power point slides
TRANSCRIPT
Use of Laboratory Use of Laboratory Tests in Kidney Tests in Kidney
DiseaseDisease
OverviewOverview
Review functions of the kidney and related testsReview functions of the kidney and related tests
Discuss specific tests and issues relating to Discuss specific tests and issues relating to interpretationinterpretation
Tests of kidney functionTests of kidney function
What does a kidney do?What does a kidney do?
Blood flow to kidney is about 1.2 L/min (1/5 of Blood flow to kidney is about 1.2 L/min (1/5 of Cardiac output)Cardiac output)
About 10% of blood flow is filtered across the About 10% of blood flow is filtered across the glomerular membrane (100 – 120 ml/min/1.73mglomerular membrane (100 – 120 ml/min/1.73m22
Tests: urea, creatinine, creatinine clearance, eGFR, Tests: urea, creatinine, creatinine clearance, eGFR, Cystatin CCystatin C
GlomerulusGlomerulus
Glomerulus MicroscopicGlomerulus Microscopic
Tests of kidney functionTests of kidney function
Kidney Functions – cont’dKidney Functions – cont’d
Selectively secretes into or re-absorbs from the Selectively secretes into or re-absorbs from the filtrate to maintainfiltrate to maintain
Salt BalanceSalt Balance Tests: Tests: NaNa++, Cl, Cl--, K, K+ + Aldosterone, ReninAldosterone, Renin
Acid Base BalanceAcid Base Balance
Tests: pH, HCOTests: pH, HCO33--, NH, NH44
++ Acid loading, Urinary Anion Acid loading, Urinary Anion GapGap
Kidney Functions – cont’dKidney Functions – cont’d
Selectively secretes into or re-absorbs from the Selectively secretes into or re-absorbs from the filtrate to maintainfiltrate to maintain
Water BalanceWater Balance Tests: Tests: specific gravity, osmolarity, water deprivation specific gravity, osmolarity, water deprivation
testing, Antidiuretic hormonetesting, Antidiuretic hormone Retention of nutrientsRetention of nutrients
Tests: Tests: proteins, sugar, amino acids, phosphateproteins, sugar, amino acids, phosphate Secretes waste productsSecretes waste products
Tests: urate, oxalate, bile saltsTests: urate, oxalate, bile salts
Kidney Function – cont’dKidney Function – cont’dEndocrine FunctionEndocrine Function
Target organTarget organ Parathyroid hormone (CaParathyroid hormone (Ca++++, Mg, Mg++++)) Aldosterone (salt balance)Aldosterone (salt balance) ADH (water balance)ADH (water balance)
ProductionProduction ErythropoietinErythropoietin 1, 25 dihydroxycholecalciferol1, 25 dihydroxycholecalciferol
Calcium MetabolismCalcium Metabolism
Renin Angiotensin SystemRenin Angiotensin System
AldosteroneAldosterone
ADHADH
Tests that predict kidney Tests that predict kidney diseasedisease
eGFReGFR Albumin Creatinine Ratio Albumin Creatinine Ratio
(aka ACR or Microalbumin) (aka ACR or Microalbumin)
Tests of Glomerular Filtration Tests of Glomerular Filtration RateRate
UreaUrea CreatinineCreatinine Creatinine ClearanceCreatinine Clearance eGFReGFR Cystatin CCystatin C
Glomerular Filtration Rate (GFR) Glomerular Filtration Rate (GFR)
Volume of blood filtered across glomerulus per unit Volume of blood filtered across glomerulus per unit timetime
Best single measure of kidney functionBest single measure of kidney function
Glomerular Filtration Rate Glomerular Filtration Rate (GFR) – cont’d(GFR) – cont’d
Patient’s remain asymptomatic until there has Patient’s remain asymptomatic until there has been a significant decline in GFRbeen a significant decline in GFR
Can be very accurately measured using “gold-Can be very accurately measured using “gold-standard” techniquestandard” technique
Glomerular Filtration Rate Glomerular Filtration Rate (GFR) – cont’d(GFR) – cont’d
Ideal MarkerIdeal Marker Produced endogenously at a constant rateProduced endogenously at a constant rate Filtered across glomerular membraneFiltered across glomerular membrane Neither re-absorbed nor excreted into the urineNeither re-absorbed nor excreted into the urine
UreaUrea
Used historically as marker of GFRUsed historically as marker of GFR Freely filtered but both re-absorbed and excreted Freely filtered but both re-absorbed and excreted
into the urineinto the urine Re-absorption into blood increased with volume Re-absorption into blood increased with volume
depletion; therefore GFR underestimateddepletion; therefore GFR underestimated Diet, drugs, disease all significantly effect Urea Diet, drugs, disease all significantly effect Urea
productionproduction
Urea Urea IncreaseIncrease DecreaseDecrease
Volume depletionVolume depletion Volume Volume ExpansionExpansion
Dietary proteinDietary protein Liver diseaseLiver disease
CorticosteroidsCorticosteroids Severe Severe malnutritionmalnutrition
TetracyclinesTetracyclines
Blood in G-I tractBlood in G-I tract
CreatinineCreatinine
Product of muscle metabolismProduct of muscle metabolism Some creatinine is of dietary originSome creatinine is of dietary origin Freely filtered, but also actively secreted into urineFreely filtered, but also actively secreted into urine Secretion is affected by several drugsSecretion is affected by several drugs
Serum Creatinine Serum Creatinine
IncreaseIncrease DecreaseDecrease
MaleMale AgeAge
Meat in dietMeat in diet FemaleFemale
Muscular body typeMuscular body type MalnutritionMalnutrition
Cimetidine & some Cimetidine & some Muscle wastingMuscle wasting
other medications other medications AmputationAmputation
Creatinine vs. Inulin ClearanceCreatinine vs. Inulin Clearance
Creatinine Clearance Creatinine Clearance
Measure serum and urine creatinine levels and Measure serum and urine creatinine levels and urine volume and calculate serum volume cleared urine volume and calculate serum volume cleared of creatinineof creatinine
Same issues as with serum creatinine, except Same issues as with serum creatinine, except muscle massmuscle mass
Requirements for 24 hour urine collection adds Requirements for 24 hour urine collection adds variability and inconveniencevariability and inconvenience
Cystatin CCystatin C
Cystatin C is a 13 KD protein produced by all cells Cystatin C is a 13 KD protein produced by all cells at a constant rateat a constant rate
Freely filteredFreely filtered Re-absorbed and catabolized by the kidney and Re-absorbed and catabolized by the kidney and
does not appear in the urinedoes not appear in the urine
eGFReGFR
Increasing requirements for dialysis and Increasing requirements for dialysis and transplant (8 – 10% per year)transplant (8 – 10% per year)
Shortage of transplantable kidneysShortage of transplantable kidneys
Large number at riskLarge number at risk
StageStage DescriptionDescription GFR GFR ML/min/1.173mML/min/1.173m22 PrevalencePrevalence33
11 Kidney Damage with Normal or Kidney Damage with Normal or ↑ ↑ GFRGFR >90>90 478,500478,500
22 Kidney Damage with Mild Kidney Damage with Mild ↓ ↓ GFRGFR 60 – 8960 – 89 435,000435,000
33 Moderate Moderate ↓↓ GFR GFR 30 – 5930 – 59 623,500623,500
44 Severe Severe ↓↓ GFR GFR 15 – 2915 – 29 29,00029,000
55 Kidney FailureKidney Failure <15 or dialysis<15 or dialysis 14,50014,500
eGFR – cont’deGFR – cont’d
Cumulative 8-year mortality rate, depending on Cumulative 8-year mortality rate, depending on serum creatinine level at baseline, in the serum creatinine level at baseline, in the
Hypertension Detection and Follow-up ProgramHypertension Detection and Follow-up Program
Serum creatinine Serum creatinine
mg/dL (mg/dL (µmol/L)µmol/L)
MortalityMortality
Rate (%)Rate (%)
0.8 - 0.99 (71 - 88)0.8 - 0.99 (71 - 88) 1010
1.1 - 1.29 (97 – 114)1.1 - 1.29 (97 – 114) 1212
1.3 – 1.49 (115 – 132)1.3 – 1.49 (115 – 132) 1616
1.5 – 1.69 (133 – 149)1.5 – 1.69 (133 – 149) 2222
1.7 – 1.99 (150 – 176)1.7 – 1.99 (150 – 176) 3030
2.0 – 2.49 (177 – 220)2.0 – 2.49 (177 – 220) 4141
≥≥2.5 (≥221)2.5 (≥221) 5454
Data from Shulman et al.Data from Shulman et al.99
eGFR – cont’deGFR – cont’d
The Old Standard: Serum The Old Standard: Serum CreatinineCreatinine
ProblemProblem
Need an easy test to screen for early decreases in Need an easy test to screen for early decreases in GFR that you can apply to a large, at-risk GFR that you can apply to a large, at-risk populationpopulation
Can serum creatinine be made more sensitive by Can serum creatinine be made more sensitive by adding more information?adding more information?
eGFR by MDRD FormulaeGFR by MDRD Formula
Mathematically modified serum creatinine with Mathematically modified serum creatinine with additional information from patients age, sex and additional information from patients age, sex and ethnicityethnicity
eGFR = 30849.2 x (serum creatinine)eGFR = 30849.2 x (serum creatinine)-1.154-1.154 x (age) x (age)-0.203-0.203
(if female x (0.742))(if female x (0.742))
Screening Test – cont’dScreening Test – cont’d
The ResultsThe Results
eGFR – cont’deGFR – cont’d
eGFR calculation has been recommended by eGFR calculation has been recommended by National Kidney Foundation whenever a serum National Kidney Foundation whenever a serum creatinine is performed in adultscreatinine is performed in adults
Guidelines & ProtocolsGuidelines & ProtocolsAdvisory CommitteeAdvisory Committee
Identification, Evaluation and Management of Identification, Evaluation and Management of Patients with Chronic Kidney DiseasePatients with Chronic Kidney Disease
Recommendations for:Recommendations for: Risk group identificationRisk group identification ScreeningScreening Evaluation of positive screenEvaluation of positive screen Follow-upFollow-up
Identify High Risk GroupsIdentify High Risk Groups
DiabetesDiabetes HypertensionHypertension Heart DiseaseHeart Disease Family HistoryFamily History High Risk Ethnic GroupHigh Risk Ethnic Group Age > 60 yearsAge > 60 years
Screen High Risk GroupsScreen High Risk Groups
eGFReGFR UrinalysisUrinalysis Albumin / Creatinine RatioAlbumin / Creatinine Ratio
Follow-up based on Screen ResultsFollow-up based on Screen Results
Kidney UltrasoundKidney Ultrasound Specialist ReferralSpecialist Referral Cardiovascular Risk AssessmentCardiovascular Risk Assessment Diabetes ControlDiabetes Control Smoking cessationSmoking cessation Hepatitis / Influenza ManagementHepatitis / Influenza Management
Creatinine Standardization in Creatinine Standardization in British ColumbiaBritish Columbia
Based on Isotope dilution /Based on Isotope dilution /mass spectrometry mass spectrometry measurements of creatinine standardsmeasurements of creatinine standards
Permits estimation and correction of creatinine Permits estimation and correction of creatinine and eGFR bias at the laboratory level.and eGFR bias at the laboratory level.
Importance of StandardizationImportance of Standardization
Low bias creatinine:Low bias creatinine: Causes inappropriately increased eGFRCauses inappropriately increased eGFR Patients will not receive the benefits of more intensive Patients will not receive the benefits of more intensive
investigation of treatment.investigation of treatment.
High bias creatinine:High bias creatinine: Causes inappropriately decreased eGFRCauses inappropriately decreased eGFR Patients receive investigations and treatment which is Patients receive investigations and treatment which is
not required. Wastes time, resources and increases not required. Wastes time, resources and increases anxiety.anxiety.
High 143.3
Low 116.0
Mean 124.6
Poor Creatinine PrecisionPoor Creatinine Precision
Incorrect categorization of patients with both Incorrect categorization of patients with both “normal” and decreased eGFR.“normal” and decreased eGFR.
Total ErrorTotal Error
TE = % bias + 1.96 CVTE = % bias + 1.96 CV Goal is <10%Goal is <10%
(requires bias (requires bias ≤ 4% and CV ≤ 3%)≤ 4% and CV ≤ 3%)
ProteinuriaProteinuria
In health:In health: High molecular weight proteins are retained in the High molecular weight proteins are retained in the
circulation by the glomerular filter (Albumin, circulation by the glomerular filter (Albumin, Immunoglobulins)Immunoglobulins)
Low molecular weight proteins are filtered then Low molecular weight proteins are filtered then reabsorbed by renal tubular cellsreabsorbed by renal tubular cells
Proteinuria – cont’dProteinuria – cont’d
Glomerular:Glomerular: Mostly albumin, because of its high concentration and Mostly albumin, because of its high concentration and
therefore high filtered loadtherefore high filtered load
Tubular:Tubular: Low molecular weight proteins not reabsorbed by tubular Low molecular weight proteins not reabsorbed by tubular
cells (e.g. alpha-1 microglobulin)cells (e.g. alpha-1 microglobulin)
Overflow:Overflow: Excessive filtration of one protein exceeds reabsorbtive Excessive filtration of one protein exceeds reabsorbtive
capacity (Bence-Jones, myoglobin)capacity (Bence-Jones, myoglobin)
Albumin Creatinine Ratio Albumin Creatinine Ratio (Microalbumin)(Microalbumin)
Normal albumin moleculeNormal albumin molecule In health, there is very little or no albumin in the In health, there is very little or no albumin in the
urineurine Most dip sticks report albumin at greater than Most dip sticks report albumin at greater than
150 mg/L150 mg/L
Urinary Albumin – cont’dUrinary Albumin – cont’d
Detection of low levels of albumin (even if below Detection of low levels of albumin (even if below dipstick cut-off) is predictive of future kidney dipstick cut-off) is predictive of future kidney disease with diabetesdisease with diabetes
Very significant biologic variation usually requires Very significant biologic variation usually requires repeat collectionsrepeat collections
Treatment usually based on timed urine albumin Treatment usually based on timed urine albumin collectionscollections
UrinalysisUrinalysis
DipstickDipstick ProteinProtein
• Useful screening testUseful screening test
• Dipstick more sensitive to albumin than other Dipstick more sensitive to albumin than other proteinsproteins
• Large biologic variationLarge biologic variation
Urinalysis – cont’dUrinalysis – cont’d
Dipstick – cont’dDipstick – cont’d HemoglobinHemoglobin
• Glomerular, tubular or post-renal sourceGlomerular, tubular or post-renal source
• Reasonably sensitiveReasonably sensitive
• Positive dipstick and negative microscopy with lysed Positive dipstick and negative microscopy with lysed red cellsred cells
Urinalysis – cont’dUrinalysis – cont’d
Dipstick – cont’dDipstick – cont’d GlucoseGlucose
• Reasonable technically, however screening and Reasonable technically, however screening and monitoring programs for diabetes are now done by monitoring programs for diabetes are now done by blood and Point-of-Care devicesblood and Point-of-Care devices
Specific GravitySpecific Gravity
Approximate onlyApproximate only Measurement of osmolarity preferred when Measurement of osmolarity preferred when
concentrating ability being assessedconcentrating ability being assessed
pHpH
pH changes with time in a collected urinepH changes with time in a collected urine Calculations to determine urine ammonium levels Calculations to determine urine ammonium levels
and response to acid-loading generally required to and response to acid-loading generally required to assess for renal tubular acidosisassess for renal tubular acidosis
Microscopic UrinalysisMicroscopic Urinalysis
Epithelial CellsEpithelial CellsSquamous, Transitional, RenalSquamous, Transitional, Renal
All may be present in small numbersAll may be present in small numbers Important to recognize possible malignancyImportant to recognize possible malignancy Comment on unusual numbersComment on unusual numbers
Renal Tubular EpithelialRenal Tubular Epithelial
Red CellsRed Cells
May originate in any part of the urinary tractMay originate in any part of the urinary tract Small numbers may be normalSmall numbers may be normal There is provincial protocol for the investigation There is provincial protocol for the investigation
of persistent hematuriaof persistent hematuria
Red CellsRed Cells
White Blood CellsWhite Blood Cells
Neutrophils often present in small numbersNeutrophils often present in small numbers Lymphocytes and moncytes less oftenLymphocytes and moncytes less often Marker for infection or inflammationMarker for infection or inflammation
NeutrophilsNeutrophils
CastsCasts
Hyaline and granular casts not always pathologic, Hyaline and granular casts not always pathologic, clinical correlation requiredclinical correlation required
Red cell casts always significant, usually Red cell casts always significant, usually glomerular injury glomerular injury
WBC casts also always significant, usually WBC casts also always significant, usually infection, sometimes inflammationinfection, sometimes inflammation
Bacterial casts only found in pyelonephritisBacterial casts only found in pyelonephritis Waxy casts found in significant kidney diseaseWaxy casts found in significant kidney disease
Hyaline CastHyaline Cast
Granular CastGranular Cast
White Cell CastWhite Cell Cast
Red Cell CastRed Cell Cast
Waxy CastWaxy Cast
Tests for Renal Tubular AcidosisTests for Renal Tubular Acidosis
Urinary Anion GapUrinary Anion Gap
(Na(Na+ + + K+ K++) – Cl) – Cl--
In acidosis the kidney should excrete NHIn acidosis the kidney should excrete NH44++ and and
the gap will be negativethe gap will be negative
RTA – cont’dRTA – cont’d
If If NHNH44++ is not present (or if HCO is not present (or if HCO33
-- is present) the is present) the
gap will be neutral or positive, implying impaired gap will be neutral or positive, implying impaired kidney handling of acid load. kidney handling of acid load.
Urine Anion Gap = (NaUrine Anion Gap = (Na++ + K + K++) –Cl) –Cl--
RTA – cont’dRTA – cont’d
Ammonium Chloride LoadingAmmonium Chloride Loading Load with ammonium chlorideLoad with ammonium chloride Hourly measurements of urine pHHourly measurements of urine pH Normal at least one pH below 5.5Normal at least one pH below 5.5
Tests of Kidney Concentrating Tests of Kidney Concentrating AbilityAbility
To differentiateTo differentiate Psychogenic polydipsiaPsychogenic polydipsia Central diabetes insipidusCentral diabetes insipidus Nephrogenic Nephrogenic diabetes insipidus diabetes insipidus
Overnight Water Deprivation Overnight Water Deprivation TestingTesting
(Serum osmolarity <295 monitor patient (Serum osmolarity <295 monitor patient weight hourly)weight hourly)
Collect urine hourly from 0600 for osmolarityCollect urine hourly from 0600 for osmolarity Baseline serum osmolarity, NaBaseline serum osmolarity, Na++, ADH , ADH When osmolarity plateaus repeat above tests and When osmolarity plateaus repeat above tests and
administer ADHadminister ADH
InterpretationInterpretation
If urine concentrates (osmolarity >600 and If urine concentrates (osmolarity >600 and serum osmolarity below <295)serum osmolarity below <295)
Normal physiology (? psychogenic polydipsia)Normal physiology (? psychogenic polydipsia)
No Urine ConcentrationNo Urine ConcentrationNo Response to ADHNo Response to ADH
Nephrogenic diabetes insipidusNephrogenic diabetes insipidus
No Urine ConcentrationNo Urine Concentration
Positive response to ADHPositive response to ADHCentral diabetes insipidusCentral diabetes insipidus
QuestionsQuestions