Multiple definitions, but most commonly used = as aboveNon-oliguric with recovery within about 14 daysRenal ischaemia generally lasts for about 4 hrs
Nephrotoxicity eman 2013
1“All drugs known to humansare poisons, only the amountor dose determine theeffects.”Paracelsus, 1490 - 1541Drug-induced nephrotoxicity
Definition and epidemiologyRisk factors of ICU nephrotoxicityPharmacology in ICU patientsMechanisms of toxicityBiomarkersPrevention of ICU nephrotoxicity
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 knownOr Urine volume < 0.5 ml/kg/h for 6 hours.Nephrotoxic Injury DefinitionNephrotoxic injury is damage to one or both of the kidneys that results fromexposure to a toxic substance.Deterioration of renal function alters the drugs and metabolites clearance leadingto : More side effects Increase nephrotoxicity Change in the drug metabolism (volume distribution)Introduction
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 thepopulation studied and the definition of AKI used– Murugan R et all, Nat Rev Nephrol 2011 7:209 - 2179Nephrotoxicity due to drugs contributes to between 8-60% of AKI cases inhospitalized 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 between1-23%.– 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.
Continue:Based on 75,000 critically ill adults, more severe AKI occurs in 4% to 25% of allICU admissions .On average, 5% to 6% of ICU patients with AKI require renal replacement therapy(RRT).Uchino S, et al: Jama 2005; 294:813–818Uchino S, et al: Critical care medicine 2006; 34:1913–1917Ostermann M, Chang RW:Critical care medicine 2007; 35: 1837–1843; quiz 1852Elderly patients are likely more susceptible to AKI from nephrotoxic agents due tothe age related decline in GFR or renal blood leading to reduced clearance of thedrug, decline in hepatic clearance, altered free drug concentration.Henrich WL. Kidney Int Suppl:S107-109.
Common risk factors associated with the development of AKIClinical settingsICU/multiple organ failureSepsis/infectionDMPreexisting CKD defined as eGFR < 60 ml/min/m2Nephrotic syndromePostoperative especially cardiac and vascular surgeryTraumaBurnsHIVNon-renal solid organ transplantationBone marrow transplantationLiver diseaseMalignancyHypertensionMorbid obesity
Patient – specific factorsAdvanced ageVolume depletionSepsis,Preexisting renal hepatic and cardiac diseasesDMMultiple nephrotoxic drugsRadiocontrast agentCommon risk factors associated with the development of AKIMedicationsNSAIDs /cox-2 inhibitorsAminoglycoside antibioticsAmphotericin BRAS blockersCalcineurin inhibitorsChemotherapeutic agentsCocaineEthylene glycolOccupational toxins (heavy metals, organic solvents)Herbal remedies
Pharmacokinetic changes in ICU patientsAltered oral drug bioavailability (decreased> increased)Increased gastric pH, insoluble drug complexesIntestinal atrophy, dysmotility and reduced transport function (intestinal edema, orhypoperfusion )Reduced intestinal and hepatic metabolismRisk factors: acute heart decomposition, liver diseases)Boucher BA et el, Cri Care Clin 2006: 255 – 271Chan 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 failureDecreased protein concentration or binding and lipid solubility of drugsAltered tissue permeabilitypH disturbancesBoucher BA et el, Cri Care Clin 2006: 255 – 271Schmith VD, et al, Clin Pharmacol Ther 2010; 87: 488 - 491
Altered drug metabolism:Liver, kidney, intestine,Hypoperfusion of these organsAltered drug cellular transportAltered CYP-450 drug metabolismVily AM et al, Crit Care, 2008, 12: 235 – 243Chan LMS, et al, EurJ Pharmaceut Sci 2004; 12 25 – 51.Altered renal drug clearance:Reduced GFRReduced proximal tubular drug secretionDialysis clearanceModality of RRT (PD, HD, CVVH)Perazella, Kidney Int. 2012; 81: 1172 – 1178Continue:
Mechanisms of NephrotoxicityIntraglomerular hemodynamicsTubular cell toxicityInflammationCrystal nephropathyThrombotic microangiopathyRhabdomylosis
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
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 monthrespectively 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.
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.
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 elicitingan 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.
Rhabdomyolysis: Muscle injury leads to lysis of myocyte releasing of intracellular contents includingmyoglobin and creatine kinase into plasma Drugs may induce rhabdomyolysis directly secondary to a toxic effect on myocytefunction, 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 effectivethan 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
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) remainthe cornerstone of diagnostic tools available to the clinician in the ICUUrine 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
New biomarkers: Enthusiasm about their usefulness seems unwarranted at present, in ICU or surgicalICU. Poor performance in patients with sepsis or with acute-on-chronic kidney disease The inability of biomarkers to improve classification of unclassifiable (structural orfunctional) AKI, in which accurate differential diagnosis of pre-renal versus intrinsicrenal AKI has the most value, illustrates another problem. Future research is necessary to clarify whether serial measurements of a specificbiomarker or the use of a panel of biomarkers may be more useful in critically illpatients at risk of AKI.Mol Diagn Ther. 2012 Aug 1;16(4):199-207
Cystatin C marker:• able to predict AKI 1-2 days earlier than SCr. But also increased when GFR islow too• Cystatin C is a low molecular weight protein produced by all nucleated cellsthat is freely filtered by the glomerulus and then reabsorbed and metabolizedby 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 whichreflect tubuar damageHilde R. et al Clin Kidney J (2012) 5: 102–108Knight EL, et al, Kidney Int 2004; 65: 1416–1421Okura T, Jotoku M, Irita J et al. Clin Exp Nephrol 2010; 14: 584–588
NAGLNeutrophil 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 NGALexpression.• 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 mouseMishra J, et al J Am Soc Nephrol 2003,14:2534-43Hilde R. et al Clin Kidney J (2012) 5: 102–108A pro-inflamatory cytokine IL-18:Urine IL-18 levels were found markedly increased in patient with AKInot in patients with UTI, CKD, nephrotic syndromesensitivty > 90% and specifity>95% for the diagnosis of AKI.Parikh CR & Devarajan . Crit Care Med 2008,364):S159-S16
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 tractinfectionLiangos O, et al. J Am Soc Nephrol 2007:18:904-912
Author Estimation formula PurposeMDRD eGFR = 186 × serum creatinine (mg perdL) −1.154 × age (years) −0.203 × (0.742if patient is female) × (1.210 if patient isblack)To assess renal function andstage chronic kidney diseaseCockcroft andGaultMale: eCrCl = ([140 – age (years)] × idealbody weight [kg]) ÷ (serum creatinine[mg per dL] × 72)To adjust drug dosing for renalfunction in adultsFemale: male eCrCl × 0.85Schwartz eCrCl = (length [cm] × k) ÷ serumcreatinine (mg per dL)To adjust drug dosing for renalfunction in childrenk = 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 adjustmedication dosages
General approaches for the prevention of AKIAvoidance of nephrotoxinsRecognition of potential nephrotoxic agentsRecognition of high risk high risk patients and clinical stetting sAvoidance of concomitant use of multiple nephrotoxinsMaintain euvolemia :CVP 8 – 12 mmHg or to 15 mmHg in patient with positive pressure ventilationEarly rehydrationMean arterial pressure > 65mmHgThird spaceIf applicable monitoring drug dose and levelsUse of lowest dose for shortest timeMinimization of nosocomial infectionUrine output hourly measurementMonitoring kidney function closely and evaluation of GFRDose adjustment accordinglyControlling BPControlling DM : tight is associated with hypoglycemia and no difference in moratlity copreto conventional glucose control
Example of specific renal protective strategiesExposure StrategyAminoglycoside antibiotics Once – daily dosingMonitoring of drug levelsAvoiding in CKD and pts at risks.Maintain trough levels < 1mcg /ml.Tumor lysis (uric acid) Allopurinol/rasburicaseIV hydration/urine alkaliniationAmphotericin B Use lipid formulationSaline hydration pre and post administrationAvoid high or rapid dose or prolonged durationEthylene glycol ingestion Ethanol/fomepizolehemodialysisrhabdomyolysis IV hydration/urine alkalinization± mannitolMethotrexate IV hydration/urine alkalinizationAcyclovir IV hydrationCalcineurin inhibitors Monitoring drug levelsLowering the doses± CCB
StrategyExposureAvoid long-term use,More than one drugAvoid in old ageMonitor cumulative consumptions and avoid itAvoid combination wit RAS blockersAcetaminophen, Aspirin, NSAIDsFluid correction before drugs initiationMonitoring s.creatinineRAS inhibitorsDiscontinue or reduce doseHydrationOral routeEstablish high urine flowAcyclovirMethotrexateSulfa ATBTriamterene
Definition:• The impairment of renal function and is measured as either a 25% increase in serumcreatinine (SCr) from baseline or 0.5 mg/dL (44 µmol/L) increase in absolute value, within48-72 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
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], pulmonaryembolism).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, andrecovery is anticipated in 2-3 weeksAcute interstitial nephritis : is usually from drugs such as penicillin, cephalosporins, andnonsteroidal anti-inflammatory drugs (NSAIDs)Acute tubular necrosis - Ischemia from prerenal causes; endogenous toxins, such ashemoglobin, myoglobin, and light chains; exogenous toxins, such as antibiotics,chemotherapeutic agents, organic solvents, and heavy metals
• Steroid use in controversial but may be used for:– Glomerular proteinuria with intake of NSAIDs, gold, penicillamine not respodingto 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"The person who takes medicine mustrecover twice, once from the disease andonce from the medicine."- William Osler, M.D.
Case 2: 52 yo male with Type 2 DMbaseline creatinine 159umol/L; BP 148/96 Ramipril 5 mg daily started and2 weeks later: BP 138/82 Serum creatinine 194umol/Laccept 20-30% increase in serum creatinine within 1-2 months of initiationin fact, this could be an indication that the drugs are exerting their desiredactions to help preserve renal functioncheck serum creatinine 1-2 weeks after initiation, then in 2-4 weeks if >30% change, decrease ACEI/ARB dose by 50% andrepeat Ser Cr in 4 weeks (exclude hypovolemia/NSAIDs, etc)if > 50% rise in Ser Cr – rule out RAS repeat serum creatinine in this patientin 1-2 weeks to ensure it has stabilizedCase 1: 82 yo female with osteoarthritis and HTNAdmitted to hospital for CAP & dehydrationMeds: Losartan 100mg daily + Naproxen 250mg BIDSerum creatinine 250 umol/LDiscontinue NSAID and hold ARB until infection treated and patient isrehydrated/creatinine reducedresume ARB and monitor serum creatinine
Sepsis:Up to 50% of ICU AKI (tubular injury/necrosis).Systemic vasodilatationRenal vasoconstructionIntravascular volume depletionAnorexiaThird spacing of fluidApoptosis rather than necrosisHeart failure:Cardiorenal syndromeNeurohormonal responseReduce cardiac outputElevated renal venous pressureSystemic hypotensionPreexisting CKD :Reduced volume of functional parenchymaeGFRAcute in top of ChronicLiver diseases :Acute hepatic failureDecompensated cirrhosisVasodilated systemic circulationRenal arteriolar vasoconstrictionAscites (intraabdomenal compartementsyndrome)