Drugs and The Kidney

Dr. Shahrzad Shahidi

Dr. Shahrzad Shahidi

Drugs & The Kidney

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-inducedARF

• 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

• Chronic tubulointer-stitial nephropathy

Glomeruli

• Minimal change disease

• Focal segmental glomerulosclerosis

• Membranous GN

• Crescentic GN

• Thrombotic micro-angiopathy

Blood vessels

• Hyalinosis

• Thrombotic micro-angiopathy

•Vasculitis

Patterns of Drug-induced Lesions

Tubulointerstitium

Acute interstitial nephritis

Chronic tubulointer- stitial nephropathy

Acute tubular injury

- Osmotic nephrosis

- Nephrocalcinosis

- Chrystal NP

Glomeruli

Minimal change disease

Focal segmental glomerulosclerosis

Membranous GN

Crescentic GN

Thrombotic micro-angiopathy

Blood vessels

Hyalinosis

Thrombotic micro-angiopathy

Vasculitis

NSAID CNINSAID

Bisphosphonates

Captopril Hydralazin

Rifampicin

CisplatinTamoxifen

Lithium

SirolimusInterferon

CNI

ACE-I

Antibiotics

DiazepamLithiumThiazids

CNI COX2-I

BarbituratesVirostatics

BisphosphonatesHES

Cisplatin

Quinolones

Clopidogrel

Quinine Phenytoin

Sulfasalazine

Ranitidin

Case PP: Female , 50 y CC: Fatigue since 1 wk agoPI: Nocturia, Polyuria 2 wksPH: Sinusitis 3 wks ago, treated with Amoxicilline

500 mg 3 tab/d for 2 wks, HTN 5 yrsFH: HTN in her mother, DM in her brotherPE: BP: 90/60, PR: 86, Pallor, dry mouth & skin.

Nocturia, Polyuria Amoxicilline Fatigue

Case • 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

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

Radiocontrast Agents

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 hypothyroidismB) RPGNC) 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-InflammatoryDrugs (NSAIDs)

Chemical Structure Generic NameAcetic acids: Diclofenac, Indomethacin,

Sulindac,

Fenamates: 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

• Hemodynamically- Induced ARF

• Acute Interstitial Nephropathy + Proteinuria

• Papillary necrosis & CRF(Analgesic nephropathy)

• Salt & water retention: Hyperkalemia, HTN

NSAIDs

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

Papillary necrosis

Analgesic Nephropathy

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

• Acyclovir (antiviral agent )

• Indinavir (antiretroviral agent, protease

inhibitor)

• Methotrexate (antineoplastic agent,

antimetabolite)

• Sulfonamide antibiotics

• Triamterene

Crystal-Induced ARF

Sulfonamide crystalsIndinavir sulfate urinary crystals

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

Crystal-Induced ARF

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 ofTherapy 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)

• 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

• Avoid dehydration

• Limit dose & duration of treatment

• Adjust the dose based on changes in

GFR

• Avoid a combination of potentially

nephrotoxic drugs

Prevention: General Rules (Cont’d)

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