cava systemic vascular resistance; sustained virologic response temperature half-life tubu lar atrophy SFLC SGA SHPT SIADH SIRS SLE SLED SNGFR SNP SNS SOB SPEP SPK spp. SPS SSc SSRI STD STEMI SV C SVR T t 1/2 TA SYMBOLS AND ABBREVIATIONS xxvi TAC TALH TB TBW TC TCC TCR T1DM T2DM tds TFT THMP TIA TIBC TIMP TIN TINU TIPS TLS TMA TMD T MP TNF TOD TOE TOR TMPT TPN TRUS TSAT TSH TTE TTP TUIP TUMT TUNA TURBT TURP U UAG tacrolimus thick ascending loop of Henle tuberculosis total body water total cholesterol tr ansitional cell carcinoma T cell receptor type 1 diabetes type 2 diabetes three times daily thyroid function test Tamm \200\223Horsfall mucoprotein transient ischaemic attack total i ron-binding capacity tissue inhibitor of metalloproteinases tubulointerstitial nephritis tu bulointerstitial nephritis and uveitis transjugular intrahepatic portosystemic shunt tumor lysis syndrome thrombotic microangiopathy thin membrane disease transmembrane pressure tumo r necrosis factor target organ damage transoesophageal echocardiography target of rapamycin thiopurine methytransferase total parenteral nutrition transrectal ultrasound transferrin saturation thyroid-stimulating hormone transthoracic echocardiography thrombotic thrombocyt openic purpura transurethral incision of the prostate transurethral microwave therapy trans urethral needle ablation transurethral resection of bladder tumor transurethral resection o f the prostate unit urine anion gap SYMBOLS AND ABBREVIATIONS xxvii U&E UF UFH UK UKM UO UPEP Ur URR USA USRDS USS UTI UV VC VDR VDRA VE VEGF VL VPI vs VTE VUR vWF VZV WCC WHO WIT wk WWII yr urea and electrolytes ultra \201 ltration unfractionated heparin United Kingdom urea kinet ic modeling urine output urine protein electrophoresis urea urea reduction ratio United Sta tes of America United States Renal Data System ultrasound scan urinary tract infection ultr aviolet vascular calci \201 cation vitamin D receptor vitamin D receptor agonist vaginal e xamination vascular endothelial growth factor viral load vasopeptidase inhibitor versus ven ous thromboembolism vesicoureteric re \202 ux von Willebrand factor varicella zoster virus white cell count World Health Organization warm ischaemia time week World War II year 1 Chapter 1 Clinical assessment of the renal patient Clinical history: introduction 2 Clinical history: symptoms and social history 4 Clinical h istory: drug, treatment, and family 6 Clinical history: additional factors 8 Physical exami nation 10 Physical examination: the circulation 12 Urine: appearance 14 Urinalysis: chemica l analysis 16 Urinalysis: further tests 18 Urinalysis: protein 20 Urinalysis: red blood cel ls 22 Urinalysis: cells, organisms, and casts 24 Urinalysis: crystals 28 Determining renal function 30 Creatinine 32 eGFR 34 GFR measurement: other methods 36 Renal function in the e lderly 38 Immunological and serological investigation 40 Diagnostic imaging: X-ray 44 Diagn ostic imaging: ultrasound 46 Diagnostic imaging: CT and MRI 50 Diagnostic imaging: IVU 52 D iagnostic imaging: nuclear medicine 54 Diagnostic imaging: angiography and uroradiology 56 Clinical syndromes: proteinuria \200\224 introduction 58 Clinical syndromes: proteinuria 6 0 Clinical syndromes: haematuria \200\224 introduction and classi \201 cation 62 Clinical syndromes: haematuria assessment 64 Clinical syndromes: microscopic haematuria 66 Clinical syndromes: microscopic haematuria screening 68 Clinical syndromes: CKD, AKI, and the nephr itic syndrome 70 Clinical syndromes: pulmonary renal syndromes 72 Clinical syndromes: urine volume and urinary tract pain 74 Clinical syndromes: tubular syndromes 76 Clinical syndrom es: bladder out \202 ow obstruction 78 Renal biopsy: introduction 80 Renal biopsy: indicat ions 82 Renal biopsy: complications 84 CHAPTER 1 Clinical assessment 2 Clinical history: introduction In nephrology, as in all branches of medicine, a competent c linical assess- ment is crucial. This should incorporate symptoms and signs: \200 Arising locally from the kidneys and urinary tract. \200 Resulting from impaired salt and water handling. \200 Caused by failing renal excretory and metabolic function. \200 Relating to a systemic disease, causing or contributing to renal dysfunction. Several additional factors need to be considered: \200 Asymptomatic patients often requir e assessment, following the discovery of an abnormal BP, urinalysis, or eGFR. Symptoms, signs, and investigation \201 ndings are organized into clinically useful syndromes (see Box 1.1). Biochemistry, radiology, and/or histopathology are almost always required for accurate diagnosis (although a thorough clinical assessment will lessen over-r eliance on expensive and potentially invasive tests). Diagnosis is often suggested by treatment, e.g. cessation of a nephrotoxic drug or restoration of adequate circulatory volume. See Table 1.1 for renal disease associations. Box 1.1 Renal clinical syndromes \200 Asymptomatic urinary abnormalities: Proteinuria ( b p. 58). \200 Microscopic haematuria ( b p. 66). Macroscopic haematuria ( b p. 62). \200 Nephritic syndrome ( b p. 71): Rapidly progressive glomerulonephritis (RPGN). Pulmonary renal syndromes ( b p. 72). \200 Nephrotic syndrome ( b p. 554. PCR in mg/mmol. ) \200 Renal tubular syndromes ( b p. 76). \200 Hypertension ( b Chapter 6). \200 Acu te kidney injury (AKI) ( b Chapter 2). \200 Chronic kidney disease (CKD) ( b Chapter 3). Past medical history \200 Urinary tract problems as a child (e.g. infections, ncturnal en uresis). \200 Previously documented renal or urinary tract disease of any kind. Ask speci \201 cally about infections, stone disease, and, in \231\202 , prostatic disease. Hypertension. When diagnosed? Who is responsible for follow-up? Current and historical trea tment? Level of control? Self-monitoring with home BP monitor? Cardiovascular risk factors or disease (e.g. IHD, CVA, PVD, dyslipidaemia). \200 Other re levant systemic disease (e.g. diabetes mellitus, connective tissue disorder, gout, in \202 ammatory bowel disease, sarcoidosis). \200 Insurance or employment medicals can provide invaluable historical benchmarks. Can they recall a past BP check or providing a urine spec imen? Have they had blood tests in the past? CLINICAL HISTORY: INTRODUCTION 3 Table 1.1 Important renal disease associations Medical condition Renal association General Hypertension Hypertensive nephrosclerosis, s i BP is associated with many renal disorders Diabetic nephr opathy CKD, renovascular disease, atheroembolism Diabetes mellitus Cardiovascular disease Liver disease Cirrhosis Hepatitis B and C In \202 ammatory SLE and other connective tissue disorders Sarcoidosis Raynaud \200\231 s Pleurop ericardial disease Haemoptysis Infection Gastroenteritis TB HIV Recurrent UTIs Streptococca l infection Endocarditis Chronic infection Dermatological Cutaneous vasculitis Livedo retic ularis Hepatorenal syndrome Membranous GN, mesangiocapillary GN (MCGN) Lupus nephritis, MCGN, and others Interstitial disease Scleroderma, SLE, cryoglobulinaemia Connective tissue disorders Vascul itis, lupus nephritis, anti-GBM disease Pre-renal AKI, haemolytic uraemic syndrome Urinary tract TB, amyloidosis HIVAN, HIVICK and others Vesicoureteric re \202 ux and chronic pyelonephritis Post-infective GN Post-infecti ve GN Amyloidosis Vasculitis, HSP, IgA nephropathy Antiphospholipid antibody syndrome Cryoglobulinaemia Malignancy Solid organ tumors Lymphoma Myeloma Other ENT problems Hearing loss Ophthalmic c onditions Membranous GN, thrombotic microangiopathy Minimal change disease, FSGS, \201 brillary GN Light chain disease, amyloid, cast nephropathy Granulomatosis with polyangiitis (Wegener \200\231 s) Alport syndrome Retinopathy and ante rior lenticonus in Alport \200\231 s Cystine deposits in cystinosis Retinitis pigmentosa i n Senior \200\223L ken syndrome Retinal oxalate deposition in hyperoxaluria Analgesic neph ropathy Antiphospholipid antibody syndrome Sickle cell nephropathy, papillary necrosis Chronic pain Thrombotic tendency Sickle cell disease CHAPTER 1 Clinical assessment 4 Clinical history: symptoms and social history Local symptoms of urinary tract disease \200 Pain: Loin pain. \200 Ureteric colic. \200 Suprapubic pain. Haematuria. \200 Change in urine appearance. \200 Changes in urine volume: Polyuria. \200 Oliguria and anuria. Lower urinary tract symptoms (LUTS): \200 Obstructive (voiding) symptoms: \200\224 Impaired size or force of the urinary stream. \200\224 Hesitancy or abdominal st raining. \200\224 Intermittent or interrupted \202 ow. \200\224 Post-micturition dribbl e. \200\224 A sensation of incomplete emptying. \200\224 Acute retention of urine. Storage ( \201 lling) symptoms: \200\224 Nocturia. \200\224 Daytime frequency. \200\224 Urgency. \200\224 Urge incontin ence. \200\224 Dysuria. Social history \200 Smoking: general CV risk in (and progression of) CKD, renovascular disease, urothelial malignancy ( 7 4-fold risk), pulmonary hemorrhage in Goodpasture \200 \231 s disease. Physical activity. \200 Occupational history: risk factors for urothelial malignancy ( b p. 750). Hydrocarbon exposure has been implicated in glomerular disease, particularly anti- GBM disease. \200 Hepatitis and HIV risk factors. \200 A patient \200\231 s understand ing of their kidney disease should be evaluated, and they should be encouraged to be involv ed in decisions about their care. CLINICAL HISTORY: SYMPTOMS AND SOCIAL HISTORY 5 Renal diseases are often chronic disorders, incurring appreciable social morbidity. Factors , such as social isolation, accommodation, and work situation, are hugely important. In ESR D, social circumstance will exert an important in \202 uence on choice of, and ability to cope with, a par- ticular dialysis modality. Livelihood may also be affected \200\224 one of the goals of RRT, wherever possible, should be to keep an individual in employment. Qual ity of life must never be forgotten amidst all the blood tests. Review of systems May provide clues to an underlying systemic condition, such as connec- ti ve tissue disorder or vasculitis. \200 Skin rashes. \200 Photosensitivity. \200 Mouth ulcers. \200 Painful, stiff, or swollen joints. \200 Myalgia. \200 Raynaud \200\231 s phenomenon. \200 Fevers. \200 Night sweats. \200 Thromboembolic episodes. \200 R ed or painful eyes. \200 ENT: Sinusitis. \200 Rhinitis. \200 Epistaxis. \200 Hearing loss. Sicca symptoms (dry eyes, dry mouth). \200 Haemoptysis. \200 Hair loss. \200 Paraesth esiae. CHAPTER 1 Clinical assessment 6 Clinical history: drug, treatment, and family Drug and treatment history \200 The importa nce of the drug history cannot be overstated \200\224 it will often tell a story of its own. 2 Ask candidly about compliance. Antihypertensive therapy \200\224 past and present. Any important tablet intolerances or side effects. Analgesics \200\224 ask speci \201 cally about common NSAIDs (by their over-the-counter names, if necessary). Then ask again. Any \200\230one-off \200\231 courses of therapy that may not be mentioned as part of regular treatment, e.g. recent antibiotics (interstitial nephritis). Oral contraceptive ( i BP). \200 Steroids, immunosuppressive agents \200\224 type and du ration. \200 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 \200 Essential hypertension: more common if one or both parents affected. \200 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 \200\231 s syndrome and variants IgA nephropathy (occasionally) FSGS (rarely) Other s (rarely) Metabolic diseases with renal involvement Non-glomerular Cystinosis, primary hyperoxaluria, inherited urate nephropathy Glomerular Fabry \200\231 s disease Non-metabolic disease Non-glomerular Nephronophthisis Glomerular Congenital nephrotic syndrome, nail-patella syndrome Benign and malignant tumors Tuberous sclerosis (renal angiomyolipoma) von Hippel \200\223 Lindau (renal cell carcinoma ) Tubular disorders Cystinuria, various inherited tubular defects Disorders with a \200\230genetic in \202 uence \200\231 Vesicoureteric re \202 ux, haemolytic uraemic syndrome, diabetic nephropathy CLINICAL HISTORY: DRUG, TREATMENT, AND FAMILY 7 Box 1.2 Important nephrotoxins ( b see Chapter 11) \200\230Pre-renal \200\231 renal insuf \201 ciency Diuretics Any antihypertensive agent ( esp. ACE-Is and ARBs that aggravate other pre-renal states) Haemodynamically mediated NSAID s and COX-2 inhibitors ACE-Is and ARBS Ciclosporin Tacrolimus Vasoconstrictors Glomerulopat hy NSAIDs Penicillamine Gold Hydralazine Interferon Anti-thyroid drugs Carbon tetrachloride and other organic solvents (e.g. glue snif \201 ng) Silica dust (? granulomatosis with po lyangiitis or Wegener \200\231 s) Thrombotic microangiopathy Chemotherapeutic agents: Acute tubular necrosis Aminoglycosides Antifungals: Amphotericin Ifosfamide Foscarnet Antivirals: Adefovir Cidofovir Tenofovir Cisplatin Heavy metals (arsenic, mercury, and cadmium) Herbal remedies Interleukin-2 Intrav enous immunoglobulin (previously with sucrose-containing formulations) Paracetamol Paraquat Pentamidine X-ray contrast agents Interstitial nephritis (these and many, many others) Ant ibiotics: Penicillins Cephalosporins Quinolones Rifampicin Sulfonamides Mitomycin Cisplatin Bleomycin Immunosuppressive agents: Ciclosporin Tacrolimus Clopidogrel Quinine Oral contraceptive Tubular crystal formation Aciclovir and other antivi rals Ethylene glycol (antifreeze) Sulfonamide antibiotics Methotrexate Indinavir (antiretro viral) Allopurinol Cimetidine (rarely ranitidine) NSAIDs and COX-2 inhibitors Diuretics 5-aminosal icylates (sulfasalazine and mesalazine) Proton pump inhibitors, e.g. omeprazole Chronic int erstitial disease Lead Lithium Analgesics Chinese herbs CHAPTER 1 Clinical assessment 8 Clinical history: additional factors Sexual, gynecological, and obstetric history \200 De creased libido and impotence are extremely common in both \231\202 and \231\200 with CKD. Irregular menses and subfertility are frequently encountered in \231\200 . Amenorrhoea is common in ESRD. Previous pregnancies and any complications (UTI, proteinuria, i BP, pre-eclampsia). Miscarr iages, 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 \231\200 or infertility in \231\202 . This may in \202 uence treatment in a \231\200 of childbearing age. Pre-treatment sperm banking can be offered in \231\202 . 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 o f many renal disorders ( i BP, AKI, CKD, the nephrotic syndrome, stone disease, dialysis). Ethnicity and renal disease \200 IgA nephropathy: Caucasians and certain Asian population s (China, Japan, and Singapore). Diabetic nephropathy: black, Mexican American, Pima Indian (a native American tribe in Sout hern Arizona, beloved of epidemiologists and geneticists). An increasing problem in the imm igrant Asian population in the UK. SLE: Asian and black patients (and more aggressive disease). \200 Hypertension and hypert ensive renal failure: black patients. \200 In the UK, the incidence of end-stage renal di sease (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 rea ssure the patient that you are familiar with) their treatment. It will also facilitate disc ussion with the patient \200\231 s renal unit. The patient on haemodialysis \200 Where d oes the haemodialysis treatment take place? \200 How many times per week do they dialyse and how many hours is each treatment? What is the patient \200\231 s current access for dialysis (e.g. an arteriovenous \201 stula, a PTFE graft, or a tunneled dialysis catheter)? What is their usual \202 uid gain between treatments? \200 Do they know their blood pre ssure at the end of a dialysis session? The patient on peritoneal dialysis \200 Are their exchanges performed manually during the day (CAPD) or automated overnight (APD)? How many exchanges do they perform? \200 How many litres is each exchange? \200 Do they have \202 uid in at the moment? \200 Do they need assistance to perform an exchange? \200 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? \200 Are the dialysis bags cle ar or cloudy on drainage? \200 When was their last episode of peritonitis? All dialysis p atients \200 How long have they been on dialysis? \200 How much urine do they pass, if any? \200 What is their dry (aka \202 esh, target, post-dialysis) weight? \200 What i s their daily \202 uid allowance? \200 Do they adhere to a renal diet? \200 Do they k now the cause of their end-stage renal disease? \200 Do they receive erythropoietin injec tions? Who performs these? \200 Have they always been on the same modality of dialysis? \200 Are they \200\230listed \200\231 for deceased donor transplantation? \200 Have th ey previously received a transplant? \200 How are they coping with dialysis? The transpla nt patient \200 When and where was the transplant performed? \200 What immunosuppressio n is the patient taking? \200 Who is responsible for their follow-up? \200 Do they know their baseline SCr? \200 Was the transplant from a living or deceased donor? \200 Do t hey use sunblock and attend a skin clinic? \200 Do they know if they had any rejection ep isodes? \200 Do they know the cause of their end-stage renal disease? \200 What mode of dialysis were they on prior to transplantation? CHAPTER 1 Clinical assessment 10 Physical examination See Fig. 1.1 for examination by area and Fig. 1.2 for examination by s ystem. General inspection Short stature (CKD in childhood) Weight Pallor Brown-yellow skin hue \200\230Sallow \200\231 complexion Hearing aid/hearing impairment (Alport \200\231s syndrom e) SVC obstruction Evidence of past or present haemodialysis access (e.g. tunneled lines, s cars from previous dialysis lines, AV fistula) Mouth Fetor Oral hygiene (SBE) Gum hypertrophy (ciclosporin) Oral candida (immunosuppressio n) Hands Metabolic flap (severe uraemia) Shortening of distal phalanges + pseudoclubbing (s evere hyperparathyroidism) Raynaud \200\231s Sclerodactyly Calcinosis Systemic sclerosis Forearms Myopathy Bony tenderness (hyperparathyroidism) Dialysis access (past or present) Skin Dry Scratch marks Bruising (uraemic bleeding tendency) Vasculitic rash Subcutaneous no dules (soft tissue calcification) Uraemic frost (severe uraemia) Transplant patient: cutane ous malignancies Nails Brittle Leuconychia Splinters (SBE) Transverse ridges (Be au \200\231s lines) Face Periorbital oedema Fig. 1.1 Examination by area. PHYSICAL EXAMINATION 11 Neurological Ophthalmic Dry, red, or painful eyes (iritis, episcleritis) Corneal calcification Conscious level Mental state Myoclonic jerks Seizures Tetany (hypocalcaemia) Peripheral neu ropathy Retina Hypertension Diabetes mellitus Vasculitis Cholesterol emboli Cardiorespiratory Respiratory pattern (? Acidosis) Blood pressure JVP Oedema Carotid bruits Apex beat Heart s ounds Pericardial rub Lung fluids Pulmonary oedema Effusion Abdomen Scars ? Tenckhoff catheter Ascites Palpation: Loin tenderness Palpable kidney(s) Palpable b ladder Transplant kidney (right or left iliac fossa) Abdominal bruit Rectal (prostate) Pelv ic exam Musculoskeletal Obstruction Bony deformity Joint inflammation Osteoarthritis (? NSAIDs) Legs Peripheral pulses Oedema Femoral bruits Restless legs Fig. 1.2 Examination by system. Palpating the kidneys \200 The kidneys are generally only palpable in very thin patients. \200 The right kidney is more accessible than the left. \200 Place the left hand poste riorly 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 \201 rm and smooth. \200 \200\230Balloting \200\231 the kidney refers to palpation whilst pushing up \201 rmly from behind. Using th is technique, it may be possible to gently \200\230bounce \200\231 an enlarged kidney bac k and forth between the hands. CHAPTER 1 Clinical assessment 12 Physical examination: the circulation 2 The ability to assess the volume status of a patien t is critical to the practice of renal medicine. In the vast majority of cases, it can be a chieved at the bedside without invasive monitoring. Hypovolaemia Salt and water (or blood) loss leads to d effective circulating volume and eve ntual shock. Signs include: \200 d BP (and d pulse pressure). \200 Postural d BP (fall in SBP >10mmHg); if it is not possible to stand the patient up, then BP measurements with t he 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). \200 d JVP. Neck veins \202 at, even if supine. \200 Cool peripheries and peripheral vasoconstriction ( (cid:2) septic patients may be vasodilated and warm). Poor urine output (UO). \200 Decreasing weight. \200 Positive response to a \202 uid challenge. \200 Positive passive leg raising test. (Much) less reliable signs include: \200 d capillary re \201 ll, poor skin turgor (foreh ead 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 \200\224 or both. (cid:2) It is possible to be simultaneously salt- and wate r-overloaded and intravascularly depleted (e.g. CCF or a nephrotic patient receiving diuret ics). See Box 1.3. Box 1.3 Volume expansion and overload Increased circulating volume i BP Elevation of the JVP Increased interstitial \202 uid Peripheral or generalized oedema Pulmonary oedema (tachyp noea, tachycardia, a third heart sound 9 basal crackles) Pleural effusion(s) Ascites Increa sing weight Both \202 uid depletion and \202 uid overload are harmful. Extremes can be rela- tively easy to recognize, but it is dif \201 cult to consistently diagnose euvol- aemia, i.e. th e point at which \202 uid administration is no longer necessary. Clinical assessment reli es on frequent evaluation of the patient \200\230 s response to \202 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 t issue perfusion and O 2 delivery. This involves the optimization of \202 uid status and c ardiac output (CO) ( reminder : O 2 delivery = heart rate \227 stroke volume \227 O 2 sat uration \227 Hb \227 1.36). The aim of haemodynamic resuscitation is to avoid both \202 uid deple- tion and overload (i.e. patient \200\230 not too dry and not too wet \200\231 ) and to opti- mize CO whilst avoiding excess catecholamine ( \200\230 enough but not more \200\231 ). To achieve thes e goals, clinical assessment may be unreliable, and non-invasive haemodynamic monitoring is often desirable \200\224 especially in patients with sepsis, hypoproteinaemia 9 cardiac f ailure. Measurement of cardiac output Historically, haemodynamic monitoring centered on mea surement of CVP and pulmonary artery occlusion pressure (PaOP or \200\230wedge pressure \200\231 ). However, many studies demonstrated that these do not accurately cor- relate wit h \202 uid status and cardiac performance, particularly in patients with cardiac failure. Instead, more dynamic parameters have increasingly supplanted them, e.g. variation in stro ke volume, arterial pressure, or pulse pressure after a \202 uid challenge. Evidence rema ins 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 patien ts. Haemodynamic monitoring used in the critical care environment \200 Pulmonary artery cathe ter (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 signi \201 cant risks ( (cid:2) damage t o chordae, arrhythmias, rupture of pulmonary artery). Use decreasing. \200 Echocardiograp hy: an excellent tool for assessment of haemodynamics but operator-dependent and not a continuous technique. Oesophageal Doppler: measures blood \202 ow velocity in descending aorta (correlates with CO). Non-invasive but dependent on operator \200\231 s skill and placement/positioning. N ot tolerated in non-ventilated patients. \200 Lithium dilution technique: measures CO via rate of change in lithium chloride concentration between venous and arterial system. Requires arterial line and CV li ne. 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. \200 Thoracic electrical bioimp edance: CO measurement via electrodes on the patient \200\231 s chest and neck. Non-invasi ve. Less accurate with pulmonary oedema, pleural effusions, and chest wall oedema. Speciali st expertise required, so not in routine use. CHAPTER 1 Clinical assessment 14 Urine: appearance 2 Examination of the urine should be considered a routine extension of th e physical examination in all patients. Appearance \200 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 bacter ia. Precipitation of phosphates can also produce turbidity in urine refrigerated for storag e. Speci \201 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 +v e for blood on dipstick examination. However: \200 If the sample is centrifuged, the supe rnatant will remain colored and continue to test +ve. No red cells are seen on microscopy. \200 Speci \201 c assays for hemoglobin and myoglob in are available. \200 Normal urine tends to darken on standing (urobilinogen oxidizes to colored urobilin) (see Box 1.4). Chyluria is a rare cause of turbid urine. It has a milky appearance (particularly after fat ty meals) and settles into layers on standing. Results from a \201 stulous connection bet ween 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 betalai ne in genetically susceptible individuals. Rarely causes diagnostic confusion. Odor Offensive urine usually denotes infection (bacterial ammonium produc- tion). Sweet uri ne suggests ketones. Certain rare metabolic diseases confer characteristic smells \200\224 one can only hope to encounter maple-syrup urine disease before isovaleric acidaemia ( \200\230 sweaty feet urine \200\231 ) (see Box 1.5). Pneumaturia \200 The presence of air bubbles in urine suggests a vesicocolic \201 stula . \200 Causes: Diverticular disease. \200 Colonic cancer. \200 In \202 ammatory bowel disease. URINE: APPEARANCE 15 Box 1.4 Colored urine Causes of a colored urine \200 Beetroot ingestion (red). \200 Blo od (pink/red to brown/black). \200 Chloroquine (brown). \200 Chyluria (milky white). \200 Hemoglobin (pink/red to brown/ Urine that darkens on standing \200 Alkaptonuria (homogentisic acid). \200 Imipenem-cil astin treatment. \200 Melanoma (melanogen). \200 Methyl dopa. \200 Metronidazole. \200 Porphyria (porphobilinogen). black). Hyperbilirubinaemia (yellow/ brown). Methylene blue (er blue). \200 Myoglobin (pink/red to brown/ black). Nitrofurantoin (brown). \200 Onchronosis (black). \200 Phenytoin (red). \200 Propofol (green). \200 Rifampicin (orange). \200 Senna (orange). Box 1.5 Proust \200\231 s chamber pot While Proust wrote lyrically about the unusual bouqu et of his urine fol- lowing asparagus ingestion, there are many who remain oblivious to a p henomenon instantly recognizable to others. Two potential explanations for this olfactory diversity have been offered: (i) the producti on of the required fragrant metabolites is subject to variation through genetic polymorphis m, i.e. some individuals excrete the perfumed compound(s), while others do not; (ii) everyo ne produces the metabolite(s), but only some have the necessary olfactory talent required t o detect it/them. The genetics are not straightforward, although an association between the ability to notice one \200\231 s own \200\230asparagus urine \200\231 and a cluster of olfac- tory recept or genes on chromosome 1 has been described. Even the identity of the relevant substances r emains uncertain, with a plethora of sulfur-containing compounds, such as methanethiol and dimethyl sulfide, 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. CHAPTER 1 Clinical assessment 16 Urinalysis: chemical analysis Osmolality and speci \201 c gravity Speci \201 c gravity Refers to the weight of a solution, with respect to an equal weight o f distilled water (normal range 1.003 \200\223 1.035 in urine). Can be estimated with a di pstick, but, for accurate measurement, an osmometer (urinometer) is required. Osmolality Refers to the solute concentration of a solution. It cannot be measured with a d ipstick. In the absence of signi \201 cant glycosuria, the concentrations of Na + , Cl \200\223 , and urea are the most important determinants in urine. The ability to vary urine osmolality (range 50 \200\223 1350mOsmol/kg) plays a central role in the regulation of pl asma osmolality (maintained across a narrow range: 280 \200\223 305mOsmol/kg). Generally speaking, speci \201 c gravity and osmolality correlate. An excep- tion is when relatively large particles, such as glucose, proteins, and radio contrast media, are presen t in the urine. These produce an i in speci \201 c gravity, with little change in osmolali ty. Uses Investigation of polyuria and hypo-/hypernatraemic states ( b p. 782). Recurrent stone formers can monitor their own urine speci \201 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 kidne ys can generate. In advanced renal insuf \201 ciency, the osmolality becomes relatively \201 xed at 7 300mOsmol/kg ( 7 1.010 speci \201 c gravity) \200\224 close to that of glom erular \201 ltrate. In this situation, the urine cannot be adequately concentrated or dil uted in response to Na + and water deple- tion and overload, respectively. This is termed i sosthenuria. Urinary pH Urinary pH ranges from 4.5 to 8.0 (usually 5.0 \200\223 6.0), depending on sys- temic acid \200\223 base status. Most people (except vegans) pass acidic urine the majori ty of the time. Isolated urinary pH measurements provide very little useful information. Th eir main clinical use is the investigation of systemic metabolic acidosis. In this situatio n, a fall in urinary pH (to around 5) is expected, as acid is excreted. Failure of this res ponse may indicate renal tubular acidosis ( b p. 824). Most urine dipsticks have an indicat or strip for estimation of pH, but, if a tubular disorder is suspected, a pH meter should b e 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.) \200 Urinary stone disease (cysteine and urate stones) ( b p. 716). \200 Poisoning ( b p. 909): Salicylates. \200 Barbiturates. \200 Methotrexate. Rhabdomyolysis ( b p. 152). \200 AKI s to cast nephropathy in myeloma ( b p. 622). CHAPTER 1 Clinical assessment 18 Urinalysis: further tests Further dipstick tests Leucocyte esterase and nitrites Increasingly used as indicators of infection. Detection of neutrophil ester- ase activity identi \201 es white cells (pyuria), while the nitrite test exploits the ability of some urinary pathogens (though not all \200\224 notably certain G ram +ve organisms, including Strep. faecalis , Staph. albus, Neisseria gonorrhoeae , as wel l as many Pseudomonas spp. and mycobacteria) to reduce nitrate l nitrite. Positivity requir es an adequate dietary nitrate intake as well as suf- \201 cient bladder dwell time (pref erably >4h). When combined, these methods possess good speci \201 city (i.e. take seri- ously if +ve) t hough only modest sensitivity (i.e. treat a \200\223 ve result with caution if infection i s likely clinically). 2 While they can serve as a useful screening test in at-risk populati ons they are not a substitute for micros- copy and culture. Bilirubin and urobilinogen \200 Conjugated ( 6 water-soluble) bilirubin l biliary excreti on 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 d ipstick +ve bilirubin indicates hepatic or cholestatic disease); (ii) the absence of dipsti ck urobilinogen in a jaundiced patient suggests biliary obstruction. Glucose Glycosuria results when tubular reabsorptive capacity for glucose is exceeded (plas ma level >10mmol/L). A valuable screening tool, but less useful for diagnosis and monitorin g of DM. \200\230 Renal \200\231 glycosuria occurs when proximal tubular injury leads to a failure to reabsorb \201 ltered glucose ( b p. 76). Causes of a +ve dipstick for ketones \200 Dipsticks semi-quantitatively detect acetoaceta te (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 \200\231 diet). \200 Alcoholic ketoa cidosis. \200 Severe volume depletion. \200 Isopropyl alcohol poisoning (hand-rubs, sol vents, and de-icers). URINALYSIS: FURTHER TESTS 19 Urinary test strips A variety of test strips for urinalysis are available. Some have a spe- ci \201 c purpose, e.g. Clinistix (glucose), Hemastix (blood), and Albustix (alb umin). Others cast a wider net, with various combinations of the following: \200 Speci \201 c gravity. \200 pH. \200 Leucocytes. \200 Nitrites. \200 Glucose. \200 Urobi linogen. \200 Bilirubin. \200 Ketones. \200 Albumin or protein. * \200 Blood. * Dip sticks able to detect microalbuminuria are also available. CHAPTER 1 Clinical assessment 20 Urinalysis: protein Introduction \200 Urinary protein excretion should not exceed 150mg/d ay, of which less than 20mg is albumin. The remainder consists mainly of non-serum-derived tubular mucoprotein, such as Tamm \200\223 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 ( \200\230 spot \200\231 ) or timed (usually 24h) samples. Proteinuria (total protein) and albuminuria (albumin) are not strictly interchangeable term s. When screening for early renal disease, speci \201 c tests for albumin are preferable. Dipsticks Convenient, highly speci \201 c, but less sensitive. Contain pH-sensitive indi- cators that change color when bound to negatively charged proteins. Predominantly detect al bumin (some are albumin-speci \201 c, e.g. Albustix ) and may not identify large amount s of other proteins, e.g. Bence \200\223 Jones. Dipsticks have completely superseded sulph osalicylic acid turbidity testing. A +ve result occurs with protein excretion \211 300mg/ L. Lower amounts of proteinuria, particularly in the context of diabetes, are termed micro- albuminuria ( b p. 60) (de \201 ned as 30 \200\223 300mg/day) and usually measured by EL ISA or radioimmunoassay (although sensitive dipsticks are available). Dipsticks are semi-quantitative. As a rough guide: 70.15 \200\2230.3g/L 70.3g/L 71g/L 72.5 \200\2235g/L >10g/L Trace + ++ +++ ++++ (cid:2) Changes in urinary concentration affect the result. If volumes are high and the urine dilute, large amounts of protein can go undetected (speci \201 c gr avity may be a clue). Concentrated morning samples are 6 preferable. 2 If +ve dipstick test of \211 1+, repeat after 1 \200\223 2wk. If persistent, verify with a protein/creatinin e ratio (uPCR) or albumin/creatinine ratio (uACR). Timed collections Historically, 24h urine collections were preferred to spot urine samples. However, they suffered from signi \201 cant drawbacks, including inaccurate collection (s ee Box 1.7) and the time required for lab processing. URINALYSIS: PROTEIN 21 Box 1.7 uACR and uPCR (see also b p. 197) \200 Untimed ( \200\230 spot \200\231 ) 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 c ollections. A \201 rst morning urine specimen is preferable. \200 2 The relationship between uACR a nd uPCR is non-linear (see Table 1.3).