What is the relevance of a positive dipstick for protein? \200 Dipsticks predominantly de tect albumin ( b p. 20). They are generally +ve if protein excretion >300mg/d. Dipstick proteinuria has a prevalence of around 5% in healthy individuals (usually trace to 1+ range). Further evaluation is mandatory to distinguish \200\230benign \200\231 from \200\230pathological \200\231 proteinuria. What is pathological proteinuria? \200 Persistent protein excretion >150mg/d implies rena l/systemic disease. \200 The amount and composition depend on the nature of renal injury. \200 Urinary electrophoresis can distinguish the source. Glomerular Failure of the glomerular barrier allows passage of intermediate and high MW pro tein. The most important cause of proteinuria in clinical practice. The predominant protein is albumin. Tubular LMW proteins, such as immunoglobulin light chains and B 2 microglobulin, normally p ass through the glomerulus and are reabsorbed by proximal tubular cells. Damage to the prox imal tubule disrupts this cycle and results in tubular proteinuria. (cid:2) This is not det ectable on dipstick examination. Over \202 ow Overproduction of LMW plasma proteins exceed s the capacity of the nor- mal proximal tubule to reabsorb them. Causes: (i) immunoglobulin light chains in myeloma; (ii) lysozyme in monomyelocytic leukemia. Dipstick examination wi ll be negative; speci \201 c assays are required. Secretory proteinuria Protein added to the urine lower in the urinary tract (e.g. bladder t umor, prostatitis). Blood (>50mL/24h) will also cause proteinuria (but not albuminuria). CLINICAL SYNDROMES: PROTEINURIA \200\224INTRODUCTION 59 Table 1.9 Causes of protein excretion Daily protein excretion Cause 0.15 \200\2231.0g/24h Mild glomerulopathies Orthostatic proteinuria Tubular proteinuria Over \202 ow proteinuria 1.0 \200\2233.0g/24h Probably glomerular >3.0g/24h Virtually always glomerular NB Proteinuria >3g does not necessarily result in the nephrotic syndrome but is often refer red to as nephrotic range. Proteinuria with accompanying microscopic haematuria strongly su ggests glomerular disease. When may proteinuria be \200\230 benign \200\231 ? Transient \200 Fever. \200 Exercis e. \200 Extreme cold. \200 Seizures. \200 CCF. \200 Severe acute illnesses. Persistent \200 Postural (orthostatic) proteinuria: Normal subjects demonstrate a small i in protein excretion on standing. Postural proteinuria is an exaggeration of this. \200 Relatively common in youn g adults ( 7 3 \200\223 5%). Rare age >30. \200 Usually <1g/24h. \200 Diagnose with a \200\230split \200\231 urine collection: 16h daytime and 8h overnight collection (simpler: \200\223 ve dipstick (or uPCR) on waking, +ve at night). Renal function remains normal, even after prolonged follow-up. \200 Remits with time (rem ains in 7 50% cases at 10 years and <25% at 20 years). Possible mechanisms: (i) trivial glomerular lesion; (ii) i circulating A2 and noradrenaline when upright l i glomerular permeability; (iii) renal vein entrapment between aorta and superior mesenteric artery l local haemodynamic disturbance ( \200\230 nutcracker \200\231 syndrome \200\224 also a possible cause of microscopic hae maturia). CHAPTER 1 Clinical assessment 60 Clinical syndromes: proteinuria What is microalbuminuria? \200 The term microalbuminuria describes albuminuria above the normal range (>30mg) but below the threshold of traditional dipsticks (<300mg). \200 A misleadin g term, implying the albumin is of lower molecular weight. This is not the case \200\224 t he \200\230micro- \200\231 pre \201 x is simply meant to re \202 ect the low amount. This has led to newer terminology, such as \200\230moderately increased albuminuria \200\231 for microalbuminuria and \200\230severely increased albuminuria \200 \231 for macroalbuminuria. It is a sensitive indicator of: \200 Early renal disease. \200 CV risk in DM, i BP, and several other conditions. It is detected by spot microalbumin/creatinine ratio, ultrasensitive dipstick, or radioimmu noassay on a 24h urine collection ( b p. 20). Clinical consequences Mild proteinuria does not produce clinical sequelae. When more severe (>3 \200\223 5g/d), a distinct clinical entity \200\224 the nephrotic syndrome \200\224 may result. Heavy proteinuria may cause frothy urine ( d surface tension). The nephrotic s yndrome ( b p. 554) Urine albumin loss l d serum albumin l oedema (through a variety of mec hanisms). The concomitant loss of other serum proteins l hyperlipi- daemia, thrombotic tend ency, i susceptibility to infection. Selectivity of proteinuria \200 This refers to size discrimination at the glomerulus. \200 Highly selective l albumin and proteins of similar MW. \200 Non-selective l larger proteins, including immunoglobulins. Selectivity is calculated by comparison of IgG and alb umin (or trans- ferrin) clearance. This requires a sample of plasma and \200\230spot \200 \231 urine specimen. serum IgG x urine Alb x 100 Selectivity index = urine IgG x serum Alb \211 10%, highly selective. 11 \200\223 20%, moderately selective (limited discriminator y value). \211 21%, poorly selective. \200 Limited clinical utility and rarely performe d in practice. May have a limited prognostic value \200\224 non-selective proteinuria suggests more severe injury to the glomerular apparatus. In children: can identify the highly selective proteinuria of minimal change disease and po tentially avoid the need for a renal biopsy. CLINICAL SYNDROMES: PROTEINURIA 61 Microalbuminuria and cardiovascular risk \200 Microalbuminuria (or \200\230high albuminu ria \200\231 ) is a marker of CV risk. \200 This applies to the general population, not just DM or i BP. \200 The mechanisms underpinning this association are poorly understood, but microalbuminuria, endothelial dysfunction, and chronic in \202 ammation ar e interrelated processes that develop and progress together. Microalbuminuria can be correlated to the risk of stroke, MI, LV dysfunction, PVD, and deat h, e.g. in the HOPE (Heart Outcomes Prevention Evaluation) trial and follow up of the Frami ngham cohort. BP reduction is the key to microalbuminuria reduction \200\224 RAS blockade with ACE inhibitors or ARBs (or both) appears to be the treatment of choice. There is no present consensus on microalbuminuria screening in non-diabetics, though screening of hypertensive patients (and other high-risk groups) is ad vocated by some authorities; e.g. the American College of Cardiology (ACC) and American Hea rt Association (AHA). See Fig. 1.10 for management. Urine PCR eGFR Normal eGFR PCR <100 Normal BP eGFR <60 or PCR >100 or PCR >100 and microscopic hameaturia Reassess at 6 \200\22312 months (PCR, eGFR, BP) Immunological and serological screen, renal USS Consider renal biopsy Annual review Fig. 1.10 Suggested outline management of proteinuria. NB Immunological and serological scr een see b p. 40. CHAPTER 1 Clinical assessment 62 Clinical syndromes: haematuria \200\224 introduction and classi \201 cation Introduction Can result from bleeding at any site in the urinary tract, from the kid- ney to the tip of the urethra. Causes range from benign to serious (see Table 1.10). Classi \201 cation Macroscopic vs microscopic \200 Macroscopic: Blood is visible to the naked eye. Gross haematuria startles the patient and 6 presents early. The patient may not recognize blood and report discoloration (pink, smoky, cola, or tea-like). 2 Macroscopic haematuria always requires investigation (presenting complaint in 7 85% of bladder and 7 40% of renal tumors). \200 Heavy bleeding with clot f ormation almost never occurs in glomerular disease. \200 Microscopic ( b p. 66): Blood only visible under high-powered microscopy. \200 Often detected on dipstick examina tion in an asymptomatic patient. Glomerular vs non-glomerular Provides a framework for considering pathology. Both can prese nt with macro- or microscopic bleeding (particularly non-glomerular haematuria). Always ass ume bleeding is non-glomerular (particularly age >40) until investigation proves otherwise. Locally agreed nephrological and urologi- cal referral and management pathways are highly desirable, particularly for microscopic haematuria. Transient haematuria \200 Exercise ( \200\230 joggers \200\231 nephritis \200\231 ). \200 Menstruation. \200 Sexual activity. \200 Viral illnesses. \200 Trauma. CLINICAL SYNDROMES 63 Table 1.10 Important causes of haematuria by age and source Age \211 40 Origin Age <40 Glomerular IgA nephropathy Thin basement membrane disease Alport \200\231s syndrome Focal GN (e.g. pos t-streptococcal) Other GN (e.g. variably present in membranous and diabetic nephropathies) Renal stones Transitional cell tumor Renal cell carcinoma Polycystic kidney disease Pyelone phritis Papillary necrosis Renal infarction Ureteral stricture and hydronephrosis Renal TB Renal vein thrombosis Non-glomerular Upper urinary tract Renal stones Pyelonephritis Polycystic kidney disease Medullary sponge kidney Hypercalciuri a/ hyperuricosuria 9 stones Renal trauma Papillary necrosis Ureteral stricture and hydronep hrosis Sickle cell trait or disease Renal infarction or arteriovenous malformation Renal TB (? HIV) Renal vein thrombosis Cystitis, prostatitis, and urethritis Bladder cancer Prostate cancer Benign prostatic hyper trophy Benign ureteral/bladder tumors Lower urinary tract Cystitis, prostatitis, and urethritis Benign bladder, ureteral polyps, and tumors Bladder c ancer Prostate cancer Urethral stricture Schistosoma haematobium Uncertain source Exercise haematuria Unexplained haematuria Over-anticoagulation Factitious haematuria CHAPTER 1 Clinical assessment 64 Clinical syndromes: haematuria assessment Clinical assessment History \200 How much bleeding? Is the urine discolored or frankly bloody? \200 Recent trauma? May be relatively trivial, e.g. contact sports. \200 Previous episodes? \200 Hi story of stone disease? \200 Relevant medications? Anticoagulants should not cause haemat uria if the INR is in the required range. Recent instrumentation of the urinary tract? \200 Any associated urinary symptoms? Urinar y infection? \200 Pain? Sudden onset of colicky \202 ank pain suggests a stone. \200 Suprapubic pain may indica te infection or clot colic. \200 2 Painless macroscopic haematuria indicates a tumor unti l proved otherwise. What part of the stream? Initial haematuria suggests an anterior urethral lesion. \200 Terminal haematuria usually arises from the posterior urethra, bladder, bladder neck, or trigone. Continuous haematuria usually originates at, or above, the level of the bladder. Cyclical haematuria in \231\200 suggests endometriosis of the urinary tract. Risk factors for urothelial malignancy ( b p. 750)? \200 Recent skin or throat infection \200\224 post-streptococcal GN. \200 Episodic macroscopic haematuria with throat infecti ons is a classical presentation of IgA nephropathy ( b p. 544). Recent travel? Schistosomiasis is the most common cause of haematuria worldwide (resist the temptation to swim in Lake Malawi!). Systemic symptoms, e.g. arthralgia, rashes, suggestive of an underlying in \202 ammatory disorder? Family history of deafness (Alport \200\231 s) or other renal disease? Physical examination (signs usually scarce) \200 Haemodynamically stable? \200 Anemia. \200 Bruising/bleeding s bleeding diathesis. \200 Skin or throat infections ( l post-in fectious GN). \200 Rashes, swollen joints ( l in \202 ammatory condition, e.g. vasculiti s). \200 Cardiorespiratory: Stigmata of endocarditis. \200 i BP and oedema ( l glomerular disease). CLINICAL SYNDROMES: HAEMATURIA ASSESSMENT 65 Abdomen: Flank tenderness ( l stone disease, pyelonephritis). \200 Masses. \200 Bruit ( l AVM). \200 Prostate. \200 Consider testicular examination and VE (? misinterpreted vaginal bleeding). Investigation of macroscopic haematuria \200 Urinalysis: (cid:2) A \200\223 ve dipstick in a patient with documented macroscopic haematuria should not stop further investigation. \200 In heavy bleeding, the dipstick of ten tests +ve for protein: interpret with caution. Urine M,C+S: infection? Ova of Schistosoma haematobium ? \200 Urine cytology: malignant c ells? Casts and dysmorphic red cells? \200 FBC, U&E, clotting, G&S ( 9 cross-match when s evere), PSA, Hb electrophoresis in black patients. Imaging: CT, with and without contrast, is the investigation of choice. If unavailable, USS + IVU. Cystoscopy (in virtually all patients): \200 9 ureterography or ureteroscopy. Angiography (rarely). May demonstrate a vascular lesion. CHAPTER 1 Clinical assessment 66 Clinical syndromes: microscopic haematuria Microscopic haematuria De \201 nition Arbitrary. >2 red cells/hpf ( b p. 22) ( 7 10 7 red cells/24h). However, it is usually a +ve dipstick, not a cell count that triggers investigation (dipsticks detect 2 \200\223 5 cells/hpf). Epidemiology Reported prevalence varies widely (0.18 \200\223 16.1%), re \202 ecting diff erences in the de \201 nition used and population screened (particularly with respect to a ge). Common in both adults and children. Predictive value The proportion that has (or develop) signi \201 cant disease depends on t he group studied and thoroughness of investigation. Overall risk of malig- nancy (2 \200 \223 10%) is less than macroscopic haematuria (5 \200\223 22%) but i with age (see Table 1 .11). Table 1.11 Risk of malignancy i Chance of malignant lesion i Chance of glomerular lesion Age >40 History of gross haematuria Analgesic abuse Smoking Alcohol abuse Occupational expo sures (b p. 750) Pelvic irradiation Previous cyclophosphamide treatment Proteinuria Dysmorphic red cells and red cell casts (b p. 22) Renal impairment i BP Evaluation \200 Pay attention to risk factors in Table 1.11. See Fig. 1.11. \200 Casts and dysmorphic cells ( b p. 22). \200 Imaging: CT is the investigation of choice. \200 If unavailable, a combination of USS (alone: may miss small stones and renal tumors <3cm diameter) and IVU (alone: may miss tumors not invol ving the PC system) is generally used. Nephrology work-up: measure BP, FBC, U&E, eGFR; quantify proteinuria (uACR/uPCR); consider immunological and serological ( \200\230 nephritic \200 \231 or \200\230renal \200\231 screen ( b p. 40) 9 renal biopsy ( b p. 82). CLINICAL SYNDROMES: MICROSCOPIC HAEMATURIA 67 Dipstick microscopic haematuria No further action, unless risk factors for urothelial malignancy \200\223ve Repeat after 1 week Dysmorphic red cells red cell casts Microscopic examination of urine Urine PCR and eGFR Proteinuria or renal impairment Isolated microscopic haematuria CONSIDER CT or IVU and ultrasound Nephrology work-up Urine cytology x 3 Follow-up: \200 \200\230Unexplained \200\231 microscopic haematuria: annual with urine d ipstick, BP and U&E. Can be undertaken in 1 care. \200 If high risk, then annual cytolog y is desirable. \200 New macroscopic haematuria or additional urinary symptomatology requ ires repeat urological evaluation. Age \211 40 or risk factors for urothelial malignancy Age <40. No risk factors for urothelial malignancy Cystoscopy No cystoscopy All \200\223ve Fig. 1.11 Suggested management of microscopic haematuria. See notes on b p. 66. CHAPTER 1 Clinical assessment 68 Clinical syndromes: microscopic haematuria screening See Table 1.12 for causes of isolated microscopic haematuria. Should we screen for microscopic haematuria? X Two-thirds of physicians include dipstick ex amination for haematuria in health checks, but the bene \201 ts of screening are yet to be established. Argument for \200 Dipstick examination is easy, acceptable to patients, and inexpensive. \200 It may assist early diagnosis of urological malignancies (where early intervention m ay be lifesaving) and intrinsic renal disease (where intervention may delay or prevent prog ression to ESRD). Argument against \200 Basic criteria for screening are not ful \201 lled. \200 Dipstic k testing is not suf \201 ciently speci \201 c, and predictive values for both malignancy and renal disease are relatively poor. Bene \201 ts of early detection have not been established for either. Microscopic haematuria and the risk of ESRD \200 A recent longitudinal study of 1.2 milli on young individuals (aged 16 \200\223 25) presenting for military service in Israel * found an initial 0.3% prevalen ce of persistent microscopic haematuria (with normal SCr and proteinuria <200mg/day). Males were affected twice as commonly as females. \200 During 21 years \200\231 follow-u p, ESRD developed in 0.7% of those with (and 0.045% of those without) initial microscopic haematuria. This gave an adjusted hazard ratio of 18.5. \200 The mean age of ESRD treatment was earli er (34 vs 38) in the haematuria cohort and attributed mainly to glomerular disease. \200 While the relevant advisory bodies do not presently advocate population screening, these re cent data have led to a call for selected screening of younger patients so that they can be followed up more closely for the development of overt renal disease. Vivante A, Afek A, Frenkel-Nir Y, et al . (2011). Persistent asymptomatic isolated microsco pic hematuria in Israeli adolescents and young adults and risk for end-stage renal disease. JAMA , 306 , 729 \200\223 36. CLINICAL SYNDROMES: MICROSCOPIC HAEMATURIA SCREENING 69 Table 1.12 Causes of isolated microscopic haematuria Finding Prevalence in 1689 adults (%) Cancer 5.1 Stones 5.0 UTI 4.3 Renal disease 2.2 No source found 43.0 Sutton JM (1990). Evaluation of hematuria in adults. JAMA, 263, 2475 \200\22380. CHAPTER 1 Clinical assessment 70 Clinical syndromes: CKD, AKI, and the nephritic syndrome Chronic kidney disease (see b Chap ter 3) The end result of any process causing renal parenchymal loss or dam- age. CKD implie s an irreversible reduction in the number of functioning nephrons and is characterized by a progressive inability of the kidneys to ful \201 ll their homeostatic responsibilities. ( cid:2) Always ensure that reversible factors have been excluded. Classi \201 cation Previously termed chronic renal failure, with an arbitrary de \201 nit ion. The NKF-KDOQI classi \201 cation is now almost universally used internationally (see Table 1.13). Table 1.13 CKD: a brief primer (see b Chapter 3) Stage Description GFR (mL/min/1.73m2) 1 Asymptomatic urinary abnormalities >90 2 Mild CKD* 60 \200\22389* 3 Moderate CKD 30 \200\22359 4 More severe CKD (complications more likely) 15 \200\22329 5 and 5D Approaching or at ESRD <15 or on dialysis (D) Patients with a GFR >60mL/min should not be considered to have CKD, unless there is concomi tant evidence of kidney damage, e.g. urinary abnormalities (proteinuria, haematuria), struc tural abnormalities (e.g. abnormal imaging), genetic disease (e.g. APKD), or biopsy-proven disease. Older nomenclature Uraemia (or uraemic syndrome): the constellation of symptoms and signs p roduced as GFR declines (originally chosen to imply retention of urine in the blood). A mul tisystem disorder with a complex pathophysi- ological basis ( b p. 212). Correlation of Ur and SCr with symptomatol- ogy is poor, so the diagnosis is part clinical, part biochemical. Azotaemia: a term previously popular in the USA and used to imply retention of nitrogenous compounds. Typically refers to early CKD, sparing uraemia for symptomatic patients. Also at tempts to play down the role of urea itself. End-stage renal disease (ESRD): generally de \201 ned as a GFR \211 5mL/min. The initiation of renal replacement therapy (RRT) is gene rally required to maintain the patient \200\231s continued well-being (Note: RRT does not h ave to wait until the patient is symptomatically uraemic, b p. 267). CLINICAL SYNDROMES: CKD, AKI, AND THE NEPHRITIC SYNDROME 71 Acute kidney injury (AKI) ( b Chapter 2.) The nephritic syndrome ( b p. 536) Acute post-inf ectious GN, particularly following pharyngitis or cellulitis with group A B -haemolytic str eptococci, provides the historical prototype for this condition and remains relatively freq uent in developing countries. Now commonly associated with a variety of other glomerular co nditions ( b p. 548). Clinical features \200 Haematuria (usually microscopic). \200 Pro teinuria. \200 i BP. \200 Circulatory overload and oedema. \200 Oliguria. \200 d GF R. 2 Rapidly progressive glomerulonephritis (RPGN) \200 The dramatic end of the nephritic sp ectrum, with rapid d GFR and (usually) oligo-anuria. Caused by an aggressive glomerular lesion, with extensive crescent formation ( b p. 532). Other renal diseases can produce an identical clinical picture (e.g. acute thrombotic microangiopathy). 3 Seek expert help. This is a life-threatening fulminant illness, and recovery of renal function is rare without early treatment. Hypertension ( b Chapter 5) The kidney has been described as both \200\230villain and vict im \200\231 in i BP. Hypertension in renal disease \200 Underlying renal disease is found in a minority of pat ients with i BP, although the possibility should always be considered (an abnormal urine di pstick provides a simple clue). i BP may be a feature of any renal disease, although particularly common in glomerular and vascular diseases. Hypertension has an extremely important bearing on the progression of renal disease ( b p. 203). Renal disease in hypertension \200 The normal kidney plays an important role in the patho genesis of essential hypertension ( b p. 452). The kidney is an important site of end-organ damage caused by i BP. CHAPTER 1 Clinical assessment 72 Clinical syndromes: pulmonary renal syndromes Introduction The combined presentation of an acute GN with pulmonary hemorrhage is one of the most dramatic scenarios in clinical medici ne. Causes ANCA +ve vasculitis ( b p. 640) 7 60% cases. Anti-GBM or Goodpasture \200\231 s dis ease ( b p. 656) 7 20%. Also SLE ( b p. 658), Henoch \200\223 Sch nlein pur- pura ( b p . 650), cryoglobulinaemia ( b p. 634), and rheumatoid vasculitis ( b p. 669). History \200 The \201 rst report of a condition simultaneously affecting lungs and kidn ey was presented in 1919 by Ernest Goodpasture, following post-mortem studies during the 19 18 \200\223 19 in \202 uenza pandemic. Four decades later, the eponymous term Goodpasture \200\231 s syndrome was adopted to describe comparable clinicopathological presentations. Subsequent realization that pulmonary renal syndromes are not a single clinical entity brou ght about further re \201 nements to the nomenclature. Goodpasture \200\231 s disease is now reserved for lung hemorrhage and crescentic GN in th e context of anti-GBM disease ( b p. 656). \200 With hindsight, it is more likely that Go odpasture \200\231 s original patient had a systemic vasculitis and not the disease that now bears his name. Clinical features \200 Acute nephritic syndrome (rapidly progressive renal failure with a n active urinary sediment). Features of an underlying systemic condition may be present (e.g. cutaneous vasculitis, sinusitis, arthritis). Pulmonary hemorrhage: Cough. \200 Dyspnoea. \200 Haemoptysis (extensive bleeding). \200 Anemia (and iron de \201 ciency). \200 Hypoxaemia and respiratory failure. \200 CXR: diffuse or patchy al veolar shadowing (indistinguishable from pulmonary oedema/ARDS). \200 CT: con \201 rms air space \201 lling. \200 Lung functi on: i diffusion capacity for carbon monoxide (KCO). \200 Bronchoscopy: bloody bronchoalve olar lavage. CLINICAL SYNDROMES: PULMONARY RENAL SYNDROMES 73 Other \200\230pulmonary renal \200\231 syndromes Pulmonary hemorrhage is rare, but respir atory dysfunction and/or radiological abnormalities are common in AKI. \200 Volume overlo ad with pulmonary oedema. \200 Infection: AKI may accompany pneumonia and vise versa. \200 A vasculitis patient receiving immunosup pressive therapy will be at risk of opportunistic infections, including fungi, viruses, and TB. Hantavirus. \200 Pulmonary emboli. \200 Acid \200\223 base disturbances. \200 Acute respiratory distress syndrome (ARDS). Hantavirus \200 Members of the Hantavirus family are widely distributed globaly and respo nsible for several clinical syndromes \200\224 often collectively referred to as \200\230 haemorrhagic fever with renal syndrome \200\231 . \200 Puumala virus (Scandinavia, Weste rn Europe) l milder renal disease. Hantaan virus (Russia, China) and Dobrava virus (Central and Western Europe) l more severe renal disease. Sin Nombre virus (North America) and Andes virus (South America) l cardiopulmonary syndrome. Spread: inhalation or contact (urine, feces) with infected rodents (vectors include mice, voles, shrews as well as rats). Person-to-person transmissio n rare. Infection can be associated with signi \201 cant morbidity and mortality, although <25% cases are severe ( 7 0.5% mortality for milder European forms, reaching 5 \200\223 10% for some others). Outbreaks can occur, e.g. during the Balkan war in the late 1990s. \200 Clinical features : Fever. \200 Respiratory failure (non-cardiogenic pulmonary oedema). \200 Systemic sepsi s (and shock). \200 AKI (proteinuria, haematuria, vascular endothelial damage, acute tubulointerstitial in \202 ammation). Diagnosis: clinical suspicion in endemic areas, serological testing, immunohistochemistry of biopsy material (including renal). Management: supportive. No speci \201 c antiviral therapy is effective. CHAPTER 1 Clinical assessment 74 Clinical syndromes: urine volume and urinary tract pain Changes in urine volume \200 Poly uria: >3L/24h. \200 Oliguria: <400mL/24h. \200 Anuria: <100mL/24h. Polyuria Excretion of a urine volume in excess of normal; >3L/day is an arbitrary cut-off. H 2 O excretion is tightly controlled, so daily volumes vary widely in an individual. It is usually frequency of micturition (especially overnight) s to the larger volume, rathe r than the volume itself, that causes the patient to pre- sent (although most patients with frequency do not have polyuria). Obtain a 24h urine collection for volume before undertaki ng further investigation. Polyuria is seen in three clinically important situations (see Ta ble 1.14): Excessive \202 uid intake. \200 Increased tubular solute load, e.g. hyperglycaemia. \200 Failure of the renal tubules to concentrate the urine (diabetes insipidus, b p. 789). Table 1.14 Conditions associated with polyuria i Fluid loss Renal tubular Nephrogenic diabetes insipidus, acquired tubular defect (e.g. caused by pyelonephritis, pos t-obstruction, chronic d K + , i Ca 2+ ), nephrotoxins (e.g. aminoglycosides, cisplatin, li thium), diuretics, Bartter \200\231 s syndrome, polyuric recovery phase of AKI Endocrine Central diabetes insipidus, Addison \200\231 s disease, hyporeninaemic hypoaldosteronism Osmotic diuresis i Fluid intake Psychological Glycosuria, mannitol, contrast agents Psychogenic polydipsia Oliguria Passage of a urine volume inadequate for excretion of the end products of metaboli sm. <400mL/24h ( 7 20mL/h). The causes of oliguria (and anuria) are analogous to those of A KI. Anuria Passage of <100mL/24h or the absence of urine \202 ow. 2 Address the following questions urgently if anuria: 1. Is the bladder catheter blocked? 2. Is the urinary tract obstructed? 3. Are the kidneys perfused? CLINICAL SYNDROMES: URINE VOLUME AND URINARY TRACT PAIN 75 Pain Loin pain \200 Renal pain is usually experienced in the loin near the costovertebral angle. Anterior radiation may cause confusion with intraperitoneal pain. \200 May also radiate t o the genitalia. \200 Usually associated with distension of the renal capsule and describ ed as a constant dull ache. Differential: nerve root irritation (commonly T10 \200\223 T12). \200 2 An aggressive an d a destructive renal disease may be painless. Ureteric colic \200 Sudden onset, extremely severe (pale, distressed, unable to settle) colic. Caused by a combination of ureteral stretching, local in \202 ammation, and hyperperistalsis (spasm of ureteral smooth muscle). Pain may not completely fade between exacerbations. Causes \200 Passage of a stone (common), blood clot, or sloughed papillae. \200 Uretera l pathology that develops slowly or produces only partial obstruction may be painless (small stone l excruciating colic; large, non-obstructing stagh orn calculus l no pain). Pattern of referred pain can sometimes help to determine the level of ureteric obstruction: \200 Upper ureter l loin \200 Mid-ureter l ipsilateral iliac foss a (may l testicle in \231\202 , labium in \231\200 , and upper thigh in both). Lower ureter l bladder irritability (frequency, dysuria, urgency) and suprapubic discomfort (may l urethra and tip of penis). The bladder Suprapubic pain \200 Usually overdistension of the bladder (acute retention) or local in \202 ammation (cystitis). Cystitis: signs of bladder irritability (below) and sharp, stabbing pain towards the end of voiding (strangury). Slowly progressive distension (e.g. neurogenic bladder) may cause no pain. Constant suprapubic pain, unrelated to retention, may not originate in the bladder. In \231\200 , consider gynecological causes. Bladder irritability \200 Dysuria, frequency, and urgency among the commonest symptoms encountered in clinical practice. Urinary infection, causing in \202 ammation of the urethra, trigone, and bladder, is (by far) the most frequent cause ( b p. 706). (cid:2) About one-third of patients with bladder cancer present with bladder irritability. CHAPTER 1 Clinical assessment 76 Clinical syndromes: tubular syndromes Introduction A degree of tubular dysfunction may occu r with any renal injury (though the clinical picture is usually dominated by d GFR). Severa l distinct clinical syndromes result from tubular defects in the context of a normal GFR. Generalized tubular dysfunction (Fanconi syndrome) Multiple tubular defects produce a disti nct clinical phenotype referred to as the Fanconi syndrome (unrelated to Fanconi \200\231 s anemia). Components may be present to a variable degree. Causes \200 Acquired: drugs (aminoglycosides, sodium valproate, ifosfamide, nucleoside re verse transcriptase inhibitors) and toxins (ethanol, cadmium, uranium, lead, mercury), myel oma, SLE, Sj gren \200\231 s. Mild forms of the syndrome are more common than was previ ously thought. \200 Inherited: cystinosis, tyrosinaemia, fructose intolerance, galactosae mia, glycogen storage disorder type I, cytochrome c oxidase de \201 ciency (all autosomal recessive). There is also an autosomal dominant idiopathic form of Fanconi syndrome. Dent \200\231 s disease and Lowe syndrome are X-linked Fanconi-like disorders. Features \200 Phosphaturia and bone disease: Impaired PO 4 reabsorption l phosphaturia l hypophosphataemia. \200 This, and impaired 1 A hydroxylation (activation) of 25-hydroxyvitamin D 3 in proximal tubular cells, produces skeletal abnormalities, including rickets (children), osteomalacia (adults), and osteoporosis. Aminoaciduria: Amino acids are usually \201 ltered at the glomerulus before reabsorption by multiple transportation carriers in the proximal tubule. \200 Fanconi syn drome l all amino acids appear in the urine in excess. \200 No clinically signi \201 can t sequelae and supplementation unnecessary. Glycosuria: Amount varies but serum glucose usually normal. \200 Clinical sequelae are rare, though h ypoglycaemia occurs in some forms (e.g. Fanconi \200\223 Bickel syndrome/glycogenosis). Renal tubular acidosis (RTA): Defective bicarbonate reabsorption in the proximal tubule results in systemic acidosis (a form of type II RTA, b p. 824). Na + loss: If severe l postural d BP, d Na + , and metabolic alkalosis result. \200 Salt supplementa tion occasionally necessary. Hypokalaemia: i delivery of Na + to the distal tubule l Na + reabsorption at the expense of K + excretion. CLINICAL SYNDROMES: TUBULAR SYNDROMES 77 Acidosis and RAS activation by volume depletion also l K + loss. \200 Clinical sequelae c ommon (muscle weakness, constipation, polyuria, cardiac arrhythmias) and supplementation often required. Proteinuria: LMW proteinuria is common ( B 2 microglobulin, lysozyme, and other tubular proteins), though excretion rates are usually low \200\223 moderate. Polyuria: Polyuria, polydipsia, and dehydration can be prominent. \200 Caused by d K + and impaired concentrating ability in the distal tubule. \200 Hypercalciuria: Rarely l nephrolithiasis/calcinosis (? protective effect of polyuria), although these may b e precipitated by treatment with vitamin D metabolites (further i urinary Ca 2+ ). Serum Ca 2+ usually normal. Isolated tubular defects Renal glycosuria \200 d proximal tubular glucose reabsorption l glycosuria (despite normal blood glucose). Clearance studies allow differentiation into different patterns implicating several defecti ve tubular transportation mechanisms. \200 The amount can be quite signi \201 cant (norm ally 1 \200\223 30g/24h) but generally a benign condition with no clinical sequelae. (cid:2) Always needs to be distinguished from DM. \200 Genetic mechanisms involved but in heritance unpredictable. Aminoaciduria \200 Causes: Inborn error of metabolism l i plasma levels and \200\230over \202 ow \200\231 . \200 Renal aminoaciduria secondary to defective tubular transportation mechanisms. Amino acid transportation is complex, involving transporters speci \201 c to single or chemically related groups of amino acids. The most important isolated aminoaciduria is cystinuria, an autosomal recessive cause of re current cystine stone formation ( b p. 719). Phosphaturia \200 Defective phosphate transportation l phosphaturia, hypophosphataemia, and disorders of the skeleton. Several described, including X-linked hypophosphataemic rickets (vitamin D-resistant rickets) and autosomal dominant hypophosphataemic rickets. FGF-23 excess, causing inhibition of phosphate reabsorption, is now known to underpin many of these disorders ( b p. 236). CHAPTER 1 Clinical assessment 78 Clinical syndromes: bladder out \202 ow obstruction Introduction \200 Main causes are sh own in Box 1.11. The likelihood of each is in \202 uenced by age and sex. Presentation is with: \200 Acute retention of urine. \200 Lower urinary tract symptoms (LUTS). LUTS are divided into two groups. Symptoms correlate poorly with underlying urinary patholo gy, so it is best to remain as descriptive as possible (see Table 1.15). (cid:2) Bladder out \202 ow obstruction (BOO) can be clinically silent in some patients, despite signi \201 cant residual bladder urine volumes and eventually progr essive urinary obstruction. Table 1.15 Symptoms of bladder out \202 ow obstruction Obstructive (voiding) symptoms Impaired size or force of stream Hesitancy or straining Inte rmittent or interrupted \202 ow Sensation of incomplete emptying Storage ( \201 lling) symptoms * Nocturia Daytime frequency Urgency Urge incontinence Dysu ria Also called irritative. \200\230 Prostatism \200\231 is no longer preferred to describe out \202 ow symptoms (ag e-matched \231\200 report similar symptoms). Examination Palpate for bladder enlargement; rectal examination, pelvic examination in \231\200 ; examine the legs neurologically, and test anal tone/sensation. Investigations \200 Urine M,C+S, U&E, and PSA (in males >40 years, b p. 772). \200 Imag ing. Bladder USS to measure residual volume post-micturition (correlation to out \202 ow obstruction is poor). Uro \202 owmetry. Full bladder emptied into a \202 ow meter to generate a \202 ow curv e (rate vs time). Normal max \202 ow >20mL/s. Further urodynamic assessment will distingu ish non-obstructive causes of low \202 ow (e.g. detrusor failure). Pressure - \202 ow studies (cystometrography). More sensitive and speci \201 c but invas ive. Bladder and rectal catheters record \201 lling and voiding bladder pressures (normog rams relate pressure to \202 ow). Videocystometrography. Fluoroscopic screening of the ureters, bladder, and urethra. Useful in the investigation of neurological bladder dysfunction. Retrograde urethrography. ? urethral stricture. CLINICAL SYNDROMES: BLADDER OUTFLOW OBSTRUCTION 79 Box 1.11 Causes of bladder out \202 ow obstruction \200 Congenital: Urethral valves and strictures. Structural: Benign prostatic hyperplasia ( b p. 758). \200 Carcinoma of the prostate ( b p. 766). \200 Bladder neck stenosis. \200 Urethral stricture. Functional: Bladder neck dyssynergia. \200 Neurological disease \200\224 spinal cord lesions, MS, di abetes. \200 Drugs \200\224 anticholinergics, antidepressants. Prostatic enlargement ( b p. 758) \200 Prostate size correlates poorly with degree of obs truction on urodynamic assessment. Impaired \202 ow is a function of two separate components: Dynamic: i sympathetic tone of prostatic smooth muscle. \200 Static: mass effect of enlar gement. CHAPTER 1 Clinical assessment 80 Renal biopsy: introduction Despite improvements in other diagnostic techniques, renal biops y and examination of histology retain pivotal roles in nephrology. Renal transplant biopsy is considered separately ( b p. 407). Indications ( b p. 82) \200 Unexplained acute or chronic kidney disease with normal renal size. \200 Histology is likely to in \202 uence treatment. \200 Histology is likely t o offer prognostic information. \200 Information concerning the activity (and potential r eversibility) and/or chronicity of a previously identi \201 ed lesion is desirable. Preparation for renal biopsy \200 (cid:2) Renal biopsy is an invasive procedure. An evalu ation of the risk-bene \201 t ratio is required in every case. Imaging: con \201 rm two normal-sized, unobstructed kidneys with normal parenchyma. BP <160/90mmHg; preferably <140/90mmHg. \200 Hb ideally >100g/L. \200 Normal clotting ( PT and APTT <1.2 x control). Platelet count >100 x 10 9 /L. Send group and save. \200 Antiplatelet agents and anticoagulants stopped >5 days prior to procedure. Ideally, do not restart for 7 days post-biopsy. Sterile urine. \200 Informed consent. Give appropriate written or visual patient information. If renal impairment, the risk of bleeding increases 7 2 \200\223 3-fold. \200 Most units will have their own policy, e.g. if urea \211 20mmol/L (55mg/ dL) or SCr \211 250 m ol/L (2.8mg/dL) or bleeding time >10min, give DDAVP 0.4 micrograms/kg IV 2 \200\223 4h pre -biopsy ( (cid:2) not if recent or ongoing angina). Contraindications \200 Uncorrected bleeding tendency (absolute contraindication). \200 Chronic kidney disease with small kidneys. \200 Multiple cysts. \200 Suspected renal ma lignancy ( b p. 743). \200 Hydronephrosis. \200 Active urinary infection. \200 Uncont rolled hypertension (>160/95mmHg). \200 Hypotension. \200 Signi \201 cant anemia. \200 Uncooperative patient. \200 Solitary kidney (only a relative contraindication). RENAL BIOPSY: INTRODUCTION 81 Technique \200 Performed percutaneously under LA via a posterior approach. \200 Sedatio n is generally avoided, as patient cooperation is essential. \200 Patient lies prone, wit