Immunological and serological
IMMUNOLOGICAL AND SEROLOGICAL INVESTIGATION 41
Complement and the kidney (See Tables 1.6 and 1.7.)
• Common investigations are immunoassays for C3 and C4 and a functional assay for the total haemolytic component (CH50).
• 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 diseases associated with high levels of circulating immune complexes associated with hypocomplementaemia.
• 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)
• A circulating IgG autoantibody against C3 convertase.
• It acts to stabilize C3 convertase to augment its function and increase the consumption of C3.
• Associated with MCGN type II (dense deposit disease).
• Measure when GN is associated with a persistently low C3.
Factor H
• An alternative pathway regulatory protein.
• Genetic defi ciency is 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
SLE d C3, d C4, d CH50
Infective endocarditis d C3, d C4, d CH50
Shunt nephritis d C3, d C4, d CH50
Post-strep GN d C3, d/n C4, d CH50
Essential mixed cryoglobulinaemia n C3, d C4, d CH50
MCGN type II d C3, n C4, d CH50
? C3 nephritic factor
Table 1.7 Antigens and their associations
Antigen Association
Double-stranded DNA Sm (Smith) Ro/SSA and La/SSB Scl-70
Centromere RNA polymerase RNP
SLE SLE
SLE, Sjögren’s syndrome Diffuse systemic sclerosis (SSc) Limited cutaneous SSc (CREST) Renal involvement in systemic sclerosis Mixed connective tissue disease
IMMUNOLOGICAL AND SEROLOGICAL INVESTIGATION 43
Diagnostic imaging: X-ray
Introduction
To select the most appropriate investigation (and maintain healthy rela-tions with the radiology department), the requesting clinician should understand the indications and limitations of imaging in renal disease.
Plain X-ray
• ‘ KUB ’ (kidneys – ureter – bladder). Essentially, a supine AXR centred on the umbilicus.
• Main role is identifi cation and surveillance of calcifi cation (see Box 1.9). Lateral and oblique fi lms may differentiate calcifi cation in line with , as opposed to in , the renal tract.
• The medial edges of both psoas muscles are usually visible — 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 ‘cuts ’ that detect small calculi. Now largely superseded by CT.
• Remember the radiation exposure of an AXR is 35 x that of a CXR.
Where are the kidneys on a plain AXR?
• Differences in attenuation between renal tissue 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 – 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 calcifi cation Urinary calculi
Most are radio-opaque to some degree; exceptions are pure uric acid and xanthine stones.
Localized calcifi cation • Tuberculosis.
• Tumours.
Nephrocalcinosis Medullary:
• Disturbed calcium metabolism:
• Hyperparathyroidism.
• Sarcoidosis.
• Vitamin D excess.
• Idiopathic hypercalciuria.
• Oxalosis. *
• Tubular diseases:
• Distal renal tubular acidosis.
• Bartter ’ s syndrome.
• Other:
• Medullary sponge kidney.
• Papillary necrosis.
Cortical:
• Trauma.
• Cortical necrosis.
• Oxalosis. *
* Causes both medullary and cortical calcifi cation.
Diagnostic imaging: ultrasound
Introduction
A front-line investigation in many forms of renal disease. Pros: provides real-time two-dimensional images, non-invasive, relatively quick, and requires little patient preparation. Cons: operator-dependent, poor pelvi-ureteric detail, no functional information, may miss small stones and masses, and only limited ‘snapshot ’ images are usually stored for later review.
Main uses
• Document one or two kidneys.
• Diagnosis of obstruction (pelvicalyceal dilatation).
• Measurement of renal size in CKD (see Table 1.8 for causes of abnormal renal size).
• Evaluation of renal masses (cystic vs solid).
• Screening for polycystic disease.
• Identify nephrocalcinosis and calculi.
• Evaluate bladder emptying.
• Estimate prostate size (may require a transrectal approach).
• Guide percutaneous procedures (e.g. renal biopsy, nephrostomy).
• Doppler USS can be used to evaluate arterial and venous blood fl ow.
Widely used for transplant assessment, but role as a screening tool in renovascular diseases uncertain ( b p. 586). (See Fig. 9.1 for USS of obstructed kidney.)
Normal appearances
• Renal length 9 – 12cm.
• Smooth outline.
• Cortex >1.5cm.
• Echotexture:
• Medulla darker than cortex.
• d Corticomedullary differentiation with i age and parenchymal disease (e.g. acute GN) ( often over-reported and
over-interpreted).
• Pelvicalyceal (PC) system poorly visualized.
• Bladder examined when full. Normal bladder wall thin and hard to delineate.
DIAGNOSTIC IMAGING: ULTRASOUND 47
Table 1.8 Causes of abnormal renal size on imaging Large kidneys
• Unilateral:
• Tumour.
• Cyst.
• Unilateral hydronephrosis.
• Compensatory hypertrophy.
• Bilateral:
• Polycystic kidney disease (and other cystic diseases).
• Infi ltration (e.g. lymphoma).
Small kidneys
• Unilateral:
• Congenital hypoplasia.
• Renal artery stenosis.
• Bilateral:
• Small smooth kidneys:
— Chronic glomerulonephritis.
— Chronic interstitial nephritis.
— Virtually any chronic renal disorder, except diabetic nephropathy.
• Small irregular kidneys:
— Refl ux nephropathy.
— Congenital dysplastic syndromes.
— TB.
— Renal infarction.
1 2 a
b
b
b
b d
a
a
a
c
c
e 4 3
6 5
7
Fig. 1.7 CT scanning in renal disease. 1. Abdominal CT scan without contrast showing a calculus in the mid-ureter with stranding around it (arrow). 2. CT scan without contrast showing (a) a dilated pelvis and (b) perirenal stranding. 3. CT scan without contrast demonstrating 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 tumour, and (c) remaining normal renal parenchyma on the left. 5. Reconstructed CT scan with contrast demonstrating (a) a normal right kidney, (b) a renal tumour 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 tumours (arrowheads).
7. CT urogram demonstrating (a) contrast in the right collecting system and (b) a fi lling defect in the collecting system, consistent with a transitional cell carcinoma. Reproduced from Barrett, J, Harris, K, Topham, P. Oxford Desk Reference of Nephrology (2008), with permission from Oxford University Press.
DIAGNOSTIC IMAGING: ULTRASOUND 49
Diagnostic imaging: CT and MRI
CT
Increased availability, better image resolution, and progressively shorter scanning times have signifi cantly increased the routine use of CT for the investigation of the urinary tract (see Fig. 1.7 for CT scans).
Indications
• Characterization of a renal or perirenal mass:
• Differentiation of simple cysts from tumours ( b p. 742).
• Tumour staging.
• Delineation of renal or perirenal collections and abscesses.
• Detection of renal and ureteric calculi (CT-KUB) ( b p. 724).
• Trauma: defi nes extent of renal and associated intra-abdominal injuries.
• Retroperitoneal disease:
• Abdominal aorta, adrenal glands, retroperitoneal masses, fl uid collections, lymphadenopathy.
• Investigation of choice in retroperitoneal fi brosis ( b p. 739).
• Obstruction: presence, level, and aetiology ( b p. 732).
• Parenchymal infection:
• Pyelonephritis may not show on USS or IVU.
• Exclude associated pyonephrosis.
• X Renovascular disease ( b p. 586).
Standard renal CT with contrast Performed for the majority of the indications.
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 vasculature.
Electron beam CT (EBCT)
Specialist tool for monitoring vascular, especially coronary, calcifi cation ( b p. 242).
MRI Indications
• Evaluation of a renal mass and tumour staging:
• In selected cases, e.g. venous invasion.
• MR urography (the MR equivalent of an IVU).
DIAGNOSTIC IMAGING: CT AND MRI 51
Gadolinium and nephrogenic systemic fi brosis
• The MR contrast agent gadolinium (Gd) has been implicated in the development of nephrogenic systemic fi brosis (NSF).
• NSF is a rare, painful, and often disabling, skin lesion that can progress to involve internal organs (including muscle, heart, and lungs). It was fi rst described in the late 1990s and only occurs in renal failure.
• The dermopathy appears scleroderma-like: erythema, plaques, induration, and peau d ’ orange, with the lower legs and forearms initially affected. Subsequent periarticular tissue involvement leads to contractures and immobility.
• Pathology: CD34 +ve fi brocyte proliferation, with dermal thickening.
Gd may be detected in the lesions. Exact pathophysiology uncertain;
however, Gd tissue deposition, with TGF- B -induced fi brosis and fi brocyte collagen production, appears important.
• 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.
• Ionic and cyclic forms bind Gd more avidly, perhaps explaining an apparent variance in risk between preparations, e.g. higher for gadodiamide and gadopentetate.
• Gd chelates are renally excreted, so half-life is GFR-dependent.
• NSF incidence increases greatly below GFR <30mL/min.
• Most reports have been in dialysis patients.
• Peritoneal dialysis (PD) patients may be at higher risk.
• 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.
• Avoid chelates that are more strongly associated with NSF, and limit the administered dose.
• If already on maintenance haemodialysis, many dialyse the patient immediately after exposure (and again at 24h). This reduces Gd half-life, but additional evidence of benefi 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 confi rmed disease, transplantation offers the best chance of improvement.
• Cases should be reported to the International NSF Registry (M http://www.icnfdr.org ).
• Renal insuffi ciency:
• Gadolinium is not nephrotoxic and is also safe if there has been a previous allergic reaction to iodinated contrast. 2 However, gadolinium has been associated with the development of nephrogenic systemic fi brosis (NSF).
• MR angiography:
• X Detection of renovascular disease ( b p. 586).
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 signifi cant decline in use (see Fig. 1.8 for IVU scan).
The procedure
• Ensure good bowel prep, NBM for 4h pre-procedure. If GFR normal, a fl uid restriction of 7 500mL/prior 24h assists contrast concentration ( dangerous if d GFR 6 often avoided).
• Includes (fi lm sequence altered, according to clinical situation):
• Plain control fi lm (? opacities pre-contrast).
• Post-contrast: bilateral nephrograms (delayed: poor perfusion, obstruction, ATN, venous thrombosis), renal outline (? ischaemic scars, refl ux, TB).
• Further exposures at 5 and 10min (PC fi lling defects: clot, tumour, sloughed papilla, stone. PC deformity: refl ux).
• Mild abdominal compression delays contrast excretion and may improve PC system views.
• Post-voiding fi lm to assess bladder outfl ow.
• Delayed fi lms (2, 6, 12, and 24h) may establish a level of obstruction.
Modifi cations
• IVU with furosemide: furosemide exaggerates and distinguishes PUJ obstruction from normal anatomical variants ( ‘ baggy ’ pelvis).
• High-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 administration 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 renal excretion and may accumulate, poten-tially causing a severe lactic acidosis, if GFR deteriorates 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 — with glycaemic control achieved by other means until GFR recovers.
Those with pre-existing signifi cant renal impairment (eGFR <30mL/
min) who are at particular risk of CI-AKI should almost certainly not be taking metformin anyway. This can be clarifi ed with the responsible clinician. An eGFR of 30 – 60mL/min is a grey area, but there is no current recommendation to stop metformin, as long as the patient is supervised appropriately through the contrast procedure ( b p. 149).
DIAGNOSTIC IMAGING: IVU 53
c
i rp
c
u
Fig. 1.8 IVU: magnifi ed view of the left kidney. Calyx (c), infundibulum (i), renal pelvis (rp), proximal ureter (u). Calyx which projects posteriorly is seen en face (arrow). Normal fold of the ureter at the ureteropelvic junction (curved arrow).
Reproduced with permission 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
• Organic radio-opaque iodides excreted by glomerular fi ltration.
• 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 – 10%), especially if history of allergy. Usually 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 ( 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. 148–151.