Myeloma Kidney Research Articles

Early Reduction of Serum-Free Light Chains Associates with Renal Recovery in Myeloma Kidney

Myeloma kidney is the major cause of severe irreversible renal failure in patients with multiple myeloma. This tubulointerstitial injury is a direct consequence of high concentrations of circulating monoclonal free light chains (FLCs) produced by a clonal expansion of plasma cells. Early reduction of serum FLCs associates with renal recovery, but the target threshold of reduction to facilitate renal recovery is unknown. To determine the relationship between the achieved FLC reduction and renal recovery, we identified 39 patients with biopsy-proven myeloma kidney, the majority of whom had severe renal failure at presentation (median estimated GFR 9 ml/min per 1.73 m²). In a multivariable analysis incorporating demographic, hematologic, and renal variables, only the achieved FLC reduction significantly predicted renal recovery (P = 0.003). The relationship between renal recovery and FLC reduction was linear with no absolute threshold for FLC reduction. A 60% reduction in FLCs by day 21 associated with recovery of renal function for 80% of the population. Patient survival strongly associated with renal recovery: the median survival was 42.7 months (range 0 to 80) among those who recovered function compared with 7.8 months (range 0 to 54) among those who did not (P < 0.02). Cox-regression analysis demonstrated that the first presentation of myeloma, the kappa isotype of FLC, and renal recovery were independent predictors of survival. In conclusion, recovery of renal function in myeloma kidney depends on early reduction of serum FLCs, and this recovery associates with a significant survival advantage.

6th International Symposium on Clinical Applications of Serum Free Light Chain Analysis (plus Hevylite)

The 6th International Symposium on Clinical Applications of Serum Free Light Chain Analysis (plus Hevylite) was held in Bath, UK on 23rd and 24th September 2010. This Symposium included measurements in monoclonal gammopathies, myeloma kidney and inflammatory diseases; data from the Multi-centre, Phase III, Randomised control trial on extended haemodialysis with the Gambro protein-leaking HCO 1100 dialyser; and presentations on Hevylite (intact immunoglobulin kappa/lambda ratios) in a variety of clinical situations.

Light chain-mediated tubulopathies.

Immunoglobulin light chains are low molecular weight proteins that are filtered through the glomerulus and reabsorbed into the proximal tubular epithelium by binding initially to a heteromeric receptor complex composed of megalin and cubilin. Saturation of this receptor-mediated endocytotic process results in the presence of free light chains in the distal nephron and urine. In the course of metabolism of monoclonal light chains, nephrotoxicity can occur, resulting in clinical manifestations that can include acute kidney injury and progressive chronic kidney disease. Patterns of tubulopathic renal injury include proximal tubular epithelial cell cytotoxicity, tubulointerstitial nephritis and cast nephropathy (also known as 'myeloma kidney'). Research efforts over the past two decades have refined understanding of the molecular mechanisms involved in light chain-mediated tubular injury and are the subject of this review.

Modelled cost-effectiveness of high cut-off haemodialysis compared to standard haemodialysis in the management of myeloma kidney

Background:Approximately 10–20% of multiple myeloma patients experience dialysis-dependent renal failure. This is principally due to myeloma kidney, a tubulointerstitial injury caused by high circulating concentrations of monoclonal free light chains. Studies have found that between 3% and 37% of patients with myeloma kidney requiring dialysis recover renal function. In-vivo studies indicate that extended haemodialysis using high cut-off dialysers (HCO-HD) can remove significant quantities of free light chains and is associated with a renal recovery rate of 63–74% in these patients.Objective:The objective of this study was to assess the cost-effectiveness of HCO-HD compared to standard HD in the management of myeloma kidney.Methods:The study used a lifetime Excel-based decision tree model that followed all patients from treatment of the initial presentation with myeloma kidney requiring dialysis to death. It was populated with published clinical data, United Kingdom costs and expert opinion, using a National Health Service perspective and 3.5% annual discounting.Results:HCO-HD was dominant to standard HD, meaning it was both more effective (greater life years and quality adjusted life years) and less costly, due to a greater increase in the proportion of patients recovering renal function. The model projected lifetime costs of £31,345 per patient for patients treated with standard haemodialysis only and £24,845 for the new treatment (discounted). The model predicted an average survival of 19.92 months for patients on standard HD and 33.90 months for the new therapy (discounted).Conclusions:The analysis found that treatment of myeloma kidney using an extended schedule of HCO-HD may substantially improve renal recovery in multiple myeloma patients compared to standard HD, resulting in greater life expectancy and cost savings due to avoided chronic dialysis. Limitations of the study include those common to rare diseases including small study sizes and limited natural history data.

Multi-Organ Involvement of Multiple Myeloma Cells In the Cases of Recent 10 Years: A Clinicopathologic Study of 81 Consecutively Autopsied Cases

AbstractAbstract 5004 Background:Despite recent progress in treatment, multiple myeloma is still uncurable disease. The impact of modern therapy on the causes of death and pathological feature of end-stage myeloma is not fully understood. Methods:We studied autopsied cases with multiple myeloma between 1979 and 2009 at National Medical Center of Global Health and Medicine, Tokyo, Japan. We compared the clinicopathological feature of the autopsied cases in recent 10 years with the cases before 2000. Statistical analysis was performed using student's t-test and chi-square test. Results:There were 81 autopsied cases between 1979 and 2009. 31 cases were autopsied in recent 10 years and the older 50 cases were before 2000. Mean age at death was 59.2 and 65.1 years old, and the mean duration of illness was 46.1 and 31.9 months, respectively. Stem cell transplantation was performed in 13 (12 autologous, 1 allogeneic) of recent cases and 3 (2 autologous and 1 allogeneic) of older cases. In recent cases, five patients were treated with bortezomib, 2 were with thalidomide and 2 were with both. Extramedullary infiltration of myeloma cells were observed in both groups. The frequent sites of involvement were spleen, liver, kidney, lymph nodes, lung, pancreas, adrenal gland and perioneum. The infiltration in liver and lung was significantly frequent in the recent cases than in the older cases (58.1% vs. 28.0%, p=0.007, and 38.7% vs. 18%, p=0.039). Infection as a cause of death was noted more frequently in the recent cases than in the older cases (41.9% vs. 18.0%, p=0.019). Amyloid deposition was detected in 16.1% and 22.0% (ns.), and myeloma kidney was noted in 48.4% and 60% (ns.). Conclusion:High dose chemotherapy with stem cell support and novel agents have been contributed to improving the survival. However, the increase in resistant bacterial and fungal infection is serious problem. Also, extramedullary relapse after autologous and allogeneic stem cell transplantation is not rare, and extramedullary progression under thalidomide has been reported. In our recent autopsied cases, the incidence of fatal infection and extramedullary involvement of myeloma cells was significantly higher than in the older cases. Disclosures:No relevant conflicts of interest to declare.

Role of plasmapheresis in the management of myeloma kidney: A systematic review

Multiple myeloma complicated by acute renal failure is a diagnosis often encountered by the practicing nephrologist. The role of plasmapheresis in such patients has been of interest for decades. Three randomized controlled trials (RCTs) and multiple observational trials have evaluated the potential role of plasmapheresis in the management of this condition. This systematic review presents the results of these trials regarding survival benefits, recovery from dialysis, and improvement in renal function. A comprehensive search revealed 56 articles. Of these, only 8 articles met our inclusion criteria (3 RCTs, 1 correction of results, and 4 observational trials). Two of the 3 RCTs showed no difference in survival benefit. Two of the 3 RCTs showed a greater percentage of patients stopping dialysis in the intervention group; however, these results were not reproduced in the largest trial. All the studies showed an improvement in renal function for patients receiving plasmapheresis; however, only 2 RCTs and 1 retrospective study showed a statistically significant improvement in renal function among patients who received plasmapheresis in comparison with a control group. Our systematic review does not suggest a benefit of plasmapheresis independent of chemotherapy for multiple myeloma patients with acute renal failure in terms of overall survival, recovery from dialysis, or improvement in renal function.

Differential progression of renal scarring and determinants of late renal recovery in sustained dialysis dependent acute kidney injury secondary to myeloma kidney

BackgroundMost cases of dialysis-dependent acute kidney injury due to myeloma cast nephropathy do not recover renal function. Renal biopsy typically shows cast formation, direct tubular injury and interstitial inflammation caused...

Myeloma Light Chain-Induced Renal Injury in Mice

We investigated the effects of human light chain (LC) protein-overload in mice kidney to gain further insights into the molecular mechanisms involved in the pathogenesis of myeloma kidney. Intact male C57BL/6, 10- to 12-week-old mice were given daily intraperitoneal (i.p.) injections of 1 ml of human ĸ-LCs (1.5 mg/ml, low dose), or (100 mg/ml, high dose) to uninephrectomized mice for 2 weeks. Intact, sham-operated or uninephrectomized control animals were given the same volume (1 ml/day) of saline, human serum albumin (10 mg/ml) or bovine serum albumin (100 mg/ml) i.p. for 2 weeks in place of LCs. The low-dose LC-treated mice had human LCs in their urine and a significant increase in monocyte chemoattractant protein-1 (MCP-1) mRNA in the kidneys. Uninephrectomized mice treated with high-dose ĸ-LCs showed tubule casts, and foci of intracytoplasmic rhomboid crystals within the proximal tubules, along with cytoskeletal disruptions and alterations in the brush-border membrane, and high concentrations of human ĸ-LC were present in their sera. High-dose LC treatment also led to increases in serum creatinine and tumor necrosis factor-α levels, and marked increases in interleukin-6 and MCP-1 expression as well as cellular apoptosis in the kidneys. These studies demonstrate that myeloma LC overload over a range of LC concentrations in mice causes significant functional and morphological kidney injury. The model should be helpful in investigating pathophysiologic mechanisms and exploring therapeutic interventions for myeloma kidney and other LC-associated renal disorders.

Myeloma kidney with isolated tubulointerstitial light chain deposition in a renal allograft

Myeloma kidney and myeloma-associated renal disorders including light chain deposition disease can occur as recurrent or de novo disease in renal allografts. These kidney disorders usually manifest with worsening allograft function and proteinuria. Identification of the precise cause of kidney disorder often requires kidney biopsy and demonstration of monoclonal light chains in the kidney. Here, we present an unusual case of light chain nephropathy in a living-related kidney transplant recipient involving light chain crystallization in the proximal tubule occurring within less than three months after transplant. The etiology of renal failure prior to transplant in our patient is not clear. To the best of our knowledge, the ultrastructural changes seen in our patient have not been described in literature previously. Our patient was treated with steroids, which resulted in short-term improvement in allograft dysfunction.

An unusual neurological complication of light chain amyloidosis

A 59-year-old female presented with acute renal failure, anaemia, immunoglobulin (Ig)G lambda paraproteinaemia, lytic bone lesions and bone marrow plasmacytosis (60%) with no evidence of amyloid deposition. Fluorescence in-situ hybridization analysis of marrow showed t(11;14)(q13;q32) and monosomy 13. Renal biopsy showed lambda light chain cast nephropathy consistent with myeloma kidney. She achieved less than a partial remission with autologous stem cell transplantation. A year later, she developed bilateral shoulder swelling with synovial thickening, and biopsy showed deposition of lambda light chain-derived amyloid. A repeat marrow biopsy confirmed myeloma-associated amyloid. In addition, a new symptom of tingling and numbness of hands and feet, initially perceived as AL amyloidosis-related small fibre neuropathy appeared. She had mild upper and lower extremity weakness and truncal numbness along with unilateral Babinski’s reflex, but no sensory level could be appreciated. She denied bladder or bowel incontinence. Magnetic resonance imaging of the cervical spine demonstrated cord compression by a tumour-like mass within the dorsal paraspinal soft tissues at the C2–3 level (left and middle panels). Surgical resection of the mass revealed an amyloidoma (right panel), and led to near complete resolution of her neurological symptoms. Subsequently, she received bortezomib-dexamethasone therapy with an excellent haematological response and stabilization of soft tissue findings. Her disease has been stable off-therapy for almost 11 months at the time of last follow-up. Myeloma-associated neurological manifestations can have diverse aetiologies. Peripheral neuropathy is not common at diagnosis in multiple myeloma (MM), and is usually related to concurrent amyloidosis or use of neurotoxic agents. Radiculopathy, on the other hand, is the most common neurological complication of MM, a result of nerve compression by paravertebral/extramedullary plasmacytoma, or infrequently, collapsed bone itself. Signs of spinal cord compression mandate urgent intervention. In our patient, compressive neuropathy resulted from a rare finding of a cervical amyloidoma. Such cases typically require prompt decompression with surgical resection of the mass to avert impending quadriparesis.

Unusual Casts in a Case of Multiple Myeloma

Multiple myeloma and lymphoproliferative disorders often cause kidney disease. The spectrum of associated kidney diseases includes myeloma kidney (cast nephropathy), amyloidosis, and monoclonal immunoglobulin deposition disease.1 Cast nephropathy is the most common form. We present interesting biopsy findings in a patient with multiple myeloma who presented with kidney failure.

Why nephrologists should perform therapeutic plasma exchange

Why nephrologists should perform therapeutic plasma exchange

A069 FLC Removal HD Improves Outcomes in Myeloma Kidney

A069 FLC Removal HD Improves Outcomes in Myeloma Kidney

Plasmapheresis as a co-treatment in acute renal failure secondary to myeloma kidney

Plasmapheresis as a co-treatment in acute renal failure secondary to myeloma kidney

Immunoassay for Human Hepcidin in Blood

We developed and validated the first ELISA for hepcidin, the principal iron-regulatory hormone that has been very difficult to measure. The competitive ELISA uses a biotin-tagged hepcidin as a tracer to quantify hepcidin in serum, plasma or urine. In healthy volunteers, the 5–95% range of serum hepcidin concentrations was 29–254 ng/ml in men (n=65) and 17–286 ng/ml in women (n=49), with median concentrations 112 vs. 65, p<0.001. The lower limit of detection was 5 ng/ml. Serum, EDTA plasma and heparin plasma hepcidin measurements were in agreement (r> 0.98). Serum and urinary hepcidin concentrations in 24 healthy subjects correlated well (r=0.82). Serum hepcidin appropriately correlated with serum ferritin (r=0.63) reflecting the regulation of both proteins by iron stores. Healthy volunteers showed a diurnal increase of serum hepcidin at noon and 8pm compared to 8am, and a transient rise of serum hepcidin in response to iron ingestion. In 18 young healthy women, serum hepcidin correlated well (p<0.05) with intestinal iron absorption both from a food (r=0.49) and supplemental iron source (r=0.51), as determined by a stable iron isotope technique. In a variety of clinical conditions associated with iron disturbances we observed the appropriate changes in hepcidin concentrations: undetectable or low in patients with iron deficiency anemia (ferritin<10 ng/ml), treated HFE hemochromatosis, and juvenile hemochromatosis, and abnormally high in patients with inflammation (CRP>10 mg/dl), multiple myeloma, or chronic kidney disease. The new blood hepcidin ELISA yields accurate and reproducible measurements that appropriately reflect physiologic, pathologic and genetic influences, and is informative about the etiology of iron disorders.

Immunoassay for human serum hepcidin

AbstractWe developed and validated the first serum enzyme-linked immunosorbent assay for hepcidin, the principal iron-regulatory hormone that has been very difficult to measure. In healthy volunteers, the 5% to 95% range of hepcidin concentrations was 29 to 254 ng/mL in men (n = 65) and 17 to 286 ng/mL in women (n = 49), with median concentrations 112 versus 65 (P < .001). The lower limit of detection was 5 ng/mL. Serum hepcidin concentrations in 24 healthy subjects correlated well with their urinary hepcidin (r = 0.82). Serum hepcidin appropriately correlated with serum ferritin (r = 0.63), reflecting the regulation of both proteins by iron stores. Healthy volunteers showed a diurnal increase of serum hepcidin at noon and 8 pm compared with 8 am, and a transient rise of serum hepcidin in response to iron ingestion. Expected alterations in hepcidin levels were observed in a variety of clinical conditions associated with iron disturbances. Serum hepcidin concentrations were undetectable or low in patients with iron deficiency anemia (ferritin < 10 ng/mL), iron-depleted HFE hemochromatosis, and juvenile hemochromatosis. Serum hepcidin concentrations were high in patients with inflammation (C-reactive protein > 10 mg/dL), multiple myeloma, or chronic kidney disease. The new serum hepcidin enzyme-linked immunosorbent assay yields accurate and reproducible measurements that appropriately reflect physiologic, pathologic, and genetic influences, and is informative about the etiology of iron disorders.

Plasma exchange for myeloma kidney: cast(s) away?

Leung et al. (this issue) present a retrospective study of 40 patients. Observations in 14/40 led to the suggestion of restitution of plasma exchange for light-chain responsive, biopsy-proven myeloma kidney until a better randomized control trial (RCT) is constructed. A careful analysis of their study and a recent RCT suggest little difference in outcome between plasma exchange and control groups. The analysis supports restitution of a better RCT of plasma exchange for myeloma kidney rather than off-label use.

Effects of PACAP on Survival and Renal Morphology in Rats Subjected to Renal Ischemia/Reperfusion

Pituitary adenylate cyclase activating polypeptide (PACAP) occurs and exerts a variety of biological functions in the nervous system and in the peripheral organs, including the urinary system. PACAP has protective effects against myeloma kidney injury and renal ischemia. Ischemia/reperfusion injury of the kidney is a major clinical problem, and based on the protective effects of PACAP in cerebral and cardiomyocyte ischemia, the aim of the present study was to evaluate the effects of a single intravenous PACAP injection on the survival and renal morphology after varying times of ischemia. Rats were subjected to renal artery clamping for 15, 30, 45, 60, or 75 min followed by reperfusion. PACAP (100 microg) was administered intravenously before arterial clamping. We found that a 15- or 30-min renal ischemia led to no renal dysfunction, and the kidneys showed normal appearance with no difference between PACAP- and saline-treated groups. Control rats with 45 min of ischemia had increased premature death rate and showed multifocal acute tubular atrophy, while a 60-min ischemia led to death of all control animals within a few days displaying severe, multifocal Grade II tubular atrophy. In contrast, all PACAP-treated animals survived with subtle morphological changes after the 45-min ischemia. After the 60-min ischemia, death rate was significantly lower in PACAP-treated rats compared to controls, and animals showed subtle focal tubular alteration. A 75-min ischemia was not performable in controls because of deaths before the termination of ischemia. PACAP-treated rats survived longer, but they also died after 5-10 days exhibiting severe focal tubular atrophy. In summary, our results clearly show that PACAP is able to prolong the renal ischemic time, decrease mortality, and attenuate tubular degeneration after renal ischemia.

Plasma Cell Leukemia with Myelofibrosis

Myelofibrosis, which is usually observed as one of the primary forms of chronic myeloproliferative disorders, is characterized by splenomegaly and fibrotic bone marrow. The disease is observed in 10 to 30% patients with multiple myeloma. The degree of the marrow fibrosis tends to correlate with the magnitude of plasma cell infiltration and therefore seems to be associated with prognostic significance. On the other hand, plasma cell leukemia which is an infrequent manifestation of multiple myeloma develops in 12% of patients with multiple myeloma. Therefore, it seems to be a very rare case to observe the coexistence of plasma cell leukemia and myelofibrosis in the same stage of disease. Moreover, it has not been clearly demonstrated whether coexistent of myelofibrosis in untreated bone marrow with plasma cell leukemia is dependent on the secondary effect of this leukemia. Here, we report a case of plasma cell leukemia with myelofibrosis, which showed a rapid development into a fatal outcome. A 59-year-old man was admitted to our hospital because of fever and progressive general fatigue on July 2, 2000. The patient had remained asymptomatic until 3 months prior to his hospitalization. The findings on admission showed that the abdomen was slightly distended and both the liver and spleen were palpable at about 8 cm below the costal margin. Laboratory findings were as follows : white blood cells, 5.1 × 10/L (myelocyte, 0.5% ; metamyelocyte, 0.5% ; neutrophil, 37.0% ; lymphocyte, 25.5% ; monocyte, 16.0% ; plasma cell, 20.5% ; and erythroblast, 2.0%) ; hemoglobin, 6.5 g/dL ; platelets, 27 × 10/L ; lactate dehydrogenase (LDH), 1,875 IU/L ; calcium, 4.9 mEq/L ; albumin, 3.0 g/dL ; uric acid, 12.4 mg/dL ; BUN, 20.3 mg/dL ; creatinine, 1.5 mg/ dL ; CRP, 1.7 mg/dL ; b 2-microglobulin, 15.9 mg/dL ; IgG, 5,060 mg/dL ; IgA, 6 mg/dL ; and IgM, 6 mg/dL. Immunoelectropheresis revealed a monoclonal component of IgG l in the patient’s serum. X-rays of cranial and appendicular bones presented no punched out lesions. Abdominal computed tomography scan showed marked hepatosplenomegaly. A bone marrow aspiration was dry tap. A bone marrow biopsy showed marked myelofibrosis (Fig. 1) and infiltration of plasma cells, which manifested the same phenotype as circulating plasma cells in peripheral blood. Immunophenotypic analysis showed that plasma cells were positive for CD38, CD40, CD44, CD49d, and CD54, and negative for CD19, CD20, CD49e, CD56, CD62L, CD126, and HLA-DR. Chromosomal study using peripheral blood revealed complex karyotypic abnormalities such as 41, X, -Y, +1, der(1;3)(3pter → 9q27?, 1p11 → 1qter), der(1;17)(q10; q10), der(3)t(3;7)(q27;q11), ins(3;?)(q27;?), del(5)(q?), -7, 8, der(8)t(1;8)(p13;q24), -10, -13, -16, -22, +mar1, +mar2, and +mar3 in all 20 analyzed cells. Based on these laboratory data, the patient was diagnosed as having plasma cell leukemia with myelofibrosis. After the patient received combination chemotherapy consisting of vincristine (0.4 mg/body day 14), doxorubicin (15 mg/body, day14), and dexamethasone (40 mg/body, day 14), the circulating plasma cells gradually decreased. However, he died of acute renal failure, possibly due to tumor lysis syndrome and myeloma kidney on day 14. Plasma cell leukemia is characterized by the existence of the increased numbers of plasma cells both in peripheral blood and common organ sites (tissue infiltration), and the prognosis of this disease is very poor. This leukemia, which is defined as a condition that circulating peripheral blood plasma cells exceeding 2 × 10/L or 20% of peripheral blood white cells, is classified into two groups ; the “primary” and the “secondary” plasma cell leukemia. The secondary plasma cell leukemia is usually observed as a terminal complication during the course of multiple myeloma. Although it is widely accepted that there is a relationship between multiple

Intravenous infusion of pituitary adenylate cyclase-activating polypeptide (PACAP) in a patient with multiple myeloma and myeloma kidney: A case study

We have recently shown significant renoprotective effects with the administration of pituitary adenylate cyclase-activating polypeptide (PACAP) in models of myeloma kidney. PACAP markedly inhibited the production of proinflammatory cytokines stimulated by immunoglobulin light chains in human renal proximal tubule epithelial cells and in the kidneys of rats infused with myeloma light chains. PACAP was also shown to suppress the proliferation of human kappa and lambda light chain-secreting multiple myeloma-derived cells. In this case study, an 81-year-old male patient with active multiple myeloma and myeloma kidney was infused intravenously with synthetic human PACAP38 at a rate of 4 pmol/kg/min for 120 min. The continuous infusion increased the level of PACAP38 in blood, with a plateau at about 0.2 nM during the infusion. The level of PACAP in the blood rapidly declined after the cessation of administration with a half-life of about 5–10 min. The continuous infusion did not significantly alter the basal glucose level, blood gases or blood pressure. There was a large reduction in free lambda light chains in urine after the start of the treatment with PACAP. These studies show that PACAP can be safely used in humans and suggest that it could be used as a novel therapeutic agent for the treatment of multiple myeloma and myeloma kidney.