Drugs and The Kidney

2. Drugs & The Kidney Drugs and The Kidney Dr. Shahrzad Shahidi Dr. Shahrzad Shahidi

3. 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

4. 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

5. 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

6. 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)

7. 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

8. Virostatics Phenytoin Sulfasalazine Quinolones Bisphosphonates Bisphosphonates Tamoxifen Interferon Sirolimus Cisplatin Quinine Cisplatin CNI Hydralazin Lithium COX2-I NSAID HES Thiazids Lithium Captopril Barbiturates Clopidogrel Rifampicin ACE-I NSAID CNI CNI Antibiotics Diazepam 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 Ranitidin

9. 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. Amoxicilline Nocturia, Polyuria Fatigue

10. 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

12. Based on Experimental AIN www.nature.com/ki/journal

13. 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

14. Radiocontrast Agents • Ionic vs. Nonionic • High (1500-1800) Low (600-850) Iso-osmolal (~ 290 mOsm/kg))

15. Radiocontrast Agents • Pathogenesis: • Renal Vasoconstriction (Adenosine, Endothelin) • Tubular Injury Oxidative stress induced damage

16. 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)

17. 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

18. 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

20. 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?

21. 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

22. Nonsteroidal Anti-InflammatoryDrugs (NSAIDs) Chemical Structure Generic 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

23. NSAIDs • Hemodynamically- Induced ARF • Acute Interstitial Nephropathy + Proteinuria • Papillary necrosis & CRF(Analgesic nephropathy) • Salt & water retention: Hyperkalemia, HTN

24. NSAIDs • Acute Interstitial Nephropathy + Proteinuria • Acute interstitial nephritis • Minimal-change glomerular disease • Proteinuria • Prognosis good after discontinuation of therapy; Corticosteroids ?

25. 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

26. Analgesic Nephropathy Papillary necrosis

27. Analgesic Nephropathy Papillary necrosis

28. 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?

30. 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 • HyperkalemiaRisk • Blunting of PG-mediated renin release

31. 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.

32. 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)

33. 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

34. Crystal-Induced ARF • Acyclovir (antiviral agent ) • Indinavir (antiretroviral agent, protease inhibitor) • Methotrexate (antineoplastic agent, antimetabolite) • Sulfonamide antibiotics • Triamterene

35. Crystal-Induced ARF Sulfonamide crystals Indinavir sulfate urinary crystals Gagnon et al. 1998, Ann Intern Med 128-321

36. 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

37. Optimal Use of ACEI/ARB • Cr ↑ 1.8 to 2.2 mg/dl in 2 wks • Accept 20-30% increase in serum crwithin 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 crin this patient in 1-2 wks to ensure it has stabilized

38. Case • 82 yo female with osteoarthritis • Admitted to hospital for CAP & dehydration • Meds: Losartan 100mg daily + Naproxen 250mg BID • Cr 3 mg/dl

39. 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

40. 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)

41. Prevention: General Rules • 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 nephrotoxicdrug • Monitor the RFT if necessary

42. Prevention: General Rules (Cont’d) • Avoid dehydration • Limit dose & duration of treatment • Adjust the dose based on changes in GFR • Avoid a combination of potentially nephrotoxic drugs

43. Conclusion • Many drugs cause AKI • Increase the risk of drug-induced AKI: • Age (particularly over 65 years) • Pre-existing renal impairment • Comorbiditiessuch as DM, HF, liver cirrhosis • Hypovolaemia • Addressing potential risk factors • Understanding of the mechanisms of nephrotoxicity involved