This case involves a 7-year-old female presenting with acute renal failure, facial swelling, and hematuria. She had been treated for malaria and pneumonia in the past month. Her creatinine was elevated at 1711 umol/L, indicating severe acute renal injury. Possible causes of her acute renal failure include an allergic reaction to antibiotics like gentamicin or cephalosporins, or nephrotoxicity from multiple antibiotic exposures over the past month. Her renal failure should be managed by discontinuing any nephrotoxic medications, aggressive hydration, and monitoring of her renal function.

1. Acute Renal Failure and
Drug-Induced Nephrotoxicity
Case Presentation
Joseph O. Oweta Intern Pharmacist ( MNRRH)
Karen Ng, BScPharm, ACPR, UBC PharmD Candidate
April 4, 2013

2. Case: NJ
• ID: NJ, 12 yofemale; ~40 kg
• PC: Fever, hematuria, facial swelling x 2 wks
(worse in morning)
• HPI:
– Unwell since 3 wks ago, high grade persistent fever
– Taken to clinic, diagnosed with malaria
– Self referral to Naguru hospital after vomiting 6-7x/d
– At Naguru hospital, treated for bronchopneumonia
and malaria  frequency of vomiting reduced
– Decreased urine output

3. Case: NJ
• NKDA
• Meds PTA:
– Ceftriaxone 1 g IV x 2
– Gentamicin 2 doses
– Hydrocortisone
– Cefixime
– Atemisinin/lumefantrines
– Salbutamol
– Paracetamol

4. Case: NJ
• PMHx:
– SVD
– Birth weight ¬5 kg; delivered in clinic
– Breastfed for 5 months then started on soft feeds.
Has been feeding well
– Immunizations UTD
– Normal growth and development
– P3 pupil, last born of 6 children, elder siblings
alive and well

5. Case: Physical Exam
Vitals T 35.8oC, HR 88, BP 110/75, RR 35
HEENT Facial swelling since 2 weeks ago; severe in the morning, reduces
throughout day
CNS Fully conscious, no focal neurological deficits
CVS S1, S2 normal; no added sounds
Resp No distress, bronchovesicular breath sounds
GI Soft, liver 3 cm below costal margin, no splenomegaly, no renal
angle tenderness
Lower abdo pain: severe, persistent
Poor appetite, no diarrhea, previous vomiting
GU Hematuria, ?reduced urine output, normal frequency (5x/day), no
dysuria

6. Case: Labs (Mar 20, 2013)
• CBC: WBC 9.97 Neut 6.57, Hgb 5.8 g/dL, Plt 624
– RBC 2.29, HCT 17.3%, MCV 75.5 fL, MCH 25.3 pg, MCHC 33.5 g/dL,
RDW-CV 16.4%
– Severe anemia, thrombocytosis
• Liver: Alb 36.6, ALT 5.3, AST 21.5, Bili: 2.3, GGT: 26.8, Total
protein 74.3
• Amylase: 69.9
• Renal: SCr 1711 umol/L, Cl: 89.8, K: 7.57, Na: 127.5, BUN: 51.2
mmol/L
• ASO ver. 2 (specific proteins) : 279.30 IU/mL (ref: 0.00-200.00)
– Mar 25
• No MPS

7. Case: Laboratory Summary
Mar 20, 2013 Mar 25, 2013
CRE 1711 394
Na 127.5 133
K 7.57 4.07
Hb 5.8 8.2

8. Case: diagnostics
• Abdo U/S (Mar 19, 2013)
– Kidneys: increased echogenicity with scarring of renal
cortex
– Bladder normal
– Uterus normal
– Liver/spleen normal
– Bowel loops normal
– U/S scan findings suggestive of renal parenchymal
disease
• Urinalysis
– Normal colour

9. Case: Diagnosis
• Diagnosis:
– Acute glomerular nephritis
– R/O nephrotic syndrome
– Severe anaemia secondary to haematuria?
– UTI??

10. Case: Treatment
• Admit to acute care unit
• Transfused x 1
• Abx
– Ceftriaxone 1 g IV q24h (Mar 20- 25)
– Prednisolone 10 mg po bid x 1 wk (Mar 20-26)
– Ampicillin 500 mg IV q6h (Mar 25-
• Paracetamol 500 mg potds x 3d)
• Folic acid 10 mg po daily x 1 month
• Multivitamins 10 mg po daily x 1 wk

11. Case: NJ
Summary:
7 yo female with 3 weeks hx of vomiting 2 wks
of body swelling starting with facial swelling that
resolves with increasing hours of day, 10 days
lower abdo pain with hematuria, presenting
with acute renal injury

12. Case:
Questions to Consider
• What is the etiology of NJ’s acute renal
failure? What are possible drug causes?
• How should NJ’s acute renal failure be
managed?
• Considering possible drug causes, which are
the most likely in NJ’s case?

13. Objectives
1. Define acute kidney injury (AKI).
2. Understand the stages of AKI based on RIFLE classification
systems.
3. Be familiar with the three pathophysiological categories of
AKI and some of the etiologies behind the three major
categories.
4. State the 3 types of intrinsic acute renal failure and the
related drug causes
5. Describe the mechanisms of drug-induced nephrotoxicities
specifically relating to acute renal failure
6. Identify patients at risk for renal injury and strategies for
prevention.

14. Acute Kidney Injury (AKI)
• Abrupt and sustained decrease in renal
function resulting in retention of nitrogenous
(urea and creatinine) and non-nitrogenous
waste products

15. The Kidney is Vulnerable
• Responsible for excretion of many drugs
• Routinely exposed to high concentrations of
drugs and metabolites
• Nephrotoxins can accumulate
– Kidney is highly vascular
– Reabsorption of glomerular filtrate increases
intraluminalnephrotoxin concentrations

16. KDIGO Definition of AKI
KDIGO = Kidney Disease: Improving Global Outcomes
• An increase in serum creatinine of ≥ 0.3 mg/dL ≥26.5
μmol/L (0.3 mg/dL ) within 48 hours
• An increase in serum creation of ≥1.5 times baseline,
which is known or presumed to have occurred within
the prior 7 days
• Urine volume <0.5 mL/kg per hour x> 6 hours
Kidney IntSuppl 2012; 2:8

17. RIFLE Classification of AKI Severity

18. Can you classify NJ’s AKI based on
RIFLE staging systems? What
information do you need?
• Missing information:
– Urine output
– Serial/repeat SCr

19. What are the four drug-related renal
syndromes?
• Drugs can cause four major renal syndromes:
1. Acute renal failure
2. Nephrotic syndrome
3. Renal tubular dysfunction with renal potassium
wasting and acidosis
4. Chronic renal failure

20. Etiology of Acute Renal Failure
• Pre-renal causes
• Intrinsic causes
• Post-renal causes

21. Etiology of Acute Renal Failure
Pre-renal •Underperfusion of otherwise normal kidney
•Quickly reversible with appropriate therapy
•Continued renal hypoperfusion can progress to
intrinsic renal failure
Intrinsic •Disease of the renal parenchyma
•Most often caused by renal hypoperfusion or
ischemia, endogenous and exogenous nephrotoxic
substances
Post-renal •Obstructions within urinary tract (e.g. blood clots,
stones)
•Extrinsic obstructions (e.g. tumors, retroperitoneal
fibrosis)

23. http://www.clevelandclinicmeded.com/medicalpubs/diseasemanagement/nephrology/acute-kidney-injury/

24. Evaluation of Etiology of AKI
• Findings that suggest prerenal causes:
– Volume depletion or shock states
– Congestive heart failure
– Severe liver disease or other edematous states
• Findings that suggest intrinsic renal disease
– Exposure to nephrotoxic drugs or hypotension
– Recent radiographic procedures with contrast
• Findings that suggest postrenal causes
– Palpable bladder or hydronephrotic kidneys
– Enlarged prostate
– Abnormal pelvic examination
– Large residual bladder urine volume
– History of renal calculi

25. Evaluationof AKI
Patients at Risk
Pre-renal AKI •Patients with compromised renal blood flow
•Bilateral renal artery stenosis
•Patients with decreased effective circulatory volume
•Cirrhosis
•Nephrotic syndrome
•Heart failure
Intrinsic AKI •Exposure to nephrotoxic drugs (see intrinsic AKI slides)
Post-renal
AKI
•Severe volume depletion
•Underlying renal insufficiency
•Bolus drug administration
•Metabolic disorders (e.g. metabolic acidosis or
alkalosis)

26. Drug Causes of AKI
Pre-renal AKI •Drugs may reduce volume or pressure or both of
blood delivered to kidney
•Diuretics, radiocontrast media, cyclosporine,
tacrolimus, NSAIDs, interleukin-2, ACEI
Intrinsic AKI •(see intrinsic AKI slides)
Post-renal
AKI
•Crystal formation: acyclovir,
sulfonamides,methotrexate, indinavir, triamterene,
vitamin C in large doses

27. Urinary Findings of AKI
Pre-renal AKI •Low urine volume and sodium excretion
•High osmolality
•Urine sediment usually without casts, RBC, WBC,
protein
Intrinsic AKI •(see intrinsic AKI slides)
Post-renal
AKI
•Urine sediment may contain RBC, WBC, crystals

28. What are the possible causes ofNJ’s
AKI?
• Prerenal: decreased fluid intake?
• Intrinsic:
– Allergic reaction to antibiotic
– Nephrotoxic antibiotics
• Postrenal: ultrasound did not demonstrate
obstruction

29. Prerenal/ Volume Responsive AKI
• Etiology:
– Renal losses
– GI losses
– Fluid sequestration, inadequate perfusion pressures
• Capillary leak (sepsis)
• Hypoalbuminemic states
– CHF
– Cirrhosis, splanchnic vasodilation, hypoalbuminemia
– Impaired renal autoregulation
• ACEI/ARBs
• Contrast, calcineurin inhibitor, ampho B, vasopressors
(osmotic vasoconstriction off AA)
• NSAIDs
• Vascular disease exacerbation

30. Prerenal/ Volume Responsive AKI
• Diagnostics
– Pre-renal urine biochemistry
• Hyaline casts or granular casts, bland sediment
• Increased osmolality> 500
• Decreased sodium
• Decreased fractional excretion of sodium, urea, uric
acid, lithium
• SCr:BUN< 12.4 signals pre-renal

31. What are the 3 types of intrinsic ARF?
1. Acute tubular necrosis (ATN)
2. Acute intrinsic nephritis (AIN)
3. Thrombotic microangiopathy

32. Differentiation Between ATN and AIN

33. Intrinsic AKI
Mechanisms of Injury
Acute Tubular
Necrosis
•Direct tubular toxicity
•Deranged cellular energy production
•Free radical injury
•Heme tubular toxicity
•Abnormal phospholipid metabolism
•Intracellular calcium toxicity
•Usual sites of injury: early or late segments of proximal tubule
Acute Allergic
Interstitial
Nephritis

34. Acute Tubular Necrosis
Aminoglycosides ATN
– Gradual increase SCr after 5-10 days
– Tubular epithelial cell damage leading to obstruction
of tubular lumen
– Non-oliguria >500 mL/day; granular casts in urine
– Risk factors:
• Combination with other nephrotoxic drugs
• Total cumulative dose; trough levels >2 mg/L
• Repeated courses of A/G
• Prolonged therapy >10 days
• Dehydration
– Management: reversible if D/C drug, adequate
hydration, monitor levels

35. Acute Tubular Necrosis
Ampho B ATN
– Direct tubular epithelial cell damage; binds to cell wall
resulting in increased tubular permeability and necrosis
– Increased SCr, BUN, decreased Mg, K (urine wasting)-
monitor q1-2d
– Distal RTA, polyuria (nephrogenic DI)
– Risk factors:
• Combo with other nephrotoxic drugs
• Total cumulative dose; daily dose > 0.5 mg/kg/day
• Dehydration
– Management: reversible if D/C drug, hydration (1L NS
daily)
– All lipid-based preps decrease occurrence of
nephrotoxicity

36. Acute Tubular Necrosis
Radiographic Contrast Media  ATN
– Onset within 12-24 hr, SCr peaks 2-5 days after
exposure, recovery usually after 4-10 d
– Direct tubular necrosis, renal ischemia
– Typically non-oliguric
– Urinalysis: hyaline and granular casts, low FENa
– Risk factors: DM, CKD, prestudy dehydration
– Management: low-osmolality nonionic contrast
agents, smallest dose, hydration

37. Acute Allergic Interstitial Nephritis
• Clinical presentation:
– Systemic manifestations of hypersensitivity
reaction (e.g. fever, rash, arthralgias)
– Onset after drug exposure:
• 1st exposure: as long as several weeks
• 2nd exposure: 3-5 days
• As short as 1 day after rifampin
• As long as 18 months with NSAIDS

38. Acute Allergic Interstitial Nephritis
Implicated Drugs:
• Penicillins
• Cephalosporins
• Cocaine
• Sulfonamides
• NSAIDs
• Diuretics
• Lithium
• Phenytoin
• Valproic acid
• Amphotericin B
• Streptokinase
• 5-aminosalicylates
• Allopurinol
• Rifampin
• Some Chinese herbs

39. Acute Allergic Interstitial Nephritis
• Urinary Findings:
– Urinalysis:
• WBC, RBC, white cell casts
• Fractional excretion of sodium often >1%
• Protein excretion usually mild
• Eosinophilia or eosinophiluria present >75% of cases
• Diagnosis:
– Diagnosis confirmed only by kidney biopsy
– Biopsy indicated only if renal failure progresses or
persists despite stopping the offending drug

40. Acute Allergic Interstitial Nephritis
Treatment
• Stop the offending drug
• Steroid therapy if renal failure persists
– Prednisone 1-2 mg/kg/day PO x 4-6 weeks
• Cyclophosphamide if recovery not seen after
trial of prednisone

41. Thrombotic Microangiography
• Clinical presentation:
– Fever, hemolytic anemia, thrombocytopenia, renal
dysfunction, CNS abnormalities, TTP
– Pathologic hallmark: hyaline thrombi in microvasculature
of many organs
• Changes in kidney:
– Afferent arterioles
– Glomerular thrombosis
– Thickening of glomerular capillary wall
• Drugs implicated:
– Cyclosporin, tacrolimus, chemotherapeutic agents,
ticlopidine, clopidogrel, estrogen-containing
contraceptives, quinine, cocaine

42. Post-Renal Nephropathy
• Rhabdomyolysis
– Intratubular precipitation of myoglobulin
– Prevention: hold statin while on clarithro/erythro or
itraconazole
• Drug-induced crystalluria
– Drug insoluble in urine crystallizes in distal tubule
– Risk factors:
• Decreased circulating volume
• Renal dysfunction
• Acid or alkaline urine pH
– Prevention:
• Dose adjustment for renal failure
• Volume expansion to enhance urinary output
• Urinary alkalinization (for weak acids)

43. Post-Renal Nepropathy
• Implicated Drugs:
• Methotrexate
– Weak acid- precipitates in acidic urine (pH < 7)
– Precipitation of MTX and its metabolites in renal tubules
– High dose MTX (12-15 g/m2)
– Prevention:
» Diuresis- U/O 100-200 mL/h x 24h post-high dose MTX
» Urinary alkalinization (sodium bicarb 25-59 mEq/L
hydration fluid)

44. Post-Renal Nepropathy
• Implicated Drugs:
• Acyclovir
– Weak acid and weak base
– Intratubular precipitation of acyclovir in dehydrated oliguric
patients
– Needle-shaped crystals
– Risks/Prevention
» IV- too fast infusion rate- infuse over 1 h
» High dose > 500 mg/m2
» Dehydration- IV NS
» Pre-existing renal failure- adjust dose
» Other nephrotoxins

45. Post-Renal Nepropathy
• Implicated Drugs:
• Indinavir
– Weak base- precipitates in alkaline urine
– Crystal nephropathy, dysuria, urinary freq, rectangular cystals
– Risk/Prevention:
» Severe volume depletion
» Recipitation prevented by consumption of ~2L fluid/d

46. Post-Renal Nepropathy
• Implicated Drugs:
• Sulphonamides
– Weak acid- precipitates in acidic urine
– Higher doses
– More common with sulfadiazine
– Risk/prevention:
» Volume depletion- maintain good fluid intake
» Renal dysfunction- adjust dose
» Urinary alkalinization (treatment)

47. Back to the case…

48. What are NJ’s drug therapy problems
associated with AKI?
• NJ’s acute renal failure may be secondary to drug-
induced nephrotoxicity and requires reassessment of
drug therapy.
• NJ requires assessment of drug therapy to optimize
hemodynamics and other strategies to prevent
further renal injury and promote resolution of AKI.

49. What are the General
Goals of Therapy for AKI?
1. Survive the insult
2. Prevent further damage/insult
3. Prevent/treat complications
4. Regain life-sustaining renal function
5. Minimize adverse effects of drug therapy

50. What are your specific
goals of therapy?
• Hemodynamics optimization
– Maintain MAP > 60
– Establish and maintain euvolemia
• Appropriate antibiotic and antifungal therapy to
treat sepsis (treating the underlying cause)
• Discontinue nephrotoxicagents
• Avoid further insults
• Electrolyte management
• Allow renal function to recover

51. Principles of Therapy
• Prevention of AKI
• Optimization of hemodynamic status
– Appropriate fluid therapy
– Vasopressors/ inotropes
• Treatment of underlying medical condition:
sepsis, hemorrhage
• Discontinuation nephrotoxic medications
• Adjust medication dosing

52. What is the pharmacotherapeutic
plan?
• Optimize hemodynamics and maintain renal perfusion
– Reassess fluid status
• If fluid overloaded, minimize fluid intake through IVs (Concentrate
meds, meds in NS)
• Cautious trial of furosemide once hemodynamically stable and off
norepinephrine
• Discontinue use of antibiotics NJ has been recently
exposed to
• Discontinue/avoid nephrotoxic agents
• Adjust medication doses for decreased GFR
• If on opioids, consider switching morphine to
hydromorphone or fentanyl

53. A Look Back At How NJ Was Treated
Do You Agree?
• Transfused x1 unit PRBC
• Abx
– Ceftriaxone 1 g IV q24h (~25 mg/kg/d) (Mar 20- 25)
– Prednisolone 10 mg po bid x 1 wk (~0.5 mg/kg/d)
(Mar 20-26)
– Ampicillin 500 mg IV q6h (~50 mg/kg/d) (Mar 25-
• Paracetamol 500 mg potdsx 3d)
• Folic acid5mg po daily x 1 month
• Multivitamins 10 mg po daily x 1 wk

54. Case (update)
• Mar 26: able to pass urine, volumes increased
to 1L/day, non bloody
• Mar 30: Normal urine output, afebrile, mild
pallor, no oedema
• No vomitting, no fever, no swelling
• Discharged Mar 30, 2013; for follow up in
renal clinic in 7 days

55. Drug-Inducted Nephrotoxicity
Key Points
• Pretreatment hydration can reduce nephrotoxic potential
of many drugs
• Renal injury can present as acute renal failure, nephrotic
syndrome, renal tubular dysfunction, or chronic renal
failure
• Early diagnosis is key
• Be aware of nephrotoxic potential of medications
• Be vigilant to exclude drugs as possible causes of renal
disease
• Manage renal failure (replace fluid volume, adjust drug
doses, steroid trials in AIN, avoid repeat exposures)