Drug induced nephrotoxicity. Naser Hadavand. Classification of Drug Induced Disordres. Definitions Type Onset Severity. Definition and Classifications of Adverse Reaction Terms. Adverse Event: Adverse Drug Reaction: Side Effect:. Comparison Type A and Type B.
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Drug induced nephrotoxicity Naser Hadavand
Classification of Drug Induced Disordres • Definitions • Type • Onset • Severity
Definition and Classifications of Adverse Reaction Terms Adverse Event: Adverse Drug Reaction: Side Effect:
Adverse Drug Reactions Unwanted effects of drugs are separated into those represent: • Augmented pharmacological effects of a substance but qualitatively normal (Type A) • Qualitatively bizarre pharmacological effects (Type B) • Long term effects (Type C) • Delayed effects (Type D) • End of use (Type E) • Failure (Type F) * Most long term effects are Type A reactions.
Drug induced nephrotoxicity Introduction • Occurs frequently in patients treated with diagnostic and therapeutic agents • Manifestation Decrease in renal function(often reversible) • Is seen in which patients?
Incidence • 5% بیماران بستری در بیمارستان دچار نارسایی حاد کلیوی می شوند. • 25% موارد نارسایی حاد کلیوی حاصل از مصرف دارو می باشد. که در 8% موارد منجر به مرگ می شود. • نارسایی کلیوی حاصل از دارو 7% کل مسمومیت های دارویی را شامل می شود.
Risk factors: • Idiosyncratic • Direct cumulative toxicity • No generalizable risk factors are applicable to all drug classes and patient situation ,Exception: ARF due to NSAIDs & ACEIs • The risk factors are: Preexisting renal insufficiency & decrease effective renal blood flow from volume depletion and HF, liver dx.
Recognition and assessment of renal toxicity: • Hospitalized patients: 1-recognized quickly 2-by lab test: BUN,Cr 3-decrease in urine out put(ACEIs,NSAIDs, Radiographic contrast) • Out patients recognized by advanced renal dysfunction • Signs
Classification of drug induced renal disease: • Based on mechanism of toxicity • Presenting of renal manifestations: CRF,ARF,Pyuria,Hematuria, Proteinuria • Therapeutic use and the various types of nephropathies they may produced Renal structural and functional alterations(produced by drugs)
Definitions: • Pseudo Renal Failure • Interstitial Nephritis • Acute interstitial nephritis • Chronic interstitial nephritis • Acute Glomerulonephritis • Acute Tubular Necrosis • Crystal nephropathy • Rhabdomyolysis • Nephrotic Syndrome • minimal-change nephropathy
Pseudo Renal Failure (Normal GFR) • ↑ BUN due to protein catabolism , Normal Cr Steroids, tetracyclines • ↑ SCr due to competitive inhibition of creatinine secretion, Normal BUN Trimethoprim, Cimetidine, Triamterene - 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 (J Int Med 1999l246:247-52; TDM 1987;9:161-5)
Definitions: • Interstitial Nephritis Interstitial nephritis (or Tubulo-interstitial nephritis) is a form of nephritis affecting the interstitium of the kidneys surrounding the tubules. This disease can be either acute, meaning it occurs suddenly, or chronic, meaning it is ongoing and eventually ends in kidney failure.
Definitions: • Interstitial Nephritis • When caused by an allergic reaction, the symptoms of acute tubulointerstitial nephritis are: - fever (27% of patients) - rash (15% of patients) - enlarged kidneys. • Other: Dysuria, and lower back pain. In chronic tubulointerstitial nephritis: nausea, vomiting, fatigue, and weight loss. hyperkalemia, metabolic acidosis, and kidney failure. • Blood tests: Eosinophilia, ↑ Cr & BUN • Urinary findings: Eosinophiluria, Isosthenuria, hematuria, Sterile pyuria: white blood cells and no bacteria
Definitions: • Acute Glomerulonephritis Glomerulonephritis, also known as glomerular nephritis, abbreviated GN, is a renal disease (usually of both kidneys) characterized by inflammation of the glomeruli, or small blood vessels in the kidneys. It may present with isolated hematuria and/or proteinuria (blood or protein in the urine); or as a nephrotic syndrome, a nephritic syndrome, acute renal failure, or chronic renal failure. Primary causes are intrinsic to the kidney. Secondary causes are associated with certain infections (bacterial, viral or parasitic pathogens), drugs, systemic disorders (SLE, vasculitis), or diabetes.
Definitions: • Acute Tubular Necrosis Acute tubular necrosis (ATN) is a medical condition involving the death of tubular cells that form the tubule that transports urine to the ureters while reabsorbing 99% of the water (and highly concentrating the salts and metabolic byproducts). Tubular cells continually replace themselves and if the cause of ATN is removed then recovery is likely. ATN presents with acute kidney injury (AKI) and is one of the most common causes of AKI.The presence of "muddy brown casts" of epithelial cells found in the urine during urinalysis is pathognomonic for ATN.
Definitions: • Crystal nephropathy Several medications that are insoluble in human urine are known to precipitate within the renal tubules. Intratubular precipitation of either exogenously administered medications or endogenous crystals (induced by certain drugs) can promote chronic and acute kidney injury, termed crystal nephropathy. Clinical settings that enhance the risk of drug or endogenous crystal precipitation within the kidney tubules include: - true or effective intravascular volume depletion - underlying kidney disease - and certain metabolic disturbances that promote changes in urinary pH favoring crystal precipitation.
Definitions: • Rhabdomyolysis Rhabdomyolysis is a condition in which damaged skeletal muscle tissue , breaks down rapidly. Breakdown products of damaged muscle cells are released into the bloodstream; some of these, such as the protein myoglobin, are harmful to the kidneys and may lead to kidney failure. The severity of the symptoms, which may include muscle pains, vomiting and confusion, depends on the extent of muscle damage and whether kidney failure develops. The muscle damage may be caused by physical factors (e.g. crush injury, strenuous exercise), medications, drug abuse, and infections. Some people have a hereditary muscle condition that increases the risk of rhabdomyolysis. The diagnosis is usually made with blood tests and urinalysis. The mainstay of treatment is generous quantities of intravenous fluids, but may include dialysis or hemofiltration in more severe cases. Rhabdomyolysis and its complications are significant problems for those injured in disasters such as earthquakes and bombings. Relief efforts in areas struck by earthquakes often include medical teams with the skills and equipment to treat survivors with rhabdomyolysis. The disease was first described in the 20th century, and important discoveries as to its mechanism were made during the Blitz of London in 1941. Horses may also suffer from rhabdomyolysis from a variety of causes.
Definitions: • Nephrotic Syndrome Nephrotic syndrome is a nonspecific kidney disorder characterised by a number of diseases: proteinuria, hypoalbuminemia and edema. It is characterized by an increase in permeability of the capillary walls of the glomerulus leading to the presence of: - high levels of protein passing from the blood into the urine (proteinuria at least 3.5 grams per day per 1.73m2 body surface area); - low levels of protein in the blood (hypoproteinemia or hypoalbuminemia), - Ascites and edema - High cholesterol (hyperlipidaemia or hyperlipemia) - Predisposition for coagulation. Kidneys affected by nephrotic syndrome have small pores in the podocytes, large enough to permit proteinuria (and subsequently hypoalbuminemia,<25g/L, because some of the protein albumin has gone from the blood to the urine) but not large enough to allow cells through (hence no haematuria). By contrast, in nephritic syndromered blood cells pass through the pores, causing haematuria.
Edema Nephrotic Syndrom Diagnosis: Pro ++++ • Proteinuria: >3.5g/d • Hypoalbuminemia: SAlb <30g/L • Edema; • Hyperlipidemia.
Definitions: • minimal-change nephropathy Minimal Change Disease (also known as Nil Lesions or Nil Disease (lipoid nephrosis)) is a disease of the kidney that causes nephrotic syndrome and usually affects children (peak incidence at 2–3 years of age). People with one or more autoimmune disorders are at increased risk of developing minimal change disease. Having minimal change disease also increases the chances of developing other autoimmune disorders. Most cases of MCD are idiopathic, however there have been causes of secondary MCD identified, including medications, immunizations, neoplasm, and infection. Case reports and literature reviews have shown an association between MCD and malignancies, particularly hematologic malignancies, such as Hodgkin’s disease, non-Hodgkin lymphomas, or leukemias. Colorectal cancer-associated MCD is uncommon and has been reported in only a few cases to date.
CLASSIFICATIONS • Anuric:< 50ml/day urine output • Oliguric: 50-400ml/day urine output • Non-oliguric: >400ml/day urine output
نارسایی کلیوی • Pre Renal: ↑BUN/ ↑ Cr >20 • Post Renal: ↑ BUN/ ↑ Cr 10 – 20 • Renal: ↑BUN/ ↑ Cr < 10
ESTIMATION OF RENAL FUNCTION CLCr(ml/min) = (140-Age)×(Wt.) 72(Scr) = ×0.85 (female) • Cockcroft and Gault Equation: • Estimates renal function when creatinine levels are at steady-state • not usually the case in acute renal failure
Serum Creatinine • Creatinine 1.0 mg/dL Normal GFR • Creatinine 2.0 mg/dL 50% reduction in GFR • Creatinine 4.0 mg/dL 70–85% reduction in GFR • Creatinine 8.0 mg/dL 90–95% reduction in GFR
Estimate Creatinine Clearance: (ml/min) Cockcroft and Gault equation: CrCl: (140 - age) x IBW / (Scr x 72) (x 0.85 for females) Note: if the ABW (actual body weight) is less than the IBW use the actual body weight for calculating the CRCL. If the patient is >65yo and creatinine<1, use 1 to calculate the creatinine clearance.
Estimate Ideal body weight in (kg) Males: IBW = 50 kg + 2.3 kg for each inch over 5 feet. Females: IBW = 45.5 kg + 2.3 kg for each inch over 5 feet. • Adjusted body weight (ABW): • ABW = IBW + 0.4(Total body weight - IBW)
داروها بیشتر باعث بروز نارسایی حاد کلیوی می شوند یا نارسایی مزمن کلیوی؟ • Definitions • Type • Onset • Severity
آیا احتمال دارد بیمار دچار نارسایی کلیوی حاصل از داروها شود بدون اینکه برون ده اداری او تغییر کند؟
آیا مرگ و میر حاصل از نارسایی حاد کلیوی ایجاد شده توسط داروها بیشتر از سایر علل آن می باشد؟
کدامیک از عوارض کلیوی حاصل از داروها وابسته به دوز دارو نیست؟ • Acute interstitial nephritis • Acute Tubular Necrosis • Obstructive
Aminoglycosides • Is once daily dosing less nephrotoxic compared to traditional dosing?
آیا فرمولاسیون دارو می تواند در بروز عارضه کلیوی نقش داشته باشد؟
Amphotericin B • Are Liposomal formulationsaffect nephrotoxicity
تشخیص زودهنگام نارسایی کلیوی حاصل از دارودرکدام بیماران رایج تر/ محتمل تر است؟ • بستری • سر پایی
در تمامی بیماران مصرف کننده ACEI افزایش کراتینین رخ می دهد؟ • درست • نادرست
در تمامی بیماران مصرف کننده ACEI افزایش کراتینین رخ می دهد؟ • درست • نادرست
آیا با افزایش کراتینین در بیماران مصرف کننده ACEI دارو باید قطع گردد؟ • بلی • خیر • بستگی دارد
عوارض کلیوی با کدامیک از داروهای زیر بیشتر رخ می دهد؟ - NSAIDs - Cyclosporine - Amphotericin-B - Radiocontrast Media - Vasopressors
برای جلوگیری از تشکیل کریستال و رسوب داروها در توبول ها بهتر است pH ادرار اسیدی باشد یا بازی؟ • اسیدی • بازی • بستگی دارد
کدام گزینه در مورد مکانیسم ایجاد عارضه کلیوی دارویی نادرست است؟ A. Tubular cell toxicity — ACE inhibitors B. Altered intraglomerular hemodynamics — ARBs C. Crystal nephropathy — Antivirals D. Rhabdomyolysis — Statins
در کدامیک از موارد زیر دارو باید قطع گردد؟ • Relative Serum Creatinine increase 50% over baseline • Absolute Serum Creatinine increase • Serum Creatinine baseline <2 mg/dl: Creatinine increase 0.5 mg/dl over baseline • Serum Creatinine baseline >2 mg/dl: Creatinine increase 1.0 mg/dl over baseline