Drug induced kidney disease
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Drug induced kidney disease
- 1. Drug Induced Kidney Disease (DIKD) Clinical Pharmacy BY: Dr.Muhammad Umair Pharm.D, M.Phil. Pharmaceutics(Clinical Pharmacy) Lecturer Lahore Pharmacy College Of Lahore Medical & Dental College (Pakistan)
- 2. DIKD/DIN ā¢ Drug induced nephrotoxicity (DIN) ā¢ Common complication of several diagnostic and therapeutic agents ā¢ Manifested as ā¢ Acidābase abnormalities, Electrolyte imbalances ā¢ Urine sĆ©diment abnormalities ā¢ Proteinuria, pyuria, and hematuria ā¢ Decline in the glomerular filtration rate (GFR) ā¢ Rise in the serum creatinine (Scr) and blood urea nitrogen (BUN)
- 3. ā¢ Often reversible on discontinuation of the offending agent ā¢ Maylead to acute Renal Failure (ARF) or end-stage renal disease (ESRD)
- 6. Epidemiology ā¢ 20% of hospital admissions due to AKI are drug related ā¢ Most of them are communityacquired ā¢ AKI: 7% of hospitalized patients, 20-30% of critically illpatients, significant source of morbidity and mortality ā¢ Up to 25% of ARF cases are attributed by use of certain drugs
- 7. Risk factors ā¢ Patient-related factors ā¢ Age, sex, race ā¢ Pre-existent renal disease ā¢ Specific disease (diabetes mellitus, multiple myeloma, proteinuric patients) ā¢ Sodium-retaining states (cirrhosis, heart failure, nephrosis) ā¢ Dehydration and volume depletion ā¢ Acidosis, potassium and magnesium depletion ā¢ Hyperuricemia, hyperuricosuria ā¢ Sepsis, shock ā¢ Renal transplantation
- 8. Risk factors ā¢ Drug-related factors ā¢ Inherent nephrotoxic potential ā¢ Dose ā¢ Duration, frequency and form of administration ā¢ Repeated exposure ā¢ Drug interactions ā¢ Combined or closely associated use of diagnostic or therapeutic agents with added or synergistic nephrotoxic potential (e.g.Radiocontrast agents, aminoglycosides, NSAIDs, cisplatin,ACEI)
- 9. CLINICAL PRESENTATION ā¢ General ā¢ The most common manifestation is a decline in GFR leading to a rise in Scr and BUN. ā¢ Symptoms ā¢ Malaise, anorexia, vomiting, shortness of breath, or edema. ā¢ Signs ā¢ Decreased urine output may be an early sign of toxicity, particularly with radiographic contrast media, NSAIDs, and ACEIs, with progression to volume overload and hypertension.
- 10. ā¢ Proximal tubular injury ā¢ Metabolic acidosis with bicarbonaturia ā¢ Glycosuria in the absence of hyperglycaemia ā¢ Reductions in serum phosphate, uric acid, potassium, and magnesium as a result of increased urinary losses ā¢ Distal tubular injury ā¢ Polyuria from failure to maximally concentrate urine ā¢ Metabolic acidosis from impaired urinary acidification ā¢ Hyperkalaemia from impaired potassium excretion
- 11. ā¢ Laboratory Tests ā¢ Achange in Scr of at least 0.5 mg/dL for subjects with a baseline Scr <2 mg/dL and ā¢ An increase of >30% for those with Scr >2 mg/dL, when correlated temporally with the initiation of drug therapy is commonly observed
- 12. Prevention ofDIKD/DIN ā¢ Avoid the use of potentially nephrotoxic agents (patients at increased risk for toxicity) ā¢ Maintain careful and adequate hydration to establish high renal tubular urine flow rates ā¢ Drug mechanism specific intervention
- 13. Injury patterns ā¢ Subtle injury or overt renal failure ā¢ Some drugs perturb renal perfusion and induce loss of filtration capacity ā¢ Others directly injure vascular, tubular, glomerular and interstitial cells ā¢ Specific loss of renal function leads to clinical findings ā¢ Microangiopathy ā¢ Acute tubular necrosis ā¢ Acute interstitial nephritis ā¢ Nephrotic syndrome, obstruction ā¢ Nephrogenic diabetes insipidus ā¢ Electrolyte abnormalities and chronic renal failure
- 14. ā¢ True incidence of DIN is difficult to determine ā¢ Markers of earlyinjury are being investigated ā¢ Detection is often delayed until an overt change in renal functional capacity is measured as an increase in BUN, Scr ā¢ Subtle renal damages associated with medications are frequently unrecognized ā¢ Tubulopathy, acidābase abnormalities, electrolyte imbalances and disorders of water balance and mild urinary sediment abnormalities
- 15. Renal pathophysiological alterations (Drug Induced) ā¢ Tubular epithelial cell damage ā¢ Acute tubular necrosis ā¢ Osmotic nephrosis ā¢ Hemodynamically mediated kidney injury ā¢ Obstructive nephropathy ā¢ Intratubular obstruction ā¢ Nephrolithiasis ā¢ Glomerular disease ā¢ Tubulointerstitial disease ā¢ Acute allergic interstitial nephritis ā¢ Chronic interstitial nephritis ā¢ Nephrocalcinosis ā¢ Papillary necrosis ā¢ Renal vasculitis, thrombosis, and cholesterol emboli ā¢ Vasculitis and thrombosis ā¢ Cholesterol emboli
- 16. 1-Tubular epithelial cell damage ā¢ Caused by either direct toxic or ischemic effects of drugs ā¢ Damage is localized in the PCT & DCT epithelia ā¢ Acute tubular necrosis ā¢ Observed as cellular degeneration and sloughing from PCT & DCT basement membranes ā¢ Osmotic nephrosis ā¢ Swellingand vacuolization of proximal tubular cells
- 17. A. ACUTE TUBULAR NECROSIS
- 18. Aminoglycoside Nephrotoxicity ā¢ Incidence ā¢ 5% to 15% of patients receiving aminoglycoside therapy ā¢ Clinical Presentation ā¢ Gradual progressive rise in Scr and in CrCl after 6 to 10 days of therapy ā¢ Nonoliguria >500 mL/day ā¢ Magnesium wasting >10 to 30 mg ā¢ Severe kidney injury does not usually develop
- 19. ā¢ Pathogenesis ā¢ Binding, intracellular transport in lysosomes ā¢ Release of lysosomal enzymes ā¢ ROS generation, Altered cell metabolism and membrane fluidity ā¢ Cellular dysfunction and death ā¢ PCT epithelial cell damage leading to obstruction of the tubular lumen ā¢ Back leakage of the glomerular filtrate across the damaged tubular epithelium ā¢ Reduction of GFR
- 20. ā¢ Risk Factors ā¢ Aggressive aminoglycoside dosing ā¢ Combination of nephrotoxic drugtherapy ā¢ Existing predisposing conditions ā¢ Prevention ā¢ Alternative therapy: fluoroquinolones, 3rd or 4th generation cephalosporins ā¢ Limit the total aminoglycoside dose administered ā¢ Avoid concomitant therapy with other nephrotoxic drugs ā¢ High intermittent dosing: Once daily dosing regimen
- 22. ā¢ Management ā¢ Measure Scr every 2 to 4 days ā¢ Maintain adequate hydration (Avoid volume depletion) ā¢ Discontinue or revised regimen ifScr increase of 0.5 mg/dL ormore ā¢ Short-term dialysis
- 23. Amphotericin-B Nephrotoxicity ā¢ Incidence ā¢ Toxicityrelates to cumulative dosage, starts from 300-400mg, 4g (at higher doses 80% incidence) ā¢ Clinical Presentation ā¢ Renal tubular potassium, sodium, and magnesium wasting ā¢ Impaired urine concentrating ability ā¢ Distal renal tubular acidosis ā¢ Decrease in renal blood flow and GFR ā¢ Rise in Scr and BUN
- 24. ā¢ Pathogenesis ā¢ Increases tubular permeability ā¢ Consequent increase in energy and oxygen requirements of epithelial cells ā¢ Reduced cellular oxygen delivery due to renal vasoconstriction ā¢ Renal medullary tubular epithelial cell necrosis and kidney injury ā¢ Risk Factors ā¢ CKD ā¢ Higher average daily doses ā¢ Volume depletion ā¢ Concomitant administration of diuretics ā¢ Rapid infusion rate
- 25. ā¢ Prevention ā¢ Liposomal amphotericin Bformulations (Targeted drug delivery) ā¢ IV infusion of NS daily during the course of therapy reduces toxicity ā¢ Management ā¢ Discontinuation and substitution of therapy ā¢ Daily monitoring of Renal function indices i.e. Scr and BUN ā¢ Daily monitoring of serum magnesium, potassium, and calcium concentrations
- 26. Cisplatin and Carboplatin Nephrotoxicity ā¢ Incidence ā¢ Previously incidence was 50-100%, now it has reduced to 6-13% ā¢ 20% to 40% decline in GFR is frequently observed ā¢ Pathogenesis ā¢ Binding to PCT cell proteins and sulfhydryl groups ā¢ Disruption of cell enzyme activity, uncoupling of oxidativephosphorylation ā¢ Initially PCT is damaged which progresses to DCT and glomerular necrosis
- 27. ā¢ Clinical Presentation ā¢ Scr reaches at peak after 10-12 days of therapy which recovers in 21 days ā¢ Dose related toxicity, cumulative response on subsequent cycles ā¢ Hypocalcaemia and hypokalaemia ā¢ Hypomagnesemia is associated with seizures, neuromuscular irritability, or personality changes, and persist long after chemotherapy ā¢ Risk Factors ā¢ Age, dehydration, renal irradiation, concurrent use of aminoglycoside antibiotics, and alcohol abuse
- 28. ā¢ Prevention ā¢ Dose reduction and decrease frequency of administration ā¢ Combination with other safer chemotherapeutic agents ā¢ Vigorous hydration (maintain 100 ml/h of urineoutput) ā¢ Start 24 hrs prior therapy: 250 ml/h 1 to 4 Lof NS ā¢ 4-8 hrs after dose: 150 to 250 ml/h ā¢ Amifostine: organic thiophosphate ā¢ Chelates cisplatin in normal cell,reduces nephrotoxicity, neurotoxicity, ototoxicity and myelosuppression
- 29. ā¢ Management ā¢ Cisplatin induced AKI is partially reversible ā¢ Daily monitoring of Renal function indices i.e. Scr and BUN ā¢ Daily monitoring of serum magnesium, potassium, and calcium concentrations ā¢ Electrolyte correction as per need ā¢ Supportive care ā¢ Dialysis
- 31. ā¢ Refers to structural changes that occur at the cellular levelin nephrons ā¢ Morphological pattern with vacuolization, swelling and ultimately, necrosis of the renal proximal tubular cells ā¢ Several drug are associated ā¢ Mannitol, LMWdextran, radiographic contrast media ā¢ Drug vehicles, such as sucrose and propylene glycol ā¢ IV immunoglobulin solutions ā¢ Plasma volume expanders: Hydroxyethyl starch
- 32. Vacuoles within PCT cells
- 33. ā¢ Pathogenesis ā¢ Renal vasoconstriction ā¢ Osmotically induced afferent arteriole constriction ā¢ Reduced blood flow and GFR ā¢ Management ā¢ Discontinuing therapy ā¢ Diluting the solution or reducing the rate of infusion ā¢ Haemodialysis
- 35. Pathogenesis ā¢ Within each nephron, blood flow and pressure are regulated by glomerular afferent and efferent arterioles to maintain intraglomerular capillary hydrostatic pressure, glomerular filtration, and urine output ā¢ Afferent and efferent arteriolar vasoconstriction are primarily mediated by angiotensin II ā¢ Afferent vasodilation is primarily mediated by prostaglandins ā¢ Arachidonic acid metabolites, natriuretic factors, nitric oxide, the sympathetic nervous system, the renināangiotensin system, and the macula densa response to distal tubular solute delivery
- 36. Normal glomerular autoregulation serves to maintain intraglomerular capillary hydrostatic pressure, glomerular filtration rate (GFR), and, ultimately, urine output
- 37. Glomerular autoregulation during āprerenalā states (i.e., reduced blood flow)
- 38. Pathogenesis of angiotensin-converting enzyme inhibitor (ACEI) nephropathy
- 39. Causative agents ā¢ ACE inhibitors ā¢ Angiotensin-II receptor blockers ā¢ NSAIDs ā¢ Selective COX-2 inhibitors ā¢ Cyclosporine, Tacrolimus
- 40. Clinical Presentation ā¢ Kidney injury can occur within days of initiating therapy ā¢ NSAIDs ā¢ Diminished urine output, weight gain, and/or oedema ā¢ Urine volume and sodium concentration are usually low,and BUN, Scr, and potassium are typically elevated ā¢ Cyclosporine, Tacrolimus ā¢ Scrrises ā¢ Crcl decreases ā¢ Hypertension, hyperkalaemia, sodium retention, and hypomagnesemia may occur
- 41. ā¢ ACEIs and ARBs ā¢ Acutely reduce GFR (Dose-related) ā¢ Normally, moderate rise of 0.1-0.3mg/dl ā¢ Detrimental cases >0.5mg/dl in 1-2 weeks ā¢ Hyperkalaemia
- 42. Management ā¢ Discontinue therapy ā¢ Management of severe hyperkalaemia ā¢ Caution: combined NSAID or COX-2 inhibitor and ACEI or ARB therapy is contraindicated
- 44. ā¢ Obstructive nephropathy is the result of mechanical obstruction to urine flow following glomerular filtration ā¢ Most commonly caused by ā¢ Intratubular obstruction or post renal obstruction ā¢ Secondary to nephrolithiasis or prostatic hypertrophy
- 45. INTRATUBULAR OBSTRUCTION ā¢ Intratubular precipitation ā¢ Acute oliguric or anuric kidney injury ā¢ Nephropathy, dysuria, urinary frequency, back and flank pain ā¢ Clinical manifestations ā¢ Tumor lysis syndrome ā¢ Chemotherapeutics ā¢ Urine uric acid/creatinine > 1 ā¢ Rhabdomyolysis ā¢ Intratubular precipitation of myoglobin ā¢ Ī²-hydroxy-Ī²-methylglutaryl-coenzyme A reductase inhibitors
- 46. ā¢ Intratubular precipitation of drugs ā¢ Acyclovir (oliguric patients) ā¢ Sulfadiazine, Ascorbic acid (high doses) ā¢ Methotrexate (in acidic urine) ā¢ Low-molecular-weight dextran therapy ā¢ Triamterene, Foscarnet (calcium-foscarnet salt crystals), Indinavir ā¢ Management ā¢ Administering the drug after vigorously prehydrating the patient, ā¢ Maintaining a high urine volume, ā¢ Urinary alkalinisation
- 47. NEPHROLITHIASIS ā¢ Formation of renal calculi or kidney stones ā¢ Occurs as the result of abnormal crystal precipitation in the renal collecting system ā¢ Intratubular precipitation of crystallinematerial ā¢ Prevalence of drug induced nephrolithiasis is 1% ā¢ Signs and Symptoms ā¢ Pain, haematuria, infection, or, occasionally, urinary tract obstruction with kidney injury
- 48. ā¢ Drugs ā¢ Triamterene, Sulfadiazine (acetylsulfadiazine crystalluria), Indinavir, ā¢ Antiviral drugs nelfinavir and foscarnet ā¢ Antibacterial agents: ciprofloxacin, amoxicillin and nitrofurantoin ā¢ Products containing ephedrine, norephedrine, and pseudoephedrine ā¢ Management ā¢ Stop using causative agent ā¢ A high urine volume and urinary alkalinisation to pH >7.15 may be protective
- 49. Glomerular disease ā¢ Hallmark of glomerular injury:Proteinuria ā¢ Patches of glomerular sclerosis, interstitial inflammation and fibrosis ā¢ Clinical manifestation ā¢ Focal segmental glomerulosclerosis ā¢ Membranous nephropathy ā¢ Direct toxicity ā¢ Immune complex formation
- 50. ā¢ Pathogenesis ā¢ Antigen release, antibody formation and glomerular immune complex deposition ā¢ Drugs ā¢ Gold therapy, penicillamine, NSAID, Chronic heroin abuse, renal lesions HIV, bisphosphonate pamidronate
- 51. TUBULOINTERSTITIAL DISEASE Involve the renal tubules and the surrounding interstitial tissue
- 52. NEPHROCALCINOSIS ā¢ Characterized by ā¢ Extensive tubulointerstitial precipitation and deposition of calcium phosphate ā¢ Marked tubular calcification ā¢ Risk factors ā¢ Hypercalcemia, hyperparathyroidism, increased bone turnover, hypercalcemia of malignancy, and increased intake of calcium or vitamin D ā¢ Prolonged intestinal transit ā¢ Oral sodium phosphate solution (OSPS) along with concomitant volume depletion
- 53. ā¢ Clinical manifestation ā¢ Low-grade proteinuria (<1.0 g/day), and a bland urinary sediment are usually observed ā¢ Causative agents ā¢ Diuretic ā¢ NSAID ā¢ ACEi ā¢ ARBs
- 54. PAPILLARY NECROSIS ā¢ Chronic tubulointerstitial nephritis ā¢ Necrosis of the renal papillae (region where collecting ducts enter the renal pelvis) ā¢ Risk Factors ā¢ Cumulative consumption of combination analgesics, phenacetin, or acetaminophen and aspirin ā¢ Caffeine in combination analgesics ā¢ Causative agents ā¢ Analgesic
- 55. ā¢ Chronic excessive consumption of combination analgesics (especially containing phenacetin) evolves insidiously over years ā¢ Difficult to recognize, misunderstood as a cause of ESRD ā¢ Diagnostic criteria ā¢ History of chronic daily habitual analgesic ingestion ā¢ Intravenous pyelography, renal ultrasound, or renal computed tomography imaging papillary calcifications ā¢ Clinical Manifestation ā¢ Pyuria, microscopic hematuria, and low levels of proteinuria ā¢ Hypertension and atherosclerotic cardiovascular disease
- 56. ā¢ Prevention ā¢ Limiting the total dose, avoiding combined use of two or more analgesics, and maintaining good hydration or NSAIDs ā¢ Management ā¢ Cessation of analgesicconsumption ā¢ Monitoring of Renal function indices
- 57. CHRONIC INTERSTITIAL NEPHRITIS ā¢ A progressive and irreversible lesion ā¢ Causative agents ā¢ Lithium ā¢ Cyclosporine ā¢ Aristolochic Acid (Chinese Herb Nephropathy)
- 58. Lithium toxicity ā¢ Long-term lithium therapy is associated with nephrotoxicity ā¢ Impaired ability to concentrate urine (nephrogenic diabetes insipidus) ā¢ Distal renal tubular acidosis ā¢ Clinical Presentation ā¢ Polydipsia (excessive thirst) and polyuria (excessive urination) ā¢ Acute tubular necrosis (acute lithium toxicity) ā¢ Proteinuria, a few red and white blood cells, and granular casts. ā¢ Nephrotoxicity may develop insidiously and only be recognized by rising BUN or creatinine concentrations or the onset of hypertension.
- 59. ā¢ Pathogenesis ā¢ Decrease in collecting duct response to antidiuretic hormone ā¢ Management ā¢ Discontinuation of lithiumtherapy ā¢ Amiloride 10-20 mg daily during continued lithium therapy ā¢ Adequate hydration, and avoidance of other nephrotoxic agents
- 60. Cyclosporine ā¢ Delayed chronic interstitial nephritis has been reported after 6 to 12 months of therapy ā¢ Clinical manifestations ā¢ Biopsy findings include arteriolar hyalinosis, glomerular sclerosis, and a striped pattern of tubulointerstitial fibrosis ā¢ Sustained renal arteriolar endothelial cell injury ā¢ Increased ET-1, decreased nitric acid, increased TGF- Ī²
- 61. Aristolochic Acid (Chinese Herb Nephropathy) ā¢ Certain weight-loss treatments containing Chinese herbs ā¢ Aristolochia fangchi (Guang fang ji), known to contain an alkaloid Aristolochic acid ā¢ Majority of cases are women ā¢ Develops within 6 to 24 months of exposure ā¢ Clinical Presentation ā¢ Mild to moderate hypertension ā¢ Mild proteinuria, glucosuria ā¢ Anaemia and shrunken kidneys are also common on initial presentation
- 62. ā¢ Pathogenesis ā¢ Aristolochic acid are metabolized to mutagenic compounds called aristolactam I and aristolactam II ā¢ Form DNA adducts ā¢ Direct DNA damage ā¢ Interstitial fibrosis with atrophy and destruction of tubules throughout the renal cortex ā¢ Prevention ā¢ Ban the use of Chinese herbs
- 63. ACUTE ALLERGIC INTERSTITIAL NEPHRITIS ā¢ An allergic hypersensitivity response ā¢ Characterized as an interstitial infiltrate of lymphocytes, plasma cells, eosinophils, and occasional polymorphonuclear neutrophils ā¢ Pathogenesis ā¢ Cell-mediated immune mechanism ā¢ Predominantly T-lymphocyte infiltrate ā¢ Humoral antibody-mediated mechanism ā¢ Presence of circulating antibody to a drugātubular basement membrane complex ā¢ Low serum complement levels ā¢ Deposition of IgG and complement in tubular basement membrane
- 64. ā¢ Clinical manifestation ā¢ Rare extrarenal symptoms (fever, rash, and eosinophilia) ā¢ Proteinuria >3.5 g/day ā¢ Management ā¢ Discontinue causative drug ā¢ Prednisone therapy ā¢ Initial dose of 1 mg/kg/day for a week, which is then tapered over 3 weeks to discontinuation
- 67. Vasculitis ā¢ Inflammation of blood vessels ā¢ Immunological reaction ā¢ Clinical manifestation ā¢ Cutaneous, renal, and pulmonary vasculitis (Propylthiouracil, Hydralazine) ā¢ Cutaneous, renal, and hepatic vasculitis (Allopurinol) ā¢ Cutaneous, renal, pulmonary, and gastrointestinal vasculitis (Isotretinoin) ā¢ Systemic polyarteritis nodosa (Minocycline) ā¢ Antineutrophil cytoplasmic antibody-positive vasculitis ā¢ Hydralazine, propylthiouracil, allopurinol, and penicillamine ā¢ High titre of antimyeloperoxidase antibodies
- 68. ā¢ Signs and Symptoms ā¢ Haematuria, proteinuria, reduced renal function, and hypertension ā¢ Withdrawing the offending drug ā¢ Tapering course of prednisone
- 69. Thrombosis ā¢ Formation or presence of a thrombus (clot of coagulated blood attached) in a blood vessel ā¢ Thrombotic Microangiopathy ā¢ Endothelial proliferation and thrombus formation in the renal and CNS vasculature ā¢ Clinical manifestation ā¢ Haemolytic uremic syndrome ā¢ Thrombotic thrombocytopenic purpura ā¢ Drugs ā¢ Mitomycin C, oral contraceptives, cyclosporine, tacrolimus, muromonab-CD3, antineoplastic agents, interferon, ticlopidine, clopidogrel, gemcitabine and quinine
- 70. ā¢ Mitomycin C ā¢ At doses <30 mg/m2 ā¢ Pathogenesis ā¢ Direct, dose related toxic effect ā¢ Clinical manifestation ā¢ Nephrotoxicity along with thrombotic microangiopathy ā¢ Systemic endothelial damage with multisystem organ failure ā¢ Interaction ā¢ 5-fluorouracil, cisplatin, bleomycin and tamoxifen
- 71. ā¢ Management ā¢ Corticosteroids ā¢ Antiplatelet agents, plasma exchange, plasmapheresis and high-dose intravenous immunoglobulin-G
- 72. Cholesterol Emboli ā¢ Abnormal particle (air bubble, clot) circulating in the blood ā¢ Drugs ā¢ Anticoagulants and thrombolytics e.g. warfarin ā¢ Pathogenesis ā¢ Aortic atherosclerotic plaques > embolized cholesterol particles ā¢ Small arteries and arterioles ā¢ Inflammatory obliterative vascular response ā¢ Renal ischemia ā¢ Signs and symptoms ā¢ Purple discoloration of the toes and mottled skin over the legs