Drugs in kidney diseases
Shiva Seyrafian
M.D. Nephrologist
1391/2/30- - 19/5/2012
Drugs and the Kidney
1.
2.
3.
4.
Drugs and the normal kidney
Drugs toxic to the kidney
Prescribing in kidney disease
Case presentation
Normal Kidney Function
•
•
•
•
•
•
•
1 Extra Cellular Fluid Volume control
2 Electrolyte balance
3 Waste product excretion
4 Drug and hormone elimination/metabolism
5 Blood pressure regulation
6 Regulation of haematocrit
7 regulation of calcium/phosphate balance
(vitamin D3 metabolism)
Pharmacokinetics
•
•
•
•
Absorption
Distribution
Metabolism
Elimination
– filtration
– secretion
Drugs and normal kidney
Effects of renal disease on drugs
Patient –related risk factors for
drug-induced nephrotoxicity







Absolute or effective intravascular depletion
Age older than 60 years
Diabetes
Exposure to multiple nephrotoxins
Heart failure
Sepsis
Underlying renal insufficiency (glumerular
filtration rate <60 ml per minute per 1.73m2)
Drugs toxic to the kidney
Amphotericin B
 Cisplatin
 Crystal-induced
 Ifosfamide
 Lead, mercury, cadmium
 Analgesics, NSAIDs
 Lithium
 Triamterene

Amphotericin B nephrotoxicity




Increase in serum creatinine occurs in 5-80%
patients, manifestations include renal insufficiency,
urinary potassium wasting and hypokalemia, urinary
magnesium wasting and hypomagnesemia, metabolic
acidosis due to type 1 (or distal) renal tubular acidosis,
and polyuria due to nephrogenic diabetes insipidus.
Risk factors: aminoglycosides, cyclosporine, non- lipid
based(liposomal amphotericin B), hypovolemia.
Nephrotoxicity is usually reversible with discontinuation
of therapy.
Recurrent renal dysfunction can occur if treatment is
reinstituted.
Crystal-induced acute kidney injury (acute
renal failure)
Acute Uric Acid Nephropathy,
 Intravenous Acyclovir, (prior hydration (with the urine output
maintained above 75 mL/h) and slow drug infusion over 1 to 2 hours) Oral

therapy is also well tolerated

Sulfonamide Antibiotics, (fluid intake above three liters per day,
monitoring the urine for crystals, and, if crystals are seen, alkalinization of
the urine to a pH above 7.15 )


Ethylene Glycol,
Megadose Vitamin C,
Crystal-induced acute kidney injury (acute
renal failure)

Methotrexate nephrotoxicity: with an acidic urine (since MTX is
poorly soluble in an acidic urine), and with volume depletion . Prevention:
alkalinization of the urine to a pH above 7.0, three liters per day of
dextrose in water to which 44 to 66 meq/L of sodium bicarbonate has
been added, begun 12 hours before MTX administration and continuing
for 24 to 48 hours.
 The acute renal failure induced by methotrexate is reversible
in almost all cases. The plasma creatinine concentration usually peaks
within the first week and returns well toward baseline levels within
one to three weeks , Leucovorin rescue

Indinavir: nephrolithiasis (nonopaque stones ), tubulointerstitial
nephritis , 150 mL/h in the three hours after each oral dose of indinavir
should minimize the risk of crystal formation .
Patients are asymptomatic or may have flank pain, hematuria, pyuria and
crystaluria.
Sulfonamide crystals
Indinavir sulfate urinary crystals
NSAIDs
Acute kidney injury (acute renal failure)
and nephrotic syndrome ;
 NSAIDs can induce two different forms of
acute kidney injury: 1-hemodynamicallymediated (ATN); and 2-acute interstitial
nephritis, which is often accompanied by the
nephrotic syndrome (membranous or minimal
change disease). The former and perhaps the
latter are directly related to the reduction in
prostaglandin synthesis induced by the NSAID.

NSAIDs …


Low-dose
aspirin
(studied
at
approximately 40 mg per day), low-dose
over-the-counter
ibuprofen,
and
perhaps sulindac appear to be safer;
however even low dose ibuprofen can
reduce the glomerular filtration rate in
patients with reduced renal perfusion .
Patients who present with acute interstitial
nephritis typically present with hematuria,
pyuria, white cell casts, proteinuria, and an
acute rise in the plasma creatinine
concentration. Spontaneous recovery
generally occurs within weeks to a few
months after therapy is discontinued.
NSAIDs …

Chronic kidney disease: daily
NSAIDs for prolonged time induce
CKD (analgesic nephropathy) due to
papillary necrosis. The NSAID-induced
inhibition of prostaglandin-mediated
afferent vasodilation may increase the
risk for acute tubular necrosis (ATN)
caused by ischemia or other
nephrotoxins, such as radiocontrast
media.
NSAIDs-Analgesic
nephropathy
Analgesic nephropathy is characterized by renal
papillary necrosis and chronic interstitial nephritis.
 It is caused by prolonged and excessive
consumption of analgesic medications that contain
phenacetin, aspirin, acetaminophen, nonsteroidal
antiinflammatory agents (NSAIDs), or salicylamide.
 Aspirin alone (in therapeutic doses) does not
appear to induce renal injury but may potentiate
the toxicity of phenacetin and acetaminophen.
 Many small studies have suggested that chronic,
especially daily, acetaminophen use has dosedependent, long-term nephrotoxicity.

NSAIDs…
Aspirin may potentiate the toxicity of
phenacetin and acetaminophen by both
depleting cortical and papillary
glutathione levels, and altering
prostaglandin-dependent renal blood flow
within the medulla, rendering it more
prone to ischemic damage.
 The effect of long-term use of selective
COX-2 inhibitors on kidney function is
unknown.

NSAIDs …
RECOMMENDATIONS:
Patients should not take NSAIDs prior to
procedures that involve the administration of
iodinated contrast media.
All NSAIDs, including topically administered
forms, should be terminated in patients
suspected of having NSAID-induced acute
interstitial nephritis. Although there is no
definitive evidence that corticosteroid therapy is
beneficial in this setting, a course of prednisone may
be considered in patients whose renal failure
persists more than one to two weeks after the
NSAID has been discontinued.
Acute Tubular Necrosis


Due to ischemia from exposure to
toxin. Death of the tube, sloughing of
Renal tubules.
Caused by:
1.
2.
3.
4.
Aminoglycosides
Amphotericin B
Radiocontrast dye
Cisplatin

Aminoglycisdes
 Gentamycin and Kanamycin, Amikacin
◦ Affecting PCT by binding of +ve charges of
AG to phospholipids in plasma, mitochondria
and lysosomal membranes. It will interfere in
the functions of organelles.
◦ Renal toxicity appears 5-10 days of treatment
by monitoring serum creatinine.
◦ AKI is reversible
Aminoglycosides
Highly effective antimicrobials
◦ Particularly useful in gram -ve sepsis
◦ bactericidal
 BUT
◦ Nephrotoxic
◦ Ototoxic
◦ Narrow therapeutic range

Prescribing Aminoglycosides
Once daily regimen now recommended
in patients with normal kidneys
 High peak concentration enhances efficacy
 long post dose effect
 Single daily dose less nephrotoxic
 Dose depends on size and renal function
 Measure levels!

Contrast-induced Nephropathy
Type of contrast agent:
1. Ionic or nonionic agents
2. High or low or iso osmolal agents: 1400-1800
(iohexol) vs. 500- 850 vs. 290 mOsm/Kg :
Iodixanol
The primary benefit of nonionic contrast agents,
whether low or iso-osmolal, is seen in high-risk
patients (eg, serum creatinine ≥1.5 mg/dL [132
micromol/L] or a GFR <60 mL/min per 1.73
m2), particularly if they are diabetic.
As a result, these agents should be used instead of
ionic high osmolal agents.

contrast-induced nephropathy
Gadolinium has been considered to carry
low or no risk of nephrotoxicity.
However, there are some reports of
reversible acute renal failure, particularly
in patients with significant renal
dysfunction.
 Pathogenesis of contrast: renal
vasoconstriction, ATN

contrast-induced nephropathy
Incidence: zero to over 50 percent
 Acute renal failure, defined as an increase in plasma
creatinine of more than 0.5 mg/dL (44 micromol/L)
above baseline.
Risk factors:
1. Underlying renal insufficiency, with the plasma
creatinine exceeding 1.5 mg/dL (132 micromol/L) or,
although not measured clinically, the GFR being less
than 60 mL/min per 1.73 m2
2. Diabetic nephropathy with renal insufficiency
3. Advanced heart failure or other cause of reduced
renal perfusion (such as hypovolemia)
4. Percutaneous coronary intervention, which also
promotes the development of atheroemboli
5. High total dose of contrast agent
6. Multiple myeloma (with older contrast agents)
Contrast-induced nephropathy


Contrast nephrotoxicity is dose dependent
and lower dose is safer.
Low dose has been variably defined as less
than 70 mL, less than 125 mL, or less than
5 mL/kg [to a maximum of 300 mL] divided
by the plasma creatinine concentration.
However, diabetic patients with a plasma
creatinine concentration above 5 mg/dL
(440 micromol/L) may be at risk from as
little as 20 to 30 mL of contrast
Contrast-induced nephropathy
CLINICAL CHARACTERISTICS:

The renal failure induced by contrast
agents begins within the first 12 to 24
hours after the contrast study. The
renal failure is nonoliguric for the vast
majority of patients. In almost all cases,
the decline in renal function is mild and
transient, with recovery of renal
function typically beginning within
three to five days.
contrast-induced nephropathy
prevention:
Hydration, mannitol, and
diuretics — Hydration is beneficial, and
the type of hydration solution may be
important. In comparison, the role of
diuretics, mannitol and other renal
vasodilators in this setting is uncertain.
 We recommend NOT
using mannitol or other diuretics
prophylactically.

contrast-induced nephropathy
Prevention
The use, if clinically possible, of ultrasonography, magnetic
resonance imaging or CT scanning without
radiocontrast agents, particularly in high-risk patients.
The use of lower doses of contrast and avoidance of
repetitive studies that are closely spaced (within 48
to 72 hours). Very small amounts of contrast (<10 mL)
have been safely used in patients with advanced kidney
disease for examination of poorly maturing
arteriovenous fistula.
Avoidance of volume depletion or nonsteroidal
antiinflammatory drugs, both of which can increase
renal vasoconstriction.
The
administration
of
intravenous
saline
or
possibly sodium bicarbonate.
The administration of the antioxidant acetylcysteine.
The use of selected low or iso-osmolal nonionic
contrast agents.
contrast-induced nephropathy
Prevention
bolus of 3 mL/kg of isotonic bicarbonate for
one hour prior to the procedure, and
continued at a rate of 1 mL/kg per hour for
six hours after the procedure. This solution
can be prepared by adding 150 meq
of sodium bicarbonate (three 50 mL ampules
of 1 meq/mL sodium bicarbonate) to 850 mL
of sterile water.
 It is not recommended routine use of
prophylactic hemodialysis for removal of
contrast in stage 3 or 4 of CKD; and for
stage 5 it is considered when there is a
vascular access.

Contrast-enhanced MRI
There are two major concerns:
 Among patients with moderate and
particularly severe renal failure, the
possible development of the severe
syndrome of nephrogenic systemic
fibrosis.
 The possible development of
nephrotoxicity, similar to that seen
with iodinated contrast agents.
Contrast-enhanced MRI

Gadolinium-based imaging should not
be performed, if at all possible, in patients
with an estimated glomerular filtration
rate less than 30 mL/min because of the
risk of nephrogenic systemic fibrosis. In
such patients, we prefer the risk of
radiocontrast nephropathy with iodinated
contrast media, using all of the preventive
measures that are available, to the risk of the
much more severe complication of NSF.
Chemotherapy-related
nephrotoxicity
Chemotherapy can cause nephrotoxicity by a
variety of different mechanisms.
Factors can potentiate renal dysfunction:
1. Intravascular volume depletion,
2. The
concomitant
use
of
nonchemotherapeutic nephrotoxic drugs (eg,
aminoglycoside antibiotics, nonsteroidal
antiinflammatory drugs) or
3. Radiographic ionic contrast media in patients
with or without preexisting renal
dysfunction,
4. Tumor-related urinary tract obstruction, and
5. Intrinsic renal disease.

Chemotherapy-related nephrotoxicity

Dose adjustment in this setting is typically
based upon two factors: an estimation of
glomerular filtration rate (GFR), which
serves as an index of the number of
functioning nephrons, and evaluation of
clinical signs of drug toxicity (eg,
neutropenia, thrombocytopenia).
Chemotherapy agents that may require dose
reduction in patients with renal insufficiency
Arsenic trioxide
Eribulin
Oxaliplatin
Bleomycin
Etoposide
Pentostatin
Capecitabine
Fludarabine
Pemetrexed
Carboplatin
Hydroxyurea
Sorafenib
Cisplatin
Ifosfamide
Streptozocin
Cladribine
Irinotecan
Topotecan
Cyclophosphamide
Lenalidomide
Vandetanib
Cytarabine (high
dose)
Lomustine
Daunorubicin
Melphalan
Epirubicin
Methotrexate
Mitomycin
Triamterene nephrotoxicity
Triamterene is a potential nephrotoxin, frequently
inducing crystalluria and cast formation, and rarely
causing stone formation or reversible acute
renal failure.
The excretion of triamterene crystals and granular
casts occurs in as many as one-half of patients.
this finding is not seen with amiloride.
Triamterene may contribute to 1 in every 200 to 250
stones.
Reversible acute renal failure is another rare problem
with triamterene (but not other potassiumsparing diuretics). Two different mechanisms have
been described: intratubular obstruction by crystals;
and concurrent therapy with a NSAID.
Lead nephropathy and lead-related nephrotoxicity
High level of lead exposure required to cause lead
nephropathy is now increasingly rare, particularly
in developed countries, due to occupational
controls and removal of lead from paint, gasoline,
and other environmental sources.
 Cortical bone lead reflects cumulative lead
exposure and the potential for endogenous
exposure since bone lead is mobilizable into the
circulation . Cortical bone lead is measured by xray fluorescence (XRF) in the mid-shaft of the
tibia. The half-life is estimated to be 10 to 30
years. lead exposure may be associated with both
hypertension and increased cardiovascular risk.

Lead nephropathy and lead-related nephrotoxicity
Manifestations:
 Chronic interstitial nephritis, is a potential
complication of prolonged (5 to 30 years),
high-level lead exposure.
 Fanconi- type syndrome 2- azotemia,
hyperuricemia and gout due to more
prolonged exposure.
 Treatment: Acute renal failure was noted in
reports from the early 1980s of calcium
EDTA therapy given at high doses
Lead nephropathy and lead-related nephrotoxicity
Diagnosis-Lead may be measured in whole
blood, bone, and, following administration of
a chelating agent, urine. If the blood lead
level is greater than 10 mcg/dL (0.48
micromol/L), levels should be rechecked four
weeks after the identified source of lead
exposure is eliminated.
Treatment —
 Minimizing further exogenous lead
exposure
 Chelation therapy: calcium EDTA three
times weekly for 6 to 50 months;
Effect of dialysis on drugs
Drugs with MW >500 daltons poorly
cleared by conventional HD membranes.
Protein or tissue binding or lipid soluble are
not dialyzed properly.
For drugs not removed by HD, it is unusual
to be removed by peritoneal dialysis.
High-flux membranes (porous) are more
permeable to drugs.
TABLE 57-2 -- Drugs That Have Active or Toxic Metabolites in Dialysis Patients
Acetaminophen
Angiotensin-converting enzyme inhibitors
Angiotensin receptor blockers
Adriamycin
Allopurinol
Amiodarone
Amoxapine
Azathioprine
Benzodiazepines
β-Blockers
Bupropion
Buspirone
Cardiac glycosides
Clorazepate
Cephalosporins
Chloral hydrate
Clofibrate
Desipramine
Diltiazem
Encainide
Esmolol
H2-blockers
Hydroxyzine
Imipramine
TABLE 57-2-- Drugs That Have Active or Toxic Metabolites in Dialysis Patients
cont…..
Isosorbide
Levodopa
Lorcainide
Meperidine
Metronidazole
Methyldopa
Miglitol
Minoxidil
Morphine
Nitrofurantoin
Nitroprusside
Procainamide
Primidone
Propoxyphene
Pyrimethamine
Quinidine
Serotonin reuptake inhibitors
Spironolactone
Sulfonylureas
Sulindac
Thiazolidinediones
Triamterene
Trimethadione
Verapamil
Vidarabine
B & C- ACEIs and ARB
◦ Angiotensin converting enzyme inhibitors (ACEI) and
angiotensin receptor blocker (ARB) are inhibiting
Renin system and decrease the blood hemodynamic:
 It produces VD and decrease perfusion pressure
and decreases GF
 At the start of the treatment a decrease of urine
volume and increase of creatinine by 30% indicates
 Damage is reversible
 Rehydration of patient is advisable
 Initiate treatment with short acting (captopril) and
titrate later with long acting
Glomerulonephritis

4 Different immunological drug induced
GN:
1. Nephrotic syndrome: NSAID, ampicillin,
rifampicin and lithium
2. Focal segmental glomeruloscerosis (FSGS):
lithium, heroin
3. Membrane nephropathy (MN): NSAID, gold
therapy, mercury, penicillamine
4. Membranoproliferative: hydralazine
Dosing in renal impairment
Loading dose does not change (usually)
 Maintenance dose or dosing interval does

T ½ often prolonged
◦ Reduce dose OR
◦ Increase dosing interval
◦ Some drugs have active metabolites that are
themselves excreted renally
 Warfarin, diazepam
References
Clinical Pharmacology: Melmon and Morrelli,
McGraw-Hill, 2000
 Taber SS and Pasko, Epidemiology of druginduced disorders: the kidney;
Exper.Opin.Drug Saf. 7(6):679-690, 2008
 Hanbook of dialysis therapy: Nissenson and
Fine, Sunders Elsevier, philadelphia, 4th
edition, 2008, (83): 1089-1195
 The Kidney at a glance: O’callaghan and
Brenner, blackwell Science,2000:38-39
 Burton Rose, drug-induced nephrotoxicity,
Uptodate 20.1 2012

case1
A 54 y/o female with resistant ALL received
IV Methotraxate for 3 days.
 After 3-4 days she developed nausea,
vomiting and azotemia was diagnosed.
 She had hypocalcemia, hyperphosphatemia
hyperuricemia and hyperkalemia. In lab exam
also severe keukopenia and pancytopenia
was found. She received G-CSF, leukoverin,
Hemodialysis and Antibiotics.
 Dx?

case2
A 65 y/o female with chronic
hypertension developed fever 39 ºc and
dysuria, flank pain. In U/A and U/C pyuria
and E-Coli 100000 cc was reported. She
received 500 mg amikacin stat and 250 mg
tid IM. Her serum Cr was 1.5 mg/dl and
BUN 26, her body weight was 50 kg.
 What is your opinion about this
prescription?

Case2…
Cr Clearance= (140-age)x BW (kg)/85 x
serum Cr
 Cr Clearance= 75 x 50/85 x 1.5
 Cr Clearance= 3750 / 127.5
 Cr Clearance= 30 ml/min
 What is your prescription?

Case3
A 38 y/o man with uncontroled
hypertension and serum Cr = 2 mg/dl and
BUN 28 mg/dl is candidate for renal
artery MRA with gadolinium, his BW is 72
kg.
 What is your opinion? Could he do the
MRA?
 What is his estimated GFR?

Case3…
Cr Clearance= (140-age)x BW (kg)/85 x
serum Cr
 Cr Clearance= 140 – 38 x 72/72 x 2
 Cr Clearance= 102x 72/ 144
 Cr Clearance= 51ml/min

case4
A 47 y/o diabetic male with IHD and
Chest pain is candidate for coronary
angiography; his serum Cr is 2.5 mg/dl and
BW is 85kg . He is consulted for using
contrast.
 What is your suggestion?
 Can he use contrast?
 Does he need prophylctic dialysis?
