9/13/2016

DRUG-INDUCED RENAL
DISEASE
Adam Bursua, Pharm.D., BCPS

Objectives

Describe mechanisms of renal injury of nephrotoxic

drugs
Identify laboratory abnormalities associated with
selected drug-induced renal diseases
Recognize medications that are commonly
associated with various types of drug-induced renal
disease
Recommend appropriate prophylactic interventions
to prevent selected drug-induced renal diseases
Recognize appropriate management for selected
drug-induced renal diseases

Drug Induced Renal Disease

Epidemiology

Community acquired AKI (acute kidney injury)

>500 per 100,000 person years

~20% drug induced

~30 per 100,000 person years will require dialysis

More common in the hospital setting

~20% of admissions for AKI attributable to drugs

AKI occurs is 7% of hospitalized patients

Drugs implicated in ~60% of cases

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Costs of Drug Induced Renal Disease

AKI (inc SrCr > 0.5mg/dl)

6.5 fold increase in odds of death

Increased length of stay by 3.5 days

Examples

AKI from Amphotericin B costs ~ $30,000

Contrast-induced nephropathy (CIN) costs > $10,000
per case

Detection of Drug Induced Renal

Disease

Laboratory
Abrupt increase in serum creatinine, BUN

Other markers of renal injury

Increase of 0.3 in SrCr

50% increase from baseline
Reduced urine output (<0.5mL/kg/hour for > 6 hours)
KIM-1, n-acetyl--glucosaminidase, -glutamyl transpeptidase, others

Symptoms

Volume overload

Malaise
Anorexia
Confusion
Nausea

Shortness of breath, edema

Practical Aspects of Detection of Drug

Induced Renal Disease

Determine a temporal relationship

Recall that SrCr may lag behind kidney insult

Review medications on the days preceding the detection of AKI

SrCR

10/5

10/6

10/7

10/8

10/9

0.8

0.9

0.9

1.1

2.2

2.6

Ask open-ended and directed questions when obtaining

medication history

10/4

What do you use for aches and pains (NSAIDS)?

Have you ever been prescribed enalapril, lisinopril, losartan, etc?

Consider all cases of AKI to be drug-induced until proven

otherwise

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Types of Drug Induced Renal Disease

Hemodynamically
mediated AKI
Tubular Epithelial Cell
Damage
Glomerular Disease
Tubulointerstitial Nephritis
(Acute Interstitial
Nephritis-AIN)
Crystal Nephropathy
Renal vasculitis
Renal Thrombosis and
Cholesterol Embolization

Hemodynamically Mediated Injury

AFFerent arteriole

Afferent

Prostaglandin mediated
vasodilation

NSAIDS decrease PG
synthesis

Efferent

Angiotensin II mediated
vasoconstriction

EFFerent arteriole

ACE-I, ARB block ATII

effects

NSAID Hemodynamic Kidney Injury

AFFerent arteriole

Blood flow
Fluid available
for filtration
-Renal Ischemia

SCr
GFR

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ACE-I/ARB Hemodynamic Kidney Injury

Arteriolar
Pressure

SCr
GFR

GFR

EFFerent arteriole

Risk Factors for ACE-I/ARB and NSAID

Hemodynamic AKI

Similar risk factors to Prerenal renal failure

Reduced renal blood flow

Volume depletion

Caution with concurrent diuretics

Hepatic disease (intravascular volume depletion)

CHF reduced renal blood flow
Bilateral renal artery stenosis-Reduced renal blood flow

Pre-existing kidney disease

Advanced age
Combined ACE-I/NSAID

Prevention/Management of ACE-I/ARB
or NSAID Hemodynamic AKI

Prevention

Avoid use in volume

depleted patients

Consider alternatives

Management

Remember cirrhotics
NSAID vs APAP
ACE/ARB vs other BP med

Suspend use of ACE/ARB

or NSAID

Close monitoring upon

initiation of therapy and
dose titration

Ensure intravascular
volume and renal blood
flow

Weigh risks and benefits

of use for future
consideration

IV fluids
Afterload reduction for
CHF patients

Manage hyperkalemia
(ACE-I/ARB especially)

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Case Study

A 72 y.o. man with hypertension, diabetes, and

osteoarthritis presents the clinic complaining of 2
days of stomach flu. A lab draw reveals a 50%
decline in his CrCl since his last visit this past summer.
His physician sends him to the ED for admission for
acute renal failure. Upon admission you call CVS
pharmacy and find out that he is taking lisinopril 40
mg, hydrochlorothiazide 25 mg, and metformin 500
mg BID.

Hemodynamically Mediated Injury

Calcineurin Inhibitors

Calcineurin inhibitors (tacrolimus, cyclosporine)

Increase thromboxane A2
RAAS and SNS activation
Reduced NO, prostacyclin, prostaglandin vasodilation

Net effect is reduced renal blood flow and GFR

Effects are dose dependent

Management

Close monitoring of levels

Always a balance between toxicity and immunosuppression

Tubular Epithelial Cell Damage

Direct cellular toxicity

Usually localized to proximal or distal tubule

Acute Tubular Necrosis (ATN)

Most common inpatient presentation of drug induced AKI

Proximal: acidosis, glycosuria, low P-K-Mg

Distal: polyuria, acidosis, high K

Many drugs implicated

Aminoglycosides, cisplatin, amphotericin B, foscarnet

Osmotically active agents (eg, IVIG, mannitol)

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Tubular Epithelial Cell Damage

Direct Cellular Toxicity

Tubular Epithelial Cell Damage

Direct Cellular Toxicity

In the case of aminoglycosides, the cationic charge facilitates

uptake into the tubular epithelial cells. Once inside the cell, the
concentrate in lysosomes and lead to cellular death.

Tubular Epithelial Cell Damage

Direct Cellular Toxicity

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Tubular Epithelial Cell Damage

Direct Cellular Toxicity

The determination of the repair response is based

on the extent and duration of the injury.

Aminoglycoside Nephrotoxicity

Common

10-25% of recipients

Toxicity is variable among drugs in the class

Thought to be correlated to the number of cationic

groups

The more positive charges, the greater cellular uptake

neomycin > gentamicin > tobramycin > amikacin

Aminoglycoside Nephrotoxicity
Risk Factors

Drug related
Large cumulative dose
Prolonged therapy
Elevated trough concentrations

Patient related factors

Renal disease, DM, increase age, poor nutrition, liver
disease, hypoalbuminemia, volume depletion, K or Mg
deficiency
Concomitant nephrotoxins

Cyclosporine, vancomycin, amp B, contrast media, cisplatin,

NSAIDS, diuretics

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Aminoglycoside Nephrotoxicity

Prevention

Avoid use (especially in high risk pts)

Use extended interval dosing (higher doses, less frequently)

Pharmacokinetic monitoring

Alternatives include FQ, cephalosporin, other BL

Tubular cell uptake is saturable
Avoid elevated trough concentrations

Management

Stop the AMG

Hydrate (flush the debris)

Usually does not lead to ESRD, reversible if caught early

Tubular Epithelial Damage

Radiocontrast Media and CIN

Iodinated contrast is widely used for diagnostic

imaging studies.

CT scans

Highlights blood vessels

Improves detail of highly vascularized organs

Tubular Epithelial Damage

Radiocontrast Media and CIN

Most common cause of hospital acquired AKI

~11% of cases
Incidence dependent of patient risk factors

Preexisting renal disease most predictive (eGFR <60)

The higher the baseline SrCr, the greater the risk of CIN

Associated with poor overall outcomes

Occurs within 48 hours of receipt

Dual mechanism

Direct cellular toxicity

Renal ischemia

Dependent on duration of exposure

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Tubular Epithelial Damage

Radiocontrast Media and CIN

Prevention

Always consider risk/benefit of contrast use

Use smallest volume possible

Keep ratio of volume of contrast: CrCL < 3.7

Avoid concurrent nephrotoxins

N-acetylcysteine, sodium bicarbonate most frequently
used preventive strategies

Evidence of benefit is conflicting

Always used in conjunction with HYDRATION with NS

Tubular Epithelial Damage Other

Implicated Drugs

Cisplatin
Dose related
Hypomagnesemia is a hallmark finding
Carboplatin has lower risk
Use IV hydration to maintain urine output 3-4 L/day

Amphotericin B
Related to cumulative dose (> 80% when dose approaches
5 gm)
Lipid formulations have lower incidence
Hydration before each dose is recommended

Glomerular Disease

Drug-induced glomerular disease is uncommon

Recall that proteinuria is the hallmark of glomerular injury

Minimal Change Glomerular Disease

Accompanied by interstitial nephritis
NSAIDS most commonly implicated
Lithium, quinolone antibiotics, interferon-

Focal Segmental Glomerulosclerosis

Heroin nephropathy
Bisphosphonates collapsing glomerulonephropathy

Massive proteinuria, rapid progression to ESRD

IV formulations, high doses, prolonged therapy have highest risk

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Tubulointerstitial Nephritis
(Acute and Chronic Interstitial Nephritis)

Pathology is in the renal interstitium rather than the tubules

Acute interstitial nephritis is a renal manifestation of
allergic reaction to an antigen (drug).
Associated with cell mediated vs humoral immune infiltration in
the interstitium
Many drugs implicated Methicillin is prototype

Chronic interstitial nephritis is less common

Associated with fibrotic changes in the interstitium
Progressive, irreversible
Lithium, calcineurin inhibitors, aristolochic acid

Detection of AIN

Clinical signs can give a clue--Renal failure with

Classic triad

Eosinophilia (23-80%) and eosiniphiluria common

Fever (>25%), Maculopapular rash (15-25%), Arthralgias (45%)

Determine temporal relationship

For most drugs onset is ~ 2 weeks

NSAID associated AIN is delayed by an mean of 6 months

from the start of treatment

May be sooner w/ previous exposure

May be accompanied by glomerular disease (proteinuria)

Frequently lacks common associated signs above

Acute Interstitial Nephritis

Many drugs/classes implicated

Antibiotics

Phenytoin, allopurinol, omeprazole, famotidine, others

Beta-lactams, FQ, rifampin, sulfamethoxazole, vancomycin

Other causes should be considered

Infections
Associated systemic disease (Autoimmune)
Idiopathic

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Acute Interstitial Nephritis

Management

Discontinue offending agent

Caution using any related drugs in the future

Corticosteroid therapy

Studies conflicting, mostly positive

Early initiation thought to be critical

Dose/Duration not consist in trials

Immune infiltration >>> fibrosis in ~ 7 days

1mg/kg/day prednisone x 1-2 weeks followed by a taper over
1-3 months

Drug Induced Crystal Nephropathy

Pathogenesis

Drug precipitation distal tubular lumen

Tubular obstruction

Interstitial nephritis
Superimposed ATN

Alternatively, drug may cause precipitation of other

crystals within the tubule

Uric acid crystals secondary to chemotherapy

Myoglobin precipitation secondary to rhabdomyolysis

Drug Induced Crystal Nephropathy

Pathogenesis

Supersaturation of poorly soluble drugs

Examples

Low urine volume leads to risk

Acyclovir is relatively insoluble at urinary pH

Foscarnet forms a crystalline complex with calcium

Phosphate nephropathy from Ca-Phosphate crystallization

Tubular precipitation in volume depleted or oliguric patients

Crystalline glomerulonephritis

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Drug Induced Crystal Nephropathy

Drug Induced Crystal Nephropathy

Drug Induced Crystal Nephropathy

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Drug Induced Crystal Nephropathy

Drug Induced Renal Vasculitis and

Thrombosis

Vasculitis is inflammation
within blood vessel walls
Signs

Hematuria
Proteinuria
Oliguria
Red cell casts

Associated symptoms

Fever
Malaise
Myalgias
arthralgias

Drug Induced Renal Vasculitis and

Thrombosis

Vasculitis

Drugs implicated

Hydralazine*, PTU*, allopurinol*, phenytoin, sulfasalazine,

penicillamine*, minocycline, adalimumab*

* antineutrophil cytoplasmic antibody (ANCA) positive

Management

Stop offending drug

Corticosteroids, other immunosuppressive therapy

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Drug Induced Renal Vasculitis and

Thrombosis

Thrombotic microangiopathy (TMA)

Clinical signs
Hemolytic anemia
Fragmented red cells
Thrombocytopenia

Pathological findings

Endothelial proliferation, swelling

Intraluminal thrombi

Differentiated from vasculitis by a lack of swelling of

the vessel walls

Drug Induced Renal Vasculitis and

Thrombosis

Thrombotic microangiopathy (TMA)

Drugs implicated (TMA)

Immune mediated

Dose-dependent/toxicity mediated

Quinine, oxaliplatin, quetiapine

Calcineurin inhibitors (cyclosporine, tacrolimus), sirolimus,
bevacizumab, clopidogrel

Management

Stop offending drug

Corticosteroids, plasmapheresis, IVIG

Recap

Drug induced renal failure is common

Detection of drug induced renal disease is an

important pharmacist intervention

Many different types/presentations

Early detection and cessation of offending agent is key

Preventive measures and appropriate management

can reduce incidence of complications

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References

Chertow GM, Burdick E, Honour M, Bonventre JV, Bates W. Acute Kidney Injury,
Mortality, Length of Stay, and Costs in Hospitalized Patients. J Am Soc Nephrol 16:
33653370, 2005.
Wang HE, Muntner P. Chertow GM, Warnock DG. Acute Kidney Injury and Mortality
in Hospitalized Patients. Am J Nephrol 2012;35:349355.
Himmelfarb J. Chapter 55. Drug-Induced Kidney Disease. In: Talbert RL, DiPiro JT,
Matzke GR, Posey LM, Wells BG, Yee GC, eds. Pharmacotherapy: A
Pathophysiologic Approach. 8th ed. New York: McGraw-Hill; 2011.
Praga M, Gonzalez E. Acute interstitial nephritis. Kid Int. 2010: 77; 956961.

Questions?

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