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University of Szeged Faculty of Medicine Albert SzentSzent-Györgyi Medical and Pharmaceutical Center First Department of Internal Medicine Acute renal failure Péter Légrády MD Acute renal diseases without renal failure or with renal failure glomeruli and / or tubuli and interstitium nephrosis and / or nephritis Definition • Quick decline in renal function (hours hours,, days, days, weeks) weeks) – the previously normal serum creatinine increases over 180 umol umol/l /l or 1.5 folder of previous value – accumulation of nitrogenous waste products – electrolyte l t l t imbalance i b l – less urine output ((usually usually,, but not always) always) • oliguria 500 ml/24 hs • anuria 5050-100 ml/24 hs Definition Acute renal failure is a syndrome defined by a sudden loss of renal function over several hours to several days. Mayo Clin Proc. 2001;76:67-74 1 Basic Facts Classic laboratory definition • Renal failure over the course of hours to days days.. • The result will be failure to excrete nitrogenous waste and electrolyte imbalance.. imbalance • Hard to define: define: in 26 studies, no two used the same definition!!! • Increase in more than 50 50% % over baseline Cr Cr.. • Decreased D d in i calculated l l t d Cr C Clearance Cl b by more than 50% 50%. • Any decrease in renal function that requires dialysis. dialysis. What constitutes the syndrome of ARF? Etiology of ARF among outpatients • Accumulation of nitrogenous waste products. • Increased sCr. sCr. • Decreased D d GFR. GFR • Derangement of extracellular fluid balance. • Acid Acid--base disturbance. • Electrolyte and mineral disorders. Prerenal (70%) Intrarenal (11%) Obstruction(17%) idiopathic(2%) AJKD 17:191-198, 1991 2 Etiology of ARF among inpatients ATN (45%) Prerenal (21%) ARF on CKD (13%) ( ) Obstruction (10%) GN/vasc (4%) AIN (2%) Atheroemboli (1%) Natural history of ARF • 48% ICU p patient atientts ts require dialysis • 58% inpt mortality among patients who develop ARF in the ICU Crit Care Med 24(2);192 24(2);192-198 198, 1996 • 36 % mortality among all inpts with ARF • 20% of survivors received dialysis JASN 9(4):692-698, 1998 KI 50:811-818, 1996 Symptoms of acute renal failure • • • • • • • • • sudden oliguria, oliguria, anuria waist pain nausea nausea,, vomitus peripheral and/or and/or pulmonary oedema hypertension Kussmaul breathing convulsions depression of consciousness hyperkalemia The amount of urine BUT! • by abdominal ultrasound (US): Oliguria: urine output less than 500 ml/24hr. – kidney size • < 10 cm and d parenchyma h < 10 mm Nonoliguria: urine output greater than 500 ml/24hr. It is chronic chronic!! Anuria: urine output less than 50 ml/24hr. 3 Clinical presentation of acute renal failure • • • • • Acute renal failure Prerenal decreased renal perfusion 80% of cases ARF settled on previous chronic kidney disease Renal intrinsic renal disease 10% of cases Postrenal obstruction 10% The pathophysiology of ARF • nephrosis syndrome ischemic nephropathy prolonged NSAID therapy prolonged ACEI therapy nephrotoxic drugs, drugs contrast agents added on renal failure acute exacerbation of some immunological GN: – – – – IgA nephropathy lupus nephritis membranoproliferative GN vasculitis Factitious ARF • Interference with laboratory measurement of Scr (Jaffe Method) Acute renal failure Prerenal Vascular Intrarenal Glomerular Postrenal Tubular Factitious Interstitial Ischemia Toxins – cefoxitin – ketoacids • Competitive inhibition of creatinine secretion in the proximal tubule – cimetidine – trimethoprim • Increased production of creatinine – fenofibrate Pigments JASN 1998;9(4):710-718 4 PrePre -renal failure • Often rapidly reversible if we can identify this early. • The elderly at high risk because of their predisposition to hypovolemia and renal atherosclerotic disease. • This is by definition rapidly reversible upon the restoration of renal blood flow and glomerular perfusion pressure. • THE KIDNEYS ARE NORMAL (>10 cm). • This will accompany any disease that involves hypovolemia, low cardiac output, systemic dilation, or selective intrarenal vasoconstriction. - 70% 70% of community acquired cases cases.. - 40% 40% of hospital acquired cases cases.. The causes of pre pre-renal ARF Reduction in effective extracellular volume • hypovolemia – – – loss of fluid (trauma, surgical, GI, renal, pulmonary, skin) bleeding hypalbuminemia • heart failure – – – – Defect of renal autoregulation • vasoconstriction of afferent arterioles myocardial dysfunction valvular disease pericardial tamponade pulmonary hypertension – – – – • hepatorenal sy sepsis hypercalcemia drugs g (NSAID, ( , cyclosporine, y p , epinephrine, norepinephrine) vasodilation of effernt arterioles – – ACEI ARB • vasodilation – – – – sepsis cirrhosis anaphylaxis drug high htc, se BUN/se creat > 80, concentrated urine (density >1020, Osm > 500 mOsm, low urine Na (< 20 mmol/l) Klinikai nephrologia. Ed.: Kakuk György, Medicina, Bp. 2004. Differential diagnosis • Hypovolemia – GI loss: nausea, ausea, vomiting, diarrhea – Renal loss: diuresis diuresis,, hypo adrenalism, adrenalism, osmotic diuresis (DM) – Sequestration: pancreatitis, peritonitis,trauma,, low albumin. peritonitis,trauma – Hemorrhage, burns, dehydration. Differential diagnosis • Renal vasoconstriction: hyper Ca, norepi, norepi, epi, epi, cyclosporine, tacrolimus tacrolimus,, ampho B. • Systemic vasodilation vasodilation:: sepsis, medications, anesthesia, anaphylaxis. • Cirrhosis Ci h i with ith ascites it • Hepato Hepato--renal syndrome • Impairment of autoregulation autoregulation:: NSAIDs, ACE, ARBs. • Hyperviscosity syndromes: MM, WM, 5 The causes of renal ARF Differential diagnosis • Low CO – – – – – – myocardial diseases valvular heart disease pericardial disease tamponande pulmonart HTN pos pressure mechanical ventillation Arterial and venous occlusions of the renal vessels • acute occlusion of renal artery – – – – atherosclerosis aorta aneurysm invasive vascular procedure jeopardy of embolism – – – severe nephrosis sy severe hypalbuminemia (< 15 g/l) ARF with kidney tumor Renoparenchymal diseases • acute tubular necrosis – – ischemic ATN toxic ATN (endogenous and exogenous toxic agents) • intrarenal obstruction • intrarenal vascular damage • • glomerular diseases interstitial diseases • thrombosis of renal vein – cristals, debris of cells, casts – – – – – – – thrombotic microangiopathy g p y HUS connected to pregnancy malignant hypertension scleroderma vasculitis cholesterol embolisation – – – – drugs infections autoimmune procedures malignant infiltrative diseases Klinikai nephrologia. Ed.: Kakuk György, Medicina, Bp. 2004. Intrinsic renal disease • Anatomic organization seems to work best.. ARF does not aequal ATN. best ATN. • 30 30% % of cases of intrinsic renal failure y evidence of f ATN on will not show any urin analysis – – – – glomerulus Vessels Interstitum tubules Common causes of acute tubular necrosis surgical operations, extended hypovolemia, sepsis ischemia exogenous aminoglikoside, amphotericine, vancomycine, contrast agent, cisplatine, acetaminofene, heavy metals, organic resolvents endogenous myoglobin, hemoglobin, light chain, urates, calcium, phosphorus, oxalate, toxic 6 ATN: Toxic ATN • Ischemic Injuries to the renal tubule: – Takes 1-2 weeks to recover from after perfusion has been normalized. normalized. – In the extreme form this can lead to bilateral renal cortical necrosis • Three phases: phases: – Initiation phase – Tubuloglomerular feedback feedback:: afferent arteriole constriction triggered by an increase in the salt delivery sensed by the macula densa densa.. – Recovery phase: phase: tubular epithelial cell repair and regeneration.. This may be associated with a marked regeneration diuretic phase. phase. Differentiation of prepre-renal kidney failure and acute tubular necrosis prepre -renal ATN urine osmol. > 500 mOsm < 350 mOsm urine Na < 20 mmol/l > 40 mmol/l FENa <1% >2% sediment negative casts, epithel cells urine creat/se. creat. > 20:1 10 10--15:1 rate of sese-creat. < 40 umol/day > 40 umol/day • Exogenous – – – – – – – Radiocontrast CSP TAC Amino glycosides Chemotherapy Ethylene glycol Tylenol • Endogenous – – – – – Myoglobin Hemoglobin Uric acid Oxylate Light chains Acute interstitial nephritis: nephritis: allergic Allergic reaction in the tubules. IT IS PARAMOUNT TO IDENTIFY THE OFFENDING AGENT AND REMOVE IT. There may be some role for steroids in the case of AIN. 7 Acute interstitial nephritis Drugs • Antibiotics – penicillines, cephalosporines, sulfonamides, rifampicine, nitrofurantoine, quinolones, macrolides, tetracycline, vancomycine, acyclovire • Analgetics/NSAIDs • Others – – 5-ASA, p paracetamol, aspirin, p amidazophene, ibuprofene, stb., thiazids, triamterem, furosemide, chlorthalidon, cimetidine, ranitidine, famotidine, omeprazole, allopurinol, propylthiouracil, phenytoine, carbamazepine, diazepam, azathioprine, cyclosporine, interferon, streptokinase, warfarin, contrast agent, captoprile, „crack”, „mega”--Vitamin C „mega” Infections • Bacteria – Streptococcus, diphtheria, Leptospira, Legionella, Pneumococcus, malta fever, typhus, Yersinia Acute nephritis syndrome • oliguria • azotemia = ARF • Viruses • Fungi • hypertension, hypertension headache • Others • red red-brown, cola cola-like colored urine – hantavirus, CMV, EBV, adenovirus, polyoma, HIV, HAV, morbilli, german measles, influenza, Coxsackie – candidiasis, histoplasmosis – mycoplasma, toxoplasma, malaria, schistosomiasis, leishmaniasis - may be with fever, rash, joint pain, eosinophiles; or only with renal failure, - pyuria, granular casts, RBCs, eosinophiles in urine in 75 % (except NSAID) - < 1.5 g protein Diseases causing acute nephritis syndrome • post post-streptococcal GN: acute diffuse proliferative GN • IgA nephropathy • membranoproliferative GN • SLE: focal or diffuse proliferative GN • oedema - periorbital, mainly in the morning (macroscopic hematuria) • active urine sediment: dysmorphic RBCs , RBC casts, WBCs, WBC and granular casts, amorphic granules quick (days, weeks) developing symptoms Rapidly progressive GN RPGN (Rapidly Progressive Glomerulonephritis)) is a Glomerulonephritis syndrome defined by the rapid loss of renal function over days to weeks due to acute glomerulonephritis.. glomerulonephritis • RPGN 8 Rapidly progressive GN • insidious beginning Rapidly progressive GN • • quick and progressive GFR decline • • oliguria • • hematuria / proteinuria • kidney size larger, structure slackened, (abdominal US) • nephritis sy., rarely nephrosis sy. • crescents > 70 % Rapidly progressive GN – treatment Rapidly progressive GN I. Anti Anti--GBM antibodies (linear IF) Goodpasture--sy., • Goodpasture • anti anti--GBM sy., • without pulmonological symptoms, only kidney affected II. Immunocomplex GN (granular IF) • primary GN: IgA GN, membranoproliferative GN • postinfectious: sepsis, abscess, endocarditis, HBV, post--streptococcal GN post • autoimmune: SLE III. ANCA associated GN (no IF = „pauci” immune) • Wegener granulomatosis • microscopic polyarteritis • Churg Churg--Strauss sy • RPGN with ANCA • „idiopathic” crescent GN Clinical features: – cold or viral prodrome Symptoms: weakness, nausea, vomitus, waist pain, hemophtysis, oliguria, rised BP Dg.: – urine: • hematuria (dysmorphic RBCs) • 100 % casts (granular, RBC) • 100 % proteinuria – kidney function: • creatinine creatinine--clearance: < 20 ml/min approx. 30 % – normal kidney size – anemia: normocyter, normochrom – serologycal disparities – histology: renal biopsy • quick diagnosis • steroid • cytotoxic agents • • • • • – cyclophosphamide, cyclophosphamide chlorambucil, chlorambucil azathioprine micophenolate mofetil plasmapheresis extracorporal immunoabsorption dialysis (depending on kidney function) transplantation 9 Rapidly progressive GN – steroid therapy • Intravenous pulse therapy followed with oral supporting therapy: – methylprednisolone 1 g/day for 33-5 days, and after – orally 1 mg/kg/day decreasing step by step to 4 4--8 mg/day for 12 12--24 months • Continuous oral therapy: – methylprednisolone 1-1.5 mg/kg for 4 4--6 weeks, decreasing step by step to supporting dose Rapidly progressive GN – plasmapheresis • change of 4 litre plasma • 7-10 times • with fresh frosened plasma Rapidly progressive GN – cytostatic therapy • cyclophosphamide – oral 150 150--200 mg/day – i. v. 10 mg/kg monthly • chlorambucil – oral 5 mg/day • azathioprine – oral 100 100--150 mg/day • dose reduction: – no. of WBCs < 4.000 – no. of platelets < 100.000 Acute urate nephropathy (AUAN) - blood uric acid level suddenly increased - insufficient proximal tubular reabsorption - uric acid crystals precipitating in tubules → damage of tubular epithel cells - bigger crystal precipitates → renal colic, obstruction of ureters Klinikai nephrologia. Szerk.: Kakuk György, Medicina, Bp. 2004. 417417-420. 10 Acute urate nephropathy (AUAN) Clinical features: • oligo oligo--anuric ARF • urate crystals in urine sediment (BUT! not with obstructed ureters) • no specific symptoms • waist p pain, renal colic • labs: uric acid ↑ (even > 900 + µmol/l), P ↑, K ↑, Ca ↓, yes tumorlysis syndrome after therapy no spontaneous tumorlysis syndrome Treatment of acute urate nephropathy Prevention With ARF • high dose (600 (600--900 mg) allopurinol started 2 days before chemotherapy or irradiation • rasburicase (urate (urate--oxidase) • normalise metabolic parameters • urine > 2500 ml/day • (parenteral) fluid intake (start it before 2 days and stop it after 22-3 days of therapy) • diuretics (furosemide, mannitol) • alkalify urine (NaHCO3) pH: 7.0 – 7.5 – ph < 7.0 uric acid precip. – ph > 7.5 xantine percip. • allopurinol in reduced dose • forced diuresis (high dose furosemide and mannitol) • hemodialysis (if P ↑ -> daily) daily) • NaHCO3 is not adviced in oliguria and it could be dangerous in hyperphosphatemia (Ca--P deposits) (Ca • rasburicase (urate (urate--oxidase) Klinikai nephrologia. Ed.: Kakuk György, Medicina, Bp. 2004. 417417-420. PostPost -renal causes If we can identify this early, this can be readily reversible. This accounts for fewer than 5% of cases of ARF. Differential diagnosis • BPH (No (No11) • Prostatitis • Prostate / Cervical cancer p fibrosis f • Retroperitoneal / disorders • Extraluminal malignancy • Neurogenic bladder / anticholinergic drug use use:: functional obstruction • Bilateral renal calculi • Myeloma light chains • Papillary necrosis • Urethritis with spasm • Inadvertent surgical ligature • Intraluminal Thrombosis • Intraluminal (collecting system) crystal disease • Uric acid • Calcium oxylate • Acyclovir • Sulfonamide • MTX 11 Acute obstruction of urinary tract Intrinsic causes – – – – – – papillanecrosis blood clot stones tumors (carcinomas carcinomas)) stricture (trauma) infections (schistosomiasis) schistosomiasis) • Extrinsic causes – – – – – pregnancy gynecological tumors prolapse of the uterus ovariall cysts prostatic hyperplasia hyperplasia,, prostatic hypertrophy – M. Crohn – aorta aneurysm – surgical causes (ligature ligature)) Acute renal failure ailure:: Diagnostic work ork-up • Chem • • Urine electrolytes • • • Urinalysis with Microscopic Mi i analysis * • Renal ultrasound BUN/Cr ratio > 1515-20 Na and CO2 may be high FeNa FeNa* * = Cr S x NaU x 100 CrU x Na S < 1 prerenal, prerenal, >1 renal • Urinary Na < 20 • Urine Osms > 500 Klinikai nephrologia. Ed.: Kakuk György, Medicina, Bp. 2004. Other useful tests • • • • 24 hour urine for protein and creatinine urine eosinophils., UPEP cholesterol,, albumin,, glucose g ANA panel, CC-ANCA , SPEP, HIV, Hepatitis B/C, ASO • Renal biopsy • Post Post--void residual or catheterization • PSA Renal failure indices • Fractional excretion of Na Na:: this will relate the clearance of Na to that of Cr. Cr. • In the case of prerenal disease Na is actively reabsorbed to restore intravascular volume. volume. • This is not the case in renal injury j y ((absorptive p mechanisms h i are broken). b k ). In broken) I either ith case Cr C is i NOT reabsorbed.. So we have the makings of a reabsorbed comparative ratio. ratio. The cut off is 1%. U Na / P Na __________ x 100% = .14% (Prerenal (Prerenal)) U Cr / P Cr 12 Additional labs Kidney and the potassium • Peak Cr: Cr: – In prerenal disease : may fluctuate with hemodynamics hemodynamics.. Rise will be rapid rapid.. This is true for contrast (5 days to peak and 7 to normal) – Atheroembolization (later peak and return to baseline), peak and return to baseline). baseline)). and ischemia ((later p – Rise will be delayed in toxin exposure. exposure. • Rhabdo Rhabdo:: elevated K, Phos Phos,, hypocalcemia with elevations in CK and UA UA.. • TLS TLS:: elevated UA, K, Phos Phos,, low Ca, elevated Cr and elevated LDH (intracellular enzyme) enzyme).. • Elevated anion gap + elevated osm gap gap:: suggests ethylene glycol / methanol exposure. exposure. • Anemia may suggest hemolysis, hemolysis, MM, or TTP TTP.. • Eosinophillia may suggest AIN, atheroembolic disease. disease. • Kidney handles it in a unique way. way. • It virtually reabsorbs 100% 100 % of the K in the proximal tubule (70 70% %) and the loop of henle (30 30% %). • We reabsorb almost all of the K before we reach the distal segments.. segments Differential diagnosis Differential diagnosis • Increased intake : rare except in iatrogenesis • Cellular release – – – – – – – TLS, Rhabdomyolysis, exercise, trauma Metabolic acidosis Insulin deficiency Hyperkalemic periodic paralysis Digoxin toxicity, beta blockers Adrenal insufficiency Succinylcholine • Impaired excretion – Renal failure – Primary hypoaldosteronism – Secondary hypoakdosteronism • ACE, ACE NSAIDs NSAIDs, Heparin Heparin, Type 4 RTA – Aldo resistance • K sparing diuretics, bactrim, pentamidine, sickle cell disease, multiple myeloma. – Gordon’s syndrome (enhanced Cl reabsorption, less K secretion, HTN) – Ureter Diversion to Jejunum. 13 Symptoms / Signs of hyperkalemia • Flaccid paralysis • Arrhythmia – Peaked T waves – PR / QRS prolongation – AV conduction delay – Loss of P waves – Sine wave – V fib Treatment • Prevention is the key. key. – – – – – – – – Appropriate volume resuscitation resuscitation.. Renal dosing of potentially toxic meds To estimate GFR When appropriate follow serum drug levels for dosage adjustment adjustment.. Use of NSAIDS, ACR, ARBs, diuretics should be used sparingly in patients who are hypovolemic or have renovascular disease. disease. Allopurinol / IVFs use in patients high risk for TLS TLS.. Ethanol for EG toxicity / NAC for tylenol toxicity. toxicity. Alkalinization of urine : to prevent MTX toxicity. toxicity. Treatment of ARF • • • • • • • Eliminate the toxic insult Hemodynamic support Respiratory support Fluid management Electrolyte management Medication dose adjustment Dialysis More prevention prevention of ARF • Diminish risk of nosocomial infection – conservative use of IV catheters – judicious use of antibiotics – hand hand--washing • Prevention of nephrotoxicity – avoid/reduce nephrotoxins – IV NS – N-acetylcysteine, acetylcysteine, sodium bicarbonate – correct hypokalemia hypokalemia,, hypomagnesemia – correct/treat other systemic diseases • Pharmacology – avoid overlapping nephrotoxins – follow drug levels closely • Attention to fluid status – Regular weights, I & O JASN 9(4):710-718, 1998 14 PrePre -renal disease Intrinsic renal Disease • Intravenious fluid fluid:: keep in mind where the loss is coming from and administer fluids accordingly accordingly.. Inotropes, p , preload p / afterafter f -load • Inotropes reduction, anti anti--arrythmics arrythmics,, mechanical aids in CHF CHF.. • Large volume paracentesis: paracentesis: to decrease intra--abdominal pressure and increase intra venous return from the kidneys. kidneys. • Intrinsic renal disease: disease: NO SPECFIC REVERSING THERAPIES FOR ISCHEMIC AND NEPHROTOXIC DISEASE. DISEASE. SUPPORTIVE CARE.. CARE • Follow electrolytes electrolytes.. Avoid further insult insult.. • GN GN:: may respond to steroids, alkylating agents, plasmapheresis. plasmapheresis. • AIN AIN:: glucocorticoids may be of use use.. • Malignant HTN: HTN: control of blood pressure pressure.. • Scleroderma: HTN and ARF may responsive to ACE. PostPost -renal treatment Predictors of dialysis in ARF • Oliguria: • • • • Foley catheter Nephrostomy tube Stenting 5% will develop a salt wasting diuresis. diuresis. – <400cc/24hr 85% will require dialysis – >400cc/24hr 30 30--40% will require dialysis • • • • • • Mechanical ventilation Acute myocardial infarction Arrhythmia Hypoalbuminemia ICU stay Multi Multi--system organ failure JASN 9(4):692-698, 1998 Arch IM 160:1309-1313, 2000 15 Contrast-induced renal Contrastfailure Dialysis needs • A : acidosis (l (life ife--threatening threatening)) • E : electrolyte abnormalities • I : intoxication (methanol, ethylene glycol, glycol isopropanol isopropanol,, theophylline theophylline,, lithium, lithium salicylates)) salicylates • O : volume overload • U : uremia ((pericarditis pericarditis,, seizures, encephalopathy) • • • • Risk is 40% for patient with diabetes Oliguria and other symptoms develop in 24 hrs Prevention: N-acetylcystine 600 mg po bid x 2d (1 before and day of) – Give 0.45% NS iv 1 ml/kg/h 12 hrs before and after – Contrast nephropathy( defined as >0.5 mg/dl increase)-increase) 21% of controls and 2% of NN-acetylcysteine group Tepel, NEJM, 2000. 16