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)