The document discusses Drug Induced Kidney Disease (DIKD), specifically drug induced nephrotoxicity. It notes that DIKD is a common complication of various therapeutic agents that can cause abnormalities in acid-base balance, electrolytes, urine sediment, decline in glomerular filtration rate, and increased creatinine and BUN. It identifies several classes of drugs that commonly cause nephrotoxicity like aminoglycosides, amphotericin B, and cisplatin. It also discusses risk factors, clinical presentation, prevention, and various pathological mechanisms of nephrotoxicity including tubular epithelial cell damage, acute tubular necrosis, osmotic nephrosis, and hemodynamically mediated kidney

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
• Drug induced nephrotoxicity (DIN)
• Common complication of several diagnostic and therapeutic agents
• Manifested as
• Acid–base abnormalities, Electrolyte imbalances
• Urine sédiment abnormalities
• Proteinuria, pyuria, and hematuria
• Decline in the glomerular filtration rate (GFR)
• Rise in the serum creatinine (Scr) and blood urea nitrogen (BUN)

3. • Often reversible on discontinuation of the offending agent
• Maylead to acute Renal Failure (ARF) or end-stage renal disease (ESRD)

6. Epidemiology
• 20% of hospital admissions due to AKI are drug related
• Most of them are communityacquired
• AKI: 7% of hospitalized patients, 20-30% of critically illpatients, significant
source of morbidity and mortality
• Up to 25% of ARF cases are attributed by use of certain drugs

7. Risk factors
• Patient-related factors
• Age, sex, race
• Pre-existent renal disease
• Specific disease (diabetes mellitus, multiple myeloma, proteinuric patients)
• Sodium-retaining states (cirrhosis, heart failure, nephrosis)
• Dehydration and volume depletion
• Acidosis, potassium and magnesium depletion
• Hyperuricemia, hyperuricosuria
• Sepsis, shock
• Renal transplantation

8. Risk factors
• Drug-related factors
• Inherent nephrotoxic potential
• Dose
• Duration, frequency and form of administration
• Repeated exposure
• Drug interactions
• 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
• General
• The most common manifestation is a decline in GFR leading to a rise in Scr and BUN.
• Symptoms
• Malaise, anorexia, vomiting, shortness of breath, or edema.
• Signs
• 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. • Proximal tubular injury
• Metabolic acidosis with bicarbonaturia
• Glycosuria in the absence of hyperglycaemia
• Reductions in serum phosphate, uric acid, potassium, and magnesium as a result of
increased urinary losses
• Distal tubular injury
• Polyuria from failure to maximally concentrate urine
• Metabolic acidosis from impaired urinary acidification
• Hyperkalaemia from impaired potassium excretion

11. • Laboratory Tests
• Achange in Scr of at least 0.5 mg/dL for subjects with a baseline Scr <2 mg/dL and
• 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
• Avoid the use of potentially nephrotoxic agents (patients at increased risk for
toxicity)
• Maintain careful and adequate hydration to establish high renal tubular urine
flow rates
• Drug mechanism specific intervention

13. Injury patterns
• Subtle injury or overt renal failure
• Some drugs perturb renal perfusion and induce loss of filtration capacity
• Others directly injure vascular, tubular, glomerular and interstitial cells
• Specific loss of renal function leads to clinical findings
• Microangiopathy
• Acute tubular necrosis
• Acute interstitial nephritis
• Nephrotic syndrome, obstruction
• Nephrogenic diabetes insipidus
• Electrolyte abnormalities and chronic renal failure

14. • True incidence of DIN is difficult to determine
• Markers of earlyinjury are being investigated
• Detection is often delayed until an overt change in renal functional capacity
is measured as an increase in BUN, Scr
• Subtle renal damages associated with medications are frequently
unrecognized
• Tubulopathy, acid–base abnormalities, electrolyte imbalances and disorders of water
balance and mild urinary sediment abnormalities

15. Renal pathophysiological alterations
(Drug Induced)
• Tubular epithelial cell damage
• Acute tubular necrosis
• Osmotic nephrosis
• Hemodynamically mediated kidney
injury
• Obstructive nephropathy
• Intratubular obstruction
• Nephrolithiasis
• Glomerular disease
• Tubulointerstitial disease
• Acute allergic interstitial nephritis
• Chronic interstitial nephritis
• Nephrocalcinosis
• Papillary necrosis
• Renal vasculitis, thrombosis, and
cholesterol emboli
• Vasculitis and thrombosis
• Cholesterol emboli

16. 1-Tubular epithelial cell damage
• Caused by either direct toxic or ischemic effects of drugs
• Damage is localized in the PCT & DCT epithelia
• Acute tubular necrosis
• Observed as cellular degeneration and sloughing from PCT & DCT basement
membranes
• Osmotic nephrosis
• Swellingand vacuolization of proximal tubular cells

17. A. ACUTE TUBULAR NECROSIS

18. Aminoglycoside Nephrotoxicity
• Incidence
• 5% to 15% of patients receiving aminoglycoside therapy
• Clinical Presentation
• Gradual progressive rise in Scr and in CrCl after 6 to 10 days of therapy
• Nonoliguria >500 mL/day
• Magnesium wasting >10 to 30 mg
• Severe kidney injury does not usually develop

19. • Pathogenesis
• Binding, intracellular transport in lysosomes
• Release of lysosomal enzymes
• ROS generation, Altered cell metabolism and membrane fluidity
• Cellular dysfunction and death
• PCT epithelial cell damage leading to obstruction of the tubular lumen
• Back leakage of the glomerular filtrate across the damaged tubular epithelium
• Reduction of GFR

20. • Risk Factors
• Aggressive aminoglycoside dosing
• Combination of nephrotoxic drugtherapy
• Existing predisposing conditions
• Prevention
• Alternative therapy: fluoroquinolones, 3rd or 4th generation cephalosporins
• Limit the total aminoglycoside dose administered
• Avoid concomitant therapy with other nephrotoxic drugs
• High intermittent dosing: Once daily dosing regimen

22. • Management
• Measure Scr every 2 to 4 days
• Maintain adequate hydration (Avoid volume depletion)
• Discontinue or revised regimen ifScr increase of 0.5 mg/dL ormore
• Short-term dialysis

23. Amphotericin-B Nephrotoxicity
• Incidence
• Toxicityrelates to cumulative dosage, starts from 300-400mg, 4g (at higher doses 80%
incidence)
• Clinical Presentation
• Renal tubular potassium, sodium, and magnesium wasting
• Impaired urine concentrating ability
• Distal renal tubular acidosis
• Decrease in renal blood flow and GFR
• Rise in Scr and BUN

24. • Pathogenesis
• Increases tubular permeability
• Consequent increase in energy and oxygen requirements
of epithelial cells
• Reduced cellular oxygen delivery due to renal
vasoconstriction
• Renal medullary tubular epithelial cell necrosis and kidney
injury
• Risk Factors
• CKD
• Higher average daily
doses
• Volume depletion
• Concomitant
administration of
diuretics
• Rapid infusion rate

25. • Prevention
• Liposomal amphotericin Bformulations (Targeted drug delivery)
• IV infusion of NS daily during the course of therapy reduces toxicity
• Management
• Discontinuation and substitution of therapy
• Daily monitoring of Renal function indices i.e. Scr and BUN
• Daily monitoring of serum magnesium, potassium, and calcium concentrations

26. Cisplatin and Carboplatin Nephrotoxicity
• Incidence
• Previously incidence was 50-100%, now it has reduced to 6-13%
• 20% to 40% decline in GFR is frequently observed
• Pathogenesis
• Binding to PCT cell proteins and sulfhydryl groups
• Disruption of cell enzyme activity, uncoupling of oxidativephosphorylation
• Initially PCT is damaged which progresses to DCT and glomerular necrosis

27. • Clinical Presentation
• Scr reaches at peak after 10-12 days of therapy which recovers in 21 days
• Dose related toxicity, cumulative response on subsequent cycles
• Hypocalcaemia and hypokalaemia
• Hypomagnesemia is associated with seizures, neuromuscular irritability, or personality
changes, and persist long after chemotherapy
• Risk Factors
• Age, dehydration, renal irradiation, concurrent use of aminoglycoside antibiotics, and
alcohol abuse

28. • Prevention
• Dose reduction and decrease frequency of administration
• Combination with other safer chemotherapeutic agents
• Vigorous hydration (maintain 100 ml/h of urineoutput)
• Start 24 hrs prior therapy: 250 ml/h 1 to 4 Lof NS
• 4-8 hrs after dose: 150 to 250 ml/h
• Amifostine: organic thiophosphate
• Chelates cisplatin in normal cell,reduces nephrotoxicity, neurotoxicity, ototoxicity and
myelosuppression

29. • Management
• Cisplatin induced AKI is partially reversible
• Daily monitoring of Renal function indices i.e. Scr and BUN
• Daily monitoring of serum magnesium, potassium, and calcium concentrations
• Electrolyte correction as per need
• Supportive care
• Dialysis

30. B. OSMOTIC NEPHROSIS

31. • Refers to structural changes that occur at the cellular levelin nephrons
• Morphological pattern with vacuolization, swelling and ultimately, necrosis
of the renal proximal tubular cells
• Several drug are associated
• Mannitol, LMWdextran, radiographic contrast media
• Drug vehicles, such as sucrose and propylene glycol
• IV immunoglobulin solutions
• Plasma volume expanders: Hydroxyethyl starch

32. Vacuoles within PCT cells

33. • Pathogenesis
• Renal vasoconstriction
• Osmotically induced afferent arteriole constriction
• Reduced blood flow and GFR
• Management
• Discontinuing therapy
• Diluting the solution or reducing the rate of infusion
• Haemodialysis

34. HEMODYNAMICALLY MEDIATED
KIDNEY INJURY

35. Pathogenesis
• 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
• Afferent and efferent arteriolar vasoconstriction are primarily mediated by
angiotensin II
• Afferent vasodilation is primarily mediated by prostaglandins
• Arachidonic acid metabolites, natriuretic factors, nitric oxide, the sympathetic
nervous system, the renin–angiotensin 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 “prerenal” states (i.e., reduced blood flow)

38. Pathogenesis of angiotensin-converting enzyme inhibitor (ACEI) nephropathy

39. Causative agents
• ACE inhibitors
• Angiotensin-II receptor blockers
• NSAIDs
• Selective COX-2 inhibitors
• Cyclosporine, Tacrolimus

40. Clinical Presentation
• Kidney injury can occur within days of initiating therapy
• NSAIDs
• Diminished urine output, weight gain, and/or oedema
• Urine volume and sodium concentration are usually low,and BUN, Scr, and potassium
are typically elevated
• Cyclosporine, Tacrolimus
• Scrrises
• Crcl decreases
• Hypertension, hyperkalaemia, sodium retention, and hypomagnesemia may occur

41. • ACEIs and ARBs
• Acutely reduce GFR (Dose-related)
• Normally, moderate rise of 0.1-0.3mg/dl
• Detrimental cases >0.5mg/dl in 1-2 weeks
• Hyperkalaemia

42. Management
• Discontinue therapy
• Management of severe hyperkalaemia
• Caution: combined NSAID or COX-2 inhibitor and ACEI or ARB therapy is
contraindicated

43. OBSTRUCTIVE NEPHROPATHY

44. • Obstructive nephropathy is the result of mechanical obstruction to urine
flow following glomerular filtration
• Most commonly caused by
• Intratubular obstruction or post renal obstruction
• Secondary to nephrolithiasis or prostatic hypertrophy

45. INTRATUBULAR OBSTRUCTION
• Intratubular precipitation
• Acute oliguric or anuric kidney injury
• Nephropathy, dysuria, urinary frequency, back and flank pain
• Clinical manifestations
• Tumor lysis syndrome
• Chemotherapeutics
• Urine uric acid/creatinine > 1
• Rhabdomyolysis
• Intratubular precipitation of myoglobin
• β-hydroxy-β-methylglutaryl-coenzyme A reductase inhibitors

46. • Intratubular precipitation of drugs
• Acyclovir (oliguric patients)
• Sulfadiazine, Ascorbic acid (high doses)
• Methotrexate (in acidic urine)
• Low-molecular-weight dextran therapy
• Triamterene, Foscarnet (calcium-foscarnet salt crystals), Indinavir
• Management
• Administering the drug after vigorously prehydrating the patient,
• Maintaining a high urine volume,
• Urinary alkalinisation

47. NEPHROLITHIASIS
• Formation of renal calculi or kidney stones
• Occurs as the result of abnormal crystal precipitation in the renal collecting
system
• Intratubular precipitation of crystallinematerial
• Prevalence of drug induced nephrolithiasis is 1%
• Signs and Symptoms
• Pain, haematuria, infection, or, occasionally, urinary tract obstruction with kidney injury

48. • Drugs
• Triamterene, Sulfadiazine (acetylsulfadiazine crystalluria), Indinavir,
• Antiviral drugs nelfinavir and foscarnet
• Antibacterial agents: ciprofloxacin, amoxicillin and nitrofurantoin
• Products containing ephedrine, norephedrine, and pseudoephedrine
• Management
• Stop using causative agent
• A high urine volume and urinary alkalinisation to pH >7.15 may be protective

49. Glomerular disease
• Hallmark of glomerular injury:Proteinuria
• Patches of glomerular sclerosis, interstitial inflammation and fibrosis
• Clinical manifestation
• Focal segmental glomerulosclerosis
• Membranous nephropathy
• Direct toxicity
• Immune complex formation

50. • Pathogenesis
• Antigen release, antibody formation and glomerular immune complex deposition
• Drugs
• 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
• Characterized by
• Extensive tubulointerstitial precipitation and deposition of calcium phosphate
• Marked tubular calcification
• Risk factors
• Hypercalcemia, hyperparathyroidism, increased bone turnover, hypercalcemia of
malignancy, and increased intake of calcium or vitamin D
• Prolonged intestinal transit
• Oral sodium phosphate solution (OSPS) along with concomitant volume depletion

53. • Clinical manifestation
• Low-grade proteinuria (<1.0 g/day), and a bland urinary sediment are usually observed
• Causative agents
• Diuretic
• NSAID
• ACEi
• ARBs

54. PAPILLARY NECROSIS
• Chronic tubulointerstitial nephritis
• Necrosis of the renal papillae (region where collecting ducts enter the renal
pelvis)
• Risk Factors
• Cumulative consumption of combination analgesics, phenacetin, or acetaminophen and
aspirin
• Caffeine in combination analgesics
• Causative agents
• Analgesic

55. • Chronic excessive consumption of combination analgesics (especially containing
phenacetin) evolves insidiously over years
• Difficult to recognize, misunderstood as a cause of ESRD
• Diagnostic criteria
• History of chronic daily habitual analgesic ingestion
• Intravenous pyelography, renal ultrasound, or renal computed tomography imaging papillary
calcifications
• Clinical Manifestation
• Pyuria, microscopic hematuria, and low levels of proteinuria
• Hypertension and atherosclerotic cardiovascular disease

56. • Prevention
• Limiting the total dose, avoiding combined use of two or more analgesics, and
maintaining good hydration or NSAIDs
• Management
• Cessation of analgesicconsumption
• Monitoring of Renal function indices

57. CHRONIC INTERSTITIAL NEPHRITIS
• A progressive and irreversible lesion
• Causative agents
• Lithium
• Cyclosporine
• Aristolochic Acid (Chinese Herb Nephropathy)

58. Lithium toxicity
• Long-term lithium therapy is associated with nephrotoxicity
• Impaired ability to concentrate urine (nephrogenic diabetes insipidus)
• Distal renal tubular acidosis
• Clinical Presentation
• Polydipsia (excessive thirst) and polyuria (excessive urination)
• Acute tubular necrosis (acute lithium toxicity)
• Proteinuria, a few red and white blood cells, and granular casts.
• Nephrotoxicity may develop insidiously and only be recognized by rising BUN or
creatinine concentrations or the onset of hypertension.

59. • Pathogenesis
• Decrease in collecting duct response to antidiuretic hormone
• Management
• Discontinuation of lithiumtherapy
• Amiloride 10-20 mg daily during continued lithium therapy
• Adequate hydration, and avoidance of other nephrotoxic agents

60. Cyclosporine
• Delayed chronic interstitial nephritis has been reported after 6 to 12 months
of therapy
• Clinical manifestations
• Biopsy findings include arteriolar hyalinosis, glomerular sclerosis, and a striped pattern
of tubulointerstitial fibrosis
• Sustained renal arteriolar endothelial cell injury
• Increased ET-1, decreased nitric acid, increased TGF- β

61. Aristolochic Acid (Chinese Herb
Nephropathy)
• Certain weight-loss treatments containing Chinese herbs
• Aristolochia fangchi (Guang fang ji), known to contain an alkaloid Aristolochic
acid
• Majority of cases are women
• Develops within 6 to 24 months of exposure
• Clinical Presentation
• Mild to moderate hypertension
• Mild proteinuria, glucosuria
• Anaemia and shrunken kidneys are also common on initial presentation

62. • Pathogenesis
• Aristolochic acid are metabolized to mutagenic compounds called aristolactam I and
aristolactam II
• Form DNA adducts
• Direct DNA damage
• Interstitial fibrosis with atrophy and destruction of tubules throughout the renal cortex
• Prevention
• Ban the use of Chinese herbs

63. ACUTE ALLERGIC INTERSTITIAL
NEPHRITIS
• An allergic hypersensitivity response
• Characterized as an interstitial infiltrate of lymphocytes, plasma cells, eosinophils,
and occasional polymorphonuclear neutrophils
• Pathogenesis
• Cell-mediated immune mechanism
• Predominantly T-lymphocyte infiltrate
• Humoral antibody-mediated mechanism
• Presence of circulating antibody to a drug–tubular basement membrane complex
• Low serum complement levels
• Deposition of IgG and complement in tubular basement membrane

64. • Clinical manifestation
• Rare extrarenal symptoms (fever, rash, and eosinophilia)
• Proteinuria >3.5 g/day
• Management
• Discontinue causative drug
• Prednisone therapy
• Initial dose of 1 mg/kg/day for a week, which is then tapered over 3 weeks to
discontinuation

65. • Causative agents

66. RENAL VASCULITIS,
THROMBOSIS, AND
CHOLESTEROL EMBOLI

67. Vasculitis
• Inflammation of blood vessels
• Immunological reaction
• Clinical manifestation
• Cutaneous, renal, and pulmonary vasculitis (Propylthiouracil, Hydralazine)
• Cutaneous, renal, and hepatic vasculitis (Allopurinol)
• Cutaneous, renal, pulmonary, and gastrointestinal vasculitis (Isotretinoin)
• Systemic polyarteritis nodosa (Minocycline)
• Antineutrophil cytoplasmic antibody-positive vasculitis
• Hydralazine, propylthiouracil, allopurinol, and penicillamine
• High titre of antimyeloperoxidase antibodies

68. • Signs and Symptoms
• Haematuria, proteinuria, reduced renal function, and hypertension
• Withdrawing the offending drug
• Tapering course of prednisone

69. Thrombosis
• Formation or presence of a thrombus (clot of coagulated blood attached) in a
blood vessel
• Thrombotic Microangiopathy
• Endothelial proliferation and thrombus formation in the renal and CNS vasculature
• Clinical manifestation
• Haemolytic uremic syndrome
• Thrombotic thrombocytopenic purpura
• Drugs
• Mitomycin C, oral contraceptives, cyclosporine, tacrolimus, muromonab-CD3, antineoplastic
agents, interferon, ticlopidine, clopidogrel, gemcitabine and quinine

70. • Mitomycin C
• At doses <30 mg/m2
• Pathogenesis
• Direct, dose related toxic effect
• Clinical manifestation
• Nephrotoxicity along with thrombotic microangiopathy
• Systemic endothelial damage with multisystem organ failure
• Interaction
• 5-fluorouracil, cisplatin, bleomycin and tamoxifen

71. • Management
• Corticosteroids
• Antiplatelet agents, plasma exchange, plasmapheresis and high-dose intravenous
immunoglobulin-G

72. Cholesterol Emboli
• Abnormal particle (air bubble, clot) circulating in the blood
• Drugs
• Anticoagulants and thrombolytics e.g. warfarin
• Pathogenesis
• Aortic atherosclerotic plaques > embolized cholesterol particles
• Small arteries and arterioles
• Inflammatory obliterative vascular response
• Renal ischemia
• Signs and symptoms
• Purple discoloration of the toes and mottled skin over the legs