Slide 1

Prof. A.C.E. KochMemorial Oration

VIDYAJYOTHI PROF.REZVI SHERIFFSENIOR PROFESOR OF MEDICINEUNIVERSITY OF COLOMBO KIDNEY FUNCTION TESTS IN CLINICAL PRACTICE & RESEARCH

QUANTITATIVE FALLACY?

Home TruthsI am not a physiologist I am a Clinician/Academic/NephrologistMixed audience keep it simpleTime is limitedKeep everybody awake Say something usefulThere should be a take home message

Arthur Cecil Elsely Koch

Born in 1922, BurgherEducated at Royal College C7LMS Colombo Medical SchoolDemonstrator/Lec/Reader/Professor of Physiology 1952Oxford UniversityWife Doris Christobel Mary FernandoSon Graham Daughter Ann

Early lessons from Prof. KochThe earliest known use of this essential invention was a potters wheel that was used in Mesopotamia (part of modern day Iraq} as early as 3500 BC. The first use of the wheel for transportation was probably on Mesopotamian chariots in 3200 BC

A wheel with spokes first appeared on Egyptian chariots around 2000 BC, and wheels seem to have developed in Europe by 1400 BC

Every breakthrough is a collective effort that combines and tweaks already existing ideas and technology in novel ways.

An Electrifying Lesson

Topic of my presentation

Plan of my Oration Brief comments on microstructure and functions of the kidneyAetiology of renal diseases in Sri LankaIdeal renal function testGlomerular Filtration rate and Serum CreatinineAcute Kidney Injury AKI and Acute Renal Failure ARFLessons from Clinical ScenariosChronic Renal Failure CRF Other helpful Renal TestsCKDu..Chronic Kidney Disease of unknown originConcluding remarks

The Nephron

200 m

1 million nephrons per kidney 2 million nephrons per person180 L filtrate per dayExchange area: ca 1.5 m

Functions of the kidney Maintaining fluid balanceExcretion of waste substances as urea, ammonia and other nitrogenous wastesMaintaining acid-base balance of the bodyEndocrine functionVitamin D metabolismHomeostasis of calcium, phosphate and magnesium

Functional Nephron

1.500 lBlood per daythrough the renal arteries

180 l Filtrate per dayin the glomeruli

60 l Urine per dayat the end of the proximal tubules

20 l Urine per dayat the beginning of the distal tubules

10 l Urine per dayat the end of the distal tubules

1,5 l Urine per dayat the end of the collecting ductsReal removal: 1,5 l urine

Glomerulus Tubulus10/27/2010

Functions of a Nephron

AETIOLOGY

ACUTE ILLNESS

RENAL COLIC ACUTE PYELNEPHRITIS ACUTE RENAL FAILURE ACUTE NEPHRITIS SURGICAL TRAUMA ACUTE TUBULAR NECROSIS SNAKE BITES POST PARTUM PROSTATE TRAUMA DRUG INDUCEDCHRONIC ILLNESS

DIABETIC NEPHROPATHY HYPERTENSIVE NEPHROSCLEROSIS OBSTRUCTIVE NEPHROPATHY INTESTITIAL NEPHRITIS INFECTIVE / RENAL TB DRUG INDUCED CONGENITAL POLYCYSTIC KIDNEYS CANCER OF THE KIDNEYS

Ideal Renal Function testPracticing clinicians need renal function tests to be ReliableValid measurement of kidney functionReproducible SimpleNon-invasive Minimal hassle to patientsCheapRepeat tests to monitor recovery and worsening

SERUM CREATININE/GLOMERULAR FILTRATION RATE SEEMS TO BE THE BEST OPTION

Glomerular Filtration RateVolume of fluid filtered from the renal glomerular capillaries into the Bowman's capsule per unit timeCentral to the physiologic maintenance of GFR is the differential basal tone of the afferent and efferent arteriolesCalculated by measuring any chemical that has a steady level in the blood, and is freely filtered but neither reabsorbed nor secreted by the kidneys. (quantity of the substance in the urine that originated from a calculable volume of blood)

Measuring GFRGlomerular Filtration Rate measurement of renal functionIu Urinary concentrationUF Urinary flow (ml / min)Ip Plasma concentration

Inulin is the gold standard

Creatinine clearance gives acceptable results

Filtration Markers of GFRInulin: Gold standard125I iothalamate: Thyroid uptake and tubular secretion can lead to overestimation99Tc-DTPA: Dissociation of DTPA leads to plasma protein binding and underestimation51Cr-EDTA: 10% lower than inulinIohexol : low adverse effects, comparable to inulinApproximations used to estimate GFR using simpler measurements as Serum Creatinine .Serum Creatinine.most useful clinically

Serum Creatinine

Break-down product of creatine phosphate in muscle, and is usually produced at a fairly constant rate by the bodyMeasured biochemicallyAdoption of a new analytical methodology from 2012 - new standardized Isotope Dilution Mass Spectrometry (IDMS) method to measure serum creatinine1

1, Laboratory ProfessionalsCreatinine Standardization Recommendationshttp://nkdep.nih.gov/labprofessionals/cs_recommendations.htm

Serum CreatinineInversely proportional to the GFRBut GFR changes with age, body habitus, muscle mass and gender.Spuriously low estimated GFRs with muscle trauma and rhabdomyolysisSpuriously high eGFRs with low muscle mass Appr cost SLRs 350 to 400/=per test..Takes 1 hourWidely available even in district hospitals and private labs..semi automated and automated now.24 hour collection for creatinine clearance has its own set of inaccuracies..but still the most sought after SLRs 1500/=. Collection cumbersome, loss of working time etc

Estimated GFREquations used to approximate GFR with Creatinine valuesMany formulasCockroft Gault (CG)Modification of Diet in Renal Disease (MDRD)CKD-EPIMayo Quadratic formula (MQ)Schwartz formula (SF)

Cockroft Gault FormulaTakes age, weight, creatinine levels and gender in to considerationWeight is in kg, and SCr is in umol/l. If mg/dl used, denominator is multiplied by 72For females, multiply by 0.85Unlike other formulae weight is taken in to account

MDRD(Modified Diet in Renal Disease) formulaTakes SCr, age, gender, race in to account. Extended formula includes serum albumin and BUN levels---- 4 or 6 variable formulae.eGFR = K1 x SCr-1.154 x Age-0.203 x K2 x K3K1; SCr in umol/l = 186, mg/dl = 32788K2; Black = 1.212, other = 1.0K3; Male = 1.0, female = 0.742

Ethnic Coefficients in SCR based GFRMDRD eGFR Chinese MDRD eGFR Japanese MDRD eGFR KoreanCKD EPID data Asians in USA

What about Sri Lanka ? 1.233 using Tc 990.808 using enzymatic0.991 using Inulin Clear.1./052 overestimation in chinese Underestimation in japanese

CG vs MDRDPatient A is a 20 year old male, 70kg in weightPatient B is a 60 year old male, 55kg in weightBelow is the comparison of eGFRs of above two patients from creatinine levels of 70-1000 umol/l

CG vs MDRDS. Creatinine = 100umol/lPatient A; eGFRCG = 84, eGFRMDRD = 88Patient B; eGFRCG = 44, eGFRMDRD = 78MDRD over estimates GFR in low BMIsS. Creatinine = 260umol/lPatient A; eGFRCG = 32, eGFRMDRD = 29Patient B; eGFRCG = 16, eGFRMDRD = 23MDRD over estimates GFR in low BMIs

CKD EPI formulaComplex equation expressed in Excel type formulaeGFR = 141 x min(SCr / K1, 1)A x max(SCr / K1, 1)-1.209 x 0.993Age x K2 x K3 K1; females = 0.7, males = 0.9A; females = -0.329, males = -0.411K2; females = 1.018, males = 1.0K3; blacks = 1.159; others = 1.0

Mayo Quadratic formulaComplex equationThis formula was developed by Rule et al in an attempt to better estimate GFR in patients with preserved kidney function. (MDRD formula tends to underestimate GFR)

MDRD, CG and CKD-EPIMDRD is superior to CG 3, 4MDRD still has poor prediction when GFR is low. 3, 4, 5

Monitoring Renal Function and Limitations of Renal Function Tests, Seminars in Nuclear Medicine, 38(1); Jan. 2008, 32-46Validation of predictive equations for glomerular filtration rate in the Saudi population, Saudi Journal of Kidney Diseases and Transplantation, 2009; 20(6), 1030-7A. Almond, S. Siddiqui, S. Robertson, J. Norrie, C. Isles Comparison of combined urea and creatinine clearance and prediction equations as measures of residual renal function when GFR is low, Q J Med 2008; 101:619624

MDRD, CG and CKD-EPICKD EPI and MDRD are comparable in accuracy6, 7 MDRD needs modifications according to the racial basis8

Pge U, Gerhardt T, Stoffel-Wagner B, Sauerbruch T, Woitas RP, Validation of the CKD-EPI formula in patients after renal transplantation, Nephrol Dial Transplant. 2011 May 5Nyman U, Grubb A, Sterner G, Bjrk J. The CKD-EPI and MDRD equations to estimate GFR. Validation in the Swedish Lund-Malm Study cohort, Scand J Clin Lab Invest. 2011 Apr;71(2):129-38. Antonios H. Tzamaloukas, Glen H. Murata, A population-specific formula predicting creatinine excretion in continuous peritoneal dialysis, Peritoneal Dialysis International, Vol. 22, pp. 6772

Acute Kidney Injuryand Acute Renal Failure

Acute kidney injury vs. Acute renal failureAcute Kidney Injury has replaced Acute Renal Failure in the acute settings such as in Intensive Care Units where nurses follow vitals closely. We now have a new brand of doctors Diplomates in Critical Care from the PGIM who are well trained in detecting AKI.There is of course professional struggles to be consultants in these units who house the most sick people in the country islandwide. So lets hope Physiological OLIGURIA will be spotted early and corrected not allowing it to drift into established acute renal failure whilst the Consultant is busy anaesthetising a very complicated and deserving case

RIFLE CriteriaThe lack of a standard definition for acute kidney injury has resulted in a large variation in the reported incidence and associated mortality. RIFLE, a newly developed international consensus classification for acute kidney injuryDefines three grades of severity - risk (class R), injury (class I) and failure (class F)

RIFLE Criteria

RIFLE CriteriaCategoryGFR CriteriaUrine Output (UO) CriteriaRiskIncreased creatinine x 1.5 or GFR decrease > 25%UO < 0.5ml/kg/h x 6 hrHigh SensitivityHigh SpecificityInjuryIncreased creatinine x 2 or GFR decrease > 50% UO < 0.5ml/kg/h x 12 hrFailureIncrease creatinine x 3 or GFR decrease > 75%UO < 0.3ml/kg/h x 24 hr or Anuria x 12 hrsLossPersistent ARF = complete loss of kidney function > 4 weeksESKDEnd Stage Kidney Disease (> 3 months)

AKIN criteriaSerum creatinine criteriaUO criteriaStage 1Increase of SCr26.2 mol/L or increase to 150199% (1.5- to 1.9-fold) from baseline22.9 fold) from baseline