Clinical Biochemistry and Renal Disease
Dr Vivion CrowleyConsultant Chemical PathologistSt James’s Hospital
What are the primary functions of the Kidney
Excretion of waste – urea, creatinine, urate
Water and electrolyte balance
Acid-base balance
Regulation of systemic circulation – Renin and Aldosterone
Production of hormones – Vit D, Erythropoietin
Participates in gluconeogenesis
What is the primary functional unit of the Kidney
Nephron
Proximal tubule – Na, K, H20, HCO3, PO4, aminoacids
Loop of Henle – Countercurrent multiplier system
Distal tubule – Na, K, Acid-base balance
Collecting duct – Osmoregulation
How do we assess Renal Function?
Glomerular filtration rate (GFR)
-key measure of functioning renal mass
-the sum of filtration rate of functioning nephrons
-Normal GFR 120-130ml/min/1.73 m2 in young adults
-decreases with age
(consider GFR as approximately 100ml/min)
Are there plasma markers of GFR?
Plasma Urea
-Breakdown product of protein metabolism-Produced in liver
Plasma Creatinine
-Derived from creatine in muscle-Related to muscle mass
Causes of abnormal plasma urea
Causes of abnormal plasma creatinine
Increases in Urea and Creatinine above the upperreference range are evident only when GFR is reduced by 50% or normal
A normal urea and crea may not reflect a normal GFR
Consider other causes of elevations in Urea and Crea
Caveats in the interpretation of PUrea and Creatinine
Urinary clearance of filtration markers is used to estimate GFR
Ideal filtration marker-Neither secreted nor absorbed by kidney tubule
Exogenous
-Inulin-IV infusion-Difficult to assay
Other markers include Cr51-EDTA, I125-iothalamate
Endogenous filtration markers of GFR
Urinary urea as a filtration marker-easy to measure-Freely filtered at glomerulus-Reabsorbed in proximal and sistal tubule-Significantly Underestimates GFR
Urinary creatinine as a filtration marker-Most commonly used-Freely filtered at glomerulus-Secreted in renal tubule-Overestimates GFR by 10-20ml/min
Requires 24h urine collection-Problematic for patients-Over or under collection
Equations using serum creatinine can be used to estimate GFR
Cockcroft–Gault equation-Uses age, wt, gender, plasma creatinine-Really an estimation of creatinine clearance
MDRD equation for eGFR-Estimate of GFR rather than Creatinine clearance-4 variable eqn.-Plasma crea, age, gender, ethnicity-Increasingly used to classify Chronic kidney Disease (CKD)
Equations used to estimate GFR
Cockcroft–Gault equation
MDRD equation for eGFR
Use of MDRD to classify CKD
Other potential markers of GFR
Plasma Cystatin C
-Cysteine protease inhibitor-Freely filterd by gloerulus-Almost completelyReabsorbed and catbolised by tubules-Plasma levels correlate with GFR-Expensive test-Not routinely available
What is Renal Failure?
A deterioration in renal function leading to a complex of symptoms and signs
Azotaemia – increase in nitrogenous substances e.g. urea, crea
Uraemia – symptoms of confusion etc. associated with azotaemia
How is Renal Failure classified?
Time of onset
Acute renal failure-An abrupt reduction in GFR-Usually over hours or days-Oliguria <400ml/day, anuria <100ml/day, polyuria>3L/day
Chronic Renal Failure
How else can renal failure be classified?
What are the causes of acute renal failure (ARF)
Prerenal•Volume depletion e.g. vomiting, diarrhoea, fistulae, renal Na wasting•Sepsis•Cirrhosis•Renal artery stenosis
Intrarenal•Vascular•Glomerular•Acute tubular necrosis (ATN)•Acute interstitial nephritis
Postrenal•Ureteral obstruction•Bladder obstruction
What is the biochemical profile associated with pre-renal failure?
Na 150 (135-145)
K 2.8 (3.5-5.0)
urea 14.0 (2.8-7.5)
Crea 118 (50-120)
HCO3 33 (20-28)
•53y old male •3/7 hx of vomiting and diarrhoea
How do you distinguish between Pre-renal failure and ATN?
What is the biochemical profile associated with established ARF e.g. ATN?
Na 150 (135-145)
K 6.5 (3.5-5.0)
Urea 40.0 (2.8-7.5)
Crea 450 (50-120)
HCO3 11 (20-28)
What are the causes of CRF?
•Diabetic nephropathy
•Glomerulonephritis
•Hypertensive nephropathy
•Tubulointerstitial disease
•Polycystic kidney disease
•Reflux nephropathy
•In many instances cause is unknown
What are the metabolic consequences of CRF
Na handling - reduced Na excretory capacity – oedema, HTH2O handling-Urine becomes isosmotic – inability to dilute or conc urineHyperkalaemiaAcidosis – RTA and high anion gapBone disease-Hypocalcaemia-Hyperphosphataemia-Secondary hyperparathyroidism-AcidosisAnaemia – reduced erythropoietinDyslipidaemiaEndocrine – hyperprolactinaemia, hypogonadism
How is progression of CRF monitored?
What is the biochemical profile associated with ESRD
65y old maleC/O malaise, tiredness, nocturiaO/E BP 182/110, pale
Na 133 (135-145)
K 6.1 (3.5-5.0)
Urea 38.5 (2.8-7.5)
Crea 628 (50-120)
HCO3 16 (20-28)
Ca 1.90 (2.20-2.75)
PO4 2.82 (0.8-1.4)
Alk Phos 225 (40-120)
Pre-dialysis Post-dialysis
Na 145 140
K 5.8 3.8
HCO3 19 26
Urea 35.2 15.5
Crea 1160 560
Ca 2.51 2.84
PO4 3.16 1.33
Alk Phos 126 153
Alb 37 44
What effect does dialysis have on ESRD biochemical profile?
Causes of Tubulointerstitial Disease
•Immunologic – SLE, Amyloidosis, Sjoogren’s syndrome, MM
•Drugs – NSAIDs, Chemotherapy
•Heavy metals- lead, cadmium, mercury
•Sickle cell disease
•Lymphoma
•Pyelonephritis
•Sarcoidosis
•Hyepruricaemia (Gout)
How does Tubulointerstitial disease manifest?
How do you check for proteinuria?
Urine dipstick-Protein – detects albumin >200-300mg/L-Does not detect Bence-Jones protein (Ig light chains)-pH, Glucose, Hb, Bilirubin, Urobilinogen-Nitrite, Leukocyte esterase
Timed urine collection-24h urine -First morning voided urine – Albumin:creatinine ratio used in detecting microalbuminuria in DM
How is proteinuria classified?
Time:Transient – exercise-related, acute illnessPersistent – requires further investigation
Cause:UTI
Overflow proteinuria- Bence-Jones, Amylase, Hb, Myoglobin, lysozyme
Orthostatic proteinuria- No proteinuria in first morning urine- Proteinuria detectable when patient ambulant
Glomerular - Leaky glomerulus – glomerulonephritis
Tubular- Tubulointerstitial disease
How do you investigate proteinuria?
What is nephrotic syndrome?
Nephrotic range proteinuria >3.5g/24hHypoalbuminaemiaOedema – periorbital, dependentHyperlipidaemia – marked hypercholesterolaemia
Causes
•Primary renal disease – glomerulonephritis•Systemic disease – DM, amyloidosis, SLE•Multiple Myeloma•Infection – HepB, HIV, TB•Malignancy•Drugs – Gold, Penicillamine•Pre-eclampsia
Biochmeical investigation of Proteinuria should include:
Urine dipstick
Urine protein/creatinine ratio ( random urine sample) >40mg/mmol suggests underlying proteinuria
24 hour urine collection for protein> 300mg/24hr suggests proteinuria
What are the most common kidney stones?
•Calcium Oxalate and Phosphate – 40%
•Calcium Oxalate – 30%
•Calcium Phosphate – 10%
•Struvite (MgNH4PO4)– 10%
•Urate – 7%
•Cystine – 2%
•Miscellaneous – Xanthine etc.- 1%
What factors predispose to nephrolithiasis?
Idiopathic Hypercalciuria
Primary hyperparathyrodism
Hyperoxaluria-1o Autsomal recessive-2o Small bowel resection, bypass or inflammation
Hyperuricosuria – associated with gout
Renal tubular acidosis
Cystinuria – cystinosis
UTI
Hypocitraturia
Idiopathic nephrolithiasis
Most likely a genetic predisposition
What is idipopathic hypercalciuria (IH)?
Hypercalciuria - Urine Ca > 10mmol/24h
IH- affects 10% of population- 40% of renal stone formers
Absoprtive hypercalciuria-Intestinal calcium hyperabsorption-? Increased sensivity to VitD
Renal phosphate leak
Renal hypercalciuria
How would you investigate a patient with Nephrolithiasis?
PlasmaNa, K, Urea, Creatinine, HCO3, Ca, PO4, Urate, PTH, VITD
Urine - Dipstick for pH, protein- 24 h urine collectionCa, PO4, Mg, UrateOccasionally – Oxalate, Citrate, Cystine, Xanthine
Direct stone analysis
Nonbiochemical investigation- microbiology, radiology
Remember Read Your Clinical Biochemistry Books!
Recommended Reading
Lecture Notes in Clinical Biochmesitry 7th EditionG Beckett, S Walker, P Rae, P Ashby (Blackwell publishing)
Clinical Chemistry 5th EditionW J Marshall, S K Bangert (Pubslished by Mosby)
An illustrated Colour text - Clinical Biochmeistry 3rd editionAlan Gaw et al (Churchill Livingston)
Handbook of Clinical biochmeistry 1st EditionR Swaminathan (Oxford University Press)
Clinical Chemistry in diagnosis and treatmentPhilip Mayne (Edward Arnold)
A Guide to Diagnostic Clinical Chemistry 3rd EditionWalmsely & White (Blackwell)
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