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Diagnostic issues in systemic lupus erythematosus

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Q1: Which three tests would you ask for next from the clinic?

This patient had blood and protein in her urine on dipstick testing with a high systemic blood pressure. These findings should alert the clinician to the possibility of renal involvement. This is very common in SLE and may be associated with substantial morbidity and mortality. Careful monitoring of the urine for signs of lupus activity is an important part of the routine assessment of lupus patients. This includes answer c, that is analysis of the urine looking particularly for cellular casts. It would be important to measure the serum urea, electrolytes and creatinine,answer f, as well as quantification of the proteinuria with a 24 hour urine collection, answer a. The latter offers important information on the prognosis and the response to treatment.

Q2: What instructions do you give to a patient in order to perform a 24 hour urine protein collection?

The patient is asked to start the 24 hour urine collection on an empty bladder. So, for instance, if the patient were to first pass urine at 9 am in the morning, they would start the urine collection at this time. This first sample is discarded. The patient is then asked to empty any urine passed until 9 am the next morning into the bottle provided and then returned to the laboratory for examination. Incomplete 24 hour urine collections due to misunderstanding of instructions or forgetfulness are very common and will of course underestimate urine protein excretion. An alternative is the estimation of proteinuria by the albumin/creatinine ratio in a single early morning urine specimen, thus avoiding the need for timed urine collection.

Q3: Can a 24 hour urine collection under/over estimate the glomerular filtration rate?

It should be noted that a 24 hour urine collection for creatinine clearance can overestimate the glomerular filtration rate (GFR). This is because creatinine is actively secreted by the renal tubules into the urine as well as being filtered by the glomerulus. Low muscle mass by reducing creatinine production will also tend to overestimate GFR by creatinine clearance.

Q4: What other tests (apart from 24 hour urine creatinine clearance) are available to measure the glomerular filtration rate?

More accurate determinations of GFR include radiolabelled chromium51EDTA, MAG 3 renograms, and inulin clearance. Inulin clearance is an accurate determination of GFR but is never used in clinical practice nowadays as it is extremely tiresome from a practical viewpoint. A MAG 3 renogram can be used, but chromium51EDTA is the most commonly used isotope in clinical practice.

Q5: What is the likely cause of this clinical picture and results?

The answer is d, SLE associated lupus nephritis. Most SLE patients who have renal involvement have deposits of immune complexes and complement in the glomerular mesangium. While such lesions may require no specific intervention, they may progress to more serious lesions. Glomerulonephritis in SLE is classified according to histological appearance using the WHO classification, which is as follows (stage and histological appearance):

Stage
I: normal
Stage
II: mesangial
Stage
III: focal proliferative glomerulonephritis
Stage
IV: diffuse proliferative glomerulonephritis
Stage
V: membranous glomerulonephritis
Stage
VI: diffuse sclerosis

Other renal lesions in SLE include tubulointerstitial inflammation and lupus cystitis.

Q6: If this patient had persistently lowered complement levels from the time of her diagnosis, both during remission and relapses of her SLE, what other diagnosis would you have to consider?

Complement is an organised system of more than 20 serum proteins (synthesised predominantly in the liver) which helps to protect the host from invading organisms. While complement is important in host defence, activation of the complement system is detrimental to the host in a variety of diseases. In SLE, C3 and C4 levels are often performed clinically. Depressed C3 and C4 levels may indicate disease activity and tissue damage, for example glomerulonephritis. Patients with SLE whose complement proteins are within the normal range may fare better than those with persistent complement consumption. However, among SLE patients there is a higher than normal prevalence of null alleles for C4; serum C4 may therefore be persistently depressed when disease is inactive; in these patients C3 may be a better measure of disease activity. Inherited deficiencies of the early components of the classical complement pathway (C1, C2, C4) also interfere with the body's ability to handle immune complexes, which clinically results in an SLE-like condition.

Q7: Which investigation would you like to do next in order to obtain diagnostic and prognostic information regarding the cause of this women's renal impairment?

A renal biopsy, answer b, would provide diagnostic and prognostic information. The various possible histological appearances have been discussed earlier. However, imaging of the kidneys before such a procedure is performed is important to confirm that there are two kidneys present. An ultrasound scan of the renal tract is the most commonly used imaging modality; it would also help to exclude coincidental scarring or obstruction, which are mandatory before renal biopsy.

Q8: What issues would you have to consider and counsel the patient for when gaining consent from a young woman for treatment with cyclophosphamide?

Although this patient was initially treated with pulsed corticosteroids, the additional use of cytotoxic agents has become the standard therapy for diffuse proliferative lupus nephritis. Azathioprine and cyclophosphamide are the most widely used immunosuppressive agents in this setting and their use is supported by several prospective trials. The most commonly used regimen is intravenous cyclophosphamide but it has never been proved in a prospective randomised control trial that cyclophosphamide is definitely superior to azathioprine in this setting. A typical regimen uses monthly boluses of cyclophosphamide (at a dose of approximately 750 mg/m2) for six months or longer, followed by additional boluses every two or three months for a total of 2–3 years. A recent trial has shown that mycophenolate mofetil may be equally effective in the treatment of lupus nephritis.3

Cyclophosphamide is a cytotoxic drug which interferes with DNA synthesis by alkylating and cross linking DNA strands. Adverse effects include myelosuppression (white blood cells more than platelets), infections, and haemorrhagic cystitis. Mesna is given with pulses in order to prevent the latter complication.

Gonadal suppression and temporary or even permanent infertility occur, which is a serious issue in women of childbearing age. The risk of ovarian failure also rises with the age of the woman. Pregnancy tests should be performed before treatment is administered and the patient should be advised not to conceive during or for a few months after treatment because of the risks of teratogenicity. Egg collection before treatment can be offered, but drugs given to stimulate egg production before harvesting can also cause disease flare-ups.

Other side effects include nausea, vomiting, diarrhoea, pulmonary fibrosis, and rashes.

For further reading see Hughes1 and Walport.2

Acknowledgments

We would like to acknowledge Dr David Davies, Consultant Pathologist at the John Radcliffe Hospital for providing the slide.

References

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