Aetiology and management of acute kidney injury in multiple myeloma

Multiple myeloma (MM) is a neoplastic proliferation of a single clone of plasma cells producing a monoclonal immunoglobulin (mIg) or a fragment of it. According to the International Myeloma Working Group, the diagnosis of MM requires the presence of  ≥10% bone marrow plasma cells and/or biopsy-proven plasmacytoma in the setting of disease-related end-organ damage [hypercalcaemia (>11 mg/dL), renal dysfunction (creatinine clearance <40 mL/min or serum creatinine >2 mg/dL), anaemia (haemoglobin <10 g/dL) or lytic bone lesions, CRAB (Calcium, Renal, Anaemia, Bone)] and/or the identification of a biomarker associated with nearly inevitable progression to end-organ damage [clonal bone marrow plasma cell percentage ≥60%, involved/uninvolved serum-free light chain (FLC) ratio ≥100 (involved FLC level must be  ≥100 mg/L) or more than one focal lesion on magnetic resonance imaging (at least 5 mm in size)]. Acute kidney injury (AKI) is very common in patients with MM and half of MM patients present with AKI. In some series, survival is reduced to <1 year in MM patients with AKI who do not recover renal function, and moreover the reversibility of MM-associated AKI is an important predictor of patient survival [1].

MM-associated AKI results from a combination of mIg-dependent and mIg-independent factors. The mIg-independent mechanisms include volume depletion, hypercalcaemia, hyperuricaemia, nephrotoxic agents [radiocontrast agents, non-steroidal anti-inflammatory drugs (NSAIDs) and renin–angiotensin system inhibitors], sepsis and rhabdomyolysis. The mIg-dependent mechanisms revolve around the biochemical properties of FLC. The diverse patterns of nephropathologic injury observed in patients with mIg-associated nephropathies reflect the diversity of the abnormal light chains, but the most common cause of AKI in MM patients is cast nephropathy (CN). In CN, FLC interact and aggregate with Tamm–Horsfall protein causing intratubular obstruction at the level of the distal convoluted tubule and collecting duct of the kidneys (Figure 1) [2]. In addition, FLC cause tubular damage as they are filtered at the glomerulus and undergo endocytosis by the megalin/cubilin receptor system in proximal tubular cells. An overload of filtered FLC causes an accumulation of FLC in proximal tubular cells and the production of inflammatory cytokines [monocyte chemottractant protein-1, interleukin (IL)-6 and IL-8] and of reactive oxygen species ultimately resulting in fibrosis [3, 4].

FIGURE 1

(A) Normal renal function. Normally, there is a 40% overproduction of light chain compared with heavy chain in plasma cells and ∼500 mg/day of these polyclonal FLCs are released into the circulation. Two-thirds of FLC production is κ-FLCs. In circulation, the κ-FLCs are monomeric [molecular weight (MW) 25 kDa] and the λ-FLCs dimeric (MW 50 kDa). FLCs are rapidly dispersed in roughly equal concentrations throughout the extracellular compartments: 15–20% in the intravascular space and 80–85% of FLC in the extravascular spaces. The precise glomerular clearance is unknown in individuals with a normal renal function, but is estimated to be 40% per hour for κ-FLC and 20% per hour for λ-FLC. FLC can also be removed through the reticulo-endothelial system but in patients with a normal renal function the contribution of the reticulo-endothelial system (RES) to FLC removal is neglible (estimated to be 1.6 × 10⁻⁴/min). All these result in serum half-lifes of 2–4 h and 3–6 h for κ-FLC and λ-FLC, respectively. The normal serum concentration for κ-FLC and λ-FLC is 3.3–19.4 mg/L and 5.7–26.3 mg/L, respectively, with a corresponding κ/λ FLC ratio of 0.26:1.65. As there is uptake and catabolism of FLCs by proximal tubular epithelial cells, only 1–10 mg/day of FLC is present in urine in normal kidney function. (B) Decreased renal function. The contribution of the RES to FLC removal increases when kidney function deteriorates. RES removal of FLC is independent of size and hence is equal for κ-FLC and λ-FLC. This explains why in patients with decreased kidney function the half-life of κ-FLC and λ-FLC is equal and the corresponding κ/λ FLC ratio is 0.37:3.17. (C) CN. There will be excessive endocytosis of FLCs in proximal tubular cells when high concentrations of FLC are present, and this will result in increased production of inflammatory and profibrotic cytokines, such as IL-6, IL-8, C-C chemokine ligand 2 (CCL2) and transforming growth factor (TGF)-β1. In the distal tubules, FLCs will interact with Tamm–Horsfall protein and precipitate to form casts mechanically blocking the tubular lumen resulting in AKI. Ultimately, this will result in irreversible progressive interstitial inflammation and fibrosis.

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In most MM patients with AKI, a precipitating factor such as dehydration, hypercalcaemia or the use of radiocontrast agents or NSAID can be identified. The risk for AKI is associated with the level of FLC excretion; renal insufficiency was found in 16% of patients with <1 g/day FLC proteinuria, 47% of patients with 1–10 g/day and 63% with >10 g/day [5]. It has been suggested that the diagnosis of light chain CN can be made presumptively if the circulating FLC levels are high (>500 mg/L) in the presence of MM and AKI [6]; however, a renal biopsy is still recommended in these patients to make a definitive diagnosis and is required if serum FLC levels are <500 mg/L and when rapid FLC measurement is not available.

The treatment of MM-related AKI includes general measures to optimize hydration status, avoid additional nephrotoxins, treat hypercalcaemia and hyperuricaemia, and most importantly decrease the serum levels of FLC rapidly. In a study including 39 patients with biopsy-proven MM-CN, only the achieved FLC reduction significantly predicted renal recovery (a 60% reduction in FLCs by Day 21 associated with recovery of renal function for 80% of the population) and patient survival strongly associated with renal recovery [7]. Reduction of FLC levels can be obtained by the rapid initiation of cytotoxic chemotherapy and by performing plasmapheresis/high cut-off haemodialysis (HCO-HD).

In the last couple of years, multiple novel therapeutics have become available for the treatment of MM and the incorporation of these novel agents into the MM treatment algorithm has led to significant improvement in the median overall survival, which now approaches 6–10 years depending on the age at diagnosis, and a cure fraction of ∼15% of patients [8]. In MM patients with AKI, at presentation urgent treatment to lower circulating FLC levels is necessary and triplet regimens such as bortezomib, thalidomide and dexamethasone, or bortezomib, cyclophosphamide and dexamethasone are recommended. The use of bortezomib in MM patients with AKI has resulted in increased number of patients recovering renal function and improved survival [9, 10]. The Velcade as Initial Standard Therapy in multiple myeloma: Assessment with melphalan and Prednisone (VISTA) trial compared the efficacy of bortezomib plus melphalan and prednisone (VMP) and melphalan and prednisone (MP) in previously untreated MM-CN patients with renal impairment. Renal impairment reversal [baseline glomerular filtration rate (GFR) <50 improving to >60 mL/min/1.73 m²] was seen in 44% of VMP-treated patients versus 34% of MP-treated patients. Younger age and less severe impairment at baseline were identified as predictors of renal impairment reversal [9]. In a study concerning newly diagnosed MM patients with severe renal failure (estimated GFR <30 mL/min/1.73 m²), of which 37% even required dialysis, bortezomib-based triplets therapy was associated with a higher probability of dialysis discontinuation (57% versus 35%). Rapid myeloma response was associated with higher rates of renal response and patients who became dialysis-independent had longer survival than those remaining on dialysis [11].

Seven per cent of MM patients will present with dialysis-dependent AKI and the role of plasmapheresis or HCO-HD to remove FLC in these patients is controversial. Although promising results were obtained in case series, randomized trials indicate a lack of benefit. In a recent French randomized clinical trial (MYRE), 98 patients with biopsy-proven MM-CN requiring HD received intensive HD (eight 5-h sessions over 10 days) with either an HCO-HD or a conventional HD. HCO-HD compared with conventional HD did not result in a statistically significant difference in HD independence at 3 months [12]. Also, in the Eulite Trial there was no difference in dialysis independence at 3 months in patients treated with HCO-HD compared with conventional HD [13]. In this trial, there were significantly more episodes of lung infection in the HCO-HD group. Therefore, we recommend plasmapheresis/HCO-HD only in the context of trials.

In conclusion, AKI is an important complication in patients of MM patients and predictor of negative outcomes. Rapid reduction of serum FLC levels using bortezomib-based highly cytotoxic chemotherapy should be started without delay. In our opinion, plasmapheresis and HCO-HD should only be used in the context of trials at this time.

CONFLICT OF INTEREST STATEMENT

None declared. The results presented in this paper have not been published previously in whole or part, except in abstract format.

ACKNOWLEDGMENTS

I would like to thank Mr Albert Herelixka for the artwork.

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