NITMED TUTORIALS INC ACUTE RENAL FAILURE - PowerPoint Presentation

1. NITMED TUTORIALS INC

2. ACUTE RENAL FAILURE

3. Acute Renal FailureDefinitionsAzotemia - the accumulation of nitrogenous wastesUremia - symptomatic renal failureOliguria - urine output < 400-500 mL/24 hoursAnuria - urine output < 100 mL/24 hours

4. Acute Renal FailureDefinitionThe loss of renal function (measured as GFR) over hours to daysExpressed clinically as the retention of nitrogenous waste products in the blood

5. Functions of the Renal SystemMaintenance of fluid balance:The kidneys maintain the fluid balance in the body by regulating the amount and makeup of fluid inside and outside (mainly) the cells.The kidneys are continuously exchanging water, (plus sodium, potassium, chloride, and other ions across their cell membranes.)Two hormones play a key role in the kidney’s ability to maintain fluid balance in the body

6. Functions of the Renal System1. ADH: controls the collecting tubules permeability to water according to the osmoreceptor’s ability to sense high concentration of solute in the plasma. (In other words when the plasma is concentrated, ADH is secreted to hold on to more water. When the plasma is dilute, ADH is not secreted so the permeability to water changes in the collecting tubules, and water is released.) 2. Aldosterone: regulates water reabsorption in the distal tubules by increasing sodium reabsorption and therefore water reabsorption when released from the adrenal cortex. (It is released as the final response in the renin angiotensin aldosterone system.) The presence of Aldosterone also helps increase the excretion of potassium.NB: when this fails fluid retention occurs

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8. Functions of the Renal SystemThe regulation of acid-base balance:The kidneys regulate acid base balance by:Excreting just enough hydrogen ions to keep the ph of the blood in the normal range.Manufacturing bicarbonate (a base) as needed to maintain ph between 7.35-7.45.When the kidneys fail: Metabolic acidosis results. Patients may develop Kussmaul respirations

9. Functions of the Renal SystemMaintenance of electrolyte balance:The kidneys function to regulate electrolyte concentrations. When the kidneys fail, electrolyte levels are not maintained: K+, Na, Phosphate, Ca+Potassium: Hypokalemia may occur… with vomiting or excessive diarrhea in early renal failure when uremic toxins begin to circulate. in the diuretic phase of acute renal failure as the kidney is unable to conserve water and electrolytes. ………………. ARRYTHMIAS, NAUSEA, and LETHARGY occur.Hyperkalemia occurs with….. decreased renal excretion of potassium both in the oliguric phase of acute renal failure and in end stage renal disease. Hyperkalemia could lead to life threatening ARRYTHMIAS!!

10. Functions of the Renal System> FailureSodium:Hyponatremia also occurs in the diuretic phase of acute renal failure when the kidneys cannot conserve sodium or water. MUSCLE WEAKNESS, CONFUSION, and ABDOMINAL CRAMPING occur.Hypernatremia occurs with decreased renal excretion of sodium. This will occur in the end stages of renal disease and the person will be on a sodium-restricted diet. ……DRY MUCOUS MEMBRANES, and OLIGURIA occurs.Calcium:Hypocalcemia occurs for two reasons:1.A hyperphosphatemia occurs because of a decreased excretion of phosphate. There is an inverse relationship between phosphate and Calcium, so a hypocalcemia occurs. ( These electrolytes are regulated by the parathyroid gland, so when the phosphate level rises out of control due to the kidneys inability to excrete it, the parathyroid hormone (from the gland) is over secreted and starts to get Calcium from the bones, due to a depletion in the serum) OSTEOPOROSIS, OSTEODYSTROPHY (bone disease), AND TETANY occurs.

11. Functions of the Renal System> Failure Hypocalcemia 2. The kidneys normally secrete an active form of vitamin D (2-3 DPG), which help the intestines absorb calcium. When there’s decreased absorption, there’s hypocalcemia.

12. Functions of the Renal SystemMaintenance of blood pressure:The kidneys help regulate blood pressure by producing and secreting the enzyme renin in response to an actual or perceived decline in extra cellular fluid volume. (Angiotensinogen) turns Renin into angiotensin I which is converted into angiotensin II (by an enzyme), the most potent vasoconstrictor in the body. Angiotensin II raises arterial blood pressure by…

13. RENIN…1. Increasing peripheral vasoconstriction2. Stimulating Aldosterone secretionAldosterone promotes the reabsorption of sodium and water to correct the fluid deficit and/or inadequate blood flow (renal ischemia)

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15. Functions of the Renal System> FailureWhen the kidneys fail:Patients are often HYPERTENSIVE.

16. Functions of the Renal SystemThe collection and elimination of metabolic waste such as urea and creatinine:The kidney’s job is to excrete the waste products of metabolism. Urea is a byproduct of protein metabolism. It is not as adequate an indicator of renal disease as elevated creatinine levels are because urea (BUN) levels elevate with an increased protein intake, trauma, dehydration etc.. Serum creatinine levels are an accurate indicator of renal function/dysfunction. The urinary excretion should equal the amount produced by the body (by skeletal muscle catabolism).

17. Functions of the Renal System> FailureWhen the kidneys fail:The patient suffers from an overload of these circulating uremic toxins.All body systems may be affected. the CNS is affected by the uremic toxins. Drowsiness, poor memory, inability to concentrate, seizures, and even come may result. GI distress may result such as nausea, vomiting, abdominal distension, diarrhea, and constipation.

18. Functions of the Renal SystemThe secretion of erythropoietin:The kidneys secrete erythropoietin when the oxygen supply in the tissue blood drops. This hormone prompts the bone marrow to produce more RBCs.When the kidneys fail: The patient becomes anemic. (Remember also they are anemic due to the increased destruction of RBCs & PLTS by the uremic toxins, and even due to their bleeding tendency secondary to their low PLTS.)

19. Functions of the Renal System> FailurePericarditis may result as pericardium is inflamed due to the buildup of these uremic wastes. A pericardial friction rub and pain may result. Pruritis may result as the excretory function of the skin attempts to excrete the waste products. A uremic frost may be notable on skin and collect on eyebrows. Skin may become a pale yellowish color, as urochrome pigments are present. Anemia and thrombocytopenia occur because the uremic toxins destroy RBCs and PLTS.

20. Assessment of Renal FunctionGlomerular Filtration Rate (GFR)= the volume of water filtered from the plasma per unit of time.Gives a rough measure of the number of functioning nephronsNormal GFR:Men: 130 mL/min./1.73m2Women: 120 mL/min./1.73m2Cannot be measured directly, so we use creatinine and creatinine clearance to estimate.

21. Assessment of Renal Function (cont.)CreatinineA naturally occurring amino acid, predominately found in skeletal muscleFreely filtered in the glomerulus, excreted by the kidney and readily measured in the plasmaAs plasma creatinine increases, the GFR exponentially decreases.Limitations to estimate GFR:Patients with decrease in muscle mass, liver disease, malnutrition, advanced age, may have low/normal creatinine despite underlying kidney disease15-20% of creatinine in the bloodstream is not filtered in glomerulus, but secreted by renal tubules (giving overestimation of GFR)Medications may artificially elevate creatinine:Trimethroprim (Bactrim)Cimetidine

22. Assessment of Renal Function (cont.)Creatinine ClearanceBest way to estimate GFRGFR = (creatinine clearance) x (body surface area in m2/1.73)Ways to measure:24-hour urine creatinine:Creatinine clearance = (Ucr x Uvol)/ plasma CrCockcroft-Gault Equation:                            (140 - age)  x  lean body weight [kg] CrCl (mL/min)    =    ——————————————— x 0.85 if                                         Cr [mg/dL]  x  72 femaleLimitations: Based on white men with non-diabetes kidney disease Modification of Diet in Renal Disease (MDRD) Equation:GFR (mL/min./1.73m2) = 186 X (SCr)-1.154 X (Age)-0.203 X (0.742 if female) X (1.210 if African-American )

23. AKI Definition-Criteria

24. RIFLE criteria for diagnosis of AKI based on The “Acute Dialysis Quality Initiative”Increase in SCrUrine outputRisk of renal injuryInjury to the kidneyFailure of kidney function0.3 mg/dl increase2 X baseline3 X baseline OR> 0.5 mg/dl increase if SCr >=4 mg/dl< 0.5 ml/kg/hr for > 6 h< 0.5 ml/kg/hr for >12hAnuria for >12 hLoss of kidney functionEnd-stage diseasePersistent renal failure for > 4 weeksPersistent renal failure for > 3 monthsAm J Kidney Dis. 2005 Dec;46(6):1038-48

25. Definition of Acute Kidney Injury (AKI) based on “Acute Kidney Injury Network”StageIncrease in Serum CreatinineUrine Output11.5-2 times baseline OR 0.3 mg/dl increase from baseline<0.5 ml/kg/h for >6 h22-3 times baseline<0.5 ml/kg/h for >12 h33 times baseline OR0.5 mg/dl increase if baseline>4mg/dlORAny RRT given <0.3 ml/kg/h for >24 hOR Anuria for >12 h

26. Acute Renal Failure- PhasesPhases:The course of acute renal failure is characterized by three phases.The oliguric phase occurs at the onset of symptoms and could last as long as eight weeks. It is characterized by a decreased urine output …(less than 400ml in 24 hours). The kidney is trying to conserve sodium and water, and therefore hypervolemia, edema, weight gain, pulmonary edema, and elevated blood pressure occur. The BUN and creatinine rise thereby causing uremic signs and symptoms. (nausea, changes in mental acuity, fatigue, pericarditis)

27. Acute Renal Failure- PhasesThe diuretic phase is marked by urine output that can range from 1-5 L/day. The kidney has lost its ability to conserve water. Hypovolemia, (fluid) weight loss, hypokalemia, hyponatremia all can result. The BUN and creatinine begin to level out. May last 7-14 days.

28. Acute Renal Failure- PhasesThe recovery phase is reached when the BUN and creatinine have returned to normal. This phase can last from 3-12 months.

29. Acute Renal Failure- Diagnostic Findings:Laboratory data and other assessments reveal the following: .....(In the oliguric phase)Decreased or absent urinary outputIncreased BUN, creatinine, sodium, potassium, chloride Decreased calcium (high phos), bicarbonate (acidosis), H/H (anemic) Metabolic acidosis

30. Causes of ARFPre-renal =vomiting, diarrhea, poor fluid intake, fever, use of diuretics, and heart failure cardiac failure, liver dysfunction, or septic shock Intrinsic Interstitial nephritis, acute glomerulonephritis, tubular necrosis, ischemia, toxinsPost-renal =prostatic hypertrophy, cancer of the prostate or cervix, or retroperitoneal disorders neurogenic bladder bilateral renal calculi, papillary necrosis, coagulated blood, bladder carcinoma, and fungus

31. Symptoms of ARFDecrease urine output (70%)Edema, esp. lower extremityMental changesHeart failureNausea, vomitingPruritusAnemiaTachypenicCool, pale, moist skin

32. Hyperkalemia SymptomsWeaknessLethargyMuscle crampsParesthesiasDysrhythmias

33. Hyperkalemia TreatmentCalcium gluconate (carbonate)Sodium BicarbonateInsulin/glucoseDiuretics (Furosemid)AlbuterolHemodialysis

34. Prerenal Acute Renal FailureVolume DepletionDecreased effective blood volumecongestive heart failurecirrhosisnephrotic syndromesepsisRenal vasoconstrictionhepatorenal syndromehypercalcemianonsteroidal anti-inflammatory drugs

35. Prerenal Acute Renal Failure:Clinical PresentationHistoryvolume loss (e.g., diarrhea, acute blood loss)heart diseaseliver diseaseevidence of infectiondiuretic usethirstorthostatic symptoms

36. Prerenal Acute Renal Failure:Clinical PresentationPhysical ExaminationBlood pressure and pulseOrthostatic changes in blood pressureSkin turgorDryness of mucous membranes and axillaeNeck veinsCardiopulmonary examPeripheral edema

37. Prerenal Acute Renal Failure: Clinical PresentationBUN:Creatinine ratio> 20:1Urine indicesOliguriausually < 500 mL/24 hours; but may be non-oliguricElevated urine concentrationUOsm > 700 mmol/Lspecific gravity > 1.020Evidence of high renal sodium avidityUNa < 20 mmol/LFENa < 0.01Inactive urine sediment

38. Fractional Excretion of SodiumEtiologies of a fractional excretion of sodium <0.01normal renal functionprerenal azotemiahepatorenal syndromeearly obstructive uropathycontrast nephropathyrhabdomyolysisacute glomerulonephritis

39. Treatment of Prerenal Acute Renal FailureCorrection of volume deficitsDiscontinuation of antagonizing medicationsNSAIDs/COX-2 inhibitorsDiureticsOptimization of cardiac function

40. Postrenal Acute Renal FailureUrinary tract obstructionlevel of obstructionupper tract (ureters)lower tract (bladder outlet or urethra)degree of obstructionpartialcomplete

41. Pathophysiology of Renal Failure in Obstructive UropathyEarlyIncreased intratubular pressureInitial increase followed by decrease in renal plasma flowLateNormal intratubular pressureMarked decrease in renal plasma flow

42. Etiologies of Postrenal Acute Renal FailureUpper tract obstructionIntrinsicnephrolithiasispapillary necrosisblood clottransitional cell cancerExtrinsicretroperitoneal or pelvic malignancyretroperitoneal fibrosisendometriosisabdominal aortic aneurysmLower tract obstructionbenign prostatic hypertrophyprostate cancertransitional cell cancerurethral stricturebladder stonesblood clotneurogenic bladder

43. Postrenal Acute Renal Failure:Clinical PresentationHistorySymptoms of bladder outlet obstructionurinary frequencyurgencyintermittencyhesitancynocturiaincomplete voiding

44. Postrenal Acute Renal Failure:Clinical PresentationHistoryChanges in urine volumeanuriapolyuriafluctuating urine volumeFlank painHematuriaHistory of pelvic malignancy

45. Postrenal Acute Renal Failure:Clinical PresentationPhysical ExaminationSuprapubic massProstatic enlargementPelvic massesAdenopathy

46. Postrenal Acute Renal Failure:Clinical EvaluationDiagnostic studiesBUN: Creatinine ratio > 20:1Unremarkable urine sedimentVariable urine chemistries

47. Postrenal Acute Renal Failure:Clinical EvaluationDiagnostic studiesPost-void residual bladder volume> 100 mL consistent with voiding dysfunctionRadiologic studiesUltrasoundCT scanNuclear medicineRetrograde pyelographyAntegrade nephrostograms

48. Treatment of Postrenal Acute Renal FailureRelief of obstructionLower tract obstructionbladder catheterUpper tract obstructionureteral stentspercutaneous nephrostomiesRecovery of renal function dependent upon duration of obstructionRisk of post-obstructive diuresis

49. Intrinsic Acute Renal FailureAcute tubular necrosis (ATN)Acute interstitial nephritis (AIN)Acute glomerulonephritis (AGN)Acute vascular syndromes Intratubular obstruction

50. Acute Tubular NecrosisIschemicprolonged prerenal azotemiahypotensionhypovolemic shockcardiopulmonary arrestcardiopulmonary bypass SepsisNephrotoxicdrug-inducedradiocontrast agents aminoglycosidesamphotericin Bcisplatinumacetaminophenpigment nephropathyhemoglobinmyoglobin

51. Pathophysiology of Acute Tubular NecrosisMechanisms of decreased renal functionVasoconstrictionTubular obstruction by sloughed debrisBackleak of glomerular filtrate across denuded tubular basement membrane

52. Acute Tubular Necrosis: Clinical PresentationHistoryAcute illnessExposure to nephrotoxinsEpisodes of hypotensionPhysical examinationHemodynamic statusVolume statusFeatures of associated illnessLaboratory dataBUN:Creatinine ratio < 10:1Evidence of toxin exposure

53. Acute Tubular Necrosis: Clinical PresentationUrine indicesUrine volumemay be oliguric or non-oliguricIsosthenuric urine concentrationUOsm  300 mmol/Lspecific gravity  1.010Evidence of renal sodium wastingUNa > 40 mmol/LFENa > 0.02Urine sedimenttubular epithelial cellsgranular casts

54. Acute Tubular Necrosis:TreatmentSupportive therapyNo specific pharmacologic treatmentsAcute dialysis for:volume overload metabolic acidosis hyperkalemiauremic syndromepericarditisencephalopathyazotemia

55. Prognosis ofAcute Tubular NecrosisMortality dependent upon comorbid conditionsoverall mortality ~ 50%Recovery of renal function seen in ~ 90% of patients who survive - although not necessarily back to prior baseline renal function

56. Acute Interstitial NephritisAcute renal failure due to lymphocytic infiltration of the interstitiumClassic triad offeverrasheosinophilia

57. Acute Interstitial NephritisDrug-inducedpenicillinscephalosporinssulfonamidesrifampinphenytoinfurosemideNSAIDsMalignancyIdiopathicInfection-relatedbacterialviralrickettsialtuberculosisSystemic diseasesSLEsarcoidosisSjögren’s syndrometubulointerstitial nephritis and uveitis

58. Acute Interstitial Nephritis:Clinical PresentationHistorypreceding illness or drug exposurePhysical examinationfeverrashLaboratory Findingseosinophilia

59. Acute Interstitial Nephritis:Clinical PresentationUrine findingsnon-nephrotic protinuriahematuriapyuriaWBC castseosinophiluria

60. Acute Interstitial Nephritis:TreatmentDiscontinue offending drugTreat underlying infectionTreat systemic illnessGlucocorticoid therapy may be used in patients who fail to respond to more conservative therapy

61. Acute GlomerulonephritisNephritic presentationproteinuriamay be in nephrotic range (> 3 g/day)hematuriaRBC castsDiagnosis usually requires renal biopsy

62. Acute GlomerulonephritisEtiologiespoststreptococcal glomerulonephritispostinfectious glomerulonephritisendocarditis-associated glomerulonephritissystemic vasculitisthrombotic microangiopathy hemolytic-uremic syndromethrombotic thrombocytopenic purpurarapidly progressive glomerulonephritis

63. Acute Vascular SyndromesRenal artery thromboembolismRenal artery dissectionRenal vein thrombosisAtheroembolic disease

64. Intratubular ObstructionIntratubular crystal depositiontumor lysis syndromeacute urate nephropathyethylene glycol toxicity calcium oxylate depositionIntratubular protein depositionmultiple myeloma-Bence-Jones protein deposition

65. Differential Diagnosis of Acute Renal FailurePrerenal ARFPostrenal ARFIntrinsic ARFacute tubular necrosisacute interstitial nephritisacute glomerulonephritisacute vascular syndromesintratubular obstruction

66. Clinical AssesmentHistory:Cancer?Recent Infections?Blood in urine?Change in urine output?Flank Pain?Recent bleeding?Dehydration? Diarrhea? Nausea? Vomiting?Blurred vision? Elevated BP at home? Elevated sugars?

67. Clinical Assessment (cont.)Family History:Cancers?Polycystic kidney disease?Meds:Any non-compliance with diabetic or hypertensive meds?Any recent antibiotic use?Any NSAID use?

68. Clinical Assessment– Physical examVital Signs:Elevated BP: Concern for malignant hypertensionLow BP: Concern for hypotension/hypoperfusion (acute tubular necrosis)Neuro: Confusion: hypercalcemia, uremia, malignant hypertension, infection, malignancyHEENT: Dry mucus membranes: Concern for dehydration (pre-renal)Abd: Ascites: Concern for liver disease (hepatorenal syndrome), or nephrotic syndromeExt:Edema: Concern for nephrotic syndromeSkin:Tight skin, sclerodactyly – Sclerodermal renal crisisMalar rash - Lupus

69. Clinical Assesment– Laboratory analysisFractional excretion of sodium: (UrineNa+ x PlasmaCreatinine) FENa= ______________________ x 100 (PlasmaNa+ x UrineCreatinine)FENa < 1% → Prerenal FENa > 2% → Epithelial tubular injury (acute tubular necrosis), obstructive uropathyIf patient receiving diuretics, can check FE of urea.

70. Clinical Assesment– UrinalysisHematuriaNon-glomerular:Urinary sediment: intact red blood cellsCauses:InfectionCancerObstructive UropathyRhabdomyolysis myoglobinuria; Hematuria with no RBCsGlomerular:Urine sediment: dysmorphic red blood cells, red cell castsCauses:GlomerulonephritisVasculitisAtheroembolic diseaseTTP/HUS (thombotic microangiopathy)

71. Clinical Assesment– Urinalysis (cont.)ProteinNeed microscopic urinalysis to see microabluminemiaCan check 24-hour urine protein collectionNephrotic syndrome - ≥ 3.5 g protein in 24 hoursAlbuminuriaGlomerulonephritisAtheroembolic disease(TTP/HUS) Thrombotic microangiopathyNephrotic syndromeTubular proteinuriaTubular epithelial injury (acute tubular necrosis)Interstitial nephritis

72. Clinical Assesment-- RadiologyRenal UltrasoundLook for signs of hydronephrosis as sign of obstructive uropathy.

73. Assesment – Urinary CastsRed cell castsGlomerulonephritisVasculitisWhite Cell castsAcute Interstitial nephritisFatty castsNephrotic syndrome, Minimal change diseaseMuddy Brown castsAcute tubular necrosis

74. Assesment– Renal BiopsyIf unable to discover cause of renal disease, renal biopsy may be warranted.Renal biopsy frequently performed in patient’s with history of renal transplant with worsening renal function.

75. Treatment of Acute Renal FailureTreat underlying causeBlood pressureInfectionsStop inciting medicationsNephrostomy tubes/ureteral stents if obstructionTreat scleroderma renal crisis with ACE inhibitorHydrationDiuresis (Lasix)DialysisRenal Transplant

76. Acute Renal Failure: Diagnostic EvaluationEvaluate for prerenal causesclinical examblood pressure orthostasiscentral venous pressures and cardiac outputintake/output recordurine sedimenturine sodiumUNa < 20 mmol/Ltherapeutic trial of volume replacementskin turgormucosal membrane hydrationFENa < 0.01

77. Acute Renal Failure:Diagnostic EvaluationEvaluate for postrenal causesbladder catheterizationrenal ultrasound

78. Acute Renal Failure:Diagnostic EvaluationEvaluation for intrinsic ARFclinical historymedicationshypotensionphysical examurinalysiscrystalsparaproteins radiocontrast agentssepsiscellscasts

79. Diagnostic Evaluation of ARFForm of ARFBUN:CrUNa (mEq/L)FENaUrine SedimentPrerenal>20:1<20< 1%NormalPostrenal>20:1>20variableNormal or RBC’sIntrinsic ATN<10:1>40> 2%Muddy brown casts; tubular epithelial cells AIN<20:1>20>1%WBC’s WBC casts, RBC’s, eosinophils AGNvariable<40<1%RBC’s, RBC casts Vascularvariable>20variableNormal or RBC’s

80. Acute Renal Failure: ManagementPrerenal ARFvolume repletioninotropic supportdiscontinue diureticsPostrenal ARFbladder catheterizationpercutaneous nephrostomy or ureteral stentsfluid management during post-obstructive diuresis

81. Acute Renal Failure: ManagementIntrinsic ARFGeneral supportive carefluid managementdiureticsbicarbonate supplementationpotassiumphosphatedrug dosingnutrition

82. Assessing fluid statusPrior to any prescription of IV fluids, the patient should have a volume assessment that includes the following parametersCapillary refillPulse rateBlood pressure (including postural drop)Jugular venous pressureRespiratory rateOedema – pulmonary or peripheralPassive leg raising testFluid balance chart reviewWeight (trend important)

83. Classification of IV fluid therapy

84. Algorithm for initial fluid resuscitation

85. Composition of IV fluidsIt is important to know the electrolyte content of fluid prescribed

86. Complications of AKI

87. Referring to a nephrologistManagement of AKI should be discussed with a nephrologist as soon as possible, and within 24 h of detection when one or more of the following is presentA possible diagnosis that may necessitate specialist treatment (eg vasculitis, glomerulonephritis, tubulointerstitial nephritis or myeloma)AKI with no clear causeInadequate response to treatmentComplications associated with AKIAKI stage 3A renal transplantChronic kidney disease (CKD) stage 4 or 5

88. Indications for HemodialysisRefractory fluid overload Hyperkalemia (plasma potassium concentration >6.5 meq/L) or rapidly rising potassium levels Metabolic acidosis (pH less than 7.1) Azotemia (BUN greater than 80 to 100 mg/dL [29 to 36 mmol/L]) Signs of uremia, such as pericarditis, neuropathy, or an otherwise unexplained decline in mental status Severe dysnatremias (sodium concentration greater than 155 meq/L or less than 120 meq/L) Hyperthermia Overdose with a dialyzable drug/toxin

89. CONCLUSIONAKI is an irreversible decline in renal function xterised by increased blood nitrogenous waste.Most causes are pre-renal of which fluid depletion accounts for over 70%Prompt detection and treatment are key to management