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Nephrotoxicity eman 2013
1. 1
“All drugs known to humans
are poisons, only the amount
or dose determine the
effects.”
Paracelsus, 1490 - 1541
Drug-induced nephrotoxicity
2. Definition and epidemiology
Risk factors of ICU nephrotoxicity
Pharmacology in ICU patients
Mechanisms of toxicity
Biomarkers
Prevention of ICU nephrotoxicity
3. AKI definition:
increase in S. Cr. By ≥ 0.3 mg/dl (≥ 26.5 µmol/l) in 48 h.
Or
increase in SCr to ≥ 1.5 times baseline, which is known
Or
Urine volume < 0.5 ml/kg/h for 6 hours.
Nephrotoxic Injury Definition
Nephrotoxic injury is damage to one or both of the kidneys that results from
exposure to a toxic substance.
Deterioration of renal function alters the drugs and metabolites clearance leading
to :
More side effects
Increase nephrotoxicity
Change in the drug metabolism (volume distribution)
Introduction
4.
5. Epidemiology:
The rates of AKI have been reported in hospitalized patients to be between 3.2%-
20% and in ICUs. This rate rises up to 22% and even to 67% depending on the
population studied and the definition of AKI used
– Murugan R et all, Nat Rev Nephrol 2011 7:209 - 2179
Nephrotoxicity due to drugs contributes to between 8-60% of AKI cases in
hospitalized patients.
– Schetz M, et allCurr Opin Crit Care 11:555-565.
– Hou SH, et all Am J Med 74:243-248.
In the ICU setting the incidence of AKI from drug nephrotoxicity ranges between
1-23%.
– Mehta RL, et all Kidney Int 66:1613-1621.
– Silvester W, et all Crit Care Med 29:1910-1915.
– Liano F, et all Kidney Int Suppl 66:S16-24.
6. Continue:
Based on 75,000 critically ill adults, more severe AKI occurs in 4% to 25% of all
ICU admissions .
On average, 5% to 6% of ICU patients with AKI require renal replacement therapy
(RRT).
Uchino S, et al: Jama 2005; 294:813–818
Uchino S, et al: Critical care medicine 2006; 34:1913–1917
Ostermann M, Chang RW:Critical care medicine 2007; 35: 1837–1843; quiz 1852
Elderly patients are likely more susceptible to AKI from nephrotoxic agents due to
the age related decline in GFR or renal blood leading to reduced clearance of the
drug, decline in hepatic clearance, altered free drug concentration.
Henrich WL. Kidney Int Suppl:S107-109.
7.
8. Common risk factors associated with the development of AKI
Clinical settings
ICU/multiple organ failure
Sepsis/infection
DM
Preexisting CKD defined as eGFR < 60 ml/min/m2
Nephrotic syndrome
Postoperative especially cardiac and vascular surgery
Trauma
Burns
HIV
Non-renal solid organ transplantation
Bone marrow transplantation
Liver disease
Malignancy
Hypertension
Morbid obesity
9. Patient – specific factors
Advanced age
Volume depletion
Sepsis,
Preexisting renal hepatic and cardiac diseases
DM
Multiple nephrotoxic drugs
Radiocontrast agent
Common risk factors associated with the development of AKI
Medications
NSAIDs /cox-2 inhibitors
Aminoglycoside antibiotics
Amphotericin B
RAS blockers
Calcineurin inhibitors
Chemotherapeutic agents
Cocaine
Ethylene glycol
Occupational toxins (heavy metals, organic solvents)
Herbal remedies
10. Pharmacokinetic changes in ICU patients
Altered oral drug bioavailability (decreased> increased)
Increased gastric pH, insoluble drug complexes
Intestinal atrophy, dysmotility and reduced transport function (intestinal edema, or
hypoperfusion )
Reduced intestinal and hepatic metabolism
Risk factors: acute heart decomposition, liver diseases)
Boucher BA et el, Cri Care Clin 2006: 255 – 271
Chan LMS, et al, Eur J Pharmaceut Sci 2004, 21: 25 – 51.
Altered volume of distribution (decreased or increased)
Decreased or increased extracellular fluid space (volume distribution)
Liver diseases, nephrotic syndrome, and heart failure
Decreased protein concentration or binding and lipid solubility of drugs
Altered tissue permeability
pH disturbances
Boucher BA et el, Cri Care Clin 2006: 255 – 271
Schmith VD, et al, Clin Pharmacol Ther 2010; 87: 488 - 491
11. Altered drug metabolism:
Liver, kidney, intestine,
Hypoperfusion of these organs
Altered drug cellular transport
Altered CYP-450 drug metabolism
Vily AM et al, Crit Care, 2008, 12: 235 – 243
Chan LMS, et al, EurJ Pharmaceut Sci 2004; 12 25 – 51.
Altered renal drug clearance:
Reduced GFR
Reduced proximal tubular drug secretion
Dialysis clearance
Modality of RRT (PD, HD, CVVH)
Perazella, Kidney Int. 2012; 81: 1172 – 1178
Continue:
16. Tubular cells injury/necrosis :
Proximal tubular cells
Concentrating and reabsorbing
Expose to high concentration of toxins
Toxins cause impairing metochondrial function, interfering with tubular transports,
increasing oxidative stress, or free radicals.
Swollen cells and filled with abundant lysosomal vacuoles
aminoglycosides, amphotericin B, antiretrovirals (adefovir , cidofovir, tenofovir), cisplatin,
contrast dye
17. Acute Tubular Necrosis:
Cidofovir or tenovir, dose dependent AKI 14-24%
Fanconi syndrome (proteinuria, glucosuria, and bicarbonate wasting.
RF improve upon discontinuation but can leads to ESKD
Aminoglycosides with AKI 7-9 - 15%
The renal toxicity was reported to be 3.9%,30% in the 1st week and after 1 month
respectively
Cephalosporins, Am-B, rifampicin, NSAIDs, contrast media, CsA,
FENa > 2%, Uosm < 350, urinary sediment: granular casts, renal epithelial cells
Elevated CPK (statins and barbiturates)
Elevated LDH and decrease haptoglobin (nitrofurantion, quinine, sulfanamide,hydralazine)
Joannidis M. et all, 2004. Int J Artif Organs 27:1034-1042.
Verhelst D, et all, 2002. Am J Kidney Dis 40:1331-1333.
Bertino JS Jr, et all. 1993.J Infect Dis 167:173-179.
Baciewicz AM, et all. 2003. Ann Pharmacother 37:182-186.
18. Allergic Interstitial Nephritis:
Dugs produce allergic reaction leading to inflammation and infiltration of immune cells
(lymphocytes, monocytes, eosinophils), leading to fibrosis and scaring
AKI is 3 – 15% of all cases.
Drugs: β-lactams, quinolones, sulfonamides, rifampin, diuretics, NSAIDs, cimitedine,
ranitidine, recombinant humanized monoclonal immunoglobulin G.
Clinical: rash, fever, eosinophilia, eosinophiluria, pyuria.
Michel DM, et all. 1998. J Am Soc Nephrol 9:506-515.
Toto RD. 1990. Am J Med Sci 299:392-410.
Barakat RK, et all, 2007.Ann Pharmacother 41:707-710.
19. Crystal Nephropathy:
Distal tubular lumen
Insolubility of drugs in urine pH dependent 49
Produced crystals precipitate in the distal tubular lumen, leading to obstruction and eliciting
an interstitial reaction 21 48
The risk increased with volume depletion, dose dependent, CKD,
Ciprofloxacin, sulfonamides , ampicilin, acyclovir (mealy in 500mg/m2) , ganciclovir,
indinavir; methotrexate 55
Tumor lysis syndrome leading to uric acid and calcium phosphate crystals
Urine test: Hematuria, renal tissue,
Perazella MA. 1999. Am J Med 106:459-465.
Fogazzi GB. 1996. Nephrol Dial Transplant 11:379-387.
Martinez F, et all. 1998. Nephrol Dial Transplant 13:750-753.
20. Rhabdomyolysis:
Muscle injury leads to lysis of myocyte releasing of intracellular contents including
myoglobin and creatine kinase into plasma
Drugs may induce rhabdomyolysis directly secondary to a toxic effect on myocyte
function, or indirectly by predisposing the myocyte to injury
Drug rhabdomyolysis charactarised by weakness, myalgia, tea-colored urine
Combination with clarythromicin, erythromicn, fibrate
Statins, cocaine heroin and ketamine
Alkalinization to keep urine pH > 6.5 by mannitol and bicarbonte which are effective
than saline.
Thrombotic microangiopathy:
Platelet thrombi in the microcirculation as in TTP.
Immune-mediated reaction or direct endothelial toxicity
Clopidogrel, ticlopidine, cyclosporine, mitomycin-C, and quinine.
low Hb, haptoglobin, high LDH
ADAMTS 13 not indicated here
23. Traditional tools:
Traditional tools to diagnose AKI (SCr) and determine etiology of AKI (clinical history,
physical examination, renal ultrasound, fractional excretion of sodium [FeNa],
fractional excretion of urea, blood urea nitrogen [BUN], and urine microscopy) remain
the cornerstone of diagnostic tools available to the clinician in the ICU
Urine microscopy can be helpful in differential diagnosis
• granular casts and renal tubular epithelial cells in acute tubular necrosis,
• cellular casts in glomerular injury,
• Eosinophiluria in acute interstitial nephritis, or atheroembolic AKI).
S. Creatinine :
• Tubular secretion
• Age, sex muscle mass, metabolism and volume status.
• Increased when GFR is low 2 -3 days after insulting the nephron
24. New biomarkers:
Enthusiasm about their usefulness seems unwarranted at present, in ICU or surgical
ICU.
Poor performance in patients with sepsis or with acute-on-chronic kidney disease
The inability of biomarkers to improve classification of 'unclassifiable' (structural or
functional) AKI, in which accurate differential diagnosis of pre-renal versus intrinsic
renal AKI has the most value, illustrates another problem.
Future research is necessary to clarify whether serial measurements of a specific
biomarker or the use of a panel of biomarkers may be more useful in critically ill
patients at risk of AKI.
Mol Diagn Ther. 2012 Aug 1;16(4):199-207
25. Cystatin C marker:
• able to predict AKI 1-2 days earlier than SCr. But also increased when GFR is
low too
• Cystatin C is a low molecular weight protein produced by all nucleated cells
that is freely filtered by the glomerulus and then reabsorbed and metabolized
by the proximal tubule
• Serum level of Cystatin C dependents on
– Clearance
– Production
– Volume of distribution.
– Increased by higher dose of corticosteroids and hyperthyriodism
– and hyperthyroidsm and decreased by hypothyroidism.
– Smoking
– Immunosuppressive therapy and malignanacy
• There is plasma Cystatin C which affected by and urinary cystatin C which
reflect tubuar damage
Hilde R. et al Clin Kidney J (2012) 5: 102–108
Knight EL, et al, Kidney Int 2004; 65: 1416–1421
Okura T, Jotoku M, Irita J et al. Clin Exp Nephrol 2010; 14: 584–588
26. NAGL
Neutrophil Gelatinase- Associated Lipocaline ( Lipocalin-2 or siderocalin)
• Superior to s.cr and cystatin C.
• In the normal kidney, only the distal tubules and collecting ducts stain for NGAL
expression.
• Response to ischemic injury in proximal tubule cells.
• Its appearance in urine is independent of the GFR
• uNGAL excretion is proportional to albumin excretion in mouse
Mishra J, et al J Am Soc Nephrol 2003,14:2534-43
Hilde R. et al Clin Kidney J (2012) 5: 102–108
A pro-inflamatory cytokine IL-18:
Urine IL-18 levels were found markedly increased in patient with AKI
not in patients with UTI, CKD, nephrotic syndrome
sensitivty > 90% and specifity>95% for the diagnosis of AKI.
Parikh CR & Devarajan . Crit Care Med 2008,364):S159-S16
27. Kidney injury molecule KIM-1 :
• Ischemia and nephrotoxic injuryof proximal tubule cells.
• It is more useful in toxic renal injury like rhabdomyolysis
• KIM-1 levels peaked 12 hours after injury in AKI in post cardiac operation.
• KIM-1 more specific to ischemic and nephrotoxic kidney injury than NGAL
• it is not significantly affected by chronic kidney disease or urinary tract
infection
Liangos O, et al. J Am Soc Nephrol 2007:18:904-912
28. Author Estimation formula Purpose
MDRD eGFR = 186 × serum creatinine (mg per
dL) −1.154 × age (years) −0.203 × (0.742
if patient is female) × (1.210 if patient is
black)
To assess renal function and
stage chronic kidney disease
Cockcroft and
Gault
Male: eCrCl = ([140 – age (years)] × ideal
body weight [kg]) ÷ (serum creatinine
[mg per dL] × 72)
To adjust drug dosing for renal
function in adults
Female: male eCrCl × 0.85
Schwartz eCrCl = (length [cm] × k) ÷ serum
creatinine (mg per dL)
To adjust drug dosing for renal
function in children
k = 0.45 (infants one to 52 weeks of age)
0.55 (children one to 13 years of age)
0.70 (males 14 to 17 years of age)
0.55 (females 14 to 17 years of age)
Formulas to assess renal function and adjust
medication dosages
29. General approaches for the prevention of AKI
Avoidance of nephrotoxins
Recognition of potential nephrotoxic agents
Recognition of high risk high risk patients and clinical stetting s
Avoidance of concomitant use of multiple nephrotoxins
Maintain euvolemia :
CVP 8 – 12 mmHg or to 15 mmHg in patient with positive pressure ventilation
Early rehydration
Mean arterial pressure > 65mmHg
Third space
If applicable monitoring drug dose and levels
Use of lowest dose for shortest time
Minimization of nosocomial infection
Urine output hourly measurement
Monitoring kidney function closely and evaluation of GFR
Dose adjustment accordingly
Controlling BP
Controlling DM : tight is associated with hypoglycemia and no difference in moratlity copre
to conventional glucose control
30. Example of specific renal protective strategies
Exposure Strategy
Aminoglycoside antibiotics Once – daily dosing
Monitoring of drug levels
Avoiding in CKD and pts at risks.
Maintain trough levels < 1mcg /ml.
Tumor lysis (uric acid) Allopurinol/rasburicase
IV hydration/urine alkaliniation
Amphotericin B Use lipid formulation
Saline hydration pre and post administration
Avoid high or rapid dose or prolonged duration
Ethylene glycol ingestion Ethanol/fomepizole
hemodialysis
rhabdomyolysis IV hydration/urine alkalinization
± mannitol
Methotrexate IV hydration/urine alkalinization
Acyclovir IV hydration
Calcineurin inhibitors Monitoring drug levels
Lowering the doses
± CCB
31. StrategyExposure
Avoid long-term use,
More than one drug
Avoid in old age
Monitor cumulative consumptions and avoid it
Avoid combination wit RAS blockers
Acetaminophen, Aspirin, NSAIDs
Fluid correction before drugs initiation
Monitoring s.creatinine
RAS inhibitors
Discontinue or reduce dose
Hydration
Oral route
Establish high urine flow
Acyclovir
Methotrexate
Sulfa ATB
Triamterene
32. Definition:
• The impairment of renal function and is measured as either a 25% increase in serum
creatinine (SCr) from baseline or 0.5 mg/dL (44 µmol/L) increase in absolute value, within
48-72 hours (max 7 days) of IV administration.
• The SCr levels peak between 2 and 5 days and usually return to normal in 14 days.
Patient related risk factors:
• Age
• CKD
• Coexisting diseases: Diabetes mellitus, Hypertension, Metabolic syndrome, Anemia,
Multiple myeloma Hypoalbuminemia,
• Renal transplant
• Hypovolemia and decreased effective circulating volumes .
Contrast-related risk factors are as follows:
• Volume of contrast
• Contrast characteristics, including osmolarity, molecular weight, volume, and viscosity.
• Ultra-low dose <50 ml was effective in reducing CIN .
Norbert Lameire, NDT Plus, 2008, 6:392 – 402.
Contrast – Associated Nephropathy
33. Complications:
• CIN is one of the leading causes of hospital-acquired acute renal failure.
• Nonrenal complications include
– Procedural cardiac complications (eg, Q-wave MI, coronary artery bypass graft
[CABG], hypotension, shock),
– Vascular complications (eg, femoral bleeding, hematoma, pseudoaneurysm, stroke),
– Systemic complications (eg, acute respiratory distress syndrome [ARDS], pulmonary
embolism).
Clinical presentation:
Acute renal failure : There may also be associated dehydration from aggressive diuresis,
exacerbated by preexisting fluid depletion; the acute renal failure is usually oliguric, and
recovery is anticipated in 2-3 weeks
Acute interstitial nephritis : is usually from drugs such as penicillin, cephalosporins, and
nonsteroidal anti-inflammatory drugs (NSAIDs)
Acute tubular necrosis - Ischemia from prerenal causes; endogenous toxins, such as
hemoglobin, myoglobin, and light chains; exogenous toxins, such as antibiotics,
chemotherapeutic agents, organic solvents, and heavy metals
35. • Steroid use in controversial but may be used for:
– Glomerular proteinuria with intake of NSAIDs, gold, penicillamine not respoding
to cessation of drug.
– All patients of hypersensitivity vasculitis due to drugs
– AIN unresponsive to drug cessation with granulomatous reaction.
– In patients with cisplatin toxicity
• Dialysis:
– Persistent azotemia
– Plasmapharesis in HUS
– PD for dug protein – bound (cisplatin, CsA, beta-lactams)
Next steps
36. 36
"The person who takes medicine must
recover twice, once from the disease and
once from the medicine."
- William Osler, M.D.
37. Case 2: 52 yo male with Type 2 DM
baseline creatinine 159umol/L; BP 148/96 Ramipril 5 mg daily started and
2 weeks later: BP 138/82 Serum creatinine 194umol/L
accept 20-30% increase in serum creatinine 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 creatinine 1-2 weeks after initiation, then in 2-4 weeks if >
30% change, decrease ACEI/ARB dose by 50% and
repeat Ser Cr in 4 weeks (exclude hypovolemia/NSAIDs, etc)
if > 50% rise in Ser Cr – rule out RAS repeat serum creatinine in this patient
in 1-2 weeks to ensure it has stabilized
Case 1: 82 yo female with osteoarthritis and HTN
Admitted to hospital for CAP & dehydration
Meds: Losartan 100mg daily + Naproxen 250mg BID
Serum creatinine 250 umol/L
Discontinue NSAID and hold ARB until infection treated and patient is
rehydrated/creatinine reduced
resume ARB and monitor serum creatinine
38. Sepsis:
Up to 50% of ICU AKI (tubular injury/necrosis).
Systemic vasodilatation
Renal vasoconstruction
Intravascular volume depletion
Anorexia
Third spacing of fluid
Apoptosis rather than necrosis
Heart failure:
Cardiorenal syndrome
Neurohormonal response
Reduce cardiac output
Elevated renal venous pressure
Systemic hypotension
Preexisting CKD :
Reduced volume of functional parenchyma
eGFR
Acute in top of Chronic
Liver diseases :
Acute hepatic failure
Decompensated cirrhosis
Vasodilated systemic circulation
Renal arteriolar vasoconstriction
Ascites (intraabdomenal compartement
syndrome)
39. EXCRETION PATHWAYS, TRANSPORT MECHANISMS &
DRUG EXCRETED.
Excretory
route
Mechanism Drug Excreted
Urine GF/ ATS/ ATR, PTR Free, hydrophilic, unchanged drugs/
metabolites of MW< 500
Bile Active secretion Hydrophilic, unchanged drugs/
metabolites/ conjugates of MW >500
Lung Passive diffusion Gaseous &volatile, blood & tissue
insoluble drugs
Saliva Passive diffusion
Active transport
Free, unionized, lipophilic drugs. Some
polar drugs
Milk Passive diffusion Free, unionized, lipophilic drugs (basic)
Sweat/
skin
Passive diffusion Free, unionized lipophilic drugs
Intestine Passive diffusion Water soluble. Ionized drugs
09-12-2010 39KLECOP, Nipani
40.
41.
42. SLOUGHING-OFF OF VIABLE & NON-
VIABLE CELLS WITH INTRALUMINAL
CELL-CELL ADHESION
INTACT TUBULAR EPITHELIUM I) LOSS OF CELL POLARITY
II) TIGHT JUNCTION INTEGRITY
III) CELL-SUBSTRATE ADHESION
CAST
FORMATION &
TUBULAR
OBSTRUCTION
TOXIC
INJURY
Hinweis der Redaktion
Multiple definitions, but most commonly used = as aboveNon-oliguric with recovery within about 14 daysRenal ischaemia generally lasts for about 4 hrs