Home About us Current issue Back issues Submission Instructions Advertise Contact Login   

Search Article 
  
Advanced search 
 
Saudi Journal of Kidney Diseases and Transplantation
Users online: 537 Home Bookmark this page Print this page Email this page Small font sizeDefault font size Increase font size 
 


 
EDITORIAL Table of Contents   
Year : 2001  |  Volume : 12  |  Issue : 2  |  Page : 145-150
Renal Failure in Multiple Myeloma "The Myeloma Kidney":State of the Art


1 Medizinische Klinik und Poliklinik V, Universität Heidelberg, Hospitalstr. 3, 69115, Heidelberg, Germany
2 Sektion Nephrologie, Medizinische Klinik und Poliklinik I, Universtität Heidelberg, Bergheimer Str. 58, 69115 Heidelberg, Germany

Click here for correspondence address and email
 

   Abstract 

Renal failure is present in about 20% of patients with multiple myeloma (MM) at diagnosis. Renal function impairment is usually caused by the so-called "myeloma kidney" and is associated with shortened survival in patients treated with conventional therapy. Renal failure is reversible in up to 50% of patients, particularly when its degree is moderate and it is related to precipitating factors such as hypercalcemia. In our experience, approximately 10% of newly diagnosed patients with MM have renal failure severe enough to require dialysis. Despite its frequency, there are few reports dealing with MM and renal failure.

Keywords: Multiple myeloma, Renal failure, Hypercalcemia.

How to cite this article:
Goldschmidt H, Lannert H, Bommer J, Ho AD. Renal Failure in Multiple Myeloma "The Myeloma Kidney":State of the Art. Saudi J Kidney Dis Transpl 2001;12:145-50

How to cite this URL:
Goldschmidt H, Lannert H, Bommer J, Ho AD. Renal Failure in Multiple Myeloma "The Myeloma Kidney":State of the Art. Saudi J Kidney Dis Transpl [serial online] 2001 [cited 2017 Jul 20];12:145-50. Available from: http://www.sjkdt.org/text.asp?2001/12/2/145/33803

   Introduction Top


Multiple myeloma (MM) is a clonal B-cell disease of slowly proliferating plasma cells, accompanied by monoclonal protein pro­duction and lytic bone lesions. Up to 50% of newly diagnosed patients have a decrease in creatinine clearance and around nine percent require dialysis because of severe renal impairment. [1] Despite progress in polychemo­therapy regimens with improvement in response rates, the median survival time with conventional chemotherapy remains 2 to 3 years. [2] High-dose chemotherapy (HDT) supported by autologous bone marrow (BM) or peripheral blood stem cell transplantation (PBSCT) has achieved higher complete remission (CR) rates and prolonged event­free as well as overall survival. [3] However, patients with renal failure are often excluded from aggressive or high-dose chemotherapy protocols because of an expected higher toxicity rate.


   Renal involvement in multiple myeloma Top


Approximately 20% of the patients with MM will develop progressive renal failure in the course of myeloma disease. Cast nephropathy is a typical renal complication found in myeloma patients. It is well known that free light chains play a crucial role in causing such renal damage. [4],[5] Experimental studies in rats and mice have shown that infusion of light chains purified from patients with renal failure may induce tubular cast nephropathy. The incidence of renal damage was much lower in animals infused with light chains from patients with no evidence of renal disease. [4],[5] This indicates that physico-chemical properties of light chains differ markedly. For example, some light chains causing Fanconi syndrome may be digested by catepsin B. In contrast, other forms of light chains forming obstructing casts in the distal tubules are resistant to proteolysis by trypsin and pepsin. [6] Some nephrotoxic light chains appear to be able to self aggregate into large polymers under physiological conditions found in the distal tubules. [7]

Also, B cells synthesize heavy and light chains in healthy controls and normally, the synthesis is more of light than heavy chains. Consequently, small amounts of light chains are regularly filtered at the glomerulus and reabsorbed in the proximal tubule where they can be catabolized. In myeloma, the capacity of the proximal tubular cells to catabolize light chains is exceeded. In consequence, light chains not reabsorbed in the proximal tubules reach the distal segment of the nephron where they can combine with the Tamm Horsfall mucoprotein (THP) and precipitate as obstruc­ting casts. Such obstruction of distal tubules results in leakage of tubular content into the interstitium and leads to the classic appearance of tubular cast and myeloma kidney.

Quite often, renal failure develops rapidly even when there is an unchanged production and serum concentration of light chains. Various factors can favor renal cast formation in myeloma patients. Dehydration, sometimes due to use of diuretics, reduces the glomerular filtration rate (GFR); this may result in an increase of plasma concentration of light chains which exceeds the capacity of the proximal tubules to reabsorb and catabolize. Hypercalcemia may induce vasocons­triction followed by a fall of GFR [Figure - 1]. Several drugs, in particular non-steroidal anti-inflammatory agents, reduce renal blood flow. Radiographic contrast agents can induce acute renal failure in myeloma patients, particularly if patients are dehydrated and ionic contrast media are used.


   Management of renal failure in multiple myeloma Top


Although as many as 50% of patients with MM may experience some degree of renal insufficiency, in the majority, renal function will improve in response to simple measures such as rehydration, correction of hyper­calcemia with bisphosphonates, hyperhyd­ration and glucocorticoids, or discon­tinuation of nephrotoxic drugs such as non­steroidal anti-inflammatory drugs.

One-half of those who recover will improve within the first six weeks. Late recovery is still possible and in one series myeloma was the most common diagnosis in patients who were able to discontinue long-term dialysis. Most of the patients who do not regain normal renal function will be left with only mild to moderate renal impairment and fewer than one per cent will require long-term renal replacement therapy. [9]

Therapeutic plasma exchange (TPE) has been proposed as a method of preventing light-chain associated renal failure by removing the light chains from the plasma. A retrospective case study suggested that TPE may offer some benefit in preventing initiation of dialysis as well as preventing acute renal failure progressing to chronic renal failure. [10] However, its efficacy has been established only in patients with the hyperviscosity syndrome. Therefore, a randomized, controlled, prospective study is needed to determine whether TPE should be recommended as a standard treatment for patients with progressive renal failure due to MM.

The incidence of renal failure certainly rises as the tumor load increases, but it is the underlying tumor burden that ultimately determines survival. Therefore, treatment of myeloma to achieve remission might also reduce the incidence of renal insufficiency.


   Therapy of multiple myeloma patients with renal impairment Top


Conventional chemotherapy

In three studies, the response rate to chemotherapy in patients with MM and renal failure ranged from 43 to 50%. [11] For newly diagnosed patients without renal failure, remission rates of up to 70% have been reported. In a recently published study, the 39% response rate of patients with renal failure was significantly lower than the 56.4% reponse rate observed in patients with normal renal function. [11] If patients who died during the first two months (early mortality) after starting treatment were excluded, the response to therapy was similar, irrespective of whether or not they had impaired renal function. The response rate of patients with renal failure treated with single alkylating agent plus prednisone (melphalan and prednisone or cyclophosphamide and prednisone) was 24%, whereas the response rate in patients who received combination chemotherapy (e.g. VAD: vincristine, adriamycin, and dexamethasone) was 50%. [11] However, Blade and co-workers found that the survival of patients treated with single alkylating agent plus prednisone (12.9 months) was nearly similar to that of those treated with combination chemotherapy (14.2 months); in contrast survival was 34.5 months for patients with normal renal function. [11] Unfortunately, the early mortality rate of approximately 30% within the first two months of diagnosis still remains a constant finding in patients with MM and renal failure. It has been stressed that in patients with renal failure, cycles of melphalan and prednisone are not the most appropriate treatment because of the need for dose adjustment of melphalan to avoid severe myelosuppression, which might carry the risk of sub-optimal treatment. Combination chemotherapy produced a more rapid response with a faster reduction in monoclonal protein production, thereby avoiding further renal damage. The VAD regimen is very effective and can be given to patients with renal failure without dose­reduction. [12] However, pulse-dexame­thasone treatment increases the risk of infections.

To achieve a fast reduction of myeloma protein, we recommend VAD-chemotherapy for patients up to the age of 65 years. Patients with renal failure should be treated as in­hospital patients to detect infections early and to start antibiotic therapy appro­priately. Patients older than 65 years should be treated with cyclophosphamide plus prednisone, because of a high incidence of complications associated with high-dose pulse glucocorticoid therapy. Antibiotic prophy­laxis is recommended for patients with MM at the time of chemotherapy. If the level of polyvalent IgG is lower than 6 g/L, we admi­nister immunoglobulins to prevent infections.

In our experience, factors that affected renal recovery include severity of renal failure, presence of hypercalcemia, and amount of proteinuria. These factors seem to be inversely related to the long-term outcome of patients with renal failure in MM. The most important prognostic factor associated with significantly longer survival is response to chemotherapy.

Since septicemia is the major cause for early mortality, prevention or early diagnosis and institution of therapy for infections is recommended.

High-dose therapy

More than 100 patients with serum creatinine > 177 µmol/L were treated with melphalan-based high-dose therapy (HDT) (melphalan > 140 mg/m 2 ). The prognosis of patients treated with HDT in stage B of MM was not different from patients without renal involvement. [13] In some centers like the University of Arkansas, patients up to the age of 80 years are treated with HDT. Results of studies have provided evidence for improved outcome for MM patients with HDT only up to 60-70 years of age. There is controversy in the literature regarding the dosage of melphalan in individuals with impaired renal function. Some case reports suggest a reduction of the melphalan dosage for severe mucositis. In contrast, Barlogie and co-workers described no change in the pharmacokinetics of high-dose melphalan among patients with renal failure. [13],[14] Their patients received standard melphalan at 200 mg/m 2 , even when on hemodialysis and early mortality remained under 5%. In our clinic, the dosage of melphalan is adjusted to the creatinine-clearance in patients with restricted renal function. [14] Hematological and non-hematological toxicity as well as tumor reduction after five courses of HDT have not been different in patients on dialysis compared to normal patients.

Supportive therapies

Bisphosphonates are potent inhibitors of bone resorption. In MM, bisphosphonates are used primarily for the treatment of hypercalcemia. They also contribute to long-term control of bone disease. The multicenter placebo controlled study of Berenson and colleagues [16] had investigated this possibility. In this study, a reduction of pathological fractures, bone pain, hypercalcemia and also an improved qualitiy of life were described in patients receiving intravenous bisphosphonates. The recent availability of more potent bisphos­phonates will open new avenues for the treatment of bone diseases in MM.

Erythropoietin is effective in anemia due to renal failure. Phase 1-2 clinical trials have had encouraging results with recombinant human erythropoietin for the treatment of the anemia of MM. Two recent randomized studies have confirmed that recombinant erythropoietin therapy is safe in MM and can decrease the need for transfusion. [17],[18] In patients with MM and renal failure, we use blood transfusions in the first three months of chemotherapy. Patients with sensitive or stable disease are then treated according to their prognosis with erythropoietin.


   Conclusion Top


Careful renal analysis in MM patients is worthwhile to detect potential renal impair­ment. In MM, cast nephropathy with renal failure can be enhanced by fluid depletion, hypercalcemia, infection, nephrotoxic drugs, contrast agents and proteinuria. In elderly patients with MM, it is essential to identify other causes of renal impairment like reno­vascular disease and prostatic obstruction.

The early mortality of MM patients with renal failure is up to 30%. This high early mortality rate is mainly due to infection and septicemia. The incidence of infections is favored by the immunosuppressive effects of myeloma disease, renal failure, cortico­steroids, and cytotoxic drugs. Prevention, earlier diagnosis, and optimal therapy of infections are recommended.

Rapid reduction, or removal of light chains by aggressive chemotherapy/HDT and/or TPE could prevent irreversible renal failure or reduce the risk of renal damage. In cases where renal failure proves to be irreversible, maintenance dialysis should be considered in virtually all patients in whom continuing myeloma treatment is warranted.

Factors affecting renal function recovery are the degree of renal failure, the presence of hypercalcemia, and amount of proteinuria. Effective and causative treatment of renal failure in combination of myeloma therapy has been proven to prolong event-free and overall survival of MM patients.

 
   References Top

1.Knudsen LM, Hippe E, Hjorth M, Holmberg E, Westin J. Renal function in newly diagnosed multiple myeloma - a demographic study of 1353 patients. Eur J Hematol 1994;53:207-12.  Back to cited text no. 1    
2.Boccadoro M, Palumbo A, Argentino C, et al. Conventional induction treatments do not influence overall survival in multiple myeloma. Br J Haematol 1997;96:333-7.  Back to cited text no. 2  [PUBMED]  
3.Attal M, Harousseau JL, Stoppa AM, et al. A prospective, randomized trial of autologous bone marrow transplantation and chemotherapy in multiple myeloma. N Engl J Med 1996;335:91-7.  Back to cited text no. 3  [PUBMED]  [FULLTEXT]
4.Sanders PW, Herrera GA, Galla JH. Human Bence Jones protein toxicity in rat proximal tubule epithelium in vivo. Kidney Int 1987;32:851-61.  Back to cited text no. 4  [PUBMED]  
5.Solomon A, Weiss DT, Kattine AA. Nephrotoxic potential of Bence Jones proteins. N Engl J Med 1991;324:1845-51.  Back to cited text no. 5  [PUBMED]  
6.Leboulleux M, Lelongt B, Mougenot B, et al. Protease resistance and binding of Ig light chains in myeloma associated tubulopathies. Kidney Int 1995; 48:72-9.  Back to cited text no. 6  [PUBMED]  
7.Myatt EA, Westholm FA, Weiss DT, Solomon A, Schiffer M, Stevens FJ. Pathogenic potential of human monoclonal immunoglobulin light chains: relationship of in vitro aggregation to in vivo organ deposition. Proc Natl Acad Sci USA 1994;91:3034-8.  Back to cited text no. 7  [PUBMED]  [FULLTEXT]
8.Winearls CG. Acute myeloma kidney. Kidney Int 1995;48: 1347-61.  Back to cited text no. 8  [PUBMED]  
9.Magee C, Vella JP, Tormey WP, Walshe JJ. Multiple myeloma and renal failure: one center“s experience. Ren Fail 1998;20: 597-606.  Back to cited text no. 9  [PUBMED]  
10.Moist L, Nesrallah G, Kortas C, Espirtu E, Ostbye T, Clark WF. Plasma exchange in rapidly progressive renal failure due to multiple myeloma. Am J Nephrol 1999;19: 45-50.  Back to cited text no. 10  [PUBMED]  [FULLTEXT]
11.Blade J, Fernandez-Llama P, Bosch F, et al. Renal failure in multiple myeloma: presenting features and predicts of outcome in 94 patients from a single institution. Arch Intern Med 1998;158: 1889-93.  Back to cited text no. 11    
12.Kyle RA. Current therapy of myeloma. In Hematology 2000, The American Society of Hematology. Education Program Book, Washington, 147-150.  Back to cited text no. 12    
13.Tricot G, Alberts DS, Johnson C, et al. Safety of autotransplants with high­dose melphalan in renal failure: a pharmaco-kinetic and toxicity study. Clin Cancer Res 1996;2:947-52.  Back to cited text no. 13  [PUBMED]  [FULLTEXT]
14.Barlogie B. Advances in therapy of multiple myeloma: Lessons from acute leukemia. Clin Cancer Res 1997;3:2605-13.  Back to cited text no. 14  [PUBMED]  [FULLTEXT]
15.Schmoll HJ, Hoffken K, Possinger K. Kompendium internistische Onkologie. Springer Verlag, 1996;Teil 1,2. Auflage: 663.  Back to cited text no. 15    
16.Berenson JR, Lichtenstein A, Porter L, et al. Efficacy of pamidronate in reducing skeletal events in patients with advanced multiple myeloma. N Engl J Med 1996; 334:488-93.  Back to cited text no. 16  [PUBMED]  [FULLTEXT]
17.Cazzola M, Messinger D, Battistel V, et al. Recombinant human erythropoietin in the anemia associated with multiple myeloma or non-Hodgkin“s lymphoma: dose finding and identification of predictors of response. Blood 1995;86:4446-53.  Back to cited text no. 17  [PUBMED]  [FULLTEXT]
18.Osterborg A, Boogaerts MA, Cimino R, et al. Recombinant human erythropoietin in transfusion-dependent anemia patients with multiple myleloma and non-Hodgkin“s lymphoma - a randomized multicenter study. Blood 1996;87:2675­-82.  Back to cited text no. 18  [PUBMED]  [FULLTEXT]

Top
Correspondence Address:
Hartmut Goldschmidt
Medizinische Klinik und Poliklinik V, Universität Heidelberg, Hospitalstr. 3, 69115 Heidelberg
Germany
Login to access the Email id


PMID: 18209365

Rights and Permissions


    Figures

  [Figure - 1]



 

Top
 
 
    Similar in PUBMED
    Search Pubmed for
    Search in Google Scholar for
  Related articles
    Email Alert *
    Add to My List *
* Registration required (free)  
 


 
    Abstract
    Introduction
    Renal involvemen...
    Management of re...
    Therapy of multi...
    Conclusion
    References
    Article Figures
 

 Article Access Statistics
    Viewed11933    
    Printed199    
    Emailed0    
    PDF Downloaded1243    
    Comments [Add]    

Recommend this journal