Drug and treatment history
• The importance of the drug history cannot be overstated — it will often tell a story of its own. 2 Ask candidly about compliance.
• Antihypertensive therapy — past and present. Any important tablet intolerances or side effects.
• Analgesics — ask specifi cally about common NSAIDs (by their over-the-counter names, if necessary). Then ask again.
• Any ‘one-off ’ courses of therapy that may not be mentioned as part of regular treatment, e.g. recent antibiotics (interstitial nephritis).
• Oral contraceptive ( i BP).
• Steroids, immunosuppressive agents — type and duration.
• Non-prescription, recreational (cocaine, IVDU), and herbal ( b p. 901) medicines.
• Current or historical exposure to important nephrotoxic drugs (see Box 1.2).
Family history
• Essential hypertension: more common if one or both parents affected.
• Diabetes mellitus (types 1 and 2): more common if close relative affected.
See Table 1.2 for inherited kidney diseases.
Table 1.2 Inherited kidney diseases
Cystic kidney diseases Adult and juvenile polycystic kidney disease Primary glomerular Alport ’ s syndrome and
variants IgA nephropathy (occasionally) FSGS (rarely) Others (rarely) Metabolic diseases with
renal involvement
Non-glomerular Cystinosis, primary hyperoxaluria, inherited urate nephropathy Glomerular Fabry ’ s disease Non-metabolic disease Non-glomerular Nephronophthisis
Glomerular Congenital nephrotic syndrome, nail-patella syndrome Benign and malignant
tumours
Tuberous sclerosis (renal angiomyolipoma) von Hippel – Lindau (renal cell carcinoma) Tubular disorders Cystinuria, various inherited tubular defects Disorders with a
‘genetic infl uence ’
Vesicoureteric refl ux, haemolytic uraemic syndrome, diabetic nephropathy
CLINICAL HISTORY: DRUG, TREATMENT, AND FAMILY 7
Box 1.2 Important nephrotoxins ( b see Chapter 11) ‘Pre-renal’ renal insuffi ciency
Diuretics
Any antihypertensive agent (esp.
ACE-Is and ARBs that aggravate other pre-renal states)
Haemodynamically mediated NSAIDs and COX-2 inhibitors ACE-Is and ARBS
Ciclosporin Tacrolimus Vasoconstrictors Glomerulopathy NSAIDs Penicillamine Gold Hydralazine Interferon Anti-thyroid drugs
Carbon tetrachloride and other organic solvents (e.g. glue sniffi ng)
Silica dust (? granulomatosis with polyangiitis or Wegener ’ s) Thrombotic microangiopathy Chemotherapeutic agents:
Mitomycin Cisplatin Bleomycin
Immunosuppressive agents:
Ciclosporin Tacrolimus Clopidogrel Quinine Oral contraceptive Tubular crystal formation Aciclovir and other antivirals Ethylene glycol (antifreeze) Sulfonamide antibiotics Methotrexate Indinavir (antiretroviral)
Acute tubular necrosis Aminoglycosides Antifungals:
Amphotericin Ifosfamide Foscarnet Antivirals:
Adefovir Cidofovir Tenofovir Cisplatin
Heavy metals (arsenic, mercury, and cadmium)
Herbal remedies Interleukin-2
Intravenous immunoglobulin (previously with sucrose-containing formulations)
Paracetamol Paraquat Pentamidine X-ray contrast agents Interstitial nephritis (these and many, many others) Antibiotics:
Penicillins Cephalosporins Quinolones Rifampicin Sulfonamides Allopurinol
Cimetidine (rarely ranitidine) NSAIDs and COX-2 inhibitors Diuretics
5-aminosalicylates (sulfasalazine and mesalazine)
Proton pump inhibitors, e.g.
omeprazole
Chronic interstitial disease Lead
Lithium Analgesics Chinese herbs
Clinical history: additional factors
Sexual, gynaecological, and obstetric history
• Decreased libido and impotence are extremely common in both ♂ and ♀ with CKD.
• Irregular menses and subfertility are frequently encountered in ♀ . Amenorrhoea is common in ESRD.
• Previous pregnancies and any complications (UTI, proteinuria, i BP, pre-eclampsia). Miscarriages, terminations? Were infants healthy and born at term?
• In CKD, maternal and fetal outcomes are importantly related to GFR, degree of proteinuria, and BP ( b p. 856).
• Cytotoxic drugs used in the treatment of glomerular disease can l premature menopause in ♀ or infertility in ♂ . This may infl uence treatment in a ♀ of childbearing age. Pre-treatment sperm banking can be offered in ♂ .
• Risk factors for sexually transmitted disease when appropriate (HIV, hepatitis B and C can all cause glomerular disease).
Dietary history
Changes in appetite and weight. Dietary habits (alcohol, vegan, ethnic diet, protein or creatine supplements). Dietary advice is an important part of the management of many renal disorders ( i BP, AKI, CKD, the nephrotic syndrome, stone disease, dialysis).
Ethnicity and renal disease
• IgA nephropathy: Caucasians and certain Asian populations (China, Japan, and Singapore).
• Diabetic nephropathy: black, Mexican American, Pima Indian (a native American tribe in Southern Arizona, beloved of epidemiologists and geneticists). An increasing problem in the immigrant Asian population in the UK.
• SLE: Asian and black patients (and more aggressive disease).
• Hypertension and hypertensive renal failure: black patients.
• In the UK, the incidence of end-stage renal disease (ESRD) is 7 3 x higher in South Asian and black patients than in Caucasians.
CLINICAL HISTORY: ADDITIONAL FACTORS 9
Approach to the patient on renal replacement therapy When managing a dialysis or transplant patient, there are a few direct questions that will help you to get to grips with (and reassure the patient that you are familiar with) their treatment. It will also facilitate discussion with the patient ’ s renal unit.
The patient on haemodialysis
• Where does the haemodialysis treatment take place?
• How many times per week do they dialyse and how many hours is each treatment?
• What is the patient ’ s current access for dialysis (e.g. an arteriovenous fi stula, a PTFE graft, or a tunnelled dialysis catheter)?
• What is their usual fl uid gain between treatments?
• Do they know their blood pressure at the end of a dialysis session?
The patient on peritoneal dialysis
• Are their exchanges performed manually during the day (CAPD) or automated overnight (APD)?
• How many exchanges do they perform?
• How many litres is each exchange?
• Do they have fl uid in at the moment?
• Do they need assistance to perform an exchange?
• Do they measure their own blood pressure at home? What have the readings been recently?
• Is the exit site of their dialysis catheter clean and dry?
• Are the dialysis bags clear or cloudy on drainage?
• When was their last episode of peritonitis?
All dialysis patients
• How long have they been on dialysis?
• How much urine do they pass, if any?
• What is their dry (aka fl esh, target, post-dialysis) weight?
• What is their daily fl uid allowance?
• Do they adhere to a renal diet?
• Do they know the cause of their end-stage renal disease?
• Do they receive erythropoietin injections? Who performs these?
• Have they always been on the same modality of dialysis?
• Are they ‘listed ’ for deceased donor transplantation?
• Have they previously received a transplant?
• How are they coping with dialysis?
The transplant patient
• When and where was the transplant performed?
• What immunosuppression is the patient taking?
• Who is responsible for their follow-up?
• Do they know their baseline SCr?
• Was the transplant from a living or deceased donor?
• Do they use sunblock and attend a skin clinic?
• Do they know if they had any rejection episodes?
• Do they know the cause of their end-stage renal disease?
• What mode of dialysis were they on prior to transplantation?
Physical examination
See Fig. 1.1 for examination by area and Fig. 1.2 for examination by system.
General inspection Short stature (CKD in childhood) Weight Pallor
Brown-yellow skin hue
‘Sallow’ complexion Hearing aid / hearing impairment (Alport’s syndrome)
Forearms Myopathy Bony tenderness (hyperparathyroidism) Dialysis access (past or present) Nails
Brittle Leuconychia Splinters (SBE) Transverse ridges (Be Face
Periorbital oedema
Mouth Fetor Oral hygiene (SBE) Gum hypertrophy (ciclosporin) Oral candida (immunosuppression)
Skin Dry Scratch marks Bruising
(uraemic bleeding tendency) Vasculitic rash Subcutaneous nodules (soft tissue calcification) Uraemic frost (severe uraemia) Transplant patient:
cutaneous malignancies Hands
Metabolic flap (severe uraemia) Shortening of distal phalanges + pseudoclubbing (severe hyperparathyroidism) Raynaud’s
Sclerodactyly Calcinosis
Systemic sclerosis SVC obstruction
Evidence of past or present haemodialysis access (e.g. tunnelled lines, scars from previous dialysis lines, AV fistula)
’s lines) au
Fig. 1.1 Examination by area.
PHYSICAL EXAMINATION 11
Neurological Conscious level Mental state Myoclonic jerks Seizures Tetany (hypocalcaemia) Peripheral neuropathy
Cardiorespiratory Respiratory pattern (? Acidosis) Blood pressure JVP Oedema Carotid bruits Apex beat Heart sounds Pericardial rub Lung fluids Pulmonary oedema Effusion Musculoskeletal Bony deformity Joint inflammation Osteoarthritis (? NSAIDs)
Legs Peripheral pulses Oedema Femoral bruits Restless legs
Ophthalmic Dry, red, or painful eyes (iritis, episcleritis) Corneal calcification
Retina Hypertension Diabetes mellitus Vasculitis Cholesterol emboli
Abdomen Scars
? Tenckhoff catheter Ascites Palpation:
Loin tenderness Palpable kidney(s) Palpable bladder Transplant kidney (right or left iliac fossa) Abdominal bruit Rectal (prostate) Pelvic exam
Obstruction
Fig. 1.2 Examination by system.
Palpating the kidneys
• The kidneys are generally only palpable in very thin patients.
• The right kidney is more accessible than the left.
• Place the left hand posteriorly in the loin and the right hand on the abdomen lateral to the umbilicus.
• On deep inspiration, the lower pole may be palpable by pushing the right hand gently inwards and upwards.
• The normal kidney surface usually feels fi rm and smooth.
• ‘Balloting’ the kidney refers to palpation whilst pushing up fi rmly from behind. Using this technique, it may be possible to gently
‘bounce ’ an enlarged kidney back and forth between the hands.
Physical examination: the circulation
2 The ability to assess the volume status of a patient is critical to the practice of renal medicine. In the vast majority of cases, it can be achieved at the bedside without invasive monitoring.
Hypovolaemia
Salt and water (or blood) loss leads to d effective circulating volume and eventual shock. Signs include:
• d BP (and d pulse pressure).
• Postural d BP (fall in SBP >10mmHg); if it is not possible to stand the patient up, then BP measurements with the patient supine, and then with the head of the bed raised, can be helpful.
• Sinus tachycardia and postural i HR ( i in HR >10 beats/min).
• d JVP. Neck veins fl at, even if supine.
• Cool peripheries and peripheral vasoconstriction ( septic patients may be vasodilated and warm).
• Poor urine output (UO).
• Decreasing weight.
• Positive response to a fl uid challenge.
• Positive passive leg raising test.
(Much) less reliable signs include:
• d capillary refi ll, poor skin turgor (forehead and anterior triangle of the neck), dry mouth and mucous membranes, sunken eyes.
Hypervolaemia
Increased ECF volume may be found with i intravascular volume, i interstitial space volume — or both. It is possible to be simultaneously salt- and water-overloaded and intravascularly depleted (e.g. CCF or a nephrotic patient receiving diuretics). See Box 1.3.
Increased circulating volume Increased interstitial fl uid i BP
Elevation of the JVP
Peripheral or generalized oedema Pulmonary oedema (tachypnoea, tachycardia, a third heart sound 9 basal crackles) Pleural effusion(s)
Ascites Increasing weight Box 1.3 Volume expansion and overload
Both fl uid depletion and fl uid overload are harmful. Extremes can be rela-tively easy to recognize, but it is diffi cult to consistently diagnose euvol-aemia, i.e. the point at which fl uid administration is no longer necessary.
Clinical assessment relies on frequent evaluation of the patient ‘ s response to fl uid challenges. In case of progressive AKI, particularly in the context of multi-organ dysfunction, a referral to critical care for haemodynamic monitoring should be considered.
PHYSICAL EXAMINATION: THE CIRCULATION 13
Invasive monitoring: a primer for the non-intensivist In critically ill patients, the main priority is to reverse/prevent organ (including renal) dysfunction through restoration of tissue perfusion and O 2 delivery. This involves the optimization of fl uid status and cardiac output (CO) ( reminder : O 2 delivery = heart rate × stroke volume × O 2 saturation × Hb × 1.36).
The aim of haemodynamic resuscitation is to avoid both fl uid deple-tion and overload (i.e. patient ‘ not too dry and not too wet ’ ) and to opti-mize CO whilst avoiding excess catecholamine ( ‘ enough but not more ’ ).
To achieve these goals, clinical assessment may be unreliable, and non-invasive haemodynamic monitoring is often desirable — especially in patients with sepsis, hypoproteinaemia 9 cardiac failure.
Measurement of cardiac output
Historically, haemodynamic monitoring centred on measurement of CVP and pulmonary artery occlusion pressure (PaOP or ‘wedge pressure ’ ).
However, many studies demonstrated that these do not accurately cor-relate with fl uid status and cardiac performance, particularly in patients with cardiac failure. Instead, more dynamic parameters have increasingly supplanted them, e.g. variation in stroke volume, arterial pressure, or pulse pressure after a fl uid challenge. Evidence remains light; other than for pas-sive leg raising, there is little evidence underpinning the use of dynamic vari-ables for prediction of volume responsiveness in non-ventilated patients.
Haemodynamic monitoring used in the critical care environment • Pulmonary artery catheter (PAC): insertion of a balloon-tipped
catheter into the pulmonary artery allows measurement of CVP, right atrial pressure, right ventricular pressure, pulmonary artery pressure, PaOP, CO, and mixed venous O 2 saturation. X Utility remains controversial. Associated with signifi cant risks ( damage to chordae, arrhythmias, rupture of pulmonary artery). Use decreasing.
• Echocardiography: an excellent tool for assessment of haemodynamics but operator-dependent and not a continuous technique.
• Oesophageal Doppler: measures blood fl ow velocity in descending aorta (correlates with CO). Non-invasive but dependent on operator ’ s skill and placement/positioning. Not tolerated in non-ventilated patients.
• Lithium dilution technique: measures CO via rate of change in lithium chloride concentration between venous and arterial system. Requires arterial line and CV line. Suitable for non-ventilated patients.
• Pulse contour analysis: continuous measurement of CO and stroke volume variation, using the arterial waveform. Underlying principle: the contour of the waveform is proportional to stroke volume and the mechanical properties of the artery. Stroke volume is calculated by the change from end-diastole to systole over time.
Requires an arterial line. Can be used in non-ventilated patients.
• Thoracic electrical bioimpedance: CO measurement via electrodes on the patient ’ s chest and neck. Non-invasive. Less accurate with pulmonary oedema, pleural effusions, and chest wall oedema.
Specialist expertise required, so not in routine use.
Urine: appearance
2 Examination of the urine should be considered a routine extension of the physical examination in all patients.
Appearance
• Depending on concentration, normal urine is clear or given a light yellow hue by urochrome and uroerythrin pigments.
• Cloudy urine may result from high concentrations of leucocytes, epithelial cells, or bacteria. Precipitation of phosphates can also produce turbidity in urine refrigerated for storage.
• Specifi c circumstances result in characteristic changes in the appearance of the urine that may assist diagnosis at an early stage (see Box 1.4).
• Blood causes a pink to black discoloration, depending on the number of RBCs and length of time present.
• Jaundice (conjugated hyperbilirubinaemia) may cause dark yellow or brown urine.
• Haemoglobinuria from intravascular haemolysis ( b p. 155) and myoglobinuria from muscle breakdown ( b p. 152) are both causes of dark urine that tests +ve for blood on dipstick examination. However:
• If the sample is centrifuged, the supernatant will remain coloured and continue to test +ve.
• No red cells are seen on microscopy.
• Specifi c assays for haemoglobin and myoglobin are available.
• Normal urine tends to darken on standing (urobilinogen oxidizes to coloured urobilin) (see Box 1.4).
• Chyluria is a rare cause of turbid urine. It has a milky appearance (particularly after fatty meals) and settles into layers on standing.
Results from a fi stulous connection between the lymphatic and urinary systems (usually malignancy, though lymphatic obstruction by Filaria bancrofti is more important worldwide).
• Beetroot can produce red urine due to enhanced intestinal absorption of the pigment betalaine in genetically susceptible individuals. Rarely causes diagnostic confusion.
Odour
Offensive urine usually denotes infection (bacterial ammonium produc-tion). Sweet urine suggests ketones. Certain rare metabolic diseases confer characteristic smells — one can only hope to encounter maple-syrup urine disease before isovaleric acidaemia ( ‘ sweaty feet urine ’ ) (see Box 1.5).
Pneumaturia
• The presence of air bubbles in urine suggests a vesicocolic fi stula.
• Causes:
• Diverticular disease.
• Colonic cancer.
• Infl ammatory bowel disease.
URINE: APPEARANCE 15
Box 1.4 Coloured urine Causes of a coloured urine
• Beetroot ingestion (red).
• Blood (pink/red to brown/black).
• Chloroquine (brown).
• Chyluria (milky white).
• Haemoglobin (pink/red to brown/
black).
• Hyperbilirubinaemia (yellow/
brown).
• Methylene blue (er . . . blue).
• Myoglobin (pink/red to brown/
black).
• Nitrofurantoin (brown).
• Onchronosis (black).
• Phenytoin (red).
• Propofol (green).
• Rifampicin (orange).
• Senna (orange).
Urine that darkens on standing
• Alkaptonuria (homogentisic acid).
• Imipenem-cilastin treatment.
• Melanoma (melanogen).
• Methyl dopa.
• Metronidazole.
• Porphyria (porphobilinogen).
Box 1.5 Proust ’ s chamber pot
While Proust wrote lyrically about the unusual bouquet of his urine fol-lowing asparagus ingestion, there are many who remain oblivious to a phenomenon instantly recognizable to others.
Two potential explanations for this olfactory diversity have been offered: (i) the production of the required fragrant metabolites is subject to variation through genetic polymorphism, i.e. some individuals excrete the perfumed compound(s), while others do not; (ii) everyone produces the metabolite(s), but only some have the necessary olfactory talent required to detect it/them.
The genetics are not straightforward, although an association between the ability to notice one ’ s own ‘asparagus urine ’ and a cluster of olfac-tory receptor genes on chromosome 1 has been described. Even the identity of the relevant substances remains uncertain, with a plethora of sulphur-containing compounds, such as methanethiol and dimethyl sulphide, proposed as the culprits.
Overall, it seems likely that there is genetic variation and that the two theories are not mutually exclusive, i.e. those who produce asparagus-perfumed urine may not always be able to detect it, while those who can might not necessarily produce it themselves.
Urinalysis: chemical analysis
Osmolality and specifi c gravity Specifi c gravity
Refers to the weight of a solution, with respect to an equal weight of distilled water (normal range 1.003 – 1.035 in urine). Can be estimated with a dipstick, but, for accurate measurement, an osmometer (urinometer) is required.
Osmolality
Refers to the solute concentration of a solution. It cannot be measured with a dipstick. In the absence of signifi cant glycosuria, the concentrations of Na + , Cl – , and urea are the most important determinants in urine. The ability to vary urine osmolality (range 50 – 1350mOsmol/kg) plays a central role in the regulation of plasma osmolality (maintained across a narrow range: 280 – 305mOsmol/kg).
Generally speaking, specifi c gravity and osmolality correlate. An excep-tion is when relatively large particles, such as glucose, proteins, and radio contrast media, are present in the urine. These produce an i in specifi c gravity, with little change in osmolality.
Uses
Investigation of polyuria and hypo-/hypernatraemic states ( b p. 782).
Recurrent stone formers can monitor their own urine specifi c gravity to maintain a dilute urine that discourages stone development.
Isosthenuria
CKD leads to a progressive d in the range of urinary osmolality that the kidneys can generate. In advanced renal insuffi ciency, the osmolality becomes relatively fi xed at 7 300mOsmol/kg ( 7 1.010 specifi c gravity) — close to that of glomerular fi ltrate. In this situation, the urine cannot be adequately concentrated or diluted in response to Na + and water deple-tion and overload, respectively. This is termed isosthenuria.
Urinary pH
Urinary pH ranges from 4.5 to 8.0 (usually 5.0 – 6.0), depending on sys-temic acid – base status. Most people (except vegans) pass acidic urine the majority of the time. Isolated urinary pH measurements provide very little useful information. Their main clinical use is the investigation of systemic metabolic acidosis. In this situation, a fall in urinary pH (to around 5) is expected, as acid is excreted. Failure of this response may indicate renal tubular acidosis ( b p. 824). Most urine dipsticks have an indicator strip for estimation of pH, but, if a tubular disorder is suspected, a pH meter should be used.
In certain situations, the therapeutic manipulation of urinary pH might be useful (see Box 1.6).
URINALYSIS: CHEMICAL ANALYSIS 17
Box 1.6 Therapeutic urinary alkalinization ( X see relevant chapters.)
• Urinary stone disease (cysteine and urate stones) ( b p. 716).
• Poisoning ( b p. 909):
• Salicylates.
• Barbiturates.
• Methotrexate.
• Rhabdomyolysis ( b p. 152).
• AKI s to cast nephropathy in myeloma ( b p. 622).
Urinalysis: further tests
Further dipstick tests Leucocyte esterase and nitrites
Increasingly used as indicators of infection. Detection of neutrophil ester-ase activity identifi es white cells (pyuria), while the nitrite test exploits the ability of some urinary pathogens (though not all — notably certain Gram +ve organisms, including Strep. faecalis , Staph. albus, Neisseria gonorrhoeae , as well as many Pseudomonas spp. and mycobacteria) to reduce nitrate l nitrite. Positivity requires an adequate dietary nitrate intake as well as suf-fi cient bladder dwell time (preferably >4h).
When combined, these methods possess good specifi city (i.e. take seri-ously if +ve) though only modest sensitivity (i.e. treat a – ve result with caution if infection is likely clinically). 2 While they can serve as a useful screening test in at-risk populations they are not a substitute for micros-copy and culture.
Bilirubin and urobilinogen
• Conjugated ( 6 water-soluble) bilirubin l biliary excretion l small bowel l converted to urobilinogen l distal reabsorption l partially excreted in the urine.
• This means: (i) unconjugated (water-insoluble) bilirubin does not pass into the urine ( 6 dipstick +ve bilirubin indicates hepatic or cholestatic disease); (ii) the absence of dipstick urobilinogen in a jaundiced patient suggests biliary obstruction.
Glucose
Glycosuria results when tubular reabsorptive capacity for glucose is exceeded (plasma level >10mmol/L). A valuable screening tool, but less useful for diagnosis and monitoring of DM.
‘ Renal ’ glycosuria occurs when proximal tubular injury leads to a failure to reabsorb fi ltered glucose ( b p. 76).
Causes of a +ve dipstick for ketones
• Dipsticks semi-quantitatively detect acetoacetate (but not B -hydroxybutyrate).
• A +ve test can be seen in:
• Diabetic ketoacidosis (and occasionally severe intercurrent illness in T2DM).
• Prolonged fasting and starvation diets (e.g. Atkins ’ diet).
• Alcoholic ketoacidosis.
• Severe volume depletion.
• Isopropyl alcohol poisoning (hand-rubs, solvents, and de-icers).
URINALYSIS: FURTHER TESTS 19
Urinary test strips
A variety of test strips for urinalysis are available. Some have a spe-cifi c purpose, e.g. Clinistix ® (glucose), Hemastix ® (blood), and Albustix ® (albumin). Others cast a wider net, with various combinations of the following:
• Specifi c gravity.
• pH.
• Leucocytes.
• Nitrites.
• Glucose.
• Urobilinogen.
• Bilirubin.
• Ketones.
• Albumin or protein. * • Blood.
* Dipsticks able to detect microalbuminuria are also available.
Urinalysis: protein
Introduction
• Urinary protein excretion should not exceed 150mg/day, of which less than 20mg is albumin.
• The remainder consists mainly of non-serum-derived tubular mucoprotein, such as Tamm – Horsfall/uromodulin.
• i excretion of albumin is a sensitive marker of renal, particularly glomerular, disease ( b p. 58).
• Protein excretion can be measured in untimed ( ‘ spot ’ ) or timed (usually 24h) samples.
Proteinuria (total protein) and albuminuria (albumin) are not strictly interchangeable terms. When screening for early renal disease, specifi c tests for albumin are preferable.
Dipsticks
Convenient, highly specifi c, but less sensitive. Contain pH-sensitive indi-cators that change colour when bound to negatively charged proteins.
Predominantly detect albumin (some are albumin-specifi c, e.g. Albustix ® ) and may not identify large amounts of other proteins, e.g. Bence – Jones.
Dipsticks have completely superseded sulphosalicylic acid turbidity testing.
A +ve result occurs with protein excretion ≥ 300mg/L. Lower amounts of proteinuria, particularly in the context of diabetes, are termed micro-albuminuria ( b p. 60) (defi ned as 30 – 300mg/day) and usually measured by ELISA or radioimmunoassay (although sensitive dipsticks are available).
Dipsticks are semi-quantitative. As a rough guide:
Trace 70.15–0.3g/L
+ 70.3g/L
++ 71g/L
+++ 72.5–5g/L
++++ >10g/L
Changes in urinary concentration affect the result. If volumes are high and the urine dilute, large amounts of protein can go undetected (specifi c gravity may be a clue). Concentrated morning samples are 6 preferable.
2 If +ve dipstick test of ≥ 1+, repeat after 1 – 2wk. If persistent, verify with a protein/creatinine ratio (uPCR) or albumin/creatinine ratio (uACR).
Timed collections
Historically, 24h urine collections were preferred to spot urine samples.
However, they suffered from signifi cant drawbacks, including inaccurate collection (see Box 1.7) and the time required for lab processing.
URINALYSIS: PROTEIN 21
Box 1.7 uACR and uPCR (see also b p. 197)
• Untimed ( ‘ spot ’ ) urine samples are now used virtually universally for the detection and monitoring of proteinuria.
• Urinary excretion of creatinine generally remains constant ( 7 10mmol/day).
• uACR and uPCR correct for variations in urinary concentration (caused by changes in hydration) and correlate well with measurements obtained from timed collections.
• A fi rst morning urine specimen is preferable.
• 2 The relationship between uACR and uPCR is non-linear (see Table 1.3).
• It can be helpful to multiply uPCR x 10 to provide an estimate of 24h excretion, e.g. uPCR of 125mg/mmol approximates to 1.25g/24h.
• In the USA and in labs where urinary Cr is measured in mg/dL, rather than mmol/L, uACR is expressed as mg/g.
• Normal: <30mg/g.
• Microalbuminuria: 30 – 300mg/g.
• Overt proteinuria: >300mg/g.
• uACR and uPCR will underestimate proteinuria when Cr excretion is high (black people, muscular build) and overestimate when Cr excretion is low (elderly, cachectic). However, they are useful for serial monitoring in individual patients.
• uACR is more sensitive than uPCR if screening for early disease in high-risk groups (especially diabetes), but total uPCR is an adequate alternative in most circumstances.
• Dipsticks that aim to estimate uPCR await further validation.
Table 1.3 Relationship between uACR and uPCR
uACR (mg/mmol) uPCR (mg/mmol) g/24h Interpretation
3–30 <0.3 Microalbuminuria
30 750 70.5 Overt proteinuria
70 7100 71
300 7350 73.5 Nephrotic range
Timed 24h collection: what to tell the patient • Non-acidifi ed, clearly labelled container.
• Pick a convenient day with minimum commitments.
• Discard fi rst urine void on that day.
• Start collection — all subsequent urine into the container (including overnight).
• First void the following day into the collection.
• Since Cr excretion, or creatinine clearance (CrCl) ( b p. 33), should be similar in two successive samples from the same patient, their measurement in ‘back to back ’ 24h collections may enhance reliability (i.e. disregard the result if CrCl differs greatly between the two).