GFR MEASUREMENT: OTHER METHODS 37 Urea \200 Synthesized in the liver as a means of ammonia excretion. \200 Rate of produc tion not constant (unlike SCr). \200 Inverse relationship with GFR. \200 In \202 uence d by a number of factors independent of GFR (see Table 1.4). Freely \201 ltered at the glomerulus but reabsorbed in the tubules: Urea movement is linked to water (under vasopressin in \202 uence) in the distal nephron. d renal perfusion l i urea reabsorption l disproportionate i urea compared to SCr. May help to differentiate \200\230pre-renal \200\231 renal dysfunction ( b p. 96). Table 1.4 In \202 uences on urea i Ur \200 High dietary protein intake \200 GI bleeding \200 Catabolic states \200 H emorrhage \200 Trauma \200 Corticosteroids d Ur \200 Low protein diet \200 Liver disease \200 Pregnancy Tetracyclines CHAPTER 1 Clinical assessment 38 Renal function in the elderly The kidneys suffer signi \201 cantly at the hands of the age ing process, with senescence associated with progressive glomerular and tubulointerstitial scarring, nephron loss, declining renal function, and downstream conse- quences for systemi c haemodynamics. These changes begin (depressingly) in the 4th decade and hasten during the 5th and 6th, with increasing clinical relevance. Pathology Macroscopic features include thinning of the renal cortex and an overall decrease in renal size. Glomerular Basement membrane thickening, mesangial matrix expansion, capillary loop changes , periglomerular \201 brosis, glomerular hypertrophy, glomeru- losclerosis ( 7 30% by age 80). Tubular Dilatation and atrophy (particularly in outer medulla), macrophage in \201 l tra- tion, and collagen deposition l interstitial \201 brosis. Vascular Intimal hyperplasia ( l stiffness) of interlobular arteries and afferent arteriole s. Pathophysiology \200 Glomerular hyper \201 ltration and hypertrophy l glomerular scleros is and scarring l further glomerular hyper \201 ltration and hypertrophy. \200 Intrarena l RAS activation l i A2 l intrarenal (including podocyte) injury. Endothelial dysfunction l d NO production l hypoxic and ischaemic damage. TGF- B overexpression l \201 brosis. \200 i oxidative stress l tissue damage. \200 AG E accumulation. \200 Arteriolar hyalinosis l failure of autoregulation l glomerular injur y. \200 General biological senescence: telomere shortening, mitochondrial loss, and enhanced apoptosis. Effect on renal function GFR The Baltimore longitudinal study (1958 \200\223 1981) used se rial measurements of CrCl to show a d GFR of 0.75mL/min/year. Recent studies have used inul in clearances to show that, although GFR progressively falls in older age groups ( \231 \202 > \231\200 ), it is not necessarily an inevitability. There may be no demonstrable de cline in normotensive, otherwise healthy, individuals, so it remains important to consider the effect associated comorbidities ( i BP, vascular disease, CCF, etc.) may be having over and above age itself. RENAL FUNCTION IN THE ELDERLY 39 Assessment of GFR SCr is less useful in the elderly because of (i) d muscle mass and (ii) d urinary Cr excretion. This means that formulas based on SCr (including MDRD, Cockcroft \200\223 Gault, and CKD-EPI) tend to underestimate GFR in those age >65 (and are not actual ly robustly validated in this population). Additional effects of renal ageing \200 d renal plasma \202 ow. \200 Microalbuminuria and overt albuminuria more common. \200 Regulation of Na + balance is impaired ( d excre tion l contributes to i BP in the context of a high-salt western diet). i K + more common ( d excretion and d aldosterone). The elderly are 6 vulnerable to the eff ect of any medication interfering with K + excretion (such as ACE-I). Water handling (both diluting and concentrating) ability is impaired. Potential consequences: \200 Nocturia is very common. \200 Inappropriately dilute urine (and reduced thirst response) despite i plasma osmolality l dehydration. Inadequate excretion following water load l hyponatraemia. Impaired distal tubular acidi \201 cation ( l mild acidosis). \200 i EPO production (alt hough the increase in response to a low Hb is actually blunted). Effects on mineral metabolism: i PTH, d calcitriol, and d PO 4 . Clinical relevance \200 d muscle mass in the elderly l d SCr. \200 2 i SCr in an elderl y patient usually represents a signi \201 cant d GFR. \200 Although age-related d GFR is common anyway, it will be exaggerated in the presence of comorbidity, such as i BP and vascular disease. X CKD is common in the elderly: In NHANES (1999 \200\223 2004), nearly 7 45% of elderly subjects had CKD ( b p. 194) by cu rrent criteria, with those aged >70 accounting for 50% of CKD overall. However, is early CKD relevant in this age group? For example, GFR 50 \200\223 59mL/min does not increase CV mortality in comparison to >60mL/min? In view of this, many believe CKD is an unhelpful term in the majority of individuals in this age group. The incidence and prevalence of ESRD is higher in the elderly (mean age of RRT is mid-60s). AKI and acute-on-chronic kidney disease are both more common. \200 The elderly are more v ulnerable to the effects of nephrotoxic drugs. \200 The elderly are also more prone to el ectrolyte imbalances occurring through disease or inappropriate medical management (e.g. indisciplined perioperative \202 uid therapy). CHAPTER 1 Clinical assessment 40 Immunological and serological investigation Introduction Immunological and serological test ing are widely (perhaps too widely) undertaken in the work-up of many forms of renal diseas e. Although help- ful, such tests are rarely diagnostic in isolation and must always be int er- preted in the context of a detailed clinical assessment. There are a few common scenarios where the \200\230renal screen \200\231 is often performed (see Table 1.5): \200 Unexplained AKI ( b p. 119) or progressive CKD. \200 Fo r correlation with histology after a renal biopsy ( b p. 82). \200 During follow-up to as sess disease activity or response to treatment. Table 1.5 Immunological testing in kidney disease Clinical context Investigation ANCA (b p. 640) Anti-GBM (b p. 656) ANA, anti-dsDNA (b p. 659) Complement com ponents C3, C4 AKI where RPGN a possibility (b p. 71). Consider: ANCA, anti-GBM Microscopic haematuria Consider: ANA, anti-dsDNA C3, C4 With consent: HBV, HCV, HIV serology Age >40: Serum protei n electrophoresis (SPEP) Urine protein electrophoresis (UPEP) Serum free light chains (SFLC ) Proteinuria Proteinuria with microscopic haematuria As above, plus: ANCA, anti-GBM ANA, anti-dsDNA, C3, C4 Age >40: SPEP, UPEP, SFLC With consent: HBV, HCV, HIV serology Nephrotic syndrome (with or without evidence of a multisystem disease) Unexplained CKD (particularly older age groups) SPEP, UPEP Suspected lymphoproliferative disorder SPEP, UPEP, SFLC, cryoglobulins Thrombotic microangiopathy (diarrhea-negative) Anti-ADAMTS13 IMMUNOLOGICAL AND SEROLOGICAL INVESTIGATION 41 Complement and the kidney (See Tables 1.6 and 1.7.) \200 Common investigations are immuno assays for C3 and C4 and a functional assay for the total haemolytic component (CH50). \200 C3 and C4 measure circulating amount, while CH50 assesses activation (it measures the 50% red cell haemolysing dose of complement). C3 and C4 can be used to screen for classical and alternative pathway abnormalities, with d iseases associated with high levels of circulating immune complexes associated with hypocom plementaemia. Low C3 implies tissue injury, with activation of either the classical or alternative complement pathway. Low C4 implies activation of the classical pathway (or a hereditary null allele). CH50 is a good screen for overall complement activity (e.g. a patient with recurrent infections). C3 nephritic factor (C3Nef) \200 A circulating IgG autoantibody against C3 convertase. \200 It acts to stabilize C3 convertase to augment its function and increase the consumption of C3. Associated with MCGN type II (dense deposit disease). \200 Measure when GN is associated with a persistently low C3. Factor H \200 An alternative pathway regulatory protein. \200 Genetic de \201 ciency i s associated with familial haemolytic uraemic syndrome and predisposes to MCGN type II. Table 1.6 C3, C4, and C50 in relation to kidney disorders Disorder C3 and C4 d C3, d C4, d CH50 SLE d C3, d C4, d CH50 Infective endocarditis d C3, d C4, d CH50 d C3, d/n C4, d CH50 Shunt nephritis Post-strep GN Essential mixed cryoglobulinaemia n C3, d C4, d CH50 d C3, n C4, d CH50 MCGN type II ? C3 nephritic factor CHAPTER 1 Clinical assessment 42 Table 1.7 Antigens and their associations Antigen Double-stranded DNA Sm (Smith) Ro/SSA and La/SSB Scl-70 Centromere RNA polymerase R NP Association SLE SLE SLE, Sj gren \200\231s syndrome Diffuse systemic sclerosis (SSc) Limit ed cutaneous SSc (CREST) Renal involvement in systemic sclerosis Mixed connective tissue di sease IMMUNOLOGICAL AND SEROLOGICAL INVESTIGATION 43 CHAPTER 1 Clinical assessment 44 Diagnostic imaging: X-ray Introduction To select the most appropriate investigation (and ma intain healthy rela- tions with the radiology department), the requesting clinician should understand the indications and limitations of imaging in renal disease. Plain X-ray \200 \200\230 KUB \200\231 (kidneys \200\223 ureter \200\223 bladder). Es sentially, a supine AXR centered on the umbilicus. Main role is identi \201 cation and surveillance of calci \201 cation (see Box 1.9). Lateral and oblique \201 lms may differentiate calci \201 cation in line with , as opposed to in , the renal tract. The medial edges of both psoas muscles are usually visible \200\224 disappearance suggests a perinephric mass or retroperitoneal collection. Tomography keeps one particular image plane in focus, blurring out images in front and behind. Moving the plane can produce serial \200\230cuts \200\231 tha t detect small calculi. Now largely superseded by CT. \200 (cid:2) Remember the radiation exposure of an AXR is 35 x that of a CXR. Where are the kidneys on a plain AXR? \200 Differences in attenuation between renal tissu e and perinephric fat mean that the kidneys are (just) visible. Usually adjacent to the upper border of the T11 through to the lower border of L3. Normal renal size is 11 \200\223 15cm (in adults). Kidneys appear bigger on an AXR than on ultrasound. Right kidney usually shorter than the left (upper limit of variation in length between right and left 1.5cm). DIAGNOSTIC IMAGING: X-RAY 45 Box 1.9 Causes of renal tract calci \201 cation Urinary calculi Most are radio-opaque to s ome degree; exceptions are pure uric acid and xanthine stones. Localized calci \201 cation \200 Tuberculosis. \200 Tumors. Nephrocalcinosis Medullary: \200 Disturbed calcium metabolism: Hyperparathyroidism. \200 Sarcoidosis. \200 Vitamin D excess. \200 Idiopathic hyperca lciuria. \200 Oxalosis. * \200 Tubular diseases: Distal renal tubular acidosis. \200 Bartter \200\231 s syndrome. Other: Medullary sponge kidney. \200 Papillary necrosis. Cortical: \200 Trauma. \200 Cortical necrosis. \200 Oxalosis. * Causes both medullary and cortical calci \201 cation. CHAPTER 1 Clinical assessment 46 Diagnostic imaging: ultrasound Introduction A front-line investigation in many forms of ren al disease. Pros: provides real-time two-dimensional images, non-invasive, relatively quick , and requires little patient preparation. Cons: operator-dependent, poor pelvi-ureteric de tail, no functional information, may miss small stones and masses, and only limited \200 \230snapshot \200\231 images are usually stored for later review. Main uses \200 Document one or two kidneys. \200 Diagnosis of obstruction (pelvicalycea l dilatation). \200 Measurement of renal size in CKD (see Table 1.8 for causes of abnormal renal size). Evaluation of renal masses (cystic vs solid). \200 Screening for polycystic disease. \200 Identify nephrocalcinosis and calculi. \200 Evaluate bladder emptying. \200 Estim ate prostate size (may require a transrectal approach). \200 Guide percutaneous procedure s (e.g. renal biopsy, nephrostomy). \200 Doppler USS can be used to evaluate arterial and venous blood \202 ow. Widely used for transplant assessment, but role as a screening too l in renovascular diseases uncertain ( b p. 586). (See Fig. 9.1 for USS of obstructed kidne y.) Normal appearances \200 Renal length 9 \200\223 12cm. \200 Smooth outline. \200 Cort ex >1.5cm. \200 Echotexture: Medulla darker than cortex. \200 d Corticomedullary differentiation with i age and parenc hymal disease (e.g. acute GN) ( (cid:2) often over-reported and over-interpreted). Pelvicalyceal (PC) system poorly visualized. \200 Bladder examined when full. Normal blad der wall thin and hard to delineate. DIAGNOSTIC IMAGING: ULTRASOUND 47 Table 1.8 Causes of abnormal renal size on imaging Large kidneys \200 Unilateral: \200 Tumor. \200 Cyst. \200 Unilateral hydronephrosi s. \200 Compensatory hypertrophy. Bilateral: Polycystic kidney disease (and other cystic diseases). \200 In \201 ltration (e.g. lymph oma). Small kidneys \200 Unilateral: Congenital hypoplasia. \200 Renal artery stenosis. Bilateral: Small smooth kidneys: \200\224 Chronic glomerulonephritis. \200\224 Chronic interstitial nephritis. \200\224 V irtually any chronic renal disorder, except diabetic nephropathy. Small irregular kidneys: \200\224 Re \202 ux nephropathy. \200\224 Congenital dysplastic syndromes. \200\224 TB. \200\224 Renal infarction. CHAPTER 1 Clinical assessment 48 1 2 a b 3 4 c a b b 5 6 d a e c 7 a b Fig. 1.7 CT scanning in renal disease. 1. Abdominal CT scan without contrast showing a calc ulus in the mid-ureter with stranding around it (arrow). 2. CT scan without contrast showin g (a) a dilated pelvis and (b) perirenal stranding. 3. CT scan without contrast demonstrati ng a small solid lesion (arrow) containing fat (low attenuation), therefore, most likely to be an angiomyolipoma. 4. CT scan with contrast demonstrating (a) a normal right kidney, (b ) a left renal tumor, and (c) remaining normal renal parenchyma on the left. 5. Reconstruct ed CT scan with contrast demonstrating (a) a normal right kidney, (b) a renal tumor in the left upper pole, (c) normal lower pole of the left kidney, (d) normal liver, and (e) spleen . 6. CT scan demonstrating multiple bladder tumors (arrowheads). 7. CT urogram demonstratin g (a) contrast in the right collecting system and (b) a \201 lling defect in the collecti ng system, consistent with a transitional cell carcinoma. Reproduced from Barrett, J, Harri s, K, Topham, P. Oxford Desk Reference of Nephrology (2008), with permission from Oxford Un iversity Press. DIAGNOSTIC IMAGING: ULTRASOUND 49 CHAPTER 1 Clinical assessment 50 Diagnostic imaging: CT and MRI CT Increased availability, better image resolution, and prog ressively shorter scanning times have signi \201 cantly increased the routine use of CT fo r the investigation of the urinary tract (see Fig. 1.7 for CT scans). Indications \200 Characterization of a renal or perirenal mass: Differentiation of simple cysts from tumors ( b p. 742). Tumor staging. \200 Delineation of renal or perirenal collections and abscesses. \200 D etection of renal and ureteric calculi (CT-KUB) ( b p. 724). \200 Trauma: de \201 nes ex tent of renal and associated intra-abdominal injuries. Retroperitoneal disease: Abdominal aorta, adrenal glands, retroperitoneal masses, \202 uid collections, lymphadenopathy. Investigation of choice in retroperitoneal \201 brosis ( b p. 739). Obstruction: presence, level, and etiology ( b p. 732). \200 Parenchymal infection: Pyelonephritis may not show on USS or IVU. \200 Exclude associated pyonephrosis. \200 X Renovascular disease ( b p. 586). Standard renal CT with contrast Performed for the majority of the indications. (cid:2) See Box 1.10, Contrast media ( b p. 53). CT-KUB Performed without contrast to identify calculi. CT-IVU Contrast scan with sequences that focus on PC system and ureters. Renal CT angiography (CTA) Software reconstructs 3D images of the intra-abdominal vasculatu re. Electron beam CT (EBCT) Specialist tool for monitoring vascular, especially coronary, calci \201 cation ( b p. 242). MRI Indications \200 Evaluation of a renal mass and tumor staging: \200 In selected cas es, e.g. venous invasion. \200 MR urography (the MR equivalent of an IVU). DIAGNOSTIC IMAGING: CT AND MRI 51 Renal insuf \201 ciency: Gadolinium is not nephrotoxic and is also safe if there has been a previous allergic reacti on to iodinated contrast. 2 However, gadolinium has been associated with the development of nephrogenic systemic \201 brosis (NSF). MR angiography: X Detection of renovascular disease ( b p. 586). Gadolinium and nephrogenic systemic \201 brosis \200 The MR contrast agent gadolinium ( Gd) has been implicated in the development of nephrogenic systemic \201 brosis (NSF). NSF is a rare, painful, and often disabling, skin lesion that can progress to involve inter nal organs (including muscle, heart, and lungs). It was \201 rst described in the late 19 90s and only occurs in renal failure. \200 The dermopathy appears scleroderma-like: eryth ema, plaques, induration, and peau d \200\231 orange, with the lower legs and forearms initially affecte d. Subsequent periarticular tissue involvement leads to contractures and immobility. Pathology: CD34 +ve \201 brocyte proliferation, with dermal thickening. Gd may be detecte d in the lesions. Exact pathophysiology uncertain; however, Gd tissue deposition, with TGF- B -induced \201 brosis and \201 brocyte collagen production, appears important. \200 Gd exposure has been implicated in >95% cases: Free Gd is relatively water-insoluble (and highly toxic) so requires chelation for in vivo use. These chelates may be ionic or non-ionic and linear or cyclical. \200 Ionic and cyclic fo rms bind Gd more avidly, perhaps explaining an apparent variance in risk between preparations, e.g. higher for gadodiamide and gadopent etate. Gd chelates are renally excreted, so half-life is GFR-dependent. \200 NSF incidence incre ases greatly below GFR <30mL/min. \200 Most reports have been in dialysis patients. \200 Peritoneal dialysis (PD) patients may be at higher risk. \200 Risk is probably <5% for an ESRD patient exposed to Gd. Prevention: If GFR <30mL/min (and especially GFR <15mL/min), Gd exposure should be limited to situations where it is deemed essential. \200 Avoid chelates that ar e more strongly associated with NSF, and limit the administered dose. If already on maintenance haemodialysis, many dialyse the patient immediately after exposur e (and again at 24h). This reduces Gd half-life, but additional evidence of bene \201 t is lacking. X Some advocate haemodialysis for patients with stage 5 CKD (eGFR <15mL/min), even if not already established on maintenance RRT. In con \201 rmed disease, transplantation offers the best chance of improvement. Cases should be reported to the International NSF Registry (M http://www.icnfdr.org ). CHAPTER 1 Clinical assessment 52 Diagnostic imaging: IVU Intravenous urography Provides a good overview of the urinary tract , particularly the PC sys- tem and ureters. Good for detecting calculi. However, the growth of CT, including CT urography, has seen a very signi \201 cant decline in use (see Fig. 1 .8 for IVU scan). The procedure \200 Ensure good bowel prep, NBM for 4h pre-procedure. If GFR normal, a \202 uid restriction of 7 500mL/prior 24h assists contrast concentration ( (cid:2) dangerou s if d GFR 6 often avoided). Includes ( \201 lm sequence altered, according to clinical situation): Plain control \201 lm (? opacities pre-contrast). \200 Post-contrast: bilateral nephrog rams (delayed: poor perfusion, obstruction, ATN, venous thrombosis), renal outline (? ischaemic scars, re \202 ux, TB). Further exposures at 5 and 10min (PC \201 lling defects: clot, tumor, sloughed papilla, stone. PC deformity: re \202 ux). Mild abdominal compression delays contrast excretion and may improve PC system views. Post-voiding \201 lm to assess bladder out \202 ow. \200 Delayed \201 lms (2, 6, 12, and 24h) may establish a level of obstruction. Modi \201 cations \200 IVU with furosemide: furosemide exaggerates and distinguishes PUJ obstruction from normal anatomical variants ( \200\230 baggy \200\231 pelvis). \200 Hig h-dose IVU: used if d GFR limits contrast excretion. Largely redundant where USS and CT are available. Metformin There is often apprehension that continued metformin use prior to IV contrast adm inistration may contribute to contrast-induced AKI (CI-AKI) ( b p. 148) post-procedure. It is important to remember that metformin is not nephrotoxic. However, it does undergo ren al excretion and may accumulate, poten- tially causing a severe lactic acidosis, if GFR det eriorates post-contrast. The pre-contrast withdrawal of metformin does not reduce the risk of CI-AKI, but, if CI-AKI develops, metformin should be stopped imme- diately \200\224 wit h glycaemic control achieved by other means until GFR recovers. Those with pre-existing signi \201 cant renal impairment (eGFR <30mL/ min) who are at part icular risk of CI-AKI should almost certainly not be taking metformin anyway. This can be c lari \201 ed with the responsible clinician. An eGFR of 30 \200\223 60mL/min is a gray ar ea, but there is no current recommendation to stop metformin, as long as the patient is sup ervised appropriately through the contrast procedure ( b p. 149). DIAGNOSTIC IMAGING: IVU 53 c i rp c u Fig. 1.8 IVU: magni \201 ed view of the left kidney. Calyx (c), infundibulum (i), renal pe lvis (rp), proximal ureter (u). Calyx which projects posteriorly is seen en face (arrow). N ormal fold of the ureter at the ureteropelvic junction (curved arrow). Reproduced with perm ission from Davison AMA, Cameron JS, Grunfeld J-P et al . (eds) (2005). Oxford Textbook of Clinical Nephrology , 3rd edn. Oxford: Oxford University Press. Box 1.10 Contrast media \200 Organic radio-opaque iodides excreted by glomerular \201 l tration. \200 Modern non-ionic, iso-osmolar agents are better tolerated than their ionic, hyperosmolar ( 7 1500mOsmol/kg) predecessors. Minor contrast reactions (urticaria, itching, nausea, vomiting, sneezing, metallic taste) common (5 \200\223 10%), especially if history of allergy. Usual ly self-limiting, but antihistamines may help. Not necessarily associated with reaction on re-challenge. 2 Severe reactions: d BP, shock, pulmonary oedema, bronchospasm, and anaphylaxis. 3 Access to resus equipment is mandatory. Mortality historically estimated as 1 in 30,000 to 1 in 75,000 but lower with non-ionic media. Corticosteroids (e.g. prednisolone 30mg bd for 24h pre- + post-procedure) are often used if history of atopy or asthma ( (cid:2) but do not guarantee non-reaction). Nephrotoxicity is dose-dependent and i if dehydration, DM, pre-existing d GFR, i age, poor CV function ( b p. 148). Prevention of nephrotoxicity and AKI is discussed on b pp. 148 \200\223151. CHAPTER 1 Clinical assessment 54 Diagnostic imaging: nuclear medicine Introduction Nuclear techniques provide functional, as well as structural, information and can complement other imaging modalities. Three types: \200 GFR estimation (e.g. 51 Cr-EDTA ) ( b p. 36). \200 Dynamic (e.g. 99m Tc-DTPA, 99m Tc-MAG 3): serial scans track renal uptake, transit, and excretion of an isotope. A time-activity curve is generated. Static (e.g. 99m Tc-DMSA): isotope is taken up and retained within functioning tissue. Demo nstrates non-functioning ( \200\230 scarred \200\231 ) renal tissue. See Fig. 1.9 for diu retic renogram. Radiopharmaceuticals \200 99m Tc-DTPA. Filtered at the glomerulus and neither reabsorbed nor secreted by the tubules. A good marker of GFR but limited utility in more severe renal impa irment (e.g. SCr >200 mol/L (72.2mg/dL)). \200 99m Tc-MAG 3. Principally excreted by tub ular secretion so useful if d GFR. Less background uptake than DTPA but more expensive. 99m Tc-DMSA. Filtered at the glomerulus, then reabsorbed and retained in the proximal tubules. Subsequent excretion is slow. Used for parenchymal imagin g. Applications \200 Function of each kidney (termed \200\230split function \200\231) (DTPA , MAG 3, DMSA). \200 Congenital abnormalities (DMSA), e.g. horseshoe kidney, ectopic pelvic kidneys. Chronic pyelonephritis and vesicoureteric re \202 ux (DMSA) ( b p. 712): Focal scarring (more than one cause). \200 DTPA-cystogram: re \202 ux follow-up and sibl ing screening. Renal transplantation: perfusion and obstruction. \200 Acute kidney injury ( b p. 120). \200 Dilated vs obstructed renal pelvis: A dilated pelvis may not indicate true obstruction. \200 Diuretic renography (DTPA or MAG 3) may differentiate the two. Arterial occlusion (DTPA, MAG 3): failure of perfusion. \200 Captopril renography in reno vascular disease ( b p. 586): \200 In renal artery stenosis (RAS), perfusion and 6 GFR ar e maintained by A2-mediated efferent arteriolar constriction. ACE-I administration will block this and alter the uptake and excretion of DTPA or MAG 3. A positive scan suggesting RAS: \200\224 Asymmetry of size and function. \200\224 Delayed time to peak activity. \200 \224 Cortical isotope retention. DIAGNOSTIC IMAGING: NUCLEAR MEDICINE 55 Sensitivity d if bilateral disease, d GFR, or pre-existing ACE-I therapy (stop 4 \200\223 5d prior). Progressively superseded, as image reconstruction in CT and MR angiography has improved. A B cps 180 L R 120 60 0 0 400 800 1,200 Seconds C Fig. 1.9 Diuretic renography. Posterior views after 1 minute demonstrate preserved parenchy mal function. The right kidney is normal, but the left appears dilated (A). The left (upper trace) and right (lower trace) renograms con \201 rm nearly symmetric uptake of tracer, b ut abnormal out \202 ow on the left (B). Images obtained after 20 min, post micturition an d 50 min (from left to right) show residual activity within the left renal pelvis (C). Adap ted from the Journal of Nucl Med 2006; 47, 11 (p1823) with the kind permission of the Socie ty of Nuclear Medicine and Molecular Imaging (SNMMI). CHAPTER 1 Clinical assessment 56 Diagnostic imaging: angiography and uroradiology Renal angiography Remains the gold standar d investigation in renovascular disease, despite increasing promise within the chasing pack . Technique A retrograde catheter is passed under \202 uoroscopic guidance via a femoral pu ncture. A \202 ush aortogram reveals number and location of renal arteries before selecti ve catheterization (intravenous digital subtraction angiogra- phy (IVDSA) is generally inad equate). Contrast nephrotoxicity ( b p. 148) is a concern, and CO 2 has been used as an alt ernative to iodinated media. Indications \200 Renovascular disease: Invasive 6 not an ideal screening test ( b p. 586). \200 May be preferred when clinical s uspicion for RAS is high, and there is an intention to proceed immediately to angioplasty and endovascular stenting. Acute renal ischaemia: Acute emboli or thrombosis, traumatic occlusion, dissection. \200 Therapeutic interventio n (e.g. thrombolysis) may be possible. Unexplained haematuria: Vascular lesions (e.g. AVM, angioma). May allow embolization. Classical polyarteritis nodosa (PAN) ( b p. 652): Intrarenal microaneurysms. Renal transplantation: Evaluation of donor anatomy prior to live kidney donation ( b p. 374), although most now perform CT angiography in this situation. Bleeding post-renal biopsy: Identify bleeding source ( 9 therapeutic embolization). Uroradiology Urethrography and cystography \200 Contrast l urethra 9 bladder. \200 Indi cations: trauma, urethral stricture, bladder diverticulae or \201 stulae. \200 CT cysto graphy increasingly used. Micturating cystourethrography (MCUG) \200 A contrast- \201 lled bladder and urethra are visualized during voiding. \200 Gold standard for diagnosis of VUR ( b p. 712). \200 D emonstrates re \202 ux and dilatation/distortion of the ureters and PC system. Pressure- \202 ow videocystometrography involves measurement of bladder pressures and urin e \202 ow rate, in addition to imaging. DIAGNOSTIC IMAGING: ANGIOGRAPHY AND URORADIOLOGY 57 Retrograde ureteropyelography \200 The ureteric ori \201 ces are cystoscopically cannula ted and contrast injected under \202 uoroscopic screening. Ureter, PUJ, and PC system can be visualized. \200 May precede insertion of a retrograde ureteric stent. Antegrade ureteropyelography (percutaneous nephrostomy) \200 A needle is placed percutane ously into the renal pelvis under \202 uoroscopic or USS guidance. Contrast media is injected to evaluate PC, ureteric, and bladder anatomy. Urine l culture and cytology. \200 Pressure studies can be undertaken in suspected PUJ ob struction (Whitaker test) ( b p. 736). Indications: relief of urinary obstruction ( b p. 734), dilation of ureteric strictures, antegrade stent placement, removal of calculi. Ileal loopography \200 The loop is \201 lled with contrast, following the introduction of a Foley catheter. Upper tract dilatation is common after ileal diversion and free re \202 ux of contrast into the ureters is almost universal \200\224 if not present, obstruction at t he ureteric insertion (most common site) should be suspected. Cystourethroscopy, ureteroscopy, and ureterorenoscopy \200 Cystourethroscopy or cystoscop y involves a visual inspection of the inside of the urethra and bladder, using either a \202 exible (outpatient, no need for anesthetic, little capacity to biopsy) or rigid (inpat ient, anesthetic, can biopsy if necessary) cystoscope. \200 Undertaken by urologists, rat her than radiologists. \200 Indications include: Investigation of micro- and macroscopic haematuria. \200 Recurrent UTIs. \200 Unexplain ed lower tract symptoms. \200 Surveillance of bladder tumors. Flexible ureterorenoscopy involves passing a small \202 exible \201 breoptic transureth ral endoscope through the bladder and as far up as the renal pelvis. Rigid ureteroscopy does not generally reach this distance and generally requires a general anesthetic, although it does allow biopsies to be taken. CHAPTER 1 Clinical assessment 58 Clinical syndromes: proteinuria \200\224 introduction Protein excretion <150mg/d is normal . 7 30mg of this is albumin; the rest is LMW protein, including B 2 microglobulin, enzymes, and peptide hormones. A small proportion is secreted by the renal tubules, includ- ing Tam m \200\223 Horsfall mucoprotein (uromodulin) (see Table 1.9; see also b p. 20). Why is abnormal proteinuria important? \200 It is a marker of intrinsic renal disease, pa rticularly glomerular injury. \200 It is a risk factor for the progression of renal insuf \201 ciency. \200 It is an independent risk factor for CV morbidity and mortality 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.