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When renal symptoms need specialist referral

Dr Clive Hall and colleagues explain which investigations are necessary and how to interpret

the results

Accurate referral of patients with renal disease depends on a judgment of the main diagnostic possibilities, based on the results of dipstix urine analysis for blood, protein, sugar, leucocytes and nitrites, a urine culture, serum creatinine level, a calculated creatinine clearance and an ultrasound examination of the kidneys and urinary tract (see box on page 62). Asymptomatic abnormalities detected by dipstix in apparently healthy individuals with normal renal and urinary tract ultrasound and sterile urine can be classified into:

lisolated asymptomatic microscopic haematuria with or without previous macroscopic haematuria

lisolated proteinuria

lmicro/macroscopic haematuria with proteinuria.

Isolated haematuria

In patients with haematuria the differential diagnosis is similar for both micro- and macroscopic haematuria. It includes major conditions, such as carcinoma of the kidney and bladder and crescentic glomerulonephritis, and also relatively minor conditions, such as small stones and some non-progressive nephropathies. However, the presence of macroscopic haematuria increases the likelihood of cancer of the kidneys or bladder, IgA nephropathy and benign and malignant prostatic disease.

In asymptomatic patients over 45 with micro- or macroscopic haematuria, the main concern is cancer of the bladder or kidney. These patients should be referred to a one-stop haematuria clinic for renal and bladder ultrasound, cystoscopy, urinary cytology and pelvic examination.

These investigations are diagnostic in some 75 per cent of patients with macroscopic haematuria and 37 per cent of those with microscopic haematuria; they reveal bladder cancer in up to

15 per cent, renal cancer in up to 7 per cent, benign and malignant prostatic disease in 29 per cent and stone disease in 6 per cent.

In asymptomatic patients under 45, the risk of renal and bladder cancer is <0.1 per="" cent="" and="" these="" patients,="" together="" with="" older="" patients="" whose="" urological="" investigations="" are="" negative,="" are="" often="" referred="" to="" a="" nephrologist="" for="" possible="" renal="" biopsy.="" although="" renal="" biopsy="" is="" diagnostic="" in="" some="" 60="" per="" cent="" of="" cases,="" revealing="" thin="" basement="" membrane="" nephropathy="" (tbmn)="" in="" 40="" per="" cent,="" iga="" nephropathy="" in="" 20="" per="" cent="" and="" being="" either="" normal="" or="" showing="" mild="" non-specific="" abnormalities="" in="" 40="" per="" cent,="" recent="" analyses="" have="" shown="" that="" routine="" renal="" biopsy="" is="" not="" indicated="" in="" these="" patients="" as="" the="" information="" gained="" seldom="" alters="" clinical="">

The prognosis of TBMN and of IgA nephropathy presenting with isolated haematuria, no proteinuria and normal renal function is good. However, annual or alternate yearly review by the GP is indicated, with treatment of blood pressure and cholesterol to strictly normal levels and referral for renal biopsy if the glomerular filtration rate (GFR) falls below 70ml/min and/or proteinuria develops and exceeds 2g/day. The

17-year risk of end-stage renal failure in individuals with isolated haematuria is only three times that of the normal population.

Isolated proteinuria

Patients with isolated nephrotic range proteinuria (>3g/day) with or without nephrotic syndrome (heavy proteinuria, oedema, hypoalbuminaemia and hypercholesterolaemia) have a 50-fold increased risk of end-stage renal failure and should always be referred for renal biopsy.

The biopsy is diagnostic in almost all cases and identifies six main types of major nephropathy which are often treatable.

lMinimal change nephropathy: likely if serum creatinine is normal and the patient is well.

lFocal and segmental glomerulosclerosis: likely if serum creatinine is normal and the patient is well.

lMembranous glomerulonephritis: a possibility in any patient with nephrotic proteinuria.

lDiabetic glomerulosclerosis: likely if there is glycosuria and hyperglycaemia.

lGlobal glomerulosclerosis: likely in a hypertensive arteriopath.

lAA amyloid: likely if there is chronic inflammation (such as rheumatoid arthritis) or chronic sepsis (such as bronchiectasis).

lAL amyloid: likely if there is a monoclonal gammopathy (such as myeloma).

In patients with isolated subnephrotic proteinuria (<3g ay)="" nephrologists="" will="" biopsy="" those="" with="" a="" reduced="" gfr=""><70ml in)="" and/or="" proteinuria="" of="">2g/day. They will review those with a normal GFR and proteinuria of <2g ay="" at="" yearly="" intervals,="" treating="" hypertension="" and="" hypercholesterolaemia="" and="" proceeding="" to="" renal="" biopsy="" if="" the="" gfr="" deteriorates="" to=""><70ml in="" and/or="" proteinuria="" increases="" to="">2g/day.

The main diagnostic possibilities are the same as for nephrotic proteinuria, except for minimal change nephropathy, which presents 'only' with nephrotic proteinuria and normal renal function.

Overall, patients with isolated 1+ proteinuria have a five-fold increased risk of ESRF over a

17-year period; those with isolated 2+ proteinuria have a 17-fold increased risk.

Haematuria and proteinuria

Patients with 2+ to 3+ microhaematuria and 2+ to 3+ proteinuria are likely to have major renal pathology, often with a reduced GFR. They have a 40- to 60-fold increased risk of ESRF over a

17-year period and should undergo renal biopsy.

Although these patients have a wide range of diagnostic possibilities, 75 per cent fall into six diagnostic groups:

lIgA nephropathy

lcrescentic glomerulonephritis

lfocal and segmental glomerulosclerosis

lglobal glomerulosclerosis

lmembranous glomerulonephritis

lmesangio-capillary glomerulonephritis.

Although IgA nephropathy is the most frequent diagnosis in this group, the most worrying diagnosis is crescentic, or rapidly progressive, glomerulonephritis. This is likely if the serum creatinine is rising rapidly, in which case very urgent referral is required for renal biopsy and immediate intensive immuno-suppressive treatment.

Untreated, the crescents progress from being cellular and potentially reversible to fibrotic and irreversible, 'strangling' the glomeruli. Crescentic glomerulonephritis is due usually to ANCA positive Wegener's granulomatosis or polyarteritis nodosa, other vasculitic disease, the most severe manifestions of other glomerulonephritis and occasionally to Goodpastures syndrome/anti-GBM disease.

IgA nephropathy is the commonest glomerulonephritis and is likely if a patient has micro-or macroscopic haematuria with or without proteinuria and/or renal impairment. IgA nephropathy is diagnosed in 20 per cent of all biopsies in the UK and 40 per cent of all biopsies that show primary glomerulonephritis; it leads to end stage renal failure in 20-40 per cent of patients over a 10-30 year period.

Adverse prognostic features in IgA nephropathy, as in all types of glomerulonephritis, include a reduced GFR, heavy proteinuria and hypertension and extensive glomerulosclerosis, interstitial fibrosis and tubular atrophy in the renal biopsy.

The referral letter

The referral letter needs to provide the following information:

lsymptoms (if any) and their duration

ldetails of the clinical examination, especially blood pressure, the presence of oedema, palpable kidneys or bladder, anaemia and the results of a pelvic examination

lresults of labstix urine analysis for blood, protein and sugar on several specimens

lserum creatinine (and electrolytes) and a measured or calculated creatinine clearance (GFR )

llevel of proteinuria in g/day, or as an albumin creatinine ratio or at least by dipstix urine analysis

lresults of the renal and bladder ultrasound, including a residual bladder volume in older males or patients with bladder outflow tract symptoms.

If available, the results of other investigations should also be included:

lblood sugar and HbA1c

lantinuclear factor and DNA binding antibodies, ANCA, compliment levels and antistreptolysin-O titre

limmunoglobulin levels, myeloma profile and Bence Jones proteinuria, especially in over-50s

lhepatitis B and C and HIV serology.

Further useful information includes:

lprevious measurements of serum creatinine (or urea) and labstix urine analysis to define time of onset and rate of progression of renal disease

ldetails of current and previous medications

lpast medical history, especially diabetes, hypertension, malignancy (carcinoma, lymphoma, myeloma), chronic infections (hepatitis B and C), HIV, endocarditis and collagen vascular disease.


Whenever renal disease is suspected, five questions need to be answered

lWhat is the GFR?

lWhat is the level of proteinuria?

lIs there microscopic and/or macroscopic haematuria?

lIs the anatomy of the kidneys and urinary tract normal?

lIs there a urinary tract infection?

The GFR can be measured as

24-hour creatinine clearance or calculated from the patient's age, weight and serum creatinine using the formula GFR ml/min = ((140 - age)/sr creatinine) x weight(kg) x 1.23 for men (1.04 for women)).

It is important to remember that, in a normally hydrated individual, the serum creatinine does not rise until the GFR has fallen to some 50 per cent of normal, ie, to approximately 40-50ml/min. Thus a measured or calculated GFR is required to detect mild renal impairment (80ml/min down to 50ml/min), but thereafter a rising serum creatinine level identifies increasingly severe renal impairment (<50 ml/min="" down="" to=""><10>

The level of proteinuria is determined most accurately by laboratory analysis of a 24-hour urine collection or measurement of the albumin:creatinine ratio in a random urine specimen. A normal ratio is <0.3, while="" ratios="" of="" 1,="" 2="" and="" 3="" represent="" proteinuria="" levels="" of="" 1,="" 2="" and="" 3g/day="">

Dipstix urine analysis for protein is a very useful, if approximate, guide to the severity of the proteinuria, but it does not allow for variations in urine concentration. However, it is a very sensitive and reliable means of detecting microscopic haematuria, and if positive for leucocytes and nitrites indicates a urinary tract infection.

The presence or absence of blood and/or protein and/or sugar in the urine, and the amounts detected by dipstix (0-3+), should be confirmed by retesting three or four urine specimens after successful treatment of any initial UTI and all the results noted.

Renal and urinary tract anatomy are examined by high-resolution ultrasound. This identifies diseases associated with structural abnormalities, such as polycystic kidneys, reflux nephropathy/chronic pyelonephritis, renal stone disease and renal cancer, and gives vital information about renal size, shape and echo texture (normal or fibrotic).

It also excludes urinary tract obstruction, may detect transitional cell carcinoma of the bladder, and measures post micturition residual bladder volume.

Presentation of

renal disease

lRenal or urinary tract symptoms or signs

lSystemic symptoms such as fever, sweats, weight loss, myalgia, arthralgia


lAs a complication of known disease that can involve the kidneys, such as diabetes, hypertension, malignancy, rheumatoid arthritis, systemic lupus erythematosis

lDrug treatment that can cause structural or functional renal damage, such as ACE inhibitors, angiotensin II receptor blockers, NSAIDs, antibiotics, allopurinol

lCan be completely asymptomatic

Clive Hall is consultant nephrologist,

Anthony Kerr, Rachel Bradley and

Philip Rushton are specialist registrars, Nephrology Unit, Royal United Hospital, Bath

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