Clinicopathological correlation and best treatment of renal disease in Multiple Myeloma
Multiple Myeloma is a fascinating haematological malignancy which may present in myriad ways. Whilst it may involve, directly or indirectly, many organ systems some of its most severe manifestations arise in the kidney and renal diseases are second only to infection as a cause of death secondary to multiple myeloma. This article gives an overview of the mechanisms by which multiple myeloma may affect the kidneys, with a particular focus on myeloma cast nephropathy, and reviews the current best treatments in these situations.
Multiple myeloma is a malignancy of plasma cells – terminally differentiated B-lymphocytes which have thus undergone immunoglobulin gene recombination and class switching. It is uncommon but carries a poor prognosis; it represents 1% of all cancers and 10% of haematological cancers. The neoplastic plasma cells cluster in the bone marrow and lytic bone lesions are responsible for the characteristic radiographic lucencies as well as the bone complications seen in the disease . 5 year mortality stands at 65% in Europe . Mortality in multiple myeloma patients may be from many causes; infection is the single most common contributor, but renal complications are a close second and it is often quoted that renal impairment is seen in 50% of patients in the course of the disease [3, 4]. In recent years there has been great progress in treating multiple myeloma with combination therapies which are superior to the previous chemotherapy regimen .
Classification of multiple myeloma is by M (monoclonal) component – the type of paraprotein produced. IgG producing myelomas are commonest, around 60% of all myelomas, and have the longest survival time. IgA secretory myelomas are next most frequent followed by those that secrete only immunoglobulin light chains – either κ or λ. Rarer still are the IgD, IgM and non secretory myelomas . IgE secretory multiple myeloma has been described but is exceedingly rare. Even tumours which secrete complete immunoglobulins of a specific class are known to often overproduce light chains, meaning that free light chains (known as Bence Jones protein) are frequently seen in the blood.
The manifestations of multiple myeloma within the kidney may be broadly classified into primary effects of the cancer on the kidneys via paraprotein production and secondary effects due to downstream complications of the disease. Renal Impairment is often present at the time of diagnosis of multiple myeloma. In one cohort of 1353 patients renal failure was seen at time of diagnosis in 31% of patients when defined as serum creatinine concentration of ≥130 μmol/l and 49% when creatinine clearance was estimated using the Cockcroft-Gault equation .
Primary effects on the kidney due to protein production
Paraprotein production by neoplastic myeloma cells may lead to a number of pathological entities in the kidney, which in turn may present as a range of clinical syndromes including Chronic Kidney Disease (CKD) and Acute Kidney Injury (AKI) . Though there are obvious connections between certain pathological and clinical entities, these do not hold for all individual cases . There is a well known association between myelomas that secrete IgD and/or immunoglobulin light chains and increased risk of renal failure [4, 6], though it remains controversial whether λ or κ light chains are more toxic in this regard . A recent case series of 190 patients with kidney biopsies taken on a background of multiple myeloma showed that paraprotein-associated lesions made up the majority of the pathology . The most common paraprotein associated kidney lesion was cast nephropathy – also known as myeloma kidney [3, 9, 10]. Interstitial pathology is more common than glomerular lesions in monoclonal gammopathies . Myeloma cast nephropathy is likely the most famous of the paraprotein associated kidney diseases in multiple myeloma, and a great deal of effort has been spent to elucidate its pathogenesis. Monoclonal immunoglobulin deposition disease (MIDD) and amyloidosis are also responsible for significant morbidity and mortality due to paraprotein associated kidney disease .
Cast nephropathy is seen in 33% of kidney biopsies taken from myeloma patients [3-. In this condition urinary Bence Jones protein in complex with secreted Tam-Horsfall protein obstructs tubular lumens. It has a high initial mortality [8, 10] and is a common indication for dialysis in myeloma patients. Cast nephropathy is associated with high tumour stage as measured by the Salmon-Durie staging system . Interstitial nephritis often accompanies cast nephropathy  and the casts cause tubular atrophy and irreversible nephron damage which often presents as AKI [8, 10, 11].
It has become apparent that the characteristics of the M component are important in determining the risk of myeloma kidney – at a simplistic level non secretory myeloma is least likely to lead to kidney disease, whilst light chain secreting myelomas carry the greatest risk of renal involvement . Subsequently it was shown that more subtle differences in the molecular biology of the immunoglobulins being produced can be important in determining risk, and that light chains of different subgroups (differentiated by variable region) preferentially deposit in different compartments of the kidney and in different forms. Thus, some subgroups predominantly produce a cast nephropathy whilst others give MIDD or amyloidosis .
The interaction of Tamm-Horsfall protein, also known as uromodulin, with urinary Bence Jones protein appears to be important for cast formation, though at high concentrations free light chains may also precipitate without this association . The key interaction appears to be between a peptide portion of the Tamm-Horsfall glycoprotein  and complementarity determining region 3 (CDR3) of the free light chain . Recently, evidence has emerged that a few specific amino acids in CDR3 are of key importance in this interaction, which may provide an explanation for the different propensities to form casts of different free light chains. Also, in an exciting development, a competitive inhibitor of the aforementioned interaction can both prevent cast formation and ameliorate the clinical picture of AKI in rodent models of the disease .
For the light chains that are prone to formation of casts an important determinant of where precipitation occurs is the isoelectric point of the protein – as the isoelectric point approaches the pH of the tubular fluid the protein precipitates out and can then form casts. Tubular fluid becomes more acidic further distal in the tubule, so lower isoelectric points allow precipitation later on in the tubule .
Proximal tubule cell cytotoxicity (proximal tubulopathy) due to direct damage from Bence Jones protein is a rare form of paraprotein mediated injury . A great deal of damage seems to be due to uptake of free light chains into the proximal tubule cells; in vitro knockout of the cubilin and megalin genes prevents both this uptake and elaboration of inflammatory cytokines such as IL-6 . Proximal tubulopathy can result in the Fanconi syndrome due to inhibition of substrate transport across the proximal tubule epithelium [8, 9]. Fanconi syndrome includes polyuria, hypokalaemia, and hypophosphataemia and a metabolic acidosis due to failure to reabsorb bicarbonate. Symptoms may include muscle weakness and those of osteomalacia.
Other rarer mechanisms of renal injury due to immunoglobulin production in myeloma include IgA nephropathy in IgA secreting myelomas, and hyperviscosity syndrome. The latter is more common in malignancies causing Waldenstrӧm macroglobinaemia .
The separate paraprotein associated renal diseases are not mutually exclusive and more than one pathological pattern may co-exist in the same patient .
Secondary effects on the kidney
As well as the direct insult of proteins elaborated by malignant plasma cells on the kidney there are several secondary factors that contribute to renal impairment in multiple myeloma. These include sequelae of the cancer such as hypercalcaemia as well as infection, to which myeloma patients are prone, drugs used in disease management and dehydration .
Hypercalcaemia is common in multiple myeloma and is well known to contribute to the renal insufficiency of myeloma patients ; it is associated with decreased overall survival . The pathogenesis of hypercalcaemia is largely based on well known interactions between the neoplastic plasma cells and the surrounding bone which triggers osteoclast activation, for example by Osteoclast Activating Factor production . Bone resorption resulting in calcium release appears to be the main cause of hypercalcaemia in multiple myeloma, but in cases where there is decreasing GFR increased renal absorption of calcium may also play a role . Hypercalcaemia may lead to nephrocalcinosis whereby the tubular epithelial cells are damaged and calcified debris in the tubular lumens leads to secondary tubulointerstitial nephritis. One of the earlier signs of this process is nephrogenic diabetes insipidus, which may leave patients severely dehydrated . Dehydration itself contributes to renal insufficiency.
Pharmacological interventions in multiple myeloma may also have an impact on renal function, for example non-steroidal anti inflammatory medications, antibiotics, contrast media  and bisphosphonate therapy are all commonly prescribed for myeloma patients and are all nephrotoxic. Zoledronate may produce AKI and patients given pamidronate have developed focal segmental glomerulosclerosis, minimal change disease  and, further to this, the nephrotic syndrome . Drugs may also feed back to worsen paraprotein associated pathology, for example use of furosemide can precipitate cast nephropathy .
The median age for presentation with multiple myeloma is in the mid 60s  and renal function is well known to decline with age . In addition, increasing age makes other causes of renal impairment such as hyaline arteriolosclerosis and glomerular lesions due to hypertension and type 2 diabetes more common; these pathological changes are not uncommonly found in myeloma patients .
Best treatment of renal impairment associated with multiple myeloma
Though renal impairment is common in patients presenting with multiple myeloma [4, 23] it is reversible in most cases . Appropriate management involves correcting any biochemical derangements such as hypercalcaemia and dehydration, stopping nephrotoxic drugs and treatment for the underlying malignancy.
Hypercalcaemia should be managed with IV saline and bisphosphonates . Though bisphosphonates themselves can lead to glomerular damage a recent meta-analysis did not find there to be a significant risk from this adverse event, nor was there any difference is frequency of renal dysfunction between different bisphosphonates . Some authors however still discourage bisphosphonate use in patients in acute renal failure . Management of hypercalcaemia may normally involve the use of loop diuretics such as furosemide once GFR has been normalised using saline infusion because these encourage calcium loss by blocking its reabsorption in the loop of Henle . Unfortunately furosemide is known to increase the risk of myeloma cast nephropathy  so its use in hypercalcaemia due to multiple myeloma may in fact worsen the patient’s situation.
Plasmapheresis is conceptually attractive as a method of removing light chains from the blood and reducing renal damage due to paraprotein from multiple myeloma. However, a recent systematic review found neither significant improvement in survival from plasmapheresis in myeloma patients, nor benefit to renal function or recovery from dialysis. However, contrary to the overall results of the review, individual RCTs have found a benefit to plasmapheresis . Thus plasmapheresis is a controversial treatment for renal disease. There has been suggestion that High Cut off Haemodialysis (HCOD) may be beneficial in removing free light chains from serum and improving renal function when used alongside bortezomib  but larger scale trials will be required in the future to confirm efficacy. There is an ongoing European effort to resolve the controversy surrounding the use of plasmapheresis in multiple myeloma patients - the Myeloma Renal Impairment Trial (MERIT) – and there is hope that it may provide a clear conclusion to the debate [9, 26].
As well as supportive therapy treatment of the underlying malignancy is important for reversing renal impairment. Suggested regimens are tabulated below:
In patients with renal impairment thalidomide has been associated with severe hyperkalaemia . Bortezomib is effective as a myeloma treatment; it also has improves renal function of patients with creatinine clearance less than 60ml/min . A part of this protective effect on the kidneys may be due to bortezomib’s action of blocking NF-κB activation and upregulating anti-apoptotic proteins and heat shock proteins such as HSP70 in proximal tubular cells. This could provide a defence against proximal tubulopathy, which appears to be driven by an inflammatory response . Taken together, these findings have lead the International Myeloma Working Group to suggest that bortezomib with dexamethasone should be the treatment of choice for myeloma associated with renal impairment .
The renal manifestations of multiple myeloma are responsible for significant morbidity and mortality. There are several distinct patterns of renal damage and both glomerular and tubulointerstitial damage can occur. It is important to realise that kidney injury in multiple myeloma can be potentiated by inappropriate management and several drugs can have severe adverse effects on renal function. Recent advances in therapy are improving outcomes for people with this spectrum of disease. In addition, our increasing understanding of the underlying characteristics of the proteins causing myeloma kidney provides hope that an effective countermeasure may soon be devised.
Story image: the results of serum electrophoresis in a multiple myeloma patient, from Wikimedia Commons
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