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Biochemical Assessment of

Renal Disease

Dr Suzannah Phillips

Senior Clinical Scientist

Royal Liverpool Hospital

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Overview

• Presentation of renal disease

• Biochemical assessment

• glomerular function• tubular function

• urinalysis

•

 Other tests

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Renal Disease

Retention of waste products Disorders in

electrolyte

balance

Disorders in water

balance - alterations in

urine output

Disorders in red

cell production

and vitamin D

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Changes in urine outputAnuriaNo urine output <50 mL/24hrs 

Oligouria

Reduced volume of urine output <400 mL/24hrs in adults

PolyuriaIncreased volume of urine output >3 L/24hrs

Frequency - increased urination but total daily volume is normal (nocturia)Dysuria - pain on urination

Presentation

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Uraemic syndrome

Cardiovascular

HypertensionPercarditis

CCF

 Anaemia

NeurologicalLethargy

Headache

Peripheral neuropathy

Muscle weakness

SkeletalRenal osteodystrophy

Stunted growth

GastrointestinalVomiting

Nausea

anorexia

DermatologicalPruritus

Pigmentation

Slow wound healing

GenitourinaryImpotence

Polyuria/Nocturia

ImmunologicalIncreased susceptibility to infection

Presentation

Azotaemia  – increased

urea

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Effect of Renal Disease

Glomerular Tubular

Reduced filtration

• Anuria/oliguria

• Increased plasma creatinine /urea

• Hyperkalaemia

• Hyperphosphataemia

• Metabolic acidosis

Damage to glomerular membrane

• Proteinuria – large proteins

• Haematuria

Reduced reabsorption (general or

specific inherited conditions).

• Polyuria, low urine osmolality

• Metabolic acidosis

• Proteinuria - small proteins

(ß2 microglobulin, amino acids)

• Glycosuria

• Anaemia,

• Hypocalcaemia

Hormonal

Presentation will depend on the cause, the relative glomerular to tubular

dysfunction and the number of nephrons affected.

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Nephrotic syndromeProteinuria (>3g/24hrs), hypoalbuminaemia,

oedema, hyperlipidaemia 

Nephritic syndromeHaematuria, proteinuria, oligouria,

hypertension, azotemia

Fanconi syndromeGlycosuria, aminoaciduria, hypokalaemia,

hypophosphataemia, hypouricaemia,

metabolic acidosis)

Presentation

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1. Glomerular filtration rate (GFR)

Clearance (ability to remove waste products)

The volume of plasma that is filtered by the kidneys and from which a

substance is completely cleared per unit of time

Assessment of Glomerular function

Clearance = Urine concentration (umol/L) x Urine Volume (mL)

Plasma concentration (umol/L) x time (min)

= mL.min-1

Ideal Marker (clearance = GFR) • Stable plasma concentration

• Freely filtered at the glomerulus

• Not secreted or reabsorbed by renal tubular cells

• Renal excretion ONLY (i.e. not metabolised by liver)

• Easy and cheap to measure

!! No marker fulfils

all these criteria

WATCH

UNITS

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1. Glomerular filtration rate (GFR)

Assessment of Glomerular function

How to collect 24 hr urine

 – Day 1 8am empty bladder (discard output) – Commence 24h urine collection

• All urine now passed until 8am next day must be collected into container.

 – Day 2 8am collect final urine output into container

Clearance  – need blood and urine sample - relies on accurate 24 hr urine

collection

Indirect measure of clearance - use plasma concentration of marker – increased levels reflect reduced clearance.

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1. Glomerular filtration rate (GFR)

Assessment of Glomerular function

Endogenous markersClearance

Plasma concentration

• Cystatin C – Protein produced by all nucleated cells – Expensive assay

• Urea

- End product of nitrogenous compound metabolism (esp amino acids)

- Freely filtered at glomerulus

- Quick, cheap & convenient

- NOT steady plasma levels effected by diet and protein catabolism e.g.raised in GI bleed

- Low in liver disease

- Some passive reabsorption in renal tubules

- Under estimation of GFR

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Assessment of Glomerular function

• Creatinine clearance / plasma

 – Used routinely

 – From breakdown of skeletal muscle cells.

 – Constant daily production

 – Normally filtered and excreted in the urine.

 – Some secretion.

 – Over estimation of GFR

 – Can correct for BSA (mL/min/1.73m2) CrCl x 1.73

BSA 

 – Quick, cheap & convenient

 – Effected by body mass /ethnicity.

 – Interferences (ketones & bilirubin). – GFR falls to <50ml/min before creatinine rises

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Calculated Glomerular filtration rate

Assessment of Glomerular function

Cr Cl (mL/min) = [(140  – age) x weight / 0.814 x serum creatinine (umol/L)]

a. Cockcroft and Gault

x 0.85 if female

b. Schwartz Formula (children)

eGFR = K x height / serum creatinine

K= constant, dependent on age

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Estimated Glomerular filtration rate (eGFR)

Assessment of Glomerular function

c. Modification of Diet in Renal Disease (MDRD)

eGFR = 175 x (Creat / 88.4)-1.154 x (Age)-0.203 x (0.742 if female) x (1.210 if black)

4 variable (creatinine, age, sex, ethnicity)

6 variable (includes serum urea & albumin)

NOT validated for use in

• Children

• Acute kidney injury

• Amputees

• pregnancy

• Malnourished

• Odematous

• Muscle wasting

Only black ethnicity accounted for ?others

Under-estimates GFR (>60 mL/min)

? Differences in assay performance:

175 – if method traceable to IDMS

NEQAS (2006) slope and intercept adjustmentfactors.

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Estimated Glomerular filtration rate (eGFR)

Assessment of Glomerular function

d. CKD Epidemiology collaboration (CKD-EPI) (2009)

More accurate than MDRD esp when GFR >60 mL/min

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2. Proteinuria (glomerular membrane integrity)

• 24h protein excretion (<0.15g/24h) >50% Tamm-Horsfall mucoprotein.

• 24 hr albumin excretion (<30mg/24)

• Albumin main protein lost when glomerular disease – most abundant proteinin plasma.

• More severe glomerular damage – loss of larger proteins (Igs).

Assessment of Glomerular function 

Classification of proteinuria

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Assessment of Glomerular function

Tests for glomerular proteinuria

• 24 hr total protein• Random urine - Protein:creatinine ratio (PCR)

• Protein Selectivity

• Microalbumin (ability to detect albumin at low levels in urine)

• Random urine - Albumin:creatinine ratio (ACR)

•http://www.nice.org.uk/nicemedia/pdf/CG073NICEGuideline.pdf  

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Assessment of Tubular function

1. Ability to excrete / retain water

Determined by ability to concentrate / dilute urine

Tests

•Urine sodium, osmolality and volume

•Serum sodium & osmolaltity

•Fluid deprivation test

2. Ability to maintain acid-base balance

Usually see metabolic acidosis

Renal tubular acidosis

•Urine / blood pH

•Anion gap•Serum bicarbonate

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Assessment of Tubular function

3. Ability to maintain electrolyte balance

Tubular proteinuria – low molecular weight proteins (α1-microglobin, Retinol

binding protein, RBP & β2-microglobin)

Serum and urine aminoacids. (specific defects – aminoaciduria).

Urine glucose – renal threshold ~10 mmol/L

4. Ability to reabsorb small proteins, amino acids & glucose

Serum sodium & potassium

Random Urine sodium & potassium

Fractional excretion of sodium (FeNa) = 100 x ((Ur Na/Serum Na) / (Ur creat/serum creat))

Trans-tubular K gradient (TTKG) = ((UrK / serum K) / (Ur osmo / serum osmo))

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Urinalysis

1. Dipstick (random)

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Urinalysis

2. Microscopy

Urine casts – due to aggregation in distal / collecting duct

Red cell

Granular (cell debris)

Hyaline (Tamm-Horsfall protein)

White cell

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Urinalysis3. Renal stones

Types of stone

 – (67%) Calcium oxalate ± phosphate (hypercalcaemia) 

 – (12%) Triple phosphate/struvite (Mg, Ca, NH4) (UTI)

 – (8%) Calcium phosphate (alkaline urine)

 – (8%) Uric acid (purine metabolism)

 –  (1-2%) Cystine (cystinuria)

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Urinalysis3. Renal stones

Formation induced by:• Increased concentration of urinary constituents above natural solubility

• Lack of physiological inhibitors of stone growth (e.g mucopolysaccarides,citrate &pyrophosphate)

• Changes in urine pH (alkaline pH favours NH4 ion formation → precipitate) 

• Seeding (i.e stone formed can be different to the nucleus that the stone startedfrom & colonisation of bacteria can accelerate stone growth)

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Urinalysis3. Renal stones

• Urine analysis – Calcium

 – Phosphate

 – Urate

 – Oxalate – Cystine

 – pH

 – Sodium

 – Magnesium

 – Citrate

 – Microbiology

• Stone analysis

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Other Specific Tests

NGAL- Neutrophil Gelatinase Associated Lipocalin

 – Marker of acute kidney injury (urine & serum)

 – Early detection of AKI

Serum glucose / HbA1c – Diabetic renal disease

Bence Jones Protein (BJP) – Multiple myeloma

 – Also serum Igs & electrophoresisImmunology Tests

 – ANCA, Anti-GBM

Imaging

 – Ultrasound

 – MRI

 – CT

 – Angiography (renal artery stenosis)