Drug Induced renal disorder

Renal toxicity Result of

• Hemodynamic changes
• Direct injury to cells and tissue
• Inflammatory tissue injury
• Obstruction of renal excretion

• ยากในการค้นพบว่าปั ญหาเกิดจากยาทำให้เกิดพิษต่อไต
• หากเกิดพิษที่ไม่รุนแรงหรื อเกิดอย่างช้าๆมักจะค้นปัญหาไม่พบ กว่าจะพบมัก
เมื่อเป็ นมากแล้ว
• มักเกิดพิษแบบ delay onset จนเกิด renal fn.เปลี่ยนไปถึงระดับ
ที่วดั ได้จึงจะทราบ
 Manifestations of drug-induced renal disorders

• Acute renal failure

• Chronic renal failure
• Nephrotic syndrome (Acute/Chronic)
• Fluid and Electrolyte disturbances
• Acid-base disorders
• Most episodes of drug-induced renal disorders are reversible
discontinue drug  renal fn. return to baseline.

• Chronic renal injury (due to medication)  Chronic tubulointerstitial

inflammation, pallillaly necrosis or prolonged proteinuria.
 Risk Injury Failure Loss ESRD Criteria
การเปลีย่ นแปลง GFR Urine Output
Risk Cr 1.5 –2 เท่าor GFR > 25% UO< 0.5 ml/kg/hr x 6 hr.

Injury Cr 2 – 3 เท่า or GFR > 50% UO< 0.5 ml/kg/hr x12hr.

Failure Cr 3 เท่า or GFR > 75% or UO< 0.3 ml/kg/hr x24hr.
Cr ≥ 4 mg/dl or Anuria x 12 hr.
(acute rise≥ 0.5mg/dl) (oliguria)

Loss Persistent Acute Renal Failure

ESRD End Stage Renal Failure
Stage of Chronic kidney disease

CLCr Stage
120 Stage 1
60-90 Stage 2
30-59 Stage 3
15-29 Stage 4
<15 Stage 5

Dose Adjustment
 Causes of Renal failure

1.Hypoperfusion
2.Vasoconstriction
3.Glomerulonephritis
4.Tubular necrosis
5.Interstitial nephritis
6.Interstitial edema
7.Outflow obstruction
 Drug-induce renal structural-functional changes
Proximal convoluted tubule (s1/s2 segment)
Glomeruli
Aminoglycoside
Interferon-α
Cephaloridine
Gold
Cadmium Cl
Penicillamine
K dichromate

Proximal straigt
tubule (s3 segment)
Renal vessel
Cisplatin
NSAIDs
Mercuric Cl
ACE Inhibitor
Dichlorovinyl-L-
Cyclosporin A cysteine

Interstitium
Cephalosporin
Pappillae Cadmium
Phenacetin NSAIDs
 Pseudo – renal failure

Steroids, tetracycline BUN (hypercatabolic effect)

Scr ไม่ เปลีย่ นแปลง
Trimethoprim. cimetidine, probenecid, triamterene,
amiloride, spironolactone  Scr (competitive with
creatinine for tublar secretion)
Ascorbic acid, cefoxitin, cephalothin, cefazolin,
cefotaxime, flucytosine, levodopa, methyldopa
interfere enzymatic measurement of creatinine by
Jeffe’ method
 Hemodynamically mediated renal failure

• Decrease total renal blood flow

• Vasoconstriction of glomerular afferent
arterioles
• Vasodilation of glomerular efferent
arterioles
• Increase Vascular permeability
• Increase collioid oncotic pressure and
blood viscocity

Mechanism
 Hemodynamically mediated renal failure

• Diuretic, alone or combination with other

antihypertensives
• ACEI & ARBs
• NSAIDs & COX inhibitor
• CyclosporinZreduce GFR in adose
dependent and reversible manner)
• Tacrolimus, triamterene, propanolol,
OKT3,dextran, epoietin

Drug
Hemodynamically mediated renal failure

Large volume losses

Renal vasoconstriction with marked tubular avidity

for NaCl uptake

Decrease urine output

Prolong vasoconstriction

Tubular dysfunction and tubular necrosis

 When the rate perfusion decrease,
the renal bed autoregulates
NSAIDs, COX II inhibitor ACEI ,ARBs

Prostaglandin  ขยาย Angiotensin IIบีบ

Afferent arterioles Efferent arterioles

Tubule
Risk Group RAS/Prostaglandin dependent

• Nephrosclerosis
• Bilateral renal artery stenosis หรือ renal
stenosis artery ในผู้ป่วยทีม่ ไี ตข้ างเดียว
• ตับแข็ง
• Hypovolumia
• Heart failure
• Chronic kidney disease
 Hemodynamically mediated renal failure
• Reversal is possible if the problem is
promptly recognized.
• Unrecognized prerenal failure can lead to
serious tubular injury and tubular necrosis.
• Changes in urine sediment are relatively
benign
• Renal function ดีข้ ึนได้ใน 1-2 วัน หลังหยุดยาและให้สาร
น้ำ เนื่องจากผลจากยาต่อไตมักมี duration~8-48 ชม.และไต
สามารถสร้าง Prostaglandin ได้ใหม่ใน 24-48 ชม.
 Some issue
• สาเหตุจาก NSAIDs-induced acute interstitial
nephritis แบ่งเป็ น (with or without nephrotic
syndrome)
• เริ่ ม ACEI ขนาดต่ำๆเลือก short-acting ค่อยๆtitrate แล้ว
จึงเปลี่ยนเป็ น long-acting
• หากสาเหตุจากยาACEIเคยเกิดมาแล้ว renal failure จาก
ยาACEIแล้วสามารถลองกลับไปใช้ใหม่ได้
• สาเหตุจาก Misoprostol (PGE analog)
• สาเหตุจาก COX-2 inhibitor/Low dose
aspirin/sulindac
 Intrarenal toxicity

ยาอาจก่ อพิษโดยตรงต่ อเซลล์ ของ

vasculature, tubules, glomeruli ทีไ่ ต

และ/หรือ อาจกระตุ้นการอักเสบของ renal interstitium

Acute intrinsic renal failure

 Intrinsic renal injury

• Vascular effect:thombotic, microangiopathy,

• Cyclosporin, tacrolimus, mitomycin C,
conjugate estrogens,quinine-6- fluorouracil,
ticlopidine, clopidogrel, interferon,
valaciclovir, gemcitabine, bleomycin
• Clinical finding: fever,
microangiopathic,hemolytic anemia,
thrombocytopenia
• Treatment: d/c medication, supportive
care,plasmapheresis if indicate
 Intrinsic renal injury

Vascular effect: cholesterol emboli

• Heparin, warfarin, streptokinase
• Clinical finding: fever,
microangiopathic,hemolytic anemia,
thrombocytopenia,
• Treatment: d/c medication, supportive
care,plasmapheresis if indicate
 Glomerular injury
• Glomerular histology and permeability
alteration often cause nephrotic range
protienuria.
• Toxic lymphokines of interstitial
inflammation might be implicated.Humeral
factor might also be involve eosinophils
& lymphocyte present in the interstitial
infiltrate.
• Red cell and white cells might be observed
in the urine,even though hypersensitivity is
not clinically event.
 Glomerular injury

• Renal biopsy เพื่อดูวา่ มี Glomerular injuryหรื อ

ไม่

• NSAIDs(mefenamic, fenbufen): minimal

change
• Gold,D-penicillamine,ACEI,foscarnet:
membranous lesion
• Interferon alfa:severe glomerular lesion
 Glomerular injury

• Gold, penicillamine, captopril, NSAIDs,

lithium, mefenamic, fenoprofen, mercury,
interferon-alfa, pamidronate, fenclofenac,
foscarnet เป็ นต้น
• Clinical finding: edema, moderate to
severe proteinuria, RBC and RBC casts
possible
• Treatment: discontinue medication and
supportive care
 Tubular injury

• Damage can be toxic / ischemic /

inflammatory / obstructive.
• Urine sediment abnormalities range from no
cell trough numerous red cells. White cells,
and/or brown granular casts,to proteinuria
and crystaluria, depending on site and
mechanism of injury
 Tubular Damage

Loss of polarity ,tight junction, integrity, cell-

substrate adhesion,simplication of brush border
Cell death
Necrosis/apoptosis
Sloughing of viable
cells with intraluminal
cell-cell adhesion
Cell-cell adhesion

Cast formation and

tubular obstruction

Cast  tubular obstruction tubular damage

 Tubular injury
• Tubular toxicity: aminoglycosides, radio contrast
media, cisplatin, neaplatin, methoxtfluran, outdated
tetracycline, amphotericinB, cephaloridine,
streptozocin, tacrolimus, carbamazepine,
mithramycin, quinolone,foscarnet, pentamidine, IV
gammaglobulin, fosfamide, zoledronate, cidofovir,
adefovir, tenofovir, mannitol,
dextran,hydroxyethylstarch
• Clinical finding: FeNa>2%,UOsm<350:urine
sediment with casts, tubular epithilium cell
 Aminoglycoside
• Prototype of drug-induce Acute tubular necrosis
(ATN)
• Usually reversible:gradual rise in Scr(5-7 d), renal
Mg++&K+ wasting, non-oligouria*
• Pertubation of glomerular filtration is late
manifestation of aminoglycoside nephrotoxicity.
• The number of cationic amino moieties seems to
correlate with the degree of nephrotoxicity:
Neomycin>Genta>Tobra>Amikacin>Netil>Streptomycin
Aminoglycoside

Swelling
 Risk factor for Aminoglycoside Nephrotoxicity
Related to AMG dosing
•Large total cummulative dose
•Prolong therapy
•High peak or trough conc.
•Recet previous AMG therapy
Related to synergistic
nephrotoxicity
AMG combination with
•Cyclosporin
•Amphotericin B
•Vancomycin
•Diuretics
Related to Predisposing condition
in the patient
•Preexisting renal insufficiency
•Increased age
•Poor nutrition
•Shock
•Gramnegative bactermia
•Liver disease
•Hypoalbuminemis
•Obstructive jaundice
•K+ or Mg++ deficiency
Irreversible Damage!
 Aminoglycoside Nephrotoxicity

Prevention Management
•Switching to alternative •Monitor Scr, concentration,
antibiotics renal fn and electrolytes
•Avoid volume depletion, •Discontinue AMG if
concomitant therapy with changes are seen.
other nephrotoxic drugs
•Limit total dose
•Decreasing the frequency
of AMG dosing to at least
daily (as direct by renal
clearance)
• Toxic tubular necrosis (Derange Na/K-ATPase loss
of brush border and apoptosis): Bisphosphonate
zoledronate 4 mg IV over 15 min (high dose)
• Osmotic nephrosis (cellular uptake
nonmetabolizable compounds such as
sucroseswellingtubular cell injury) : IV Ig,
mannitol, dextran, hydroxyethyl starch
• Ischemic tubular injury (acute vasoconstriction) :
immunosupressives, radiocontrast agents,
amphotericin B
 Amphotericin B
Mech. Clinical presentation Prevention
• ทำลาย tubular cell โดยตรง
•Non-oligouria,distal •Limiting cumulative
•Afferent arterio RTA,impaired renal activity to dose
concentrate urine,K+/Na+/Mg+
constriction จาก •Avoid concomitant
tubuloglomerular +wasting,increase BUN,Scr
nephrotoxiin
feedback •Tubular fn & filtration may
•Avoid volume
•Deoxycholate(solvent) improve but damage may be
depletion,hypoK
ทำลาย tubular cell โดยตรง irreversible
•Provide
•Renal vasoconstriction hydration,Na+ load (
Risk
effect ของ amphotericin B ให้ full Na+ diset if no
•Baseline renal dysfunction C/I, 1L NSS daily)
•Dose-dependent acute
renal vasoconstriction •Higher average daily dose -Ca blocker,
•Cumulative dose>2-3 •Diuretic use with depletion mannitol มักไม่เกิดประโยชน์
g:direct distal tubular Management
•Rapid infusion •Switch to another drug
injury •Avoid systemic
•Concomitant use with administration
•ATN at higher dose •K/Mg replacement
nephrotoxins
 Fanconi-type abnormality of reabsorption

• Saliuresis,kaliuresis, decrease ammonium excretion and

glucosuria,proteinuria,bicarbonaturia and phosphaturia
• Cidofovir,adefovir
• Human organic anion transporter(hOAT)
• Proximal tubule
• Probenecid blocks hOATminimizing intracellular
accumulation of drugs(+salicylate, urate,methotrexte nucleoside
analogs)
• Prophylaxis with probenecid can be considered in pt. recieveing
cidofovir and adefovir whose baseline Scr> 1.5 mg/dl.
• เลีย่ งการให้ nephrotoxic agent อืน่ ๆในช่ วงเวลา 1 สั ปดาห์ หลังขากหยุดยา cidofovir
 Interstitial Injury
Mech. Clinical finding Treatment
•Drug-renal tubular •1/3 pt. hypersens classic •d/c drug  supportive
Ag. induce symtomp (fever, rash, care
immuneRx(mediated= arthralgia, eosinophilia,
•Steriod 0.5-1 mg/kg/d
T cell)deposition urine sediment show pyuria,
no of day of renal
interstitium tublitis white cell cast, hematouria,
failure lower than no
mild-moderate proteinuria
•Some drug induce treat (in some study)
deposition of •Renal failure occurs in
•careful evaluation of
antitubular basement early stages
renal fn for initiation new
membrane Ab.
medication
•Numerous drugs
Acute interstititial
nephritis
•Penicillin, methicillin, ampicillin, rifampin, sulfonamide, thiazide,
cimetidine, phenytoin, allopurinol, cephalosporins, cytosine,
arabinoside, furosemide, interferon, NSAIDs, ciprofloxacin, ranitidine,
clarithromycin, telithromycin, pantoprazole, omeprazole, atazanavir, etc
 Obstructive nephropathy Intratubular
crystalluria and/or renal lithiasis
Risk Clinical finding
•similar to those for Renal colic with frank or loin pain, or dysuria
metabolic etiology of
nephrolithiasis High dose acyclovir, ganciclovir, MTX, indinavir
•Hx/presence of renal  intratubular obstruction, tubular injury, acute
lithiasis,low urine renal compromise, CRF
vollume,abnarmality
low/high
pH,hypercalciuria and
hypocitraturia.
•High/prolonged dosing
regimentsincrease
urinary drug excretion
and poor aqueous srug
solubility
Obstructive nephropathy
Extrinsic renal blockage:
1.Ureteral obstruction
•2nd to retropertoneal fibrosis
•Methylsergide, ergotamine, dihydroergotamine, methyldopa,
pindolol, hydralazine, atenolol
•Clinical finding: benign urine sediment, hydronephrosis on
ultrasound.
•Treatment: d/c drug, decompress uretal obstruction
2.Bladder dysfunction
•Tricyclic antidepressants, disopyramideAnticholinergic effect
•Cyclophosphamide, isophosphamideBladder fibrosis
Hemorrhagic cystitis
Obstructive nephropathy

Chemotherapy Obstructive
•Tumor-lysis syndrome (โดยเฉพาะ hematologic malignancy)
•เกิด -Acute oliguria/anuria
-Acute uric nephropathy หลังchemotherapy
•ป้ องกันโดย hydration,alkalinization,allopurinol (600-800 mg/day *3-
4 day)
Nephrolithiasis

(not true nephrotoxicity (with out renal failure))

Formation of kidney stone
•Triamterene
•Sulfadiazinetoxoplasma gondii >>> hydration, alkalinization
•Indinavir  Crystaluria, nephrolithiasis >>> maintain urine
volincrease daily fluid intake to at least 1.5 L during indinavir
therapy
•Mg trisilicate-Al(OH)3  Mg-Ammonium phosphate stone
 Ca phosphate precipitation
•Laxative abuse  Unusual formation of ammonium urate stone
•Allopurinol
Rhabdomyolysis
•Lovastatin ,ethanol, cocaine or heroine abuse, codeine,
barbiturate, diazepam
•Clinical finding: elevate CPK,ATN urine sediment
•Treatment: d/c drug + supportive care

Severe hemolysis
•Quinine, quinidine, sulfonamides, hydralazine, triamterene,
nitrofurantoin, mephenytoin
•Clinical finding: high LDH, decrease hemoglobin
•Treatment: d/c drug + supportive care
 Chronic Interstitial fibrosis

• Lithium,5-aminosalicylic acid, mesalazine,

ifosfamide
• Cidofovir, acyclovir, indinavir
• Cyclosporin, tacrolimus
• Usually progressive, irreversible with interstitail
fibrosis, no systemic symptoms
 Lithium
•เกิด Nephrogenic diabetic
insipidus Nephrogenic
diabetic insipidus: most
common
•Interstitial fibrosis
Prevention & management
•Decrease urinary
concentration, increased Na •Maintaining Li level
excretion and polyuria •Avoid dehydration
Risk •Monitoring renal fn.d/c drug if Scr
drop
•Elevated lithium
level,particularly in •อาการ polyuria,polydipsia หายได้ ถ้าหยุดยา หรืออาจให้
association with dehydration amiloride หรือ NSAIDs หากยังคงต้ องให้ Li ต่ อ
•Concomitant with neuroleptic
agent and ACEI
•Cumulative damage
chronic nephrotoxicity
Tubulointerstitial nephritis: papillary necrosis

Analgesic nephropathy
•Papillotoxin: paracetamol, phenacetin, ASA
•Hemodynamic factor: NSAIDs

High-dose Dapsone
 Analgesic nephropathy

Analgesic use is most common cause of papillary necrosis

Mech.
•Drug = high reactive metabolite +glutathione ไม่ พอ  tissue damge
•High levels at the papillary tip
•Inhibit of vasodilation PGs by NSAIDs medullary ischemia
•PGs ช่ วย oxidise reactive metabolite ที่ medulla ด้ วย
Diagnosis criteria (most sensitive & specific)
•Hx chronic daily anagesic ingestion
•IV pyelography, renal ultrasound/CT  decreased renal mass and bumpy
renal contours
•Papillary calcification( อาจพบ pyelonephritis: small kidney with thin renal
cortices and blunted calyces)
 Analgesic nephropathy

Analgesic syndrome Prevention

•HT& atherosclerosis CVD •Limit dose
•GI cp\omplication •Avoid 2 or more analgesic
•Hematologic complication: combination
anemia, agranulocytopenia •Maintain good hydration
•Skeletal complication ลด renal ischemic & papillary
•Psychosomatic aspect conc.

Urogenital transitional •Use para in renal

carcinomas& renal cell insufficiency pt.
cancers
 Hyponatremia
increase ADH secretion and sensitivity

Thiazide, Clinical finding:

chlopropramide, urine osmolality
vincristine, is less than
IV cyclophosphamide, maximally
cytoxan, clofibrate, diluted in
narcotics, haloperidal, presence of low
thioridazine, serum Na
amitriptyline,
fluphenazine, NSAIDs,
acetaminophen Treatment
Discontinue drug, consider fluid
 Hypokalemia/ hypomagnesemia
(increase urinary excretion)

Gentamycin,
Clinical finding:
cisplatin, Treatment
Increase urine
diuretics, excretion of K+ & Discontinue drug,
carboplatin, Mg++ despite low replace K+ and Mg++
serum levels
nedaplatin
 Hyperkalemia
(antialdersterone or antiadrenergic effect:
blocking Na channel)

ACEIs,
Beta-blockers, Clinical finding
heparin, Decreased urine K+
excretion with high serum
NSAIDs,
K+
K+sparing Treatment
diuretics,
Discontinue drug, treat
trimethoprim, hyperkalemia,low K+ diet
cyclosporin,
pentamidine
 Renal tubular acidosis from renal tubular injury
(decreased acid excreation:inability to reabsorb bicarbonate)

•Amphotericin B, toluene, Clinical finding

Li, cyclamate, analgesics,
Hyperchloremic metabolic
vitamin D intoxication,
acidosis with or
foscarnet,
hypokalemia
•Carbonic anhydrase
inhibitor, outdated
Treatment
tetracycline, mafenide
acetate, 6- Discontinue drug,
mercaptopurine, supportive treatment,
sulfanilamide, cidofovir, HCO3 replacement if
tenofovir, indicated
 Renal tubular acidosis
(decreased aldersterone levels and response)

Clinical finding
Hyperkalemia,
Cyclosporin, hyperchloremic
tacrolimus metabolic acidosis

Treatment
Treat hyper K+, consider HCO3 therapy, low K+ diet,
avoid concurrent medications associated with hyper K+
 Metabolic alkalosis
(increase K+ and H+ secretion in distal nephron)

Loop and thiazide diuretics

Clinical finding
Alkalemia, hypo K+, hypo Cl-

Treatment
Discontinue drug,
volume replace if neccessary
 Nephrogenic diabetes inspidus
(decreased ADH response in collecting tubule)

Li,demeclocycline,
cyclophosphamide,
ifosphamide, Clinical finding
vincristine, cidofovir,
Polyuria
tenofovir,
didanosine, foscarnet Unresponsive to ADH

Treatment
Discontinue drug, supportive therapy
 Principles for pharmacotherapy

• Knows the potential nephrotoxicity of Dx

and therapeutic pharmacologic agents.
• Compare the potential risks and expected
benefits for each course of treatment.
• Consider alternative diagnostic and
therapeutic approaches.
• Use the lowest dose and shortest course
of therapy that is efficacious.
• Monitor appropriately for potential toxicity.
• Monitor therapy if toxicity is occurs.