Nephrology 2 Euan Green Mr Betts. Assessment of renal function History and examination clues Blood tests and associated formulae Urine tests incl. 24h.

Nephrology 2

Euan Green

Mr Betts

Assessment of renal function

• History and examination clues

• Blood tests and associated formulae

• Urine tests incl. 24h clearance

• Nuclear medicine techniques

• Chronic renal failure

• 1)How does autoregulation of renal blood flow work?

• 2) Why do you get hypertension in chronic renal failure?

• 3) What are the implications of chronic renal failure?

MCQ

1. CKD stage 5 equates to an eGFR <5mls/min

2. CKD stage 1 equates to an eGFR 75-90mls/min

3. Those identified with CKD stage 2 should be referred to a nephrologist

4. The CKD classification is based solely on eGFR

5. CKD stage 3 has been subdivided into those with an EGFR < or >= 45mls/min

MCQ

1. CKD stage 5 equates to an eGFR <5mls/min

2. CKD stage 1 equates to an eGFR 75-90mls/min

3. Those identified with CKD stage 2 should be referred to a nephrologist

4. The CKD classification is based solely on eGFR

5. CKD stage 3 has been subdivided into those with an EGFR < or >= 45mls/min

Chronic kidney disease

Kidney damage= persistent microalbuminuria, persistent proteinuria, persistent haematuria, structural abnormalities of the kidneys demonstrated on ultrasound scanning or other radiological tests, or biopsy-proven chronic glomerulonephritis)

Why should we detect kidney disease

1. The scale of the problem– 0.1% of the population on dialysis (40,000 in the

UK)– Costing the NHS an average of £20,000 per patient

per year (3% of the NHS budget)– 4.5% of the population have moderate or severe

renal failure but not yet on dialysis

2. Patients with renal failure are considered to be in the highest risk category for heart disease (20% per 10 years)

3. Death– Patients with CKD are more likely to die

than require dialysis– 27,998 CKD patients followed for 5 years:

Stage GFR (ml/min) RRT Death

2 60-89 1.1% 19.5%

3 30-59 1.3% 24.3%

4 15-29 19.9% 45.7%

Keith DS, AIM 2004;164:659-663

4. Poor outcome of unreferred CKD– East Kent study 601,000 population– Using opportunistic serum creatinine

– Males - serum creatinine 180 mol/L

– Females - serum creatinine 135 mol/l

– Approximate to GFR < 30-40ml/min/1.73m2

– Prevalence 4708 unreferred– Outcome (over 31 months)

• Median survival 28 months• Cardiovascular 40%• Infection 26%• Cancer 16%• End stage renal failure <5%

Case 1

• A 45 year old man has been referred for a vasectomy under GA

• His pre-op bloods show renal impairment (eGFR 70) and he’s brought back to clinic to assess this unexpected finding.

• How would you assess for evidence of renal dyfunction?

Case 1• History

– Age– Co-morbidities

• Hypertension• Diabetes• Vascular disease• Obesity• Smoking• Structural urinary tract abnormalities• Liver disease• Cancers

Case 1

• Concurrent illness– Dehydration from D&V– Recent URTI– Recent surgery

• Drugs– Lots– Remember X-ray contrast and other once offs

• Family history

Case 1

• Examination– Blood pressure– Abdominal masses (bladder, kidneys, ascites)– Signs of fluid retention (peripheral oedema,

pulmonary oedema, JVP)– Fluid balance– Changes in weight

Bicohemistry Tests

• Tests– Urine dipstick– Urine tests

• Microscopy

• 24 hour urine collection

• Urinary Albumin:creatinine ratio

– Blood tests

MCQ1. All proteins except albumin cause a colour

change on urine dipstick

2. Prolonged periods of standing can underestimate proteinuria

3. A urinary albumin:creatinine ratio of 25mg/mmol is normal

4. Creatinine clearance is always an overestimate of GFR

5. Creatinine is freely filtered at the glomerulus and neither secreted, nor reabsorbed

MCQ1. All proteins except albumin cause a colour

change on urine dipstick

2. Prolonged periods of standing can underestimate proteinuria

3. A urinary albumin:creatinine ratio of 25mg/mmol is normal

4. Creatinine clearance is always an overestimate of GFR

5. Creatinine is freely filtered at the glomerulus and neither secreted, nor reabsorbed

Case 2

• Friday at 20:05 On call referral:

• A man has pitched up in A&E with a note.– “Dear urologist, This 60 year old chap had dipstick

haematuria so I sent him for a CT urogram yesterday. The report says ‘mild bilateral hydronephrosis, images in the pelvis are uninterpretable due to streak artefact from bilateral hip replacements. Clinical correlation advised’. His creatinine is 150 today. Please clinically correlate as discussed with your SHO.”

Case 2

• A&E have helpfully done a urine dipstick which shows– Blood ++– Protein ++

• They’ve done a post void bladder scan which is normal

• They’ve confirmed the creatinine result

• In doing so he’s reached 3 hours and 59 minutes in the department and the bed manager has admitted him under urology after discussing with the SHO.

Urine dipstick• Protein

– Tetrabromophenol reaction with albumin causes a colour change (yellow to blue/green)

• Trace 5-20mg/dL• + ~30mg/dL• ++ ~100 mg/dL• +++ ~300mg/dL• ++++ >2000mg/dL

– False +ve• Orthostatic proteinuria• Iodinated contrast• Alkaline urine

• Blood– Peroxidase reaction– (See BAUS consenus statement on haematuria)

Case 2

• You take a history and examine him and there’s nothing to find

• He’s a medical negligence lawyer whose best friends is your trusts chief exec. and refuses to go home until this is all sorted.

• The med reg says he won’t see the patient over the weekend unless you can convince him this is more likely to be medical than surgical

• X-ray won’t scan him at the weekend as he’s well• What tests can you do to help?

Urine microscopy• RBCs

• Infection, glomerular disease, malignacy

• WBCs• Infection, glomerulopnehritis, malignancy, TB, intersitial nephritis, inflammation

• Crystals• Seen with stones, cystinuria, gout

• Casts– Hyaline casts (clear and colourless)

• Seen with exercise, fever, concentrated urine (often in normal subjects)

– Red cell casts• Seen in GN, vasculitis, malignant hypertension

– White cell casts• Pyelonephritis, proliferative glomerulonephritis

– Epithelial casts• Acute tubular necrosis, acute glomerulonephritis

– Granular casts• GN, diabetic nephropathy, amyloidosis, intersitial nephritis

Urine electrolytes

Prerenal/GN ATN/Obstruction

Urinary Na <20 >40

Urine to plasma creatinine

>30 <20

Renal failure index <1 >1

FE Na <1 >1

Urine osmolality >500 <400

Urine electrolytes

CastsWBC RBC

Granular Hyaline

24 Hour urine collection

• Void , discard urine, note time

• Collect all urine 24 hours

• Exactly 24 hours later empty bladder and collect urine

• Provide serum sample for creatinine

• Measure volume, protein, creatinine, sodium

Protein

• Excrete 80-150mg/day• Minimum concentration for dipstick detection 20-

30 mg/dl• Glomerular disease

– suspected >1g/24 hours– certain > 3g/24 hours

• Tubular disease - <3g/24 hours • Overflow – abnormal immunoglobins

– Myeloma – bence jones protein

Urinary Albumin:Creatinine ratio• Proteinuria is a measure of renal disease• 24 urinary protein estimation is a pain

– 3 samples over 2 months

• Spot microalbuminuria test is subject to variability• Comparing with creatinine improves its accuracy

• Normal <2.5mg/mmol• <30 ‘acceptable’• 30-70 warrants a retest• >70mg/mmol NICE suggests referral to nephrology

Case 3

• 60 yr old woman

• Mild renal impairment (eGFR 59)

• Hypertension

• 4 cm exophytic, enhancing, solid, left renal mass

• Has a partial nephrectomy

• Seen for follow-up 3 months later

Case 3

• She wants to know how much kidney function has she got left?

• Biochemical tests

• Nuclear medicine tests

Case 3

• Biochemical tests– Assess overall function– Various methods for refining assessment, but

none perfect

• Radiological tests– Can assess overall and relative function– Can give additional information eg Scars,

drainage

Blood tests

• Urea– Varies with protein and catabolic states

– Freely filtered

– Reabsorbed at variable rate dependant on water reabsorption

– Not a reliable indicator of function

• Creatinine– Freely filtered and secreted into distal tubule

– Varies with muscle mass

0

20

40

60

80

100

120

140

0 100 200 300 400 500 600 700 800

Serum Creatinine mmol/L

Cre

atin

ine

Cle

ara

nce

ml/m

in

• Serum creatinine not sensitive indicator in early renal impairment• Need GFR to fall below 60-80ml/min before there is rise in Serum Cr • An abnormal creatinine indicates a loss of 50% of renal function

MCQ1. MDRD formula is not valid for children

2. The Cockcroft & Gault formula is an alternative to MDRD for calculating eGFR

3. MDRD formula uses 3 variables to calculate eGFR

4. Your path lab should use the same formula as the online MDRD calculator

5. eGFR is accurate an reproducible in acute renal failure

MCQ1. MDRD formula is not valid for children

2. The Cockcroft & Gault formula is an alternative to MDRD for calculating eGFR

3. MDRD formula uses 3 variables to calculate eGFR

4. Your path lab should use the same formula as the online MDRD calculator

5. eGFR is accurate an reproducible in acute renal failure

Formulae

• Used to improve on serum creatinine, but all suffer from its limitations

• Estimated creatinine clearance – Cockcroft-Gault

• Estimated GFR– MDRD (4 and 6 variable)– CKD-EPI– Mayo

Cockcroft and Gault formula

• Creatinine clearance =

(140-age) x body weight in Kg72 x serum creatinine in mg/dL

• Multiply by 0.85 for women• May be more accurate than timed urine collections• Assumptions:

– Lean body weight (hence in obesity, will overestimate)

– Volume distribution and Creatinine production is in steady state (hence will overestimate in low protein diet)

MDRD

• 4 variable (Creatinine, Age, Gender, Race)• 6 variable (Albumin, Urea)

• eGFR=32788 x [creatinine in μmol/L]-1.154 x Age-0.203

• x 1.212 if black

• x 0.742 if female

• Should be automatically reported by your lab every time serum creatinine is checked.

• Be aware of its limitations

Limitations of MDRD

• It is only an estimate, significant error is possible. Likely to be inaccurate in extremes of body type• malnourished, • amputees,• It is not valid in pregnant women

• Some racial minorities may not fit the MDRD equation well. Originally validated for US white and black patients.

• Not so good near normal: The MDRD equation tends to underestimate normal or near-normal function. Routine reporting of eGFR values >90 is not recommended.

Limitations of MDRD• Creatinine level must be stable: eGFR calculations assume

that the level of creatinine in the blood is stable over days or longer. They are not valid if it is changing.

• The MDRD equation is not valid for under-18s. Use the Counahan-Barrat method for children

• Different equations: from April 2006 in the UK, local laboratories should calculate eGFR on all samples sent for creatinine measurement. The equation they use will take into account local variations in accuracy of creatinine assays, so eGFR values obtained in this way should be a little more accurate than those generated by any of the online calculators

CKD-EPI

• eGFR = 141 x min([creat]/κ,1)α x max([creat]/κ,1)-1.209 x 0.993Age x 1.018 [if female] x 1.159 [if black]

• κ = 0.7 if female.κ = 0.9 if male.

• α = -0.329 if femaleα = -0.411 if male

• min = the minimum of Scr/κ or 1max =  the maximum of Scr/κ or 1

• Probably more accurate than MDRD

• Certainly better if GFR > 60mls/min

• New (2009) and MDRD remains the NICE approved formula

There’s an app for that!

EMQA. Inulin clearance E. Cockcroft and Gault

B. Cr51 EDTA F. Tc99m DMSA

C. Tc99m DTPA G. 24hr urinary creatinine clearance

D. MDRD 6 variable H. eGFR

Which of the above:

1. Could be used to assess GFR and renal drainage at the same time

2. Is the gold standard for assessment of glomerular filtration rate

3. Is not an assessment of overall renal function

EMQA. Inulin clearance E. Cockcroft and Gault

B. Cr51 EDTA F. Tc99m DMSA

C. Tc99m DTPA G. 24hr urinary creatinine clearance

D. MDRD 6 variable H. eGFR

Which of the above:

1. Could be used to assess GFR and renal drainage at the same time B

2. Is the gold standard for assessment of glomerular filtration rate A

3. Is not an assessment of overall renal function F

Creatinine Clearance• 24 urinary creatinine measurement allows

calculation of creatinine clearance• Clearance = UV/P

(U = urine concentration, V = flow rate, P = plasma concentration)

• Usually adjusted for body surface area

• Normal >120ml/min/1.73m2

• Creatinine clearance is 20% higher than GFR due to tubular excretion of creatinine

Glomerular filtration rate

• GFR determined by using substance– Neither metabolised nor synthesised– Secreted into plasma at constant rate – freely filtered at glomerulus – Neither secreted or absorbed further down nephron

• Inulin clearance is the gold standard for GFR measurement– Polysaccharide– Filtrated (not reabsorbed, secreted or metabolised by the kidney)– Continuous infusion– Measure Inulin in urine and blood until steady state reached– Expensive, time consuming, impractical

Isotopic GFR

• Cr51 EDTA (closest in clearance pattern to inulin)• Tc99m DTPA (short half life, but can do a renogram at

the same time)

• Blood sample for background count• Known dose of radiopharmaceutical given• Time for equilibration• Samples at 2,3 and 4 hours• Volume of distribution worked out• Rate of clearance calculated by slope intercept

Renography• A study of the uptake, transit and elimination by the

kidney of an intravenous dose of a radionucleotide• Gives information on drainage and relative function• Limited anatomical information• Use of diuretic improves discrimination between

obstructed and non-obstructed patterns

• Tc99m MAG-3• I131 Hippuran• T99m DTPA

• See nephrology 1 for renograms in detail

DMSA scan• Dimercaptosuccinic acid

• Bound in proximal tubules

• Excellent imaging of functioning areas of cortex

• IV injection with imaging 3 hours later

• Multiple views to allow better visualisation

• Can calculate relative function

• Look for areas of poor function ie scars

• May need to wait 6 months after last insult for areas to recover

Summary of nuclear medicine

Renography Rel. funct. Scarring Imaging GFR

MAG3 Yes Yes No Yes No

DMSA No Yes Yes Yes No

DTPA Yes Yes No Yes Yes

EDTA No No No No Yes

Hipp Yes Yes No Yes No

Chronic kidney disease

Kidney damage= persistent microalbuminuria, persistent proteinuria, persistent haematuria, structural abnormalities of the kidneys demonstrated on ultrasound scanning or other radiological tests, or biopsy-proven chronic glomerulonephritis)

Case 4

• 65 yr old man• Cystectomy + ileal conduit urinary diversion for

refractory CIS• eGFR 39 mls/min pre-op• Has looked at his consent form after the op and

wants to talk to you about the fact that someone has written ‘decline in renal function on it’ He wants to know how you’re going to monitor it?

Case 4• Renal surveillance post diversion

– Isotopic GFR– Renography– Regular BP check

• Slow decline in function over the 5 years following his surgery

• Disease free• GFR now 28mls/min/1.73m2

• What are you going to do?

Case 4

• Make sure it’s not post renal– Renogram

– Loopogram

• Not obstructed

• What next ?

MCQ

Which of the following should be referred for a nephrology opinion?

1. CKD stage 3B

2. Hypertension that remains poorly controlled after 2nd line therapy

3. ACR >30mg/mmol

4. Those with a decline in GFR of > 5 ml/min/1.73 m2 within 1 year

5. Those with a decline in GFR of > 10 ml/min/1.73 m2 within 5 years

MCQ

Which of the following should be referred for a nephrology opinion?

1. CKD stage 3B

2. Hypertension that remains poorly controlled after 2nd line therapy

3. ACR >30mg/mmol

4. Those with a decline in GFR of > 5 ml/min/1.73 m2 within 1 year

5. Those with a decline in GFR of > 10 ml/min/1.73 m2 within 5 years

Who should be referred for nephrology assessment

• Stage 4 and 5 CKD (with or without diabetes)

• Higher levels of proteinuria (ACR ≥ 70 mg/mmol) unless known to be due to diabetes and already appropriately treated

• Proteinuria (ACR ≥ 30 mg/mmol) together with haematuria

• Rapidly declining eGFR (> 5 ml/min/1.73 m2 in 1 year, or > 10 ml/min/1.73 m2 within 5 years)

• Hypertension that remains poorly controlled despite the use of at least four antihypertensive drugs at therapeutic doses

• People with, or suspected of having, rare or genetic causes of CKD

• Suspected renal artery stenosis.

Case 4

• Consider renal referral

• He wants to know what the possible problems from poor kidneys are

• Make sure it’s not post renal– Renogram

– Loopogram

• Not obstructed

• What next ?

Manifestations of CKD

Functions of the kidney• Regulation of water and electrolytes• Maintenance of acid/base balance• Excretion of waste products, water soluble toxic substances and drugs• Endocrine functions - erythropoietin and vitamin D

• Patients with CKD stage 3 or lower (GFR >30 mL/min) generally are asymptomatic and do not experience clinically evident disturbances in water or electrolyte balance or endocrine/metabolic derangements.

• Generally, they clinically manifest with CKD stages 4 and 5 (GFR

<30 mL/min).

System Clinical manifestations

Renal / Electrolytes Oedema, hyponatremia, hyperkalemia, metabolic acidosis,hyperuricemia, hyperphosphatemia, hypocalcemia (NB: symptomsof uremia correlate only inconsistently with the level of urea)

Gastrointestinal Anorexia, nausea, vomiting, malnutrition

Cardiovascular Accelerated atherosclerosis, systemic hypertension, pericarditis

Haematological Anaemia, immune dysfunction, platelet dysfunction

Musculoskeletal Renal osteodystrophy, muscle weakness, growth retardation inchildren, amyloid arthropathy caused by beta2-microglobulin deposition

Neurological Encephalopathy, seizures, peripheral neuropathy

Endocrine Hyperlipidemia, glucose intolerance caused by insulin resistance,amenorrhea and infertility in women, impotence

Skin Pruritus

• Water retention - loss of concentrating ability, ADH resistance thus polyuria initially

• Sodium balance remains virtually normal till late in CRF as kidneys can markedly increase the amount of Na excretion per nephron by reducing tubular reabsorption. Subsequently, Hypertension and fluid overload develops due to Na retention

• Potassium balance: plasma potassium level are also maintained until very late in CKD, mainly because of an increase in renal excretion of potassium per functioning nephron and an increase in potassium output in the stool.

Water and electrolyte disturbances

Acid base balance• Metabolic acidosis

Reduced reabsorption of HCO3 (proximal tubules)

Reduced NH4 synthesis NH3 + H+ NH4 (proximal tubules)Reduced ability to excrete the hydrogen ions (distal tubules)

• Chronic acidosis Phosphate is used as a buffer. Associated with worsening of hyperparathyroid-induced kidney bone disease and negative calcium balance, enhanced skeletal muscle breakdown and catabolism, growth retardation in children, and probably faster progression of GFR loss

Cardiovascular disease

• Patients with renal failure are considered to be in the highest risk category for heart disease, at least 20% per 10 years. Current cardiovascular guidelines now recommend screening for reduced GFR in people over 40 years old as part of their cardiovascular risk assessment.

• Left ventricular hypertrophy is a particularly common form of heart disease and carries a high mortality. LVH tends to develop relatively early in the course of the renal failure and is normally established when dialysis starts.

• Heart disease accounts for over 70% of the mortality of ESRF patients (commonest cause of death)

Cardiovascular disease

Anaemia of chronic renal disease

• Usually apparent when GFR <30 ml/min (or <45 in diabetics as red cell survival is reduced)

• Anaemia is multifactorial in nature. Mostly due to erythropoietin deficiency (which is produced by interstitial cells of renal cortex), reduced RBC survival and uraemic suppression of RBC synthesis

• NICE recommends checking for anaemia in those with eGFR <45 and treating those with Hb <11g/dL

Renal osteodystrophy

• Causes include:– Reduced Vitamin D availability– Increased serum phosphate– Reduced serum calcium– Reduced response to PTH.– Uraemia induced

(nodular) hyperplasia

Signs and symptoms of bone disease

• Biomechanical bone pain• Soft tissue and tendon calcification• Tendon rupture/ avulsion• Calciphylaxis (ectopic calcification)• Pseudogout and pseudoclubbing• Vertebral fractures (with height loss)• Vascular calcification (enhancing cardiac

risk)

Management of CKD

• Prevent progression• Modify risk factors (eg hypertension)• Drugs (eg ACE inhibitors)• Minimise adverse effects

– Phosphate binders– Erythropoetin– Primary prevention of Cardiac disease

• Renal replacement therapy

• Is covered in Nephrology 4