Why does multiple myeloma cause renal failure

It is not surprising that the diagnosis of a paraproteinemic renal lesion is hampered by the general lack of sensitivity and specificity of currently available noninvasive tests. The gold standard for diagnosis remains renal biopsy with demonstrated evidence of deposition of monoclonal proteins in the area of injury [ 68 ]. The measurement of serum concentration of the clonal FLCs and that of urine level of albumin may be considered the landmarks for screening algorithms in patients with cast nephropathy [ 69 ].

On the other hand, significant amount of albumin in urine is frequently associated with amyloidosis or MIDD. Amyloid deposits may be confirmed on biopsy of subcutaneous fat or of one of the minor salivary glands.

If both are negative, then a kidney biopsy is required to search for amyloid, MIDD, or an unrelated glomerulopathy such as diabetic nephropathy.

Patients with CKD and a monoclonal protein need special care, being at increased risk of AKI; renal biopsy is necessary to determine the cause of kidney damage. Identification of novel toxic nephropathy and AKI biomarkers has been designated as a top priority by the American Society of Nephrology. The concept of developing a new toolbox for earlier diagnosis of disease states is also prominently featured in the National Institute of Health NIH road map for biomedical research.

In , the Acute Kidney Injury Network AKIN , a collaborative group of investigators from all major critical care and nephrology societies, proposed a staging system based on serum creatinine and urine output and consisting of 3 categories mild, moderate, and severe in a way similar to those risk, injury, and failure used by the RIFLE staging system. Despite these working classification systems, the diagnosis of AKI is problematic, as current diagnoses rely on two functional abnormalities: functional changes in serum creatinine and oliguria.

Both of these are late consequences of injury and not markers of the injury itself. Most importantly, the measurement of serum creatinine does not identify the cell type that is acutely injured, even though this localization determines the natural history of the disease and its response to therapy.

Neutrophil gelatinase-associated lipocalin NGAL has emerged as the most promising marker of AKI in a number of clearly defined clinical contexts [ 71 ].

NGAL, also known as lcn2, is one of the most upregulated transcripts in the early postischemic mouse kidney and this finding has been confirmed in several other transcriptome profiling studies. Downstream proteomic studies have also revealed NGAL to be one of the earliest and most robustly induced proteins in the kidney after ischemic or nephrotoxic AKI in animal models, and NGAL protein is easily detected in the blood and urine soon after AKI [ 72 ].

A second very promising biomarker of kidney damage is kidney injury molecule 1 KIM-1 , a type-1 transmembrane glycosylated protein with IgG-like domains in the ectodomain of the protein. Downstream proteomic studies have also shown KIM-1 to be one of the most highly induced proteins in the kidney after AKI in animal models, and a proteolytically processed domain of KIM-1 is easily detected in the urine soon after AKI [ 73 ].

An advantage of KIM-1 over NGAL is that it appears to be more specific to ischemic or nephrotoxic AKI and not significantly affected by prerenal azotemia, urinary tract infections, or chronic kidney disease. In a small human cross-sectional study, KIM-1 was found to be markedly induced in proximal tubules in kidney biopsies from patients with established AKI primarily ischemic.

However, patients with AKI induced by contrast media did not have significant increase in urinary KIM-1 concentration [ 76 ]. New encouraging perspectives for improving the current state in clinical diagnosis and in the identification of nephrotoxic injuries are emerging from metabolomics studies [ 81 ]. Metabolomics aims to identify unique fingerprints of specific injuries and functions, for example, diseases or effects of exposure to toxic compounds [ 82 ]. Kidney impairment, a major risk factor for developing CI-AKI, is one of the more frequent clinical features of symptomatic multiple myeloma.

Other coexisting morbidities include anemia, hypercalcemia, and potentially nephrotoxic drugs like NSAIDs, chemotherapeutic agents, and antibiotics. Often, multiple factors may coexist, like kidney impairment with anemia, infections with nephrotoxic drugs, diabetes with aging, and increasing the risk of CI-AKI [ 84 ]. The management of patients with plasma cell dyscrasia requiring the intravascular administration of iodinate contrast media should include a assessment of the risk before administration; b pharmacological and nonpharmacological preventive measures for reducing such risk factors; c monitoring after administration; d early accurate diagnosis of CI-AKI.

When a recent serum creatinine value is not available, a simple questionnaire e. However, dipstick testing is reliable for the identification of albuminuria but it is not able to identify Bence Jones proteinuria. Since serum 2 -microglobulin increases with both higher tumor burden and diminished renal function, it was suggested that evaluation of -microglobulin levels may be useful before intravenous injection of iodinate contrast agents to patients with multiple myeloma [ 51 ].

Serum -microglobulin likely serves as a marker of patients who are at a higher risk of developing CI-AKI. According to previous results published elsewhere, a value of -microglobulin below 2.

According to the KDIGO AKI guideline, pharmacological and nonpharmacological preventive measures for reducing risk factors for CI-AKI in patients with multiple myeloma include a the use of either iso-osmolar or low-osmolar rather than high-osmolar iodinated contrast media strength of recommendation 1B ; b extracellular volume expansion at the time of radiocontrast media administration with either isotonic sodium chloride or sodium bicarbonate solutions strength of recommendation 1A.

It is desirable not to use oral fluids alone strength of recommendation 1C , while it is recommended to use oral N -acetylcysteine NAC together with intravenous isotonic crystalloids strength of recommendation 2D.

Following evidence in animal model that aciduria increases the nephrotoxicity of Bence Jones protein independently of urinary flow rate [ 88 , 89 ], alkalinization of the urine through oral bicarbonate has been recommended in patients with multiple myeloma and Bence Jones proteinuria to prevent or treat myeloma cast nephropathy. In a trial performed in myeloma patients presenting with renal failure, patients were randomized to receive either sodium bicarbonate to render their urine neutral or no supplement.

Patients randomized to receive alkali fared marginally better than the others, but the difference was not significant [ 90 ]. Urine alkalinization is now recommended by consensus documents on the management of renal failure in multiple myeloma patients [ 4 ]. On the basis of recent evidence, it is reasonable to correct marked anemia in patients with mild-to-moderate kidney impairment before contrast studies.

The combination of kidney disease with anemia significantly increases the risk of CI-AKI with reported incidences of 6. This emergency treatment is based on high-dose dexamethasone. Bisphosphonates are effective for controlling malignancy-related hypercalcemia; nevertheless, they can further impair renal function and cause symptomatic hypocalcemia in patients with acute renal failure and their use is discouraged in such patients [ 91 ].

Although the reduction of hypercalcemia has been considered optional in the KDIGO AKI guideline, we suggest correcting high concentrations of serum calcium before contrast media studies, being a risk factor for acute kidney impairment.

Finally, as a preventive measurement in multiple myeloma patients at high risk for CI-AKI, it is desirable to discontinue the therapeutic administration of NSAIDs, aminoglycosides, high dose diuretics, antineoplastic drugs, and metformin 48 hours before contrast media administration.

Multiple myeloma inpatients monitoring consists of measurement of serum creatinine together with the calculation of eGFR at 12 and 48 hours after contrast media injection. If there is evidence of CI-AKI, it is recommended to repeat these tests on days 3—5 after contrast media administration, monitoring also urine output, and it is reasonable to prolong the discontinuation of the therapeutic treatment with NSAIDs, aminoglycosides, high dose diuretics, antineoplastic drugs, and metformin [ 70 ].

Finally, diagnosis of CI-AKI can be improved by adding the measurement of serum cystatin C, which allows for an earlier assessment of changes in renal filtration [ 92 ]. Urine NGAL may be also useful for assessing the presence of kidney injury and damage, often preexistent in patients treated with nephrotoxic drugs. Data from recent meta-analyses have led to the conclusion that the overall incidence of CI-AKI is low, not exceeding 6. Nevertheless, this could result from comorbidities and the nephrotoxic chemotherapy administered to these patients in combination with intravenous iodinated contrast medium.

In a retrospective study on more than 50, patients divided in two subgroups intravenous contrast-enhanced and contrast-unenhanced CT scan it was found that the incidence of CI-AKI was not significantly different from AKI caused by other factors [ 94 ], confirming similar results published previously [ 95 ]. The use of NGAL and KIM-1 as tandem markers for early detection and later confirmation, respectively, of kidney injury in patients at high risk should be considered.

We should avoid redundant laboratory tests, like Bence Jones proteinuria, since this test cannot be considered as a surrogate biomarker of kidney function.

The authors declare that there is no conflict of interests regarding the publication of this paper. This is an open access article distributed under the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Article of the Year Award: Outstanding research contributions of , as selected by our Chief Editors. Read the winning articles. Journal overview. Special Issues. Academic Editor: Michele Andreucci. Received 01 Nov Revised 13 Mar Accepted 13 Mar Published 30 Apr Abstract The spectrum of kidney disease-associated monoclonal immunoglobulin and plasma cell malignancies is remarkably broad and encompasses nearly all nephropathologic entities. Introduction The kidney is susceptible to insult from a variety of exogenous e.

Kidney Diseases Associated with Plasma Cells Dyscrasias Monoclonal gammopathies refer to a spectrum of disorders characterized by the monoclonal proliferation of lymphoplasmacytic cells in the bone marrow and, sometimes, tissue deposition of monoclonal immunoglobulins Igs or their components [ 2 ]. Table 1. Kidney disease in plasma cell dyscrasias [ 14 , 18 ].

Table 2. Main risk factors for acute kidney injury AKI or acute tubular necrosis ATN in patients with malignant plasma cell dyscrasias. View at: Google Scholar S. Rajkumar, R. Kyle, and F. Dimopoulos, E. Terpos, A. Chanan-Khan et al. Heher, H. Rennke, J. Laubach, and P. View at: Google Scholar G. Merlini, A. Wechalekar, and G. Rosenbaum, J. Jasielec, J. Laubach, C. Prada, P. Richardson, and A. Glavey, M. Gertz, A. Dispenzieri et al.

Kastritis, A. Anagnostopoulos, M. Roussou et al. Haynes, S. Read, G. Collins, S. Patients and Methods Medical records of patients from our institution with MM and renal failure diagnosed between January and December were reviewed.

The statistical methods consisted of Kaplan-Meier survival curves, the log-rank test, logistic regression analysis, and the Cox proportional hazards model for survival analysis. Results Renal failure was observed in 94 Patients with renal failure had more advanced disease than the others. However, when patients dying within the first 2 months of treatment were excluded, no significant differences in the response rate were found between patients with renal failure and those with normal renal function.

Conclusions Renal failure was present in almost one fourth of patients with MM. Patients with reversible renal failure had longer survival than those not recovering renal function.

When patients dying within the first 2 months of treatment were excluded, the response rate was not affected by renal function. Factors associated with renal function recovery were degree of renal failure, presence of hypercalcemia, and amount of proteinuria. Response to chemotherapy and severity of renal failure were the only independent factors associated with survival.

Renal insufficiency is usually caused by the so-called myeloma kidney and is associated with shortened survival. The purpose of this study is to report the presenting features, the response to therapy, and the factors associated with the reversibility of renal insufficiency and survival in 94 patients with MM and renal failure from a single institution. From January to December , patients at our institution were diagnosed as having MM.

Patients were classified according to the staging system of Durie and Salmon. All patients received supportive care with hydration and transfusions when needed. Hypercalcemia was treated with forced diuresis with saline solution and furosemide plus glucocorticoids. No bisphosphonates or calcitonin were used in this phase of the disease in our patients. Chemotherapy regimens consisted of cycles of melphalan and prednisone 31 patients ; cyclophosphamide and prednisone 4 patients ; vincristine sulfate, cyclophosphamide, melphalan, and prednisone VCMP; 22 patients ; alternating cycles of VCMP and vincristine, carmustine, doxorubicin hydrochloride Adriamycin , and prednisone 23 patients ; and vincristine sulfate, Adriamycin, and dexamethasone phosphate VAD; 1 patient.

Seven patients received low doses of alkylating agents on a continuous basis or prednisone alone, and 6 patients received no treatment because of their extremely poor clinical condition. Alkylating agents ie, melphalan and cyclophosphamide , as well as carmustine and Adriamycin, were usually given at half doses in the first 2 cycles of chemotherapy; if no severe myelosuppression was observed in patients who recovered renal function, the doses of these agents were increased in subsequent courses.

In addition to the supportive care and chemotherapy, patients were actively treated with dialysis when needed. Thus, 34 patients received renal replacement therapy with dialysis. The characteristics and outcomes of some of the patients included in this study requiring maintenance dialysis have been reported in detail elsewhere. Patients who did not fulfill the criteria for objective or partial response were considered treatment failures.

Survival curves were plotted according to the method of Kaplan and Meier 13 and were statistically compared by means of the log-rank test. Renal failure was present in 94 Table 1 shows the main characteristics at presentation of patients with and without renal failure.

Patients with renal insufficiency had a poorer performance status, more advanced skeletal involvement, higher serum lactate dehydrogenase levels, and a higher degree of anemia and hypercalcemia. Patients with renal failure more frequently had Bence Jones myeloma than did those with normal renal function. The average time to renal function recovery was 1. In all except 2 of these patients, renal function was recovered in less than 4 months.

If patients who died within the first 2 months of initiation of treatment are excluded, there are no significant differences in the response rate between patients with renal failure and those with normal renal function. The median survival of the 94 patients with renal failure was 8. No significant differences were found between patients treated with a single alkylating agent plus prednisone and those receiving combination chemotherapy median survival, Adverse events in patients undergoing dialysis are largely similar to those observed in controls and in those with mild-to-severe impairment, with the exception of renal and metabolic adverse events, which were found to be more common in patients undergoing dialysis.

In a subanalysis of the APEX trial, bortezomib was effective in patients with renal impairment, including those with severe renal impairment, 66 with response rates and time to response similar across all subgroups of patients with varying degrees of renal function. Time to progression and overall survival were not substantially affected in patients with severe to moderate renal impairment compared to those with no or mild renal impairment or to the overall APEX population. Similarly, patients treated with bortezomib-based therapies experienced similar clinical benefit irrespective of renal function status in another retrospective series.

Toxicity was mild to moderate and comparable in both frequency and severity to that observed in patients with normal renal function. Furthermore, renal function improved in four patients who no longer required dialysis. Reversal of renal failure was observed in five of eight patients seven newly diagnosed, one previously treated with acute myeloma-induced renal failure who were treated with bortezomib-based therapy. It was suggested that bortezomib may improve kidney function not only through rapid reduction of toxic monoclonal light chains, but also through its action on nuclear factor-kappa B: bortezomib may reduce inflammation in myeloma kidney disease through its inhibitory effect on nuclear factor-kappa B, which has been shown to be activated in renal tubular cells of proteinuric patients.

Of 51 patients enrolled, 32 were evaluable at the time of reporting. Improvements in renal function were noted preferentially in patients with a significant antimyeloma response to bortezomib. Although overall toxicity appears to be slightly higher in patients with renal failure than in those with normal renal function, tolerance is improved in patients whose disease responds to treatment and whose renal function improves to the extent that tolerability is comparable to that in patients with normal renal function.

Median serum creatinine in 24 patients at each cycle of treatment with bortezomib-based regimens. These data provide evidence for the activity and safety of bortezomib in this specific subset of patients.

Response to bortezomib is independent of renal function and tolerability is comparable to that seen in patients with normal renal function, whereas response is rapid, a factor that is crucial in patients with deteriorating renal function. Lenalidomide, a thalidomide analogue, is the first of the second-generation immunomodulatory drugs IMiDs.

Ongoing trials show that lenalidomide is also very active in newly diagnosed patients with either low or high dose dexamethasone or in combination with MP. Recommendations for lenalidomide use in patients with renal impairment have been formulated on the basis of a pharmacokinetic study in 30 patients with various degrees of renal impairment. Patients were stratified into various groups on the basis of their creatinine clearance.

High-dose therapy with autologous stem cell transplantation ASCT has been associated with improved progression-free survival in several studies. In patients with renal impairment, the use of ASCT is limited because of increased toxicity.

Overall survival is adversely affected by the degree of renal impairment. In view of the above data and because we now have more treatment options for patients with myeloma and renal failure, it is likely that the application of high-dose therapy to such patients will decrease. Myeloma-induced renal failure is associated with significant morbidity and increased early mortality.

Rapid intervention to reverse renal insufficiency is critical. Supportive care measures are essential and antimyeloma therapy should be initiated as soon as possible. High-dose dexamethasone-based regimens remain the cornerstone in the treatment of these patients, owing to their rapid antimyeloma activity. The addition of novel agents can further increase the rapidity of response and perhaps the probability of restoring renal function. The limited experience with thalidomide indicates that this agent can be administered in patients with renal failure.

Bortezomib can be safely administered to patients presenting with renal failure, and the combination of bortezomib with high-dose dexamethasone may be the treatment of choice for such patients. Renal failure in multiple myeloma. Pathogenesis and prognostic implications.

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Hypercalcemia can also be caused by overactive parathyroid glands. Untreated cases can lead to many different symptoms like coma or cardiac arrest. There are several ways that the kidneys can be kept healthy in people with myeloma, especially when the condition is caught early. Drugs called bisphosphonates, most commonly used to treat osteoporosis, can be taken to reduce bone damage and hypercalcemia.

People can get fluid therapy to rehydrate the body, either orally or intravenously. Anti-inflammatory drugs called glucocorticoids can reduce cell activity. And dialysis can take some of the strain off kidney function. Finally, the balance of drugs administered in chemotherapy can be adjusted so as not to further harm the kidneys.

Kidney failure is a common effect of multiple myeloma. Damage to the kidneys can be minimal when the condition is identified and treated in its early stages. Treatment options are available to help reverse kidney damage caused by the cancer. It's important to go to your appointments with your own set of questions for your doctor.

Here's what to ask about progressive multiple myeloma…. A doctor answers questions about targeted therapy for multiple myeloma.