Drugs and The Kidney
Drugs &
The Kidney
Dr. Shahrzad Shahidi
Dr. Shahrzad Shahidi
Introduction
• The heart pumps approximately 25% of CO
into the kidneys
• Any drug in the blood will eventually reach
the highly vascularized kidneys
• May potentially cause drug-induced renal
failure
• The drug may be filtered or secreted into the
lumen of the renal tubules
• The concentrated drug exposes the kidney
tissue to far greater drug concentration per
surface area
Clinical Presentation
• Drug-induced renal disease can mimic renal disease
from other causes, such as autoimmune disease &
infection
• A thorough PEx & medical Hx should be performed
• Increase in serum Cr & BUN
• Additional urine tests: Pr excretion, Cr
concentration, osmolality or Na excretion
• A thorough & accurate review of all medications,
including all prescription, over-the-counter &
herbal medications
• Importance of dose & duration of exposure
• Rule out all other causes of kidney failure
Pseudo Renal Failure
• ↑ BUN due to protein catabolism
– Steroids, tetracyclines
• ↑ SCr due to competitive inhibition of cr
secretion
– Trimethoprim, Cimetidine
• Trimethoprim
– 15-35% rise SCr fully expressed after 3 days
– More sig in pts with pre-existing renal dysfunction
– Can occur with normal doses
– Completely reversible when drug is discontinued
Mechanisms of nephrotoxin-induced
ARF
• Direct nephrotoxicity
– Tubuloepithelial injury
– ATN (e.g.,aminoglycosides)
– Osmotic nephrosis (e.g., hypertonic solutions, IV IG)
• Interstitial nephritis
– Acute allergic interstitial nephritis (e.g., penicillins)
– Chronic interstitial nephritis (e.g., calcineurin inhibitors)
– Papillary necrosis (e.g., NSAIDs)
• Glomerular disease
– Glomerulonephritis (e.g., gold, penicillamine, ACE inhibitors)
– Renal vasculitis (e.g., hydralazine)
• Obstructive uropathy
– Crystalline nephropathy (e.g., acyclovir, indinavir)
• Indirect nephrotoxicity
– Decreases intrarenal blood flow (e.g., ACE inhibitors, NSAIDs)
Patterns of Drug-induced Lesions
Tubulointerstitium
• Acute tubular injury
- Osmotic nephrosis
- Nephrocalcinosis
- Crystal NP
• Acute interstitial
nephritis
Glomeruli
• Minimal change
disease
Blood vessels
• Hyalinosis
• Thrombotic
• Focal segmental
glomerulosclerosis micro-angiopathy
• Vasculitis
• Membranous GN
• Crescentic GN
• Chronic tubulointer- • Thrombotic microstitial nephropathy
angiopathy
Patterns of Drug-induced Lesions
Tubulointerstitium
Glomeruli
Acute interstitial
Antibiotics
NSAID
nephritis
ACE-I
Diazepam
Chronic
Lithium tubulointerstitial nephropathy
Thiazids
COX2-I
CNI tubular injury
Acute
Minimal change
Lithium
NSAID
disease
Virostatics
- Osmotic nephrosis
HES
Bisphosphonates
- Nephrocalcinosis
Ranitidin
- Chrystal NPCisplatin
Barbiturates
Quinolones
Sirolimus
Focal segmental
Interferon
glomerulosclerosis
Bisphosphonates
Captopril
Hydralazin
Membranous GN
Crescentic
GNRifampicin
CNI
Thrombotic microCisplatin
Tamoxifen
angiopathy
Blood vessels
Hyalinosis
CNI
ThromboticClopidogrel
microSulfasalazine
angiopathy
Vasculitis
Quinine
Phenytoin
Case
PP: Female , 50 y
CC: Fatigue since 1 wk ago
PI: Nocturia, Polyuria 2 wks
PH: Sinusitis 3 wks ago, treated with Amoxicilline
500 mg 3 tab/d for 2 wks, HTN 5 yrs
FH: HTN in her mother, DM in her brother
PE: BP: 90/60, PR: 86, Pallor, dry mouth & skin.
Amoxicilline
Nocturia, Polyuria
Fatigue
Case
•
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•
•
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•
Hb: 10 g/L
FBS: 80 mg/dl
BUN: 60 mg/dl
Cr: 4
mg/dl
Na: 124 meq/L
K: 6
meq/L
UA: 9 mg/dl
• U/A:
– SG 1.007
– Pr +
– Glu +
– RBC 6-8/HPF
– WBC 10-15/HPF
– WBC cast 0-1/LPF
• U/C: Neg
Based on Experimental AIN
www.nature.com/ki/journal
Pre-renal causes
• Vasoconstriction
– Contrast agents
– Amphotericin, noradrenalin,
immunosuppressive agents such as
tacrolimus & cyclosporine
– Iodinated contrast media, in particular, have
been shown to inhibit the synthesis of nitric
oxide in renal artery smooth muscle
Radiocontrast Agents
 Ionic vs. Nonionic
 High (1500-1800)
Low (600-850)
Iso-osmolal (~ 290 mOsm/kg))
Radiocontrast Agents
•
Pathogenesis:
– Renal Vasoconstriction
(Adenosine, Endothelin)
– Tubular Injury
Oxidative stress induced damage
Radiocontrast Agents
• Risk Factors:
– Underlying renal disease (Cr >1.5mg/dl)
– Diabetic nephropathy, HF,
Hypovolemia
– Multiple Myeloma
– Dose (lower doses safer but not
necessarily safe)
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
Prevention:
– Use of alternative diagnostic
procedures in high risk patients
– Avoidance of volume depletion or
other nephrotoxins
– Low-doses of low- or iso-somolar
agent
– IV saline
Case
• 65 year old male with H/o HTN, ventricular arrythmias
controlled on Amiodarone, OA on NSAIDs. presents with
puffiness on face on waking up. Has bilateral pitting edema.
• U/A: 3+ pr, RBC 3-5/HPF, WBC 15-20/HPF
• 24 h urine pr : 4 g
• BUN: 80 mg/dl , Cr: 5 mg/dl , Serum Albumin : 2.8 g/dl, TSH : Nr
• The most likely Diagnosis?
A) Amiodarone induced hypothyroidism
B) RPGN
C) NSAIDs induced nephrotic syndrom & interstitial nephritis
• The most likely Management & Follow up?
Nephrotic syndrome
• Abnormal amounts of Pr in the urine
• Drugs : NSAIDs, penicillamine & gold,….
• Damage the glomerulus & alter the ability of
the glomerulus to prevent Pr from being
filtered
• Stopping the drug may resolve the damage to
the glomerulus
Nonsteroidal Anti-Inflammatory
Drugs (NSAIDs)
Chemical Structure
Generic Name
Acetic acids:
Fenamates:
Diclofenac, Indomethacin, Sulindac,
Meclofenamate, Mefenamic acid
Napthylalkanones:
Nabumetone
Oxicams:
Meloxicam , Piroxicam
Propionic acids:
Fenoprofen, Flurbiprofen, Ibuprofen,
Ketoprofen, Naproxen, Oxaprozin
Pyranocaboxylic acid:
Etodolac
Pyrrolizine carboxylic acid:
Ketorolac
Selective COX-2 inhibitors:
Celecoxib, Rofecoxib
NSAIDs
• Hemodynamically- Induced ARF
• Acute Interstitial Nephropathy + Proteinuria
• Papillary necrosis & CRF(Analgesic
nephropathy)
• Salt & water retention: Hyperkalemia, HTN
NSAIDs
• Acute Interstitial Nephropathy +
Proteinuria
 Acute interstitial nephritis
 Minimal-change glomerular disease
 Proteinuria
 Prognosis good after discontinuation
of therapy; Corticosteroids ?
NSAIDs
• Analgesic nephropathy
(Chronic Interstitial Nephritis & Papillary necrosis )
– Single vs. combined analgesics
– Dose dependent (at least 1 kg)
– Patients with history of depended behaviors
– Slowly progressive ; Asymptomatic,
sometimes hematuria, flank pain, or urinary
infections.
– Being responsible for 1% to 3% of ESRD cases
Analgesic Nephropathy
Papillary
necrosis
Analgesic Nephropathy
Papillary necrosis
NSAIDs/COX II Inhibitors
• Physician would like to switch previous
patient from Naproxen to Celecoxib
• Are Cox II inhibitors less likely to cause
ARF compared to NSAIDs?
NSAIDs/COXibs
• Use with caution in CKD (grade 3 or greater)
• Inhibit renal vasodilatory prostaglandins E2 & I2
– Produced by COX-2
• Reversible reduction in GFR
– Higher risk if intravascular volume depletion
– Management: D/C drug, use alternate analgesia
• HTN
– Edema, sodium and water retention
– Mean increase SBP 5 mm Hg
• Hyperkalemia Risk
– Blunting of PG-mediated renin release
Osmotic nephrosis
• A morphological pattern with vacuolization &
swelling of the renal proximal tubular cells.
• The term refers to a nonspecific histopathologic
finding rather than defining a specific entity.
• It has a broad clinical spectrum that includes AKI &
CKD in rare cases.
• High doses of mannitol, soucrose-containing IVIg,
contrast dye , dextrans & starches are nephrotoxic
• Mechanism: uptake of these large molecules by
pinocytosis into the proximal tubule cells.
Post-renal failure
• Usually results from a mechanical barrier
to moving urine from the collecting
tubules into the bladder
• Mechanical obstruction :
– Bladder retention (in BPH, Neurogenic
bladder)
– Kidney stones
– Drugs that precipitate in the kidney
(acyclovir, ganciclovir)
DRUGS OF ABUSE
• Cocaine & heroin
• Cocaine use can cause renal artery
thrombosis (clotting), severe HTN &
interstitial nephritis
• Long-term cocaine use can lead to CRF
• Tobacco use increase the progression
rate of CKD
• Long-term tobacco use also increases the
risk of kidney cancer
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
Case
• 52 yo male with Type 2 DM
• Baseline cr 1.8 mg/dl; BP 145/90
• Enalapril 10 mg daily started & 2 weeks
later: BP 135/80
• Serum cr 2.2 mg/dl
Optimal Use of ACEI/ARB
• Cr ↑ 1.8 to 2.2 mg/dl in 2 wks
– Accept 20-30% increase in serum cr within 1-2
months of initiation
• In fact, this could be an indication that the drugs are
exerting their desired actions to help preserve renal
function
• Check serum cr 1-2 wks after initiation, then in 2-4 wks
• If > 30% change, decrease ACEI/ARB dose by 50% &
repeat Ser Cr in 4 wks (exclude hypovolemia/NSAIDs, etc)
• If > 50% rise in Ser Cr – rule out RAS
• Repeat serum cr in this patient in 1-2 wks to
ensure it has stabilized
Case
• 82 yo female with osteoarthritis
• Admitted to hospital for CAP &
dehydration
• Meds: Losartan 100mg daily + Naproxen
250mg BID
• Cr 3 mg/dl
Optimal Use of ACEI/ARB
• Cr on admission 3 mg/dl in patient with
CAP & dehydration
– Discontinue NSAID & hold ARB until
infection treated & patient is rehydrated/cr
reduced
• Resume ARB & monitor serum cr
Causes of AKI after Initiation of
Therapy with ACE Inhibitor or ARB
• BP insufficient for adequate renal perfusion
– Poor cardiac output
– Low systemic vascular resistance (e.g., as in sepsis)
– Volume depletion (GI loss, excess diuretic use, …)
• Presence of renal vascular disease*
– Bilateral renal artery stenosis
– Stenosis of dominant or single kidney
– Afferent arteriolar narrowing (caused by HTN, cyclo..)
– Diffuse atherosclerosis in smaller renal vessels
• Vasoconstrictor agents (NSAIDs, cyclosporine)
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
• Monitor the RFT if necessary
Prevention: General Rules (Cont’d)
• Avoid dehydration
• Limit dose & duration of treatment
• Adjust the dose based on changes in GFR
• Avoid a combination of potentially
nephrotoxic drugs
Conclusion
• Many drugs cause AKI
• Increase the risk of drug-induced AKI:
– Age (particularly over 65 years)
– Pre-existing renal impairment
– Comorbidities such as DM, HF, liver cirrhosis
– Hypovolaemia
• Addressing potential risk factors
• Understanding of the mechanisms of
nephrotoxicity involved