Center for Clinical Pharmacology Department of Medicine University of Pittsburgh School of Medicine

Nephrotoxic Drugs
Stevan P. Tofovic MD, PhD, FAHA, FASN
tofovic@dom.pitt.edu 412-648-3363

Nephrotoxic Drugs

Radiocontrast Agents Aminoglycosides Nonsteroidal Anti-Inflammatory Drugs (NAIDs) Angiotensin-Converting Enzyme Inhibitors (ACEIs) Lithium Crystal-Induced Acute Renal Failure Calcineurin inhibitors (Cyclosporine, Tacrolimus)

Nephrotoxic Drugs
Patient- Related Risk Factors

Age, Sex Previous renal disease Diabetes, Multiple myeloma, Lupus, Proteinuric disease Salt retaining diseases (Chirrosis, Heart Faiure, Nephrosis) Acidosis, potassium or magnesium depletion Hyperuricemia, Hyperuricosuria Kidney transplant

Nephrotoxic Drugs
Drug - Related Risk Factors

Inherent nephrotoxic effects Dose Duration, frequency and form of administration Repeated exposure Drug interaction (synergistic toxic effects)

Radiocontrast Agents
Ionic vs. Nonionic High (1500-1800) Low (600-850) Iso-osmolal (~ 290 mOsm/kg)) Plasma: 285 mOsm/kg CSF: 310 mOsm/kg

Radiocontrast Agents

First generation - Ionic monomers,

hyperosmolal; Diatrizoate, Iothalamate

Second generation: Nonionic

monomers, lower osmolality Iopamidol, Iohexol, Iopromide, Ioversol

Newest agents: Nonionic dimers, isoosmolal Iodixanol

Radiocontrast Agents

Pathogenesis:

Renal Vasoconstriction
(Adenosine, Endothelin)

Tubular Injury
Oxidative stress induced damage

Adenosine and Tubuloglomerular Feedback

JGC
Renin release
Adenosine Vasoconstriction

A1

TGF MD

MD - Macula Densa TGF - Tubuloglomerular Feed-back JGC - Juxtaglomerular Cells

A2
Vasodilatation

PGC GFR

Radiocontrast Agents

Risk Factors:

Underlying renal disease (Cr >1.5mg/dL) Diabetic nephropathy, Heart Failure, i.e. Hypovolemia Multiple Myeloma (lower doses safer but not necessarily safe)

Dose

Radiocontrast Agents

Incidence

Negligible when renal function is normal (even if diabetic) 4 -11% in patients with Cr 1.5 4.0 mg/dL 50% if Cr > 4.0 mg/dL and in diabetic nephropathy

Diagnosis

Characteristic rise in plasma Cr following administration of the agent

Radiocontrast Agents

Therapy: Hydratation ; Mannitol ? Diuretics ? Acetylcystein, theophyllin, calcium channel blockers Prevention:

Use of alternative diagnostic procedures in high risk

patients
Avoidance of volume deletion or other nephrotoxins Low-doses of low- or iso-somolar agent

Aminoglycosides
Amikacin Gentamicin Neomicin Netilmicin Kanamicin Streptomycin Tobramycin
[AMIKIN ] [GARAMYCIN ] [NETROMYCIN ] [KANTREX ] [TOBREX, NEBCIN ]

Aminoglycosides
Patient- Related Risk Factors

Age Previous renal disease Dehydratation, Volume depletion Potassium or magnesium depletion Liver Disease (renal hypoperfusion) Sepsis ( endotixuns, volume depletion, renal hypoperfusion)

Aminoglycosides
Drug - Related Risk Factors

Inherent nephrotoxic effects Gentamicin > Amikicin & Tombamycin Prolonged high trough levels (> 2.0 ng/ml) Dose; Duration; Frequency Single daily dose; Post-antibiotic effect Drug interaction: Cephalothin Cyclosporin A;

Aminoglycosides

Pathogenesis
Number of cationic amino groups Bind at negatively charged sites at brush border membrane of proximal tubules More distal segments may be also affected (polyuria, hypomagnesemia)

Incidence

In 10-20% of patients increase in plasma Cr of 0.5-1 mg/dL

Aminoglycosides

Diagnosis- Clinical Course

Change in baseline creatinine (day 35) Nonoliguric acute renal failure Enzymuria, tubular proteinuria; Urine sediment may show granular and epithelial cell cats

Prevention Therapy
General rules of prevention of nephrotoxicity Discontinuation of the treatment

Nonsteroidal AntiInflammatory Drugs (NSAIDs)

Chemical Structure / Activity Generic Name ________________________________________________________ Acetic acids: Diclofenac, Indomethacin, Sulindac, Fenamates: Napthylalkanones: Oxicams: Propionic acids: Pyranocaboxylic acid: Pyrrolizine carboxylic acid: Selective COX-2 inhibitors: Meclofenamate, Mefenamic acid Nabumetone Meloxicam and Piroxicam Fenoprofen, Flurbiprofen, Ibuprofen, Ketoprofen, Naproxen, Oxaprozin Etodolac Ketorolac Celecoxib, Rofecoxib, Valdecoxib,

Hemodynamically- Induced ARF Acute Interstitial Nephropathy + Proteinuria Papillary necrosis and chronic renal failure (Analgesic nephropathy) Salt and water retention; Hyperkalemia; Hypertension

Nonsteroidal AntiInflammatory Drugs (NSAIDs)

Nonsteroidal AntiInflammatory Drugs (NSAIDs)

Hemodynamycally- Induced ARF

Inhibition of prostaglandins synthesis Renal prostaglandins are primarily vasodilators NSAIDs do not impair renal perfusion in normal subjects Patients at risk: Preexisting renal disease (glomerular disease nephrotic syndrome ,lupus); Hypercalcemia; Congestive Heart

Nonsteroidal AntiInflammatory Drugs (NSAIDs)

Hemodynamycally- Induced ARF (Contd)

Mild to moderate oliguric ARF that begins within several days after initiation of treatment Hyperkalemia unproportional to the renal failure, and low fractional excretion of sodium. If recognized early, reversible after discontinuation of NSAID.

Nonsteroidal AntiInflammatory Drugs (NSAIDs)

Acute Interstitial Nephropathy + Proteinuria

Prolonged use of NAIDs (elderly women) Acute interstitial nephritis Minimal-change glomerular disease Proteinuria No evidence of allergic hypersensitivity; T-cell infiltration; EM fusion of epithelial foot processes

Analgesic nephropathy (Papillary necrosis and chronic renal failure)

Nonsteroidal AntiInflammatory Drugs (NSAIDs)

Acetaminophen [Tylenol]; Ibuprofen [Advil, Motrin] Aspirin, Naproxen

Pre- vs. Post-Phenacetin-Era Single vs. combined analgesics Nephrotoxicity is cumulative dosedependent ( 2-3 pounds; 3 pills/day for several years)

Patients with history of depended behaviors

Nonsteroidal AntiInflammatory Drugs (NSAIDs)

Analgesic nephropathy (Papillary necrosis and chronic renal failure) contd

Phenacetin is converted to acetaminophen Renal risk of chronic acetaminophen monotherapy is unknown Aspirin alone not toxic, but potentiates the effects of phenacetin and acetaminophen The effects of long-term use of COX-2

Nonsteroidal AntiInflammatory Drugs (NSAIDs)

Analgesic nephropathy (Papillary necrosis and chronic renal failure) contd

Pathogenesis: Renal damage mainly in the medulla Initially thickening of the vasa recta; patchy areas of tubular necrosis; later papillary necrosis Slowly progressive GRF; Asymptomatic, sometimes hematuria, flank pain, or

Analgesic nephropathy

Nonsteroidal AntiInflammatory Drugs (NSAIDs)

100% Women 80% Headache 80% GI disturbance 35% Urinary Tract Infections

Excessive consumption of analgesics

 Papillary

Nonsteroidal AntiInflammatory Drugs (NSAIDs)

necrosis

 Papillary

Nonsteroidal AntiInflammatory Drugs (NSAIDs)

necrosis

Nonsteroidal AntiInflammatory Drugs (NSAIDs)

Salt and water retention: Renal PGs also may have a natriuretic effect, and antagonize the effects of ADH
Not important it the basal state, but may be significant when there is neurohumoral activation/volume depletion

Hyperkalemia: Renal PGs inhibits renin release

(Hyporeninemic-hypoaldosteronism-induced K+

Hypertension: Renal PGs also may lower

ACE Inhibitors-Induced Acute Renal Failure

First group of antihypertensive drugs shown to be renoprotective High renin patients are at risk:
Bilateral (>70%) renal artery stenosis Moderate to Severe congestive hart failure Volume deleted (excessive use of diuretics)

ACE Inhibitors-Induced Acute Renal Failure

Control of Renin Secretion

Macula densa pathway: Inhibition of

Na++ reabsorption Na++ delivery to the macula densa renin secretion

Intrarenal baroreceptor pathway:

BP/ Renal hypoperfusion intrarenal baroreceptor activty renin secretion

Beta-adrenergic receptor pathway: Sympahtetic activity (i.e., BP )

activation of 1 receptors renin secretion

ACE Inhibitors-Induced Acute Renal Failure

INTRAGLOMERULAR PRESSURE
Arterial pressure Afferent arteriole

Angiotensin II
+

+
20 mmHg

Angiotensin II + ++

Efferent arteriole

Bowmans capsule

Renin Angiotensin System and Efferent Arteriolar Constriction

Renal ischemia Renin release Angiotensin II formation Efferent arteriolar constriction Increased intraglomerular pressure Maintained renal function

ACE Inhibitors and Efferent Arteriolar Constriction

Renal ischemia
Warnings for use of ACEIs !!!

Renin release

Angiotensin II formation Efferent arteriolar dilation Reduced intraglomerular pressure Reduced GFR

CONGESTIVE HEART FAILURE

diuretics adrenergic stimulation
Low blood pressure

renin

Angiotensinogen

AngI

X +
AngII

ACEIs +++
poor renal perfusion sodium depletition

Afferent arteriole

Efferent arteriole
Maintenance of GFR at low rate

ACEIs may cause renal failure

Calcineurin Inhibitors

Cyclosporin A [SANDIMMUNE, NEORAL] Tracolimus [PROGRAF] Mechanism or action Cyclosporin vs Tracolimus

Calcineurin Inhibitors
Acute nephrotoxicity

Azotemia: renal vasoconstriction, reduced RBF and GFR; Oliguric ATN with high doses Relatively more dose-dependent Largely reversible; Calcium channel blockers (+/-) Difficult to differentiate from acute rejection

Calcineurin Inhibitors
Chronic nephrotoxicity

Factors responsible for chronic nephrotoxicity are not well understood. Relatively less dose-dependent Sustained renal vasoconstriction/renal ischemia; Renin-Angiotensin System Cyclosporineinduced hypertension

Calcineurin Inhibitors
Chronic nephrotoxicity

obliterative arteriolopathy vacuolization of the tubules focal areas of tubular atrophy interstitial fibrosis

Crystal-Induced ARF

Acyclovir (antiviral agent ) Indinavir (antiretroviral agent, protease inhibitor) Methotrexate (antineoplastic agent, antimetabolite) Sulfonamide antibiotics Triamterene

Crystal-Induced ARF

Sulfonamide crystals

Indinavir sulfate urinary crystals

Gagnon et al. 1998, Ann Intern Med 128-321

Amphothericin B

Used for the treatment of often lifethreatening fungal infections. Tubular injury and renal vasoconstriction proposed to have an important role in pathogenesis Drop in GFR mediated at least in part via TGF mechanisms Volume expansion (salt loading) may reduces drop in GFR but not tubular toxicity Usually reversible with discontinuation of therapy The new liposomal (phospholipid

Nephrotoxic Drugs
Prevention: General Rules

Be aware of nephrotoxic potential of specific drugs Identify patients at risk Be aware of increased risk in elderly Asses the benefit/risk ratio for Rx of potentially nephrotoxic drug

Nephrotoxic Drugs
Prevention: General Rules
(Contd)

Avoid dehydration/Be aware of volume depletion Limit dose and duration of treatment Adjust the dose based on changes in GFR