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

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-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)

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
- drug related renal pathology can affect all kidney compartments
- the tubulointerstitium is commonly involved, best known examples NSAID and antibiotics
- immunologically mediated vs. toxic/ischemic damage, dose is important for the latter
- drugs should be considered in all primary tubulointerstitial diseases
- glomeruli und vasculature is only infrequently affected (w/o CNI arteriolopathy), mimicks many primary renal diseases
- personal awareness

8. 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
NSAID
CNI
Bisphosphonates
Captopril
Hydralazin
Rifampicin
Cisplatin
Tamoxifen
Lithium
Sirolimus
Interferon
ACE-I
Antibiotics
Diazepam
Thiazids
COX2-I
Barbiturates
Virostatics
HES
Quinolones
Clopidogrel
Quinine
Phenytoin
Sulfasalazine
- multiple drugs have been implicated, this list is far from complete - frequency is unknown
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: meq/L
UA: mg/dl
U/A:
SG 1.007
Pr +
Glu +
RBC 6-8/HPF
WBC /HPF
WBC cast 0-1/LPF
U/C: Neg

11. Diffuse interstitial inflammatory infiltrate – composed of lymphocytes, monocytes, and plasma cells-extensive loss of parenchyma

12. Based on Experimental AIN
Mechanisms whereby a drug (or one of its metabolites) can induce acute interstitial nephritis (AIN). (A) The drug can bind to a normal component of the tubular basement membrane (TBM) and act as a hapten. (B) The drug can mimic an antigen normally present within the TBM or the interstitium and induce an immune response that will also be directed against this antigen. (C) The drug can bind to the TBM or deposit within the interstitium and act as a planted ("trapped") antigen. (D) The drug can elicit the production of antibodies and become deposited in the interstitium as circulating immune complexes.

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 Renal Vasoconstriction (Adenosine, Endothelin)
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 The most likely Management & Follow up?
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-Inflammatory Drugs (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. (Chronic Interstitial Nephritis & Papillary necrosis )
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
Hyperkalemia Risk
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. Gagnon et al. 1998, Ann Intern Med 128-321
Crystal-Induced ARF
Sulfonamide crystals
Indinavir sulfate
urinary crystals
Gagnon et al. 1998, Ann Intern Med

36. Case Baseline cr 1.8 mg/dl; BP 145/90
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 cr within 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 cr in 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
Community-acquired pneumonia

40. Causes of AKI after Initiation of Therapy 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)
Clinical features of renal vascular disease include vascular bruits (areas of the epigastric, femoral, and carotid arteries), prior rise in serum creatinine level of more than 30%, fall in eGFR of more than 20% after beginning of treatment with an ACE inhibitor or ARB, and a history of flash pulmonary edema.

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 nephrotoxic drug
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
Comorbidities such as DM, HF, liver cirrhosis
Hypovolaemia
Addressing potential risk factors
Understanding of the mechanisms of nephrotoxicity involved