Guidelines on the Diagnosis and Management of Multiple Myeloma

9. The Management of Patients With Renal Failure

A degree of renal impairment occurs in up to 50% of patients with myeloma at some stage of the illness (Alexanian, Barlogie and Dixon, 1990). Up to 20% of patients will present with renal failure. Advanced renal failure requiring dialysis or other major intervention occurs in 3-12% (Clark, Shetty and Soutar, 1999).

A modest increase in the serum creatinine indicates a substantial degree of renal impairment. Urgent intervention is required to correct early renal impairment and prevent long-term renal damage (Winearls, 1995). Patients with suspected myeloma and abnormal renal function need to be seen as a matter of urgency.

The pathogenesis of renal failure in myeloma is multi-factorial. Immunoglobulins, particularly the light chain component, can damage the kidney directly causing proximal tubular damage and myeloma cast nephropathy. Other factors include dehydration, hypercalcaemia, hyperuricaemia, infection, nephrotoxic drugs (e.g. non-steroidal anti-inflammatory drugs (NSAIDs) and some antibiotics). Less frequently, amyloid, light chain deposition disease, and plasma cell infiltration may occur (Clark, Shetty and Soutar, 1999).

Where not otherwise specified the following recommendations are based on clinical experience of haematologists and renal physicians. Published evidence in this field is limited and the recommendations are predominantly Grade C based on level IV evidence.

Responsibility for the overall management of myeloma patients with chronic renal failure will usually rest with the specialist haematological oncology team; but there needs to be clear communication and liaison with the specialist renal teams to optimise the care and outcome for the individual patient.

Early Management of Renal Failure

• Rehydrate with intravenous fluid to achieve a urine flow of over 3 litres/day (Ganeval et al, 1992; MacLennan et al, 1989; MRC, 1984). It may be of benefit to include bicarbonate in the IV fluid regimen to achieve a urine above pH7.0. Volume replacement should be guided by monitoring of central venous pressure
• Avoid potentially nephrotoxic drugs, including NSAIDs. It is important to check on usage of over-the-counter NSAIDs
• Treat infection rapidly and vigorously with appropriate antibiotic therapy, intravenously if necessary
• Correct hypercalcaemia with intravenous bisphosphonate in those patients not responding to rehydration alone. The kidney is the only route of excretion for bisphosphonates. However it appears from pharmacokinetic studies that no dose adjustment of pamidronate is necessary in patients with moderate to severe renal failure (GFR >10ml/min but <20ml/min). With GFR <10ml/min dosage is determined by the uncorrected serum calcium level; Ca²⁺ >4.0mmol/l give 60mg Pamidronate; Ca²⁺ <4.0mmol/l give 30mg. Alternatively, 30mg of pamidronate, repeated after 24 hours if no improvement is seen, is used in many units and appears to be safe. A 50% reduction in the dosage of clodronate is recommended in mild to moderate renal failure (GFR 10-50ml/min); it is contra-indicated if creatinine clearance is less than 10ml/minute (APBI, 1999; Bunn & Ashley, 1999) [see bisphosphonates 2002 revision].
• Seek the advice of a nephrologist if renal function does not improve within 48 hours
• Renal biopsy is desirable but not essential. It will help guide management, identifying those patients with: acute tubular necrosis, which will usually improve with time alone; amyloid and light chain deposition disease, which do not respond to measures other than control of myeloma; and cast nephropathy which may improve with rapid reduction of light chain concentration
• Plasma exchange is theoretically beneficial in cast nephropathy but because the evidence from the only two small randomised trials is conflicting plasma exchange should preferably be used in a trial setting (Zucchelli et al, 1988; Johnson et al, 1990)
• Dialysis should be offered to patients where appropriate for the management of the renal failure

Choice of Chemotherapy Regimen

The theoretical benefit of the rapid reduction of paraprotein and light chains and the need for dosage reduction due to impaired excretion both influence the choice of therapy.

• Melphalan is hydrolysed and excreted via the kidneys so bone marrow suppression may develop when full doses are used. The extent of drug accumulation is variable in each individual and cannot be predicted from the degree of renal impairment (Osterborg et al, 1989(b)). Initial doses should be reduced to 50% if the GFR is below 40-50 ml/min and titrated against bone marrow toxicity in subsequent courses. Melphalan should not be used in patients where the GFR is below 30 ml/min
• Cyclophosphamide metabolites are excreted in the urine. Caution in renal impairment with dose reduction is recommended by the manufacturers and if the GFR is 10-50 ml/min the dose should be reduced by 25%, and by 50% if GFR is less than 10 ml/min
• Vincristine, adriamycin and dexamethasone do not require dosage adjustment in the presence of renal impairment and can be safely used in patients with severe renal failure (Aitchison et al, 1990)
• High dose dexamethasone alone is effective as a single agent in this setting (Alexanian et al, 1992) and is practical as initial therapy since it can be given "immediately" without the need to wait for central line insertion to administer VAD
• Idarubicin toxicity is potentially increased in patients with renal impairment as the kidneys excrete its active metabolite, idarubicinol. Most available data are on patients with creatinine levels below 200 micromol/l. A number of current trials allow inclusion of patients with higher levels of serum creatinine, but there are presently insufficient data to recommend routine use of oral idarubicin or to guide dose modification in patients with creatinine levels above 200 µmol/l

Recommendations:

General points in management

• NSAIDs should be avoided because of their adverse effect on renal blood flow
• use opiates (from morphine to dextropopoxyphene) with caution because they accumulate rapidly leading to problems with drowsiness and respiratory depression
• consider the early use of radiotherapy for bone pain
• dosage adjustment of bisphosphonates may be required in renal failure
• patients with chronic renal impairment and anaemia should receive erythropoietin therapy

Later Treatment

Both haemodialysis and peritoneal dialysis are equally effective long-term renal replacement therapies. Renal transplantation is an option for only a very small number of highly selected patients with good prognosis disease and who have achieved plateau after treatment of their myeloma (Humphrey et al, 1975; Walker and Bear, 1983). As regards further treatment of the myeloma, HDT with autologous SCT can be performed but the risks are increased and it should take place only in a centre with appropriate expertise.

 

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