drugs and the kidney dr. shahrzad shahidi drugs & the kidney

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  • Drugs and The Kidney Dr. Shahrzad Shahidi Drugs & The Kidney
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  • 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
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  • 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
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  • 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
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  • 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)
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  • Patterns of Drug-induced Lesions T ubulointerstitium 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
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  • 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 NSAIDCNI NSAID Bisphosphonates Captopril Hydralazin Rifampicin Cisplatin Tamoxifen Lithium Sirolimus Interferon CNI ACE-I Antibiotics Diazepam Lithium Thiazids CNI COX2-I Barbiturates Virostatics Bisphosphonates HES Cisplatin Quinolones Clopidogrel Quinine Phenytoin Sulfasalazine Ranitidin
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  • 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. Nocturia, PolyuriaAmoxicilline Fatigue
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  • 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
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  • Based on Experimental AIN www.nature.com/ki/journal
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  • 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
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  • Ionic vs. Nonionic High (1500-1800) Low (600-850) Iso-osmolal (~ 290 mOsm/kg )) Radiocontrast Agents
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  • Pathogenesis: Renal Vasoconstriction (Adenosine, Endothelin) Tubular Injury Oxidative stress induced damage Radiocontrast Agents
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  • 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
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  • 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
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  • 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
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  • 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 ?
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  • 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
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  • Nonsteroidal Anti-Inflammatory Drugs (NSAIDs) Chemical StructureGeneric Name Acetic 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
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  • Hemodynamically- Induced ARF Acute Interstitial Nephropathy + Proteinuria Papillary necrosis & CRF(Analgesic nephropathy) Salt & water retention: Hyperkalemia, HTN NSAIDs
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  • NSAIDs Acute Interstitial Nephropathy + Proteinuria Acute interstitial nephritis Minimal-change glomerular disease Proteinuria Prognosis good after discontinuation of therapy; Corticosteroids ?
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  • 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
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  • Analgesic Nephropathy Papillary necrosis
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  • Analgesic Nephropathy
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  • 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?
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  • 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
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  • 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.
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  • 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)
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  • 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
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  • Acyclovir (antiviral agent ) Indinavir (antiretroviral agent, protease inhibitor) Methotrexate (antineoplastic agent, antimetabolite) Sulfonamide antibiotics Triamterene Crystal-Induced ARF
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  • Sulfonamide crystals Indinavir sulfate urinary crystals Gagnon et al. 1998, Ann Intern Med 128-321 Crystal-Induced ARF


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