycosides
Mechanism of toxicity:
• In the kidney, aminoglycosides exclusively accumulate in proximal
tubular cells via endocytic pathways -> transported to the
endosomal compartment -> accumulates in the lysosomes ->
secretory pathway to the Golgi apparatus and ER
• ER stress: disruption of normal protein folding -> accumulation of
misfolded and unfolded proteins induces their aggregation and
subsequent cytotoxicity -> acute tubular necrosis
• Destabilize intracellular membranes -> redistribution of the drug
throughout the cytosol -> acts on the mitochondria -> induce
apoptosis
• In the lysosomes, aminoglycosides bind to phospholipids ->
inhibition of phospholipase activity -> phospholipid accumulation -
> tubular cell death

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Aminoglycosides
• Factors associated with increased risk of nephrotoxicity:
– Drug dosage
– Duration of administration
– Dosing interval
– Preexisting renal disease
– Dehydration
– Hepatic dysfunction
– Sepsis
– Concomitant nephrotoxic and diuretic drugs Patzer (2008)
• Cochrane review of 13 RCT showed:
• Once- and three-times-daily equally effective in CF pulmonary
exacerbations
• The percentage change in creatinine significantly favoured once-
daily treatment in children, MD -8.20 (95% CI -15.32 to -1.08), but
showed no difference in adults, MD 3.25 (95% CI -1.82 to 8.33).
Smyth AR (2010)

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Vancomycin
• Nephrotoxicity occurs in 12–43% of adults treated with
vancomycin. (Rybak 2009)
Mechanism of toxicity:
• Proximal renal tubular cells are the main nephron segment
impaired by vancomycin
• Energy-dependent transport of vancomycin from the blood to the
proximal tubular cells across the basolateral membrane
• Exposure to high doses over long time -> oxidative stress and
mitochondrial damage

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Vancomycin
• Factors associated with increased risk of nephrotoxicity:
– Drug dosage
– Duration of administration
– Preexisting renal disease Patzer (2008)
– Critical illness
– Concomitant nephrotoxic
• A retrospective chart review in NICU
• AKI occurred in 2.7% of patients
(increase in SCr of at least 0.5 mg/L
or an increase of at least 100% from
lowest trough previously available)
Bhargava (2017)
Fit plot between vancomycin trough concentrations and post vancomycin creatinine.
The plot depicts a positive co-relation between the two parameters

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Calcineurin Inhibitor (Cyclosporin A)
• Acute toxicity (reversible):
– Afferent arteriolar vasospasm
– Renal hypoperfusion and decreased GFR
– Reversible with decrease the dose or discontinuation
• Tubular toxic effects:
Renal cell apoptotic mechanisms of CyA-induced

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Calcineurin Inhibitor (Cyclosporin A)
• CNI Nephropathy:
– Proximal tubular injury -> tubular atrophy
– Diffuse interstitial fibrosis or striped interstitial fibrosis
– Arteriopathy: constrictive proliferation with mucoid thickening
and arterial hyalinosis

17. S L I D E 16
CNI Nephropathy
(a) proximal tubular epithelial cell showing the fine isometric vacuoles; (b) typical striped fibrosis pattern (c) an afferent
arteriole showing the characteristic nodular hyaline arteriosclerosis; (d) similar nodule in a non-afferent arteriole

18. S L I D E 17
Calcineurin Inhibitor
• Tacrolimus
– Similar side effect profile
– Less cosmetic effects
• Gingival hyperplasia
• Hirsutism
– Less hyperlipidemia
• In a Prospective study of 41 patients divided
• Hirsutismus and gingival hyperplasia were seen in 10%, and 15% of
CsA group, while it wasn’t observed at all in the Tac group
• No difference in nephrotoxicity or hepatotoxicity
(Ozan 2013)

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NSAIDs

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NSAIDs
Medical Pharmacology, TMWeb, Tulane University

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NSAIDs
• Case series of 7 children aged 13–17.5 years developed AKI after
treatment with various NSAIDs
– (6/7) used more than one kind of NSAID
– 1 to 4 days between NSAID use and symptoms
– Flank pain (4/7), abdominal pain (3/7), and vomiting (3/7)
– All patients had nonoliguric AKI
– Microscopic hematuria and proteinuria (5/7) patients
– Biopsy done in three patients:
• Mild interstitial inflammation in one patient
• Normal in two patients
– All patients were treated with intravenous fluids
• One patient received corticosteroids
– Renal function was completely normalized in all patients within 7–16
days
Krause 2005

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Acute Interstitial Nephritis
• Usually present with rise in sCr and non-specific symptoms
• Nausea, vomiting, malaise, back/flank pain, or asymptomatic
• Allergic-type symptoms like fevers, rash, peripheral eosinophilia
• UA: WBC casts, hematuria, mild proteinuria, or bland urine
• Non-Oliguria AKI, tubular dysfunction and even Fanconi syndrome
• Treatment:
– Discontinuation of offending agent
– Rarely might need a biopsy if:
• Unclear diagnosis
• When considering steroid therapy
• Or, if started steroids but no response in one week

23. S L I D E 22
Singh AK, Colvin RB. N Engl J Med 2003;349:2055-2063.
Acute Interstitial Nephritis

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White Blood Cell Casts Red Blood Cell Casts
Hyaline Casts Muddy Brown Granular Casts
Waxy Casts
Fatty Casts

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Low power view of severe acute interstitial nephritis
showing diffuse interstitial inflammatory infiltrate
Inflammatory process predominantly in the interstitium.
Insert shows a higher magnification, with arrows
pointing to eosinophils in the interstitium

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Nephrotoxic Injury Negated by Just-in-time Action (NINJA)
• Automated system using EHR data in patients with 3+ nephrotoxic
medications or 3+ days of IV aminoglycoside exposure

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• 1,749 patients with 2,358 admissions were included. 575 individual
AKI episodes were observed (47% stage 1, 33% stage 2, and 20%
stage 3)
• Nephrotoxic medication exposure rate decreased by 38% (from
11.63 to 7.24 patients/1000 patient days)
Nephrotoxic Injury Negated by Just-in-time Action (NINJA)

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• AKI rates decreased by 64% (from 2.96 to 1.06 patients with
AKI/1000 patient days) during the study period.
Nephrotoxic Injury Negated by Just-in-time Action (NINJA)

29. S L I D E 28
15 y/o male presents with back pain and malaise. He took
ibuprofen and naproxen last week. No fever. Normal urine
output. Normal BPs. No edema. Serum creatinine 3.6
mg/dL.
The most likely finding on urinalysis would be:
a) 1+ heme, 1+ LE, >100 WBC/hpf
b) Bland urine with trace protein
c) Dysmorphic RBCs, RBC casts, heavy protein
d) Muddy brown casts, debris

30. S L I D E 29
Summary

31. S L I D E 30
References
• Avner, et al. Pediatric Nephrology. 2016
• Bhargava, et al. The association between vancomycin trough concentrations and acute kidney injury in
the neonatal intensive care unit. BMC Pediatr. 2017 Feb 11;17(1):50.
• Ekmekçioğlu, et al. Comparison of tacrolimus with a cyclosporine microemulsion for
immunosuppressive therapy in kidney transplantation. Turkish journal of urology. 2013;39(1):16-21.
• Goldstein SL, Mottes T, Simpson K, Barclay C, Muething S, Haslam DB, Kirkendall ES. A sustained
quality improvement program reduces nephrotoxic medication-associated acute kidney injury. Kidney
Int. 2016 Jul;90(1):212-21
• Krause, et al. Acute renal failure, associated with non-steroidal anti-inflammatory drugs in healthy
children. Pediatr Nephrol. 2005 Sep;20(9):1295-8.
• Patzer L. Nephrotoxicity as a cause of acute kidney injury in children. Pediatr Nephrol.
2008;23(12):2159–73.
• Prentice, et al. A randomized comparison of liposomal versus conventional amphotericin B for the
treatment of pyrexia of unknown origin in neutropenic patients. Br J Haematol. 1997;98: 711–718
• Rao, et al. Intravenous acyclovir and renal dysfunction in children: a matched case control study. J
Pediatr. 2015 Jun;166(6):1462-8.
• Rybak, et al. Therapeutic monitoring of vancomycin in adult patients: a consensus review of the
American Society of Health-System Pharmacists, the Infectious Diseases Society of America, and the
Society of Infectious Diseases Pharmacists. Am J Health Syst Pharm. 2009;66(1):82–98.
• Smyth, et al. Once-daily versus multiple-daily dosing with intravenous aminoglycosides for cystic
fibrosis. Cochrane Database Syst Rev. 2014;2.
• Uijtendaal, et al. Once-daily versus multiple-daily gentamicin in infants and children. Ther Drug Monit.
2001;23 (5):506–13.
• Vandecasteele, et al. Recent changes in vancomycin use in renal failure. Kidney Int. 2010;77(9):760–4.

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Extra Slides

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Classification of nephrotoxic medications
Pathophysiology Drugs known to cause acute kidney injury
Prerenal
NSAIDs, ACE inhibitors, cyclosporine A (CyA), norepinephrine, AT2-
receptor antagonists, diuretics, interleukins, cocaine, mitomycin C,
tacrolimus, estrogen, quinine
Acute tubular
necrosis
Antibiotics: aminoglycosides, cephalosporins, amphotericin B,
rifampicin, vancomycin, foscarnet, pentamidine
NSAIDs, glaphenin, contrast media, acetaminophen, CyA, cisplatinum,
immunoglobulin, dextran, maltose, sucrose, mannitol, heavy metals
Acute interstitial
nephritis
Antibiotics: ciprofloxacin, methicillin, penicillin G, ampicillin,
cephalosporins, oxacillin, rifampicin
NSAIDs, glaphenin, acetylsalicylic acid (ASA), fenoprofen, naproxen,
phenylbutazone, piroxicam, tolmetin, zomepirac, contrast media,
sulfonamides, thiazides, phenytoin, furosemide, allopurinol,
cimetidine, omeprazole, phenindione
Tubular
obstruction
Sulfonamides, methotrexate, methoxyflurane, glaphenin, triamterene,
acyclovir, ethylene glycol, protease inhibitors
Hypersensitivity
angiitis
Penicillin G, ampicillin, sulfonamides
Thrombotic
microangiopathy
Mitomycin C, CyA, oral contraceptives