An Approach to Management and Diagnosis of Acute Renal Failure Acute Kidney Injury Renal Failure Shining a Light on Black Boxes of Understanding Franchot van Slot MD/PhD Multicare Health Systems, Hospitalist Adjunct Professor, Pacific University of PA Studies Disclosures: No conflicts of interest to report AKI/ARF Definitions • Transition meant to reflect spectrum of renal insult, increased mortality even with minor rises, but general dfinition is the same: • An Acute decline in GFR • Chronic kidney disease= existing >3 months KDIGO criteria • Kidney Disease: Improving Global Outcomes • Followed previous AKIN and RIFLE criteria Criteria: • Increase Cr ≥ 0.3 within 48 hours • Increase Cr ≥ 1.5x baseline in <7 days • Urine volume <0.5ml/kg/h for >6 hours • Stage 1: 1.5-1.9x baseline or ≥0.3mg/dl • Stage 2: 2.0-2.5x baseline or UO<0.5mg/kg/h x ≥12h • Stage 3: 3.0x baseline or increase Cr ≥4.0 or UO <0.3ml/kg/h x ≥24h or anuria ≥12h or RRT or if age <18yo GFR <35ml/min/1.73m2 http://4.bp.blogspot.com/-88O6JKhocCg/Tobdp5yKiI/AAAAAAAAACw/B2VSw3OkrNM/s200/ microscope.gif Adapted from BaileyBio.com Adapted from: Wikimedia Commons https://en.m.wikipedi a.org/wiki/File:Kidney _Cross_Section.png Introduction • • • • Shedding light on black boxes Relatively traditional approach Focused on management, diagnosis A systematic approach – Getting out of cookie-cutter mindset: the dose and hope strategy – Few tests required to dramatically narrow down cause • History • The importance of plumbing • Medicine works best in the direction: History, Diagnosis, Treatment Outline • • • • • • • • • Introduction Epidemiology and consequences Normal Kidney function General, practical anatomy Pre, intrinsic, and post renal failure and causes Diagnosis Treatment New Directions Conclusion Epidemiology • • • • • • 2 million patients per year 700,000 deaths 2-5% hospitalized patients1,2 30% may be preventable3,4,5 5-20% ICU patients1,2 Cr rise ≥ 0.5 associated with: – 6.5 fold increased risk of death – 3.5 day increased LOS – $7000 increased hospital cost after adjustment7 • ICU mortality with multiorgan failure >50%8 • If RRT required mortality increasec to 80%8,9 Kidney Functions • • • • • • • • Volume homeostasis Blood pressure homeostasis Water balance Electrolyte balance Acid excretion, bicarbonate regeneration Detoxification Hematopoiesis Vitamin D hydroxylation AKI complications • • • • • • • • • Volume overload Hyperkalemia Metabolic acidosis Hypocalcemia Hyperphosphatemia Mental status changes Hyperuricemia Hypermagnesemia Platelet dysfunction Hospitalist Anatomy Heart Aorta Kidney Renal Artery Renal Vein Major Calyx Ureters Bladder Prostate Urethra Urethral sphincter -Image adapted from multiple sources see bibliography Hospitalist Anatomy Heart Aorta Kidney Renal Artery Renal Vein Major Calyx Ureter Uterus, ovaries Bladder Urethra -Image adapted from multiple sources see bibliography Prerenal ~50-70% (Plumbing) Intrinsic ~10-30% (Biochemistry) Postrenal ~10-30% (Plumbing) Image adapted from multiple sources see bibliography History • The Trump Card, most important factor in diagnosis • A good history will often reveal multiple contributors to renal failure • Do not allow isolated lab values to get in the way. They count less than historical details. Prerenal Requirements -Cardiac Output -Volume -Blood Pressure -Oxygen Carrying Capacity -Clear path Image adapted from multiple sources see bibliography Prerenal Requirements: Cardiac Output • Cardiomyopathy – “cardiorenal syndrome” • Valvular disease – Aortic stenosis – Mitral regurgitation • Tamponade Prerenal Requirements: Volume • Direct volume losses – – – – n/v/d Diuretics Osmotic diuresis (DKA/HHS) Reactive diuresis: UTI, post-obstructive diuresis • Insensible losses – Sweating, tachypnea, fever, burns • Poor PO intake • Third spacing – Cirrhosis – Nephrotic syndrome – malignancy Prerenal Requirements: Blood Pressure • Severe sepsis • Iatrogenic – Antihypertensives – diuretics • Hemorrhage – Trauma – Surgery – GI bleed, retroperitoneal bleed, etc • Endogenous factors – – – – Cirrhosis Hypothyroid Adrenal insufficiency Abdominal compartment syndrome Prerenal Requirements: Oxygen Carrying Capacity (Hgb) • Acute losses – – – – – Trauma Surgery Hemolysis Phlebotomy GI bleed, occult bleeds, etc. • Failure of hematopoiesis – Iron, vitamin deficiencies – CKD – Malignancy • Chronic losses – Anticoagulants – Bruising – PUD, esophagitis Prerenal Requirements: Clear Path • Aortic dissection • Mural thrombus • Renal artery stenosis – Atherosclerotic disease – External compression • Proximal glomerulus – NSAIDs – ACEI/ARBs Postrenal Requirements -Clear path Image adapted from multiple sources see bibliography Postrenal Problems • Ureteral – Stones • Bilateral or unilateral c contralateral disease • Hemorrhage/clot • Extrinsic compression – Mass – fibrosis – Surgical • Stent obstruction • ligation – Stricture – Congenital abnormalities (valves) Postrenal Problems • Bladder – Obstructed foley – Bladder CA, outlet or bilateral ureteral obstruction – Bladder stone – Neurogenic bladder (caution) • Prostate – – – – BPH Prostate CA Prostatitis Post surgical • Urethra – Stricture – Urethritis – Foreign body Female and Pregnancy • Ureteral – Bilateral ureteral obstruction (or unilateral c contralateral disease • Gravid uterus • Fibroid • Ovarian, endometrial, cervical CA • Bladder/urethra – Suspensory bladder ligament laxity • Age, multiparity, other surgery • Prolapse: rectovaginal – Pelvic floor relaxation • Previous prolonged labor, multiparity age • Post-menopausal estrogen decline From Wikimedia commons Hepatorenal • • • • • Poor prognosis Diagnosis of exclusion Often precipitated by SBP Pathophysiology unclear Known prerenal component ? – Hypoalbuminemia – Hypotension • Postulated Postrenal (vein) Adapted from: Wikimedia Commons https://en.m.wikipedia.org/ wiki/File:Kidney_Cross_ Section.png – Improved with agents that decrease portal HTN – Improved with TIPS procedure • Type I: 2x increase in Cr to >2.5 in <2 weeks • Type II: hepatorenal syndrome not meeting Type I criteria Intrinsic Renal Requirements -Prerenal function -Postrenal function -Normal oxygenation -Normal genetics -Euglycemia -Normotension -Normal immune function -To be kept away from doctors Image adapted from multiple sources see bibliography Intrinsic Renal Problems •DM •HTN •ATN •Tubulointerstitial diseases •AIN •Autoimmune •Idiopathic •Iatrogenic •Drugs Diabetes -Major cause of CKD, less frequently seen acutely -Slowly progressive, generally taking 10-15 years to be clinically apparent -May not always be an obvious cause -late care -renal failure increases half life of insulin and may be euglycemic on presentation if renal failure is severe -caution with long acting insulin, especially if not yet on HD HTN • Often goes hand-in-hand with DM • Like DM more typically slow, progressive • Commonly seen as acute cause in malignant HTN • Results in nephrocalcinosis ATN (acute tubular necrosis) • Wastebasket term in many respects • Typically reserved for ischemic causes of ARF • Most prerenal causes left unchecked will result in ATN • Estimated to be present in 45-70% ICU pts6 – 35-50% of sepsis patients10 ATN Causes • Severe sepsis • Nephrotoxins – – – – – – – Antibiotics: aminoglycosides, pentamidine, HIV drugs Heme pigments: rhabdomyolysis, hemolysis Chemo: cisplatin Contrast agents: iodinated, gadolinium IVIG Volume expanders: mannitol, hetastarch Synthetic drugs: cannabinoids, SPICE, K2 Tubulointerstitial Disease • • • • • • • • • Cast nephropathy: multiple myeloma Urate nephropathy Sjogren’s Polycystic kidney disease Medullary cystic disease Reflux nephropathy Sarcoidosis Nephrocalcinosis Acute phosphate nephropathy (phos containing bowel prep) AIN- acute interstitial nephritis • • • • • Perhaps best thought of as allergic interstitial nephritis Important to think of as is very often reversible Should give urine eosinophils, high negative predictive value In theory any agent could cause it Induced by a number of drugs – Antibiotics • Sulfa a common cause now in the wake of MRSA • Beta-lactam (methicillin), Cephalosporins*, ciprofloxacin, ethambutol, isoniazid, macrolides, rifampin, tetracycline, vancomycin, acyclovir – Other drugs • allopurinol, amlodipine, azathioprine, captopril, carbamazepine, clofibrate, cocaine, creatine, diltiazem, famotidine, indinavir, mesalazine, omeprazole, phenteramine, phenytoin, pranlukast, propylthioruacil, quinine, ranitidine • NSAIDs* • Furosemide, thiazides, triamterene • Other causes – SLE, Sjogren’s – Etc. Autoimmune • Vasculitis HUS/TTP Scleroderma SLE Polyangiitis c granulomatosis (dz formerly known as Wegener’s Antiglomerular basement membrane disease (formerly known as Goodpasture’s) – IgA vasculitis (disease formerly known as Henoch-Schonlein purpura) – Polyarteritis nodosa – Membranoproliferative glomerulonephritis: – – – – – • IE, SLE, Hep B, C, complement dysregulation, microangiopathy • Monoclonal immunoglobulin deposition • Parasitic, fungal, shunt nephritis – Mixed cryoglobulinemia Autoimmune-Other • • • • • • • • Focal segmental glomerulosclerosis Post-infectious glomerulonephritis Thin basement membrane disease Hereditary nephritis (Alport syndrome) Mesangial proliferative glomerulonephritis Fibrillary glomerulonephritis C3 (complement) glomerulonephritis HIVAN (HIV associated nephropathy) Nephrotic syndrome -Technically will not be in differential for ARF as it does not typically give Cr rise -Distinguished from nephritic syndrome or glomerulonephritides by protein loss (nephritis denotes inflammation, essentially requires rbc loss) -Defined as Proteinuria>3.5g/24h, hypoalbuminemia, and peripheral edema -without edema it is “nephrotic range proteinuria” (seen in DM, etc) -In children minimal change disease is major cause -In adults primary causes: FSGS, membranous nephropathy, minimal change disease secondary causes: DM, amyloidosis, SLE -Hyperlipidemia, thrombotic disease frequently seen due to hepatic response to low oncotic pressure, loss of -Higher risk of infection, sepsis -May see malnutrition, hormone imbalance due to renal losses, anorexia, GI sx’s -Maltese cross: fat droplets under polarized light in U/A -fatty casts -Treatment: Immunosuppression, ACEI/ARBs, Na restriction, diuresis, statin Diagnosis • Does not require many labs to dramatically narrow diagnosis • History is key • Assessment of volume status – Clinical – Laboratory • Imaging Labs: CBC • CBC – Hgb • anemia cause of prerenal failure itself • Hemoconcentration can be clue to hypovolemia – Often poor platelet function (despite normal values in renal failure) Labs: CMP • CMP – – – – – – – – – Hypo/hypernatremia give clues to volume status Serum Na in association with other labs K as marker for acidosis, renal clearance HCO3 marker for acidosis BUN is independent variable in need to be dialyzed (uremia) Cr Hypercalcemia as marker for hypovolemia Phos clearance dependent on renal function Albumin for intravascular volume status, liver function marker • Others – Uric acid – Magnesium – UPEP, SPEP Labs: U/A -Don’t underestimate the power of a u/a -Probably every inpatient should have u/a done, definitely every ARF pt -Specific gravity very good marker of volume status -Protein clues to diagnosis: nephrotic syndrome, DM -no protein but elevated spot protein/Cr ratio: paraproteinemia: paraproteins +charged, unlike albumin -LE marker of UTI - but +LE but sterile culture may also suggest interstitial nephritis -occult blood without rbc’s -hemolysis -rhabdomyolysis Labs: U/A • -rbc’s: – required for nephritis dx, need to distinguish from traumatic cath • Dysmorphic rbc’s suggests nephritis • History and clearance of rbc’s should demonstrate traumatic – May point to stone, malignancy, postrenal inflammation • • • • • • • • • -wbc’s: AIN (especially eos), glomerulonephritis -renal tubule epithelial cells: ATN Acanthocytes: glomerular hematuria -Casts: -hyaline membrane: more c/w prerenal -muddy brown casts: more c/w ATN -rbc: kidney inflammation, nephritic syndrome -wbc: kidney inflammation -fatty: c/w nephrotic syndrome Urine Sodium • Low in prerenal disease • High in ATN due to impaired tubule function • High in setting of diuretics Starling Forces Pi Pc πc πc Jv=Kf([Pc-Pi] – ϭ[Лc – Лi] P= hydrostatic pressure π= oncotic pressure c= capillary Kf = filtration constant ϭ= reflection coefficient π= albumin, intravascular proteins, rbc component i= interstitial Osmolality • Major osmolar contributors in ECF: Na, BUN, glucose • Calc. osmolality= 2[Na+] + [Glucose]/18 + [BUN]/2.8 • Therefore Na is major player but glucose can be • Kidney holds on to Na, BUN in hypovolemia BUN/Cr • Ratio >20:1 felt to be consistent with prerenal • Breaks down a lot – Upper GI bleed – Tissue breakdown – Steroid therapy • Probably best thought of as a poor man’s FeNa FeNa and FeUrea • Fractional Excretion of Sodium (FENa) = (PCr * UNa ) x 100 (to give %) (PNa x UCr) – <1% consistent with prerenal (hypovolemia) – Limited in chronic prerenal dz, glomerulanephritis, vasculitis, CIN – May not give reliable result in setting of diuretics, in which case can send: • Fractional Excretion of Urea (FEUrea) = (SerumCr * UUrea ) x100 (%) (SerumUrea x UCr) – <30-35% consistent with prerenal Imaging • Poor man’s u/s, rich man’s PVR: bladder scan • (PVR) • Ultrasound: – Prerenal: Renal artery stenosis – Intrinsic: echogenicity, size (<7cm definitive for CKD) – Postrenal: hydronephrosis, stones, bladder volume • Echo: EF, valvular dz, IE, mural thrombus, PFO • CT: – – – – – Prerenal: dissection Intrinsic: radiodensity Stones Extrinsic intraabdominal factors e.g. Masses, post-surgical Liver evaluation Kidney Biopsy • • • • • Typically reserved for intrinisic renal failure Many cases of intrinsic failure will progress to biopsy Generally well tolerated Risks of bleeding, kidney loss, infection Ideally risks are balanced against diagnostic need – How clear is diagnosis? – Will it change management? – How high risk is pt to receive it? • …But it is often easy to justify – – – – Considerable overlap to many intrinsic causes Surprisingly many patients with >1 diagnosis on pathology More than one type of renal insult with known Dx (e.g. SLE) Major management differences depending on Dx Treatment: Prerenal. -All treatment with ARF geared toward treating the cause and the resulting consequences In prerenal: -If hypovolemic, give IVF -If hypervolemic (e.g. CHF), diurese -If hypervolemic but intravascularly dry, reverse third spacing where possible -If severely anemic, transfuse -And… stop the damn fool thing you’re doing: diuretics, antihypertensives, ACEI/ARB’s Treatment: Postrenal. -Relieve proximal obstructions: -ureteral stent, -lithotripsy -percutaneous nephrostomy -Relieve distal obstructions: -Foley catheter, place or replace -suprapubic catheter -continuous bladder irrigation -TURP, TURBT -dilation of stricture -remove foreign body -Deliver the parasite obstructing the flow -Remove the mass -Surgery to restore normal anatomy -estrogen replacement (possibly as effective as abx for UTI) Treatment: Hepatorenal • Increase systemic blood pressure – – – – Midodrine Albumin Terlipressin, ornipressin, vasopressin Norepinephrine • Decrease renovascular constriction – Clonidine acutely • Decrease portal blood pressure – Octreotide – Consider TIPS, weighed against risks, contrast agent • Dialysis for reversible liver failure or transplant candidates Treatment: Intrinsic. -Many cases typically irreversible -Secondary prevention is generally the rule -DM management -HTN management -improve oxygenation/hemodynamics -For reversible causes: Stop the damn fool thing you’re doing: -stop or change antibiotics -stop or change chemotherapeutics if possible -Immune modulating agents -steroids, DMARDs, monoclonal antibodies -Supportive care for electrolyte abnormalities, acidosis -Hemodialysis Acute hemodialysis Indications: AEIOU Acidosis: -ph <7.1 may be independent reason to dialyze as may create hemodynamic instability, arrhythmia, vasodilation, impaired response to catecholamine Electrolytes: -hyperkalemia, hypercalcemia, hyperphosphatemia Ingestions: -Li, methanol/ethylene glycol Overload: volume -CHF, pulmonary edema Uremia: -may cause encephalopathy, cardiac dysfunction ESRD • Causes* – DM 44% – HTN/nephrosclerosis 28% – Glomerulonephritis 6% – Cystic kidney disease 2% *2012 Annual Report, US Renal Data System New Directions •Cystatin C •NGAL (neutrophil gelatinase associated lipocalin • may provide earlier diagnosis of ARF •Interleukin 18 •KIM-1 (kidney injury molecule •Alk Phos •“anti-inflammatory” •In trials to prevent tissue damage in AKI •3D printing •Bladder (done) •Kidney (coming) http://www.cbsnews.com/ Conclusions -Take a thorough history -Take a systematic approach -Consider prerenal, intrinsic, and postrenal with every evaluation -March from heart to urethral meatus cataloging possible problems -Remember: ~90% of the time it’s just plumbing -Isolate your category/categories of problems -Initial confirmatory studies: FeNa, u/a, bladder scan -Clarify diagnosis/diagnoses: -imaging -specialized labs -biopsy -Treat the problem Bibliography 1. Kaufman et al, Am J Kidney Dis 1991; 17: 191-198 2. Nash et al, Am J Kidney Dis 2002; 39:930–936 3. Stevens et al, QJM 2001; 94:533-40 4. Vijayan et al, Semin Nephrol 1998; 18:523-532 5. Davidson et al, Arch Int Med 1991; 151:1809-1812 6. Mehta et al, Kidney Int, 2004; 66: 1613-1621 7. Chertow et al, J. Am. Soc. Nephrol, 2005; 16:3365-3378. Liano et al, Kidney Int, 1996; 50: 811-818 9. Cosentino et al, Nephrol Dial Transp 1994; 9:179-812 10. Liangos et al, Clin J. Am. Soc. Nephrol 2006; 1:43-51 -Images adapted from following sources where not otherwise indicated • Wikimedia Commons https://en.m.wikipedia.org/wiki/File:Kidney_Cross_Section.png • www.medicinenet.com - by Melissa Conrad Stöppler • http://www.urologyhealth.org