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NDT Advance Access originally published online on January 5, 2006
Nephrology Dialysis Transplantation 2006 21(3):582-590; doi:10.1093/ndt/gfi318
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© The Author [2006]. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Editorial Review

Myeloma – new approaches to combined nephrological–haematological management

Marion Haubitz1 and Dietrich Peest2

1 Department of Nephrology, 2 Department of Haematology, Haemostaseology, and Oncology, Hannover Medical School, Hannover, Germany

Correspondence and offprint requests to: Prof. Marion Haubitz, Department of Nephrology, Hannover Medical School, Hannover, Germany. Email: haubitz.marion{at}mh-hannover.de

Keywords: AL amyloidosis; cast nephropathy; high-dose chemotherapy; kidney transplantation; light chain deposition disease; multiple myeloma



   Introduction
Top
 Introduction
Diagnosis
 Cast nephropathy
 Histology
 Clinical manifestation
 Treatment and prognosis
 AL amyloidosis
 Light-chain deposition disease
 Renal replacement therapy and...
 References
 
Multiple myeloma (MM) is a haematopoietic malignancy of terminal differentiated clonal plasma cells. The clinical symptoms are caused by diffuse or multilocular infiltration of the bone marrow with osteolysis and suppression of the normal haematopoesis, as well as by the production of monoclonal immunoglobulins or fragments (light chains or heavy chains). The incidence is approximately 3–4/100 000/year. MM is a disease of the elderly. Approximately 15% of patients are aged 60 years or younger and a further 15% between 60 and 65 years. Fewer than 2% of the patients are younger than 40 years at diagnosis. This age distribution has implications for the population eligible for specific types of treatment, such as high-dose therapy and stem cell transplantation.



   Diagnosis
Top
 Introduction
 Diagnosis
Cast nephropathy
 Histology
 Clinical manifestation
 Treatment and prognosis
 AL amyloidosis
 Light-chain deposition disease
 Renal replacement therapy and...
 References
 
The presenting features include symptoms of bone disease, typically unexplained backache and sometimes fractures, anaemia, renal insufficiency of different degrees, oedema (caused by a nephrotic syndrome and/or cardiac failure), hypercalcaemia, severe bacterial infections and bleeding abnormalities (less frequently leucopenia/thrombocytopenia), peripheral neuropathy and symptoms from hyperviscosity. The diagnosis of MM is confirmed by demonstration of a monoclonal protein in the serum and/or urine and/or lytic lesions on X-ray together with an increased number of plasma cells in the bone marrow (bone marrow aspirate, trephine biopsy showing more than 10% clonal plasma cells).

Kidney involvement is seen in 50% of the patients, but completely different diseases are found (Table 1). Moreover, more than one renal manifestation is often seen in a single patient. Most of the renal impairment is caused by deposition of monoclonal immunoglobulins or fragments as the kidney is especially prone to deposition. This is probably due to the high plasma flow and glomerular filtration and to the dominant role of the renal tubuli regarding light-chain metabolism [1]. The pathogenicity of the deposition could be shown in an animal model [2].


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  		Table 1. Renal manifestation in patients with MM

 
Effective and high-quality care requires an interdisciplinary approach, especially in patients with renal involvement. This starts with an adequate diagnostic work-up, not only concerning MM, but also the renal manifestation. In many patients a kidney biopsy is essential for a decision on individual treatment.

This review concentrates on renal manifestations with direct deposition of immunoglobulins and light chains: cast nephropathy, AL amyloidosis and light-chain deposition disease (LCDD). Heavy-chain deposition is rarely seen in patients with myeloma; clinically these patients do not differ from those with LCDD [3]. Renal impairment in MM can also be aggravated or even attributed to other factors like hypercalcaemia, dehydration, infection or the effects of nephrotoxic drugs. For example, hypercalcaemia occurs in about one-third of the patients, caused by osteoclasts activated by the malignant clone via mediators like TNF, IL-6 or prostaglandins; in some patients elevated levels of PTH-related peptide are found [4]. Treatment strategies will have to deal with MM on the one hand and renal disease on the other. Conventional chemotherapy, high-dose chemotherapy with autologous stem cell support and allogeneic stem cell transplantation will be adressed. The latter approach may ‘cure’ the disease in a few cases. There are new approaches regarding combined allogeneic bone marrow and kidney transplantation with the chance of inducing tolerance towards the renal transplant.



   Cast nephropathy
Top
 Introduction
 Diagnosis
 Cast nephropathy
Histology
 Clinical manifestation
 Treatment and prognosis
 AL amyloidosis
 Light-chain deposition disease
 Renal replacement therapy and...
 References
 
Nearly one third of the patients with MM develop cast nephropathy, a manifestation that depends on the presence of free light chains. Up to 85 g monoclonal light chains are synthesized per day compared to 0.9 g polyclonal ones in healthy persons. Light chains are freely filtered, absorbed and catabolized in the proximal tubular cells. In MM they seem to accumulate in the lysosomes, resistant to proteases and degradation due to structural changes. The resulting atrophy of the proximal tubulus cells is one main factor for renal insufficiency. The remaining light chains leave the proximal tubulus. Fluid absorption leads to their concentration. In the distal tubuli and the collection duct, the aggregation and co-precipitation of light chains with Tamm-Horsfall protein results in the formation of casts followed by tubular obstruction. Disruption of the basement membrane leads to leakage into the interstitium followed by a cellular reaction. Precipitation depends on the type of light chains [2], the affinity to Tamm-Horsfall protein, the concentration – influenced by any reduction in glomerular filtration rate (for example, dehydration) – and the tubulus function.



   Histology
Top
 Introduction
 Diagnosis
 Cast nephropathy
 Histology
Clinical manifestation
 Treatment and prognosis
 AL amyloidosis
 Light-chain deposition disease
 Renal replacement therapy and...
 References
 
Typical hyaline, fractured casts (strong stain with Eosin, weak with PAS), are seen in the distal tubuli and the collecting ducts (rarely in the proximal tubuli) together with degenerative changes and atrophy of tubular cells (Figure 1A). They are surrounded by multinucleated cells of macrophage origin (Figure 1B). In the tubulointerstitium infiltrating inflammatory cells are seen, accompanied by fibrosis and tubular atrophy. Rhomboid or needle-shaped crystals are found in the casts, which can be suspected in light microscopy and seen in electron microscopy [5]. Immunohistologically {lambda}-light chains are detected frequently, but {kappa}-light chains rarely. The glomeruli are usually normal with the exception of a slightly increased matrix.


Figure 1
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  		Fig. 1. Cast nephropathy. Typical fractured casts in the tubuli (A) surrounded by macrophages (B) (PAS staining, 630x).

 


   Clinical manifestation
Top
 Introduction
 Diagnosis
 Cast nephropathy
 Histology
 Clinical manifestation
Treatment and prognosis
 AL amyloidosis
 Light-chain deposition disease
 Renal replacement therapy and...
 References
 
The possibility of a MM-associated renal disease should be considered in any patient, especially the elderly, with unexplained renal failure, normal sized kidneys and a bland urine deposit. In patients with cast nephropathy, mainly Bence-Jones protein is found in the urine and only low amounts of albumin. Proteinuria is below 3 g/24 h in about three-fourths of the patients [6]. This differentiates cast nephropathy from AL amyloidosis and LCDD, where most of the patients develop a nephrotic syndrome. Patients often present with impaired renal function. MacLennan et al. found that 43% of 998 patients younger than 75 years and participating in treatment studies had a creatinine value higher than 130 µmol/l [7] and about 10% of the patients had severe renal insufficiency up to end-stage renal disease (ESRD). Interestingly, the incidence of renal insufficiency requiring dialysis is more than 50% in patients primarily seen by nephrologists [8]. Severity of renal insufficiency, age of the patients and the fact that cast nephropathy is mainly found in patients with high tumour burden [8] might have led nephrologists to a fatalistic view regarding treatment strategies. However, haematologists should be contacted early, since the tumour requires immediate adequate treatment in most cases and different therapeutic options are presently available. To prevent acute renal deterioration or failure, one has also to be aware of the risk of hypercalcaemia, dehydration, infections and non-steroidal antiphlogistic drugs. Radiographic contrast media, however, seem to play a minor role [9] and the risk can be very substantially diminished by hydration of the patient.



   Treatment and prognosis
Top
 Introduction
 Diagnosis
 Cast nephropathy
 Histology
 Clinical manifestation
 Treatment and prognosis
AL amyloidosis
 Light-chain deposition disease
 Renal replacement therapy and...
 References
 
Conventional chemotherapy
The combination of melphalan and prednisone (MP) was introduced by Alexanian et al. in 1969 for systemic treatment of MM [10]. Presently, MP is still standard for primary remission induction in elderly patients, while high-dose chemotherapy with autologous stem cell support (see below) was established for younger patients [11]. A meta-analysis including 6633 patients treated in 27 randomized trials either with polychemotherapy combinations or with MP showed a median overall survival of 2.5 years and a median response duration of 1.5 years with no differences between either treatment group, though the response rate was significantly higher in patients receiving polychemotherapy [12]. Furthermore, subgroup analysis of patients with creatinine below 130 µmol/l (n = 2540), between 130 and 200 µmol/l (n = 522) and above 200 µmol/l (n = 595) showed no differences in outcome between MP or polychemo-therapy treated patients. Although the contribution of renal clearance to the overall melphalan elimination appears to be low, dose reduction should be considered in patients with renal insufficiency, since increased bone marrow suppression was observed. Maintenance treatment after remission induction is not generally recommended, since no or only marginal survival benefit could be demonstrated [13,14].

High-dose chemotherapy
McElwain and Powles were the first to describe high-dose melphalan treatment in MM [15]. The response rate was high, but mortality was high too. During the following years, treatment-associated mortality could be reduced to less than 5% in patients younger than 60–65 years with good performance status by the addition of autologous bone marrow or peripheral blood stem cell support [16–19]. In a prospective randomized trial 5 year, progression-free survival was estimated at 28% vs 10% using conventional treatment and the 5 year overall survival was estimated at 52% vs 12% [11]. In a second trial, the median progression-free survival was 32 vs 20 months and the median overall survival 54 vs 42 months [20].

In most protocols patients receive pretreatment with 4–6 cycles of conventional chemotherapy to reduce tumour cell load. The combination of vincristine, adriamycin and dexamethason is often applied for this purpose. It is effective and melphalan, which is toxic to stem cells and should not be given before stem cell harvest, can be avoided. For several years, most centres have used peripheral blood stem cells (PBSC) instead of bone marrow due to better results. PBSC can be collected from the peripheral blood after stimulation with granulocyte colony stimulating factor during the regeneration phase after a cytoreductive chemotherapy cycle e.g. with cyclophosphamide. For the following high-dose chemotherapy melphalan at a dose of 200 mg/m2 is widely used. After 1 or 2 days the autologous PBSC are intravenously reinfused. Regeneration of the peripheral blood will be around day 12–14. High-dose chemotherapy and stem cell support has also been successfully used in MM patients with renal failure ([21]: six patients, one ESRD; [22]: six patients, including two with LCDD, four ESRD; [23]: 14 patients; [24]: 81 patients, including 38 with LCDD, 38 ESRD; [7]: 19 patients, one ESRD). Renal failure had no impact on the quality of stem cell collection and did not affect engraftment [24]. Complete response rate in patients with renal insufficiency seems to be comparable to patients with normal renal function and is not affected by dialysis dependence. However, treatment-related mortality and morbidity is higher (29% compared to 3.4% [23]). Severe mucositis and haematological toxicity occur [25,26] and pulmonary complications and encephalopathy are significantly higher in ESRD patients [24]. A reduction of 25–50% of the melphalan dose seems to be necessary in patients with creatinine clearance below 30 ml/min [24–26]. Recovery of renal function after high-dose chemotherapy is uncommon [24].

Allogeneic bone marrow or PBSC transplantation
Allogeneic bone marrow or PBSC transplantation has been applied in selected young patients with a compatible family donor or matched unrelated donor [27,28]. A graft vs myeloma effect has been postulated and is discussed to be the reason for long-term survival observed in some MM patients who received a stem cell allograft [29]. However, transplantation-related mortality is up to 40% (mainly due to graft vs host disease and infections), and the 5-year survival rate (20–30%) is even less than in patients after high-dose chemotherapy and autologous stem cell support [30]. In single patients a nephrotic syndrome has been seen after allogeneic transplantation where the glomerular lesion (membranous nephropathy or minimal change/focal segmental glomerulosclerosis) might be an equivalent for graft vs host disease in the kidney ([31], own experience).

In order to reduce treatment related mortality, protocols with reduced conditioning before PBSC transplantation are currently under investigation [32]. After transplantation, intensive immunosuppressive treatment is necessary to prevent rejection and to obtain a stable haematopoetic chimerism. After reaching stable reconstitution of haematopoesis, immunosuppression is gradually tapered and donor lymphocytes can be infused, both to induce a graft vs myeloma effect. Since an anti-tumour effect of this treatment will appear late, after several months, this concept will be successful only in patients with stable disease. Therefore, sequential high-dose chemotherapy with autologous stem cell support followed by allotransplantation after reduced conditioning (auto/allo concept) may be successful [33,34]. Data on allogeneic bone marrow or PBSC transplantation in MM with severe kidney impairment are not sufficient to give any recommendations for this patient group.

New developments
Recently, thalidomide has been introduced for treatment in MM. An anti-angiogenetic activity of the drug could be demonstrated and patients with a tumour progress have been shown to have an increased angiogenesis in their bone marrow. However, the exact mechanism of thalidomide action in MM is unknown. In a phase I/II trial, 84 MM patients with advanced disease were treated. One-third of the patients experienced a remission; main side effects were constipation and severe sensomotoric polyneuropathy [35]. Thalidomide can be used in a normal dose in patients with renal insufficiency and even in ESRD [36]. Analogues of thalidomide are in development, one (CC-5013) has already been successfully used in MM [37].

Bortezomib is a reversible inhibitor of the 265 proteasome in mammalian cells with cytotoxic activity in vitro and in animal tumour models. It has been used in a phase II trial with 202 pre-treated MM patients with advanced disease [38]. The response rate was 35%. Main side effects were cytopenia, severe diarrhoea, disturbances of serum electrolytes and polyneuropathy. Experiences in a limited number of patients with renal insufficiency support the opinion that bortezomib may be used in these patients with comparable dose, effectiveness and toxicity as in MM patients with normal renal function [39].

Supportive therapy
In patients with MMs supportive therapy include, rehydration, treatment of hyperuricaemia and hypercalcaemia. Intravenous (i.v.) bisphosphonates can rapidly reverse hypercalcaemia by the inhibition of osteoclasts. In MM patients with extended bone disease, long-term bisphosphonate treatment can significantly reduce skeletal related events [40]. However, i.v. bisphosphonates bear the risk of renal failure in MM. Therefore kidney function should be monitored, dose has to be adapted and infusion time should be prolonged. In an acute hyperviscosity syndrome, plasmapheresis should be applied. Plasmapheresis has also been recommended for the removal of light chains to increase the chance of renal recovery in patients with acute renal injury. However, controlled trials are missing [41].



   AL amyloidosis
Top
 Introduction
 Diagnosis
 Cast nephropathy
 Histology
 Clinical manifestation
 Treatment and prognosis
 AL amyloidosis
Light-chain deposition disease
 Renal replacement therapy and...
 References
 
In AL amyloidosis monoclonal immunoglobulin light chains or light-chain fragments are deposited extracellularly in tissues as insoluble fibrils. Approximately 15–35% of patients with AL amyloidosis have MM and 15% of all MM patients develop AL amyloidosis.

Histology
Light microscopy of kidney biopsies reveals amorphic hyaline material (diffuse or nodular) primarily in the mesangium and along the glomerular basement membrane, and in the capillary loops during the further course of the disease (Figure 2A). After Congo red staining, amyloid appears faintly red and shows the characteristic apple-green birefringence under polarized light (Figure 2B and C). Amyloid may be found even in small arteries and the tubular basement membrane. The heterogenicity of the amyloid leads to different clinical manifestations. Patients with glomerular deposition will present with a nephrotic syndrome while patients with vessel deposition are characterized by reduced perfusion and pronounced renal insufficiency. Immunohistochemically, {kappa}- or {lambda}-light chains can be found. In electron microscopy, amyloid deposits are characterized by non-branching fibrils with a 7–10 mm diameter randomly oriented.


Figure 2
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  		Fig. 2. (A) AL amyloidosis. Expansion of the mesangium with accumulation of weakly PAS positive material without cell proliferation (400x). (B) Strong Congo red staining of the material in the glomeruli and the wall of the arteriole (400x). (C) Congo red staining under polarized light: apple-green birefringence of amyloid (400x).

 
Clinical manifestation
AL amyloidosis can affect the kidney (50% of the patients) and any other organ except for the central nervous system. The heart is frequently involved (initially one-third of the patients) resulting in restrictive cardiomyopathy. Other typical organs with amyloid are the liver, the autonomic nervous system disease (with orthostatic hypotension and nausea from delayed gastric emptying) and the peripheral nervous system. A rare but potentially serious manifestation is an acquired bleeding diathesis, in many cases due to affinity of factor X to amyloid.

Renal manifestation is characterized by a severe nephrotic syndrome and progressive renal impairment. On diagnosis 43% of the patients had elevated creatinine values [42,43]. Microhaematuria may occur. In contrast to other renal diseases, most patients are normotensive or hypotensive.

Treatment and prognosis
The prognosis of patients with AL amyloidosis is poor with a median survival of 5 to 18 months [42,44]. Cardiac involvement is responsible for 40% of the deaths [42,44]. As strategies to interfere with and reverse the process of amyloid deposition [45,46] were disappointing [47] or were not followed further, the only therapeutic approach is the reduction of light-chain production.

Treatment with oral MP improves survival significantly by a few months as demonstrated in a randomized trial (median survival 16–18 months) [48,49]. High-dose chemotherapy with melphalan and autologous stem cell support seems to be more effective (4-year survival of about 60%) [50,51]; however, randomized trials are still missing. In those patients with complete haematological remission after high-dose chemotherapy, a reduction of proteinuria could be reached in 50–71% of the patients [52,50]. Skinner et al. [49] reported a median survival of 4.6 years in 312 patients (MM excluded). Recently Gertz et al. [53] described 171 selected patients receiving high-dose chemotherapy for primary amyloidosis including 15 patients with serum creatinine higher than 177 µmol/l and 95 patients with proteinuria higher than 3g/day. About two-thirds of the patients responded with at least 50% reduction in proteinuria, and only 12 of these died (median survival should exceed 6 years). However, higher toxicity was seen in patients with renal insufficiency or ESRD [53, 54]. Mortality was associated with higher creatinine values [53] as well as the number of organs involved and cardiac manifestation [49, 54]. In 15 ESRD patients with AL amyloidosis, Casserly et al. reported a higher incidence of mucositis and the need of more erythrocyte and platelet transfusions [54] and a tendency to lower survival rates. All the patients with cardiac involvement died, despite the fact that patients with heart failure were excluded. In conclusion, although the data support the use of high-dose treatment, randomized studies are urgently needed, as patients selected for high-dose chemotherapy represent a favourable prognostic group no matter what treatment is chosen.



   Light-chain deposition disease
Top
 Introduction
 Diagnosis
 Cast nephropathy
 Histology
 Clinical manifestation
 Treatment and prognosis
 AL amyloidosis
 Light-chain deposition disease
Renal replacement therapy and...
 References
 
LCDD is characterized by non-fibrillar deposition of monoclonal light chains or their fragments in different organs. Renal manifestation often dominates the disease [55]. Two-thirds of the patients have a myeloma but one-third do not meet the criteria, and in 6% no monoclonal protein can be found in the urine or serum by standard laboratory techniques. In renal biopsies LCDD is half as frequently found as cast nephropathy.

Histology
Tubular lesions are characterized by non-fibrillar deposition of eosinophilic, PAS-positive material along the tubular basement membrane, mainly of the distal tubuli, the loop of Henle and sometimes the collecting ducts. There is atrophy of tubular cells but no light-chain casts. Nodular glomerulosclerosis is often found (Figure 3) resembling that of diabetic nephropathy. However, the nodules are fairly regular in LCDD, thickening of the glomerular basement membrane is not uniform and exudative lesions and extensive hyalinosis of the efferent arterioles are not seen. Immunohistologically, mainly {kappa}-light chains are found in the noduli. On electron microscopy, fine or coarse granular electron-dense deposits are seen in the mesangium and along the glomerular and tubular basement membrane.


Figure 3
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  		Fig. 3. Light-chain nephropathy. Nodular expansion of the mesangium without cell proliferation (PAS staining, 400x).

 
Clinical manifestation
At diagnosis, most of the patients present with severe renal insufficiency (median creatinine 3.8 mg/dl; [55]). Especially in patients with MM (median creatinine 4.7 mg/dl) a rapid progressive deterioration of renal function up to ESRD is seen. Proteinuria of more than 1 g is found in more than 80% of the patients and 40% develop nephrotic syndrome. One-third of the patients present with microhaematuria. Cardiac involvement and liver manifestations are often seen (symptomatic in about 30%) [55]. Less frequently, spleen and peripheral nervous system involvement is found, but rarely that of other organs (bowel, lung, skin).

Therapy and prognosis
In contrast to AL amyloidosis the prognosis of patients with LCDD is much less homogeneous, varying from 1 month to 10 years, probably as extrarenal deposits can be totally asymptomatic. Regarding renal survival, higher age and reduced renal function at presentation were independently associated with ESRD, whereas renal function, age and extrarenal deposition of light chains and MM were negatively associated with patient survival [55]. Patients with MM should be treated accordingly. In patients with ‘idiopathic disease’ a therapeutic decision is much more difficult. Alkylating agents, mostly MP, were used with limited success [55, 56] (median survival of 4 years). However, high-dose chemotherapy and stem cell support seems promising in young patients (5 and 11 patients, respectively [55,56]). Renal improvement is possible even in some patients requiring dialysis.



   Renal replacement therapy and transplantation in patients with multiple myeloma
Top
 Introduction
 Diagnosis
 Cast nephropathy
 Histology
 Clinical manifestation
 Treatment and prognosis
 AL amyloidosis
 Light-chain deposition disease
 Renal replacement therapy and...
References
 
Patients with ESRD may be treated with haemodialysis or peritoneal dialysis. With respect to haemodialysis, hypotension and problems with the fistula in patients with AL amyloidosis have to be taken into account. Regarding peritoneal dialysis, an increased risk of infection has to be considered due to MM and/or therapy. Historical data in patients with ESRD and MM show low survival rates (about 50% after 1 year and 25% after 3 years) [41]. Magee's data [58] on 24 patients (mainly with cast nephropathy) receiving conventional treatment were even worse, with a median survival of 8 months, which is the same for patients with AL amyloidosis [42]. Haemodialysis and peritoneal dialysis seem to be comparable [55]. High-dose chemotherapy is feasible in selected MM patients with ESRD, improving the prognosis [24].

Data on renal transplantation are sparse. Eight transplanted patients with MM have been reported up to 1996 [59] with only very few later on. Only a few patients with AL amyloidosis have been reported, with a high post-transplant mortality due to infections [60]. However, long-term survival in individual patients has been shown following high-dose chemotherapy [61] with stem cell support [54]. Recently Leung et al. [62] described a sequential living donor kidney transplantation followed by high-dose chemotherapy and autologous stem cell support for non-MM patients with AL amyloidosis. In five of seven patients renal allograft function was stable, and plasma-free light chains were normal in four patients after a mean follow-up of 18 months. Negative results have been reported in patients with LCDD mainly due to recurrence of the disease in the transplant and/or MM progression [63,64]. High-dose chemotherapy in patients, younger than 65 years with a good performance may lead to better results [57]. It has to be stressed that long-term graft survival may be reached for non-MM LCDD patients (2 patients with 8 years and more than 6 years, respectively) despite recurrence of LCDD [65].

Recently a promising new approach has been published in two MM patients with ESRD [66]. They were treated with a combined kidney and allogeneic bone marrow transplantation (HLA-matched sibling) using a non-myeloablative conditioning regimen in an effort to achieve donor-specific allotolerance. Although, multilineage lymphohaematopoietic chimerism was transient and less than 1% of the donor cells were found in the recipient after 3–4 months, the authors deduce from their data an anti-tumour activity (graft vs myeloma effect) in the treated patients. No rejection of the renal transplant occurred despite discontinuation of immunosuppression after 73 and 77 days, respectively. Meanwhile, another four patients have been transplanted accordingly and only one acute tubulointerstitial rejection has been seen, that could be treated easily (Dr Fehr, Boston at the Congress of the German Society of Nephrology). However, further studies are necessary to establish this concept of treatment.

In conclusion, in MM patients with renal involvement and in other patients with renal impairment induced by monoclonal immunoglobulins, treatment strategy has to consider both plasma cell clone and renal manifestations. Combined nephrological and haematological management is therefore necessary. Several treatment options for these patients have been proposed and tested in studies with limited numbers of patients. However, controlled trials are rare and should be performed in the future. Factors justifying differentiated therapeutic strategies should be defined to improve the outcome of these patients, whose prognosis is poor.



   Acknowledgments
 
The histological figures were provided by Dr Mengel, Department of Pathology, Medical, School Hannover.

Conflict of interest statement. None declared.



   References
Top
 Introduction
 Diagnosis
 Cast nephropathy
 Histology
 Clinical manifestation
 Treatment and prognosis
 AL amyloidosis
 Light-chain deposition disease
 Renal replacement therapy and...
 References
 

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Received for publication: 1.11.05
Accepted in revised form: 14.11.05


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