The kidney and monoclonal free light chains
SECTION 2 - Multiple Myeloma
|The kidney and monoclonal free light chains|
|Monoclonal serum free light chains:|
Renal failure is a major cause of morbidity and mortality in patients with MM. At initial presentation, up to 50% of patients have renal impairment (serum creatinine >1.5mg/dL or >130μmol/L); 12 to 20% have acute renal failure (ARF) and 10% become dialysis-dependent. These patients represent 2% of the dialysis population and there are approximately 5,000 new diagnoses worldwide each year. A review of a large European registry showed that renal morbidity is a considerable burden: of the 159,367 patients on renal replacement therapy, the median survival was 0.91 years in MM and light chain deposition disease (n=2,453) versus 4.46 years in non-MM patients .
While reversible factors such as dehydration, hypercalcaemia and medication are frequently involved, monoclonal FLCs are the most potent cause of irreversible renal failure. Large amounts of sFLCs readily pass through the glomerular fenestrations and overwhelm the absorptive capacity of the proximal tubules. On entering the distal tubules, they co-precipitate with Tamm-Horsfall protein to form waxy casts that both block the flow of urine and cause interstitial inflammation . Furthermore, high concentrations of FLCs are directly toxic to tubular cells .
Studies have analyzed renal recovery rates after FLC removal by plasma exchange. While this is a logical approach, results have been disappointing. Although an early report was optimistic , the largest and most recent controlled trial (97 patients) showed no clinical benefit . A subsequent editorial in the Journal of the American Society of Nephrology (JASN) listed the shortcomings of this study, including the failure to monitor either serum or urine FLC concentrations . It was noted, “This resembles anti-hypertensive treatment without measuring blood pressure.” Clearly, the efficiency of plasma exchange for FLC removal could not be judged.
Because FLCs are relatively small protein molecules (κ~25 kDa: dimeric λ~50 kDa) they are present in similar concentrations in serum, extravascular compartments and interstitial fluid . Thus, the intravascular compartment may contain only 15 to 20% of the total amount. A series of 3.5-litre plasma exchanges that removed 65% of intravascular FLCs on each occasion would have little overall impact, particularly if production were not reduced at the same time by chemotherapy. An alternative approach is to remove FLCs by haemodialysis. Although this is not possible with routine dialyzers due to their small pore sizes (12-15kDa), a new generation of high cut-off dialyzers allows FLC removal . By using extended dialysis, large amounts of FLCs can be removed without the attendant clotting and deproteination problems that may limit the extended use of plasma exchange.
This chapter discusses the normal renal handling of FLCs, their role in renal failure in MM, clinical case studies and current management strategies such as plasma exchange. A mathematical model of FLC removal is presented and plasma exchange is compared with the utility of haemodialysis. Finally, clinical evidence for the beneficial use of “FLC removal haemodialysis” is presented.
13.2. Normal FLC clearance and metabolism
In normal individuals, sFLCs are rapidly cleared by the kidneys depending upon their molecular size (Figure 13.1 and Chapter 3). Monomeric FLCs, characteristically κ, are cleared in 2-4 hours at 40% of the glomerular filtration rate (GFR). Dimeric FLCs, typically λ, are cleared in 3-6 hours at 20% of the GFR, while larger polymers are cleared more slowly. Removal is prolonged to 2-3 days in MM patients who are in complete renal failure, in which case FLCs are removed by the liver and other tissues. In contrast, IgG has a normal serum half-life of 21 days that is not affected by renal impairment.
After filtration by the glomeruli, FLCs enter the proximal tubules and bind to brush border membranes via low-affinity, high-capacity receptors called cubulins and megalins . Binding provokes internalisation of the FLCs, subsequent proteolysis into smaller peptides and finally their excretion into the urine flow. The concentration of FLCs leaving the proximal tubules depends therefore upon the amount in the glomerular filtrate, competition for binding uptake from other proteins and the absorptive capacity of the tubular cells. A reduction in GFR, due to loss of nephrons, increases sFLC concentrations so that more are filtered by the remaining functioning nephrons. Subsequently, and with increasing renal failure, hyperfiltering glomeruli leak albumin and other proteins, which compete with FLCs for absorption thereby causing more to enter the distal tubules.
FLCs entering distal tubules can bind to Tamm-Horsfall protein (uromucoid). This is the predominant protein in normal urine and is thought to be important in preventing ascending urinary infections. It is a glycoprotein (85kDa) that aggregates into high molecular weight polymers of 20-30 units. Interestingly, it contains a short peptide motif that has a high affinity for FLCs .
13.3. Nephrotoxicity of monoclonal FLCs
The main renal pathology in the context of MM and ARF is myeloma kidney (cast nephropathy). This is caused by precipitation of FLCs with uromucoid as waxy casts and is characteristically found in ARF associated with MM (Figures 13.2A and 13.2B) . The casts obstruct tubular fluid flow, leading to disruption of the basement membrane and interstitial damage. Rising concentrations of sFLCs are filtered by the remaining functioning nephrons which become blocked, leading to a vicious cycle of further increases in sFLC concentrations and progressive renal damage. This may explain why some MM patients, without apparent pre-existing renal impairment, suddenly develop catastrophic and irreversible renal failure. The process is aggravated by other factors such as dehydration, diuretics, hypercalcaemia, infections and nephrotoxic drugs.
Monoclonal FLCs cause renal impairment by several mechanisms, a variety of which may contribute to both acute and chronic renal failure.
Mechanisms of renal FLC toxicity
- Activation of inflammatory mediators in the proximal tubule epithelium.
- Proximal tubule necrosis.
- Fanconi syndrome (renal tubule acidosis) with FLC crystal deposition.
- Cast nephropathy.
- AL amyloidosis (Chapter 15).
- Light chain deposition disease (Chapter 17).
In MM, monoclonal sFLC concentrations are abnormal in >95% of patients (Chapter 11) and a wide range of values are observed. Importantly, their toxicity also varies considerably. This was elegantly shown by Sanders and Brooker  using isolated rat nephrons and is, in part, related to variable affinity for Tamm-Horsfall protein. However, despite much effort to show otherwise, particular molecular charge and κ or λ type are not now considered relevant to FLC toxicity. Furthermore, highly polymerised FLCs (a frequent finding in MM - Chapter 4) are probably not nephrotoxic because they cannot pass through the glomerular fenestrations. This may partly account for the lack of renal damage in some patients who have very high sFLC concentrations.
The amount of sFLCs necessary to cause renal impairment was studied by Nowrousian et al . They showed that the median serum concentrations associated with overflow proteinuria (and hence potential for tubular damage) were 113mg/L for κ and 278mg/L for λ. These are approximately 5-10 fold higher than normal serum concentrations, and presumably relate to the maximum tubular reabsorption capacity of the proximal tubules. Since the normal daily production is ~500mg, increases to ~5g/day are likely to be nephrotoxic in most patients.
As renal impairment develops, progressive increases occur in both the monoclonal sFLCs and the polyclonal non-tumour sFLCs (Chapter 20). Concentrations of monoclonal sFLCs below 300mg/L are rarely associated with renal impairment as judged by the associated normal levels of the non-tumour FLCs (Figure 8.2). These concentrations are somewhat higher than those observed by Nowrousian et al. , in patients with renal impairment, but are in the same general range.
Several urine studies have related urine FLC excretion rates to renal impairment. Typically, the associated renal impairment rises with increasing urine FLCs. One study showed that 7%, 17% and 39% of patients had renal impairment with excretions rates of <0.005g/day, 0.005-2.0g/day, and >2g/day, respectively . However, FLC excretion is an indicator of renal damage in addition to its cause.
The causal relationship between sFLC concentrations and renal impairment is illustrated in the 3 patients described below (Figures 13.3A, 13.3B and 13.4) . In each case, urine FLC concentrations were low and were not indicative of the underlying renal deterioration.
The patient shown in Figure 13.3A had been diagnosed with intact immunoglobulin MM 3 years earlier, with IgAλ and λ FLC monoclonal protein expression. She had a good initial response to vincristine, adriamycin (doxorubicin), dexamethasone (VAD) but was frail. Over a 7-month period, her serum λ FLC levels increased from 1,500 to 2,800 mg/L, then to 4,500 mg/L and finally to 15,000 mg/L in month 9, while serum creatinine had increased slightly to 120 μmol/L. Her medication was not changed from thalidomide, cyclophosphamide and pulsed dexamethasone on account of her frailty. Unfortunately, the sharp rise in sFLCs led to ARF which was apparent one month later (as shown by the high creatinine concentration). She failed to respond to therapy and died shortly after.
Figure 13.3B illustrates a patient who developed ARF that responded to chemotherapy and haemodialysis. As in Figure 13.3A, the sFLC concentrations were a sensitive indicator of impending renal failure and concentrations appeared to reach a threshold before ARF developed. Although renal function was deteriorating by the 4th month, the patient felt well and declined treatment, only to present with renal failure one month later. The potential seriousness of the high FLC concentrations had not been fully appreciated. She was given VAD and put on haemodialysis for 6 weeks. This produced a good response of the MM but only partial renal recovery. It is of note that sFLC concentrations were consistently more sensitive than serum creatinine as a marker of falling GFR.
Figure 13.4 shows sFLCs, immunoglobulins and creatinine results in another patient over a 30-week period. Total protein and IgG tests indicated stable disease during the first 18 weeks of monitoring. However, the serum creatinine increased from 1.2 to 3.0 mg/dL (130 to 240 μmol/L). sFLC measurements showed unexpectedly high κ concentrations at 500 mg/L with a κ/λ ratio of 4.04, despite undetectable urinary FLC. It was considered that the high FLC concentrations might be causing renal damage, so chemotherapy was commenced. Over the ensuing 2 months the serum κ and serum creatinine returned to almost normal concentrations.
13.4. Diagnosis of myeloma kidney using sFLC analysis
The diagnosis of renal failure from MM has been based upon testing for FLCs in the urine together with serum protein electrophoresis (SPE) and serum immunofixation electrophoresis (sIFE). Positive results are followed by a renal biopsy. Since sFLC tests are more sensitive than urine tests, it is logical to commence with sFLC analysis alone. SPE and sIFE are irrelevant since they test for intact monoclonal immunoglobulins, which do not cause myeloma kidney.
To confirm the diagnostic accuracy of sFLC analysis we reviewed an unselected cohort of 142 patients who had presented with dialysis-dependent ARF of unknown cause. Of the 41 patients with monoclonal gammopathies, 40 had MM with abnormal sFLC ratios and 1 had monoclonal gammopathy of undetermined significance (MGUS) (Figure 13.5). Receiver operating characteristic (ROC) curve analysis showed that a slightly modified sFLC ratio range increased the specificity from 93% to 98% with no loss of sensitivity (Chapter 20). In comparison, urine testing for monoclonal FLCs was negative in one of the 24 MM patients that were assessed  and 17 had inadequate urine samples.
These results indicate that sFLC κ/λ ratios are a sensitive and specific, yet simple method for identifying monoclonal FLC production in patients with MM and ARF. Rapid diagnosis in these patients will allow early initiation of renal biopsies for confirmation of myeloma kidney followed by high cut-off haemodialysis and the appropriate chemotherapy (Figure 13.6).
13.5. Removal of FLCs by plasma exchange
Clearly, the pre-renal load of sFLCs is an important factor in renal toxicity. It seems logical that renal recovery might occur if sFLC concentrations were lowered rapidly. This hypothesis is supported by the work of Leung  and colleagues who studied patients with biopsy proven myeloma kidney and serial FLC measurements. A reduction of greater than 50% in sFLC concentrations was associated with renal recovery. Historically, it has been suggested that plasma exchange might improve patient outcomes by FLC removal.
Several early studies indicated renal function improvement using plasma exchange. For example, in 1988, Zucchelli et al. , compared MM patients on peritoneal dialysis (control group) with plasma exchange (some patients were also on haemodialysis). Only 2 of 14 in the control group had improved renal function compared with 13 of 15 in the plasma exchange arm, and survival was better (P<0.01). However, as peritoneal dialysis is less effective than haemodialysis for removing FLCs (Chapter 20), the comparison was not ideal.
This early success was not repeated in subsequent controlled trials. Johnson et al.  in 1990, compared 10 patients on forced diuresis with 11 who had forced diuresis and plasma exchange and found no difference in outcome. Most recently, a large study was reported by Clark et al.  Patients were treated with chemotherapy and were randomly allocated to receive additional plasma exchange. Again, there was no statistically significant benefit for plasma exchange.
13.6. Model of FLC removal by plasma exchange and haemodialysis
In order to understand the effectiveness of plasma exchange, we developed a compartmental mathematical model that was applicable to patients being treated for MM and renal failure . The following parameters were considered: sFLC concentrations at clinical presentation; monomeric κ and dimeric λ clearance rates with and without renal failure; partition of sFLC between vascular and extravascular compartments (including oedema fluid); flow of FLCs between compartments; half-life of sFLC in renal failure; sFLC production rates; and tumour killing rates with chemotherapy. Data from patients with MM were fitted to the model to analyse rates of sFLC removal. Simulations were conducted to compare 6 and 10 plasma exchange treatments (of 3.5L each over 12 days) with 5 different haemodialysis protocols. Chemotherapeutic tumour killing rates that were considered comprised 100% on the first day; 10%, 5%, and 2% per day and no killing.
In renal failure the half-life of sFLCs is approximately 3 days. Assuming a starting concentration of 10,000mg/L, it would take approximately 20 days for the FLCs to be metabolised assuming complete tumour killing with the first chemotherapy dose (Figure 13.6: 1). More realistically, 10% of the tumour might be destroyed per day by aggressive chemotherapy, resulting in a slower FLC reduction (Figure 13.6: 2). Addition of plasma exchange procedures increased removal rates by approximately 25% but concentrations were not reduced below toxic levels (500mg/L) at 4 weeks. The rapid reductions in sFLC concentrations during the procedure and their subsequent re-entry from the extra-vascular to the intra-vascular compartment can be seen.
Results from the model calculations suggest that plasma exchange is not effective unless used intensively. One report on 3 patients undergoing plasma exchange suggested no benefit (Figure 13.7) , while another report, on one patient, considered it was helpful . Lack of success can be explained by on-going high production rates and re-entry of FLCs from extravascular compartments (including oedema fluid).
It should be noted that peritoneal dialysis does not remove FLCs efficiently (Chapter 20). Presumably, this is because the volume of exchanged fluid is much lower than in haemodialysis.
13.7. Removal of FLCs by haemodialysis
As an alternative to plasma exchange, sFLCs can be removed more effectively by haemodialysis, provided the pore sizes of the membranes are large enough. Conventional dialysers have a molecular weight cut-off around 15-20kDa so the filtration efficiency for FLCs is very low. However, some of the new “protein-leaking” dialysers have much larger pores, particularly the Gambro high cut-off dialyser (Figure 13.8) . Furthermore, haemo-diafiltration is more effective at removing small protein molecules than haemodialysis. Indeed, there are sporadic reports of patients with AL amyloidosis and end-stage renal failure who appear to have improved survival when haemo-diafiltration is instigated. But, there is currently inadequate clinical data to provide a clear conclusion in amyloidosis patients.
Model calculations (Figures 13.6 and 13.9 and Table 13.1) indicate that the prolonged use of high cut-off dialysers could reduce κ sFLC concentrations to less than 0.5g/L in 2-3 days with ~95% of the sFLC removed. Dimeric λ molecules are considerably larger so they are removed more slowly. Based upon these modelling results, we assessed the utility of various dialysers for sFLC removal in patients with MM. The Gambro high cut-off membrane with pores that are large enough to filter FLCs was the most efficient by a considerable margin. Figure 13.10 shows the rapid removal of λ FLCs in a patient with MM using the Gambro high cut-off dialysis membrane over a 6-hour period. Also shown are the large amounts of FLCs in the dialysate fluid. A total of nearly 40 grams of FLCs were removed in a single dialysis session.
|Method of FLC
|Chemotherapy tumour killing rates/day|
|PE x 6 in 10 days||29(10)||24(49)3||17(52)||9(121)||3(10g/L)a|
|PE x 10 in 10 days||40(8)||34(29)||25(52)||13(121)||4(10g/L)a|
|HD 4hrs x 3/week||60(7)||54(19)4||53(31)||51(73)||50(3.6g/L)a|
|HD 4hrs daily||76(4)||73(13)5||72(23)||71(55)||70(1.9g/L)a|
|HD 8hrs daily||87(3)||85(7)||84(14)||83(29)||82(1.0g/L)a|
|HD 8hrs alt. days||79(4)||73(13)||72(19)||70(47)||69(1.5g/L)a 7|
|HD 12hrs daily||91(2)||89(5)6||89(8)||88(16)||88(0.7g/L)a|
|HD 18 hrs daily||93(2)||93(3)||93(4)||92(8)||91(0.6g/L)a|
Table 13.1. Model calculations of the efficiency of therapeutic removal of sFLCs. Numbers are the additional percentage of FLC removed by therapeutic intervention compared with normal metabolism over 3 weeks. Numbers in parentheses are the time in days for sFLC concentrations to reduce to 5% of the starting concentrations (from 10g/L to 0.5 g/L). For superscript numbers 1 to 8, the simulations are shown in Figures 13.6 and 13.9 and Table 13.1. asFLC concentrations at day 150 for simulations in which reductions to 0.5 g/L were not achieved. PE: plasma exchange. HD: hemodialysis. NA: not applicable.
13.8. Recovery from renal failure following FLC removal by haemodialysis
Intensive application of FLC removal haemodialysis has been applied to 17 patients with cast nephropathy by Hutchison , in Birmingham, UK. Examples of the clinical response in 3 patients who presented with ARF are shown in Figures 13.11, 13.12 and 13.13. The first of the 3 figures shows good FLC reductions with renal recovery (Figure 13.11). In the second, the patient failed to respond to the initial chemotherapy but responded to bortezomib (Figure 13.12). Haemodialysis was unable to produce sustained FLC responses without accompanying satisfactory chemotherapy. The third patient failed to achieve renal recovery (Figure 13.13): this patient developed sepsis and chemotherapy was stopped. Despite multiple prolonged periods of haemodialysis and removal of 1.7Kg of FLCs, there was no recovery of renal function. sFLC concentrations oscillated during treatment in much the same manner as shown from model calculations in Figure 13.9 (line 7).
It should be emphasised that all patients needed both effective chemotherapy to switch off FLC production together with rapid reduction of the pre-renal load, for renal recovery to occur (Figure 13.15A). Of the 19 patients studied, 6 had early infective complications resulting in their chemotherapy being withheld. The patients did not achieve an early FLC reduction and only one subsequently became independent of dialysis. The remaining 13 patients had chemotherapy and dialysis and all had an early reduction in serum FLCs and subsequent renal recovery.
The renal recovery rate of 17 of these patients is shown in Figure 13.14A, alongside historical recovery rates in a case-matched population at the same hospital. Clearly, the patients receiving intensive FLC removal had better renal recovery rates. Of these two populations, when only those patients with documented tumour responses to chemotherapy were assessed, all 12 patients treated with FLC removal haemodialysis had renal recovery (Figure 13.14B). This was in contrast to the control group, where only 1 patient had renal recovery out of 7 who responded to chemotherapy. This suggests an additional benefit of dialysis over chemotherapy alone.
Figure 13.15B analyses patient survival in the 19 patients treated with FLC removal haemodialysis. The 5 patients in the treated group who died were those who failed to regain renal function. All 12 patients who became independent of renal replacement therapy remained alive at 6 months. GFR continued to improve for several months after dialysis independence was achieved. Furthermore, this was associated with complete disappearance of the casts in the patient in whom serial renal biopsies were available (Figure 13.16).
These initial findings have now been repeated by many independent studies of FLC removal by HCO haemodialysis . Overall, these suggest that renal recovery is possible in most patients with MM presenting with ARF from cast nephropathy. Alternative strategies for FLC removal by haemodialysis not using a high cut-off membrane have been proposed, including utilising the combination of haemodiafiltration and adsorption . The capacity of these strategies for FLC removal needs to be compared directly with high cut-off haemodialysis.
Other groups have suggested that high rates of renal recovery are possible with modern chemotherapy alone, particularly using combinations that include bortezomib. Ludwig et al. , showed recovery in 40% of patients, but none had renal biopsies and few were dialysis-dependent. Even better recovery rates, at 73% of patients, were reported by Kastritis et al. , but again patient selection was unsatisfactory . The control group in the plasma exchange study of Clark et al.  also had 40% renal recovery and were in a similar clinical state. This suggests that few patients with dialysis-dependent cast nephropathy will recover renal function with chemotherapy alone. Supporting evidence comes from a retrospective study that showed only 25% recovery in dialysis-dependent patients with cast nephropathy given bortezomib and conventional haemodialysis . However, for patients with non-dialysis-dependent renal impairment, several studies now support the use of a chemotherapy regime containing a novel agent (bortezomib or thalidomide) in preference to historic regimes to improve renal outcomes .
The clinical challenge will be to identify and rapidly treat patients after diagnosis. Traditionally, ARF due to MM has been identified by serum and urine studies for monoclonal FLCs. Our data suggest that all patients with MM can be identified using sFLC tests alone (Figure 13.5), and concentrations are usually greater than 500mg/L . Renal biopsy is also essential to specifically identify cast nephropathy. Other causes of ARF in MM are not associated with huge concentrations of sFLCs and do not require intensive high cut-off haemodialysis for renal recovery.
Return of higher GFR rates is likely to be better with rapid reduction of sFLCs to normal concentrations. We have experience of 2 patients whose FLC removal haemodialysis was not commenced until one month after initial presentation with ARF. Recovery to dialysis independence was slow with barely satisfactory GFR at 6 months, despite complete MM remission.
A German and UK multi-centre, prospective, randomised controlled trial comparing the Gambro high cut-off dialyser with conventional haemodialysis is currently underway. It is planned to recruit 90 MM patients presenting with ARF and cast nephropathy. These patients will receive bortezomib, dexamethasone and doxorubicin with randomisation to intensive FLC removal haemodialysis or conventional haemodialysis.
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- ↑ Tsakiris DJ, Stel VS, Finne P, Fraser E, Heaf J, de Meester J, et al. Incidence and outcome of patients starting renal replacement therapy for end-stage renal disease due to multiple myeloma or light-chain deposit disease: an ERA-EDTA Registry study. Nephrol Dial Transplant. 2010 Apr;25(4):1200-6 PMID: 20037169
- ↑ Herrera GA, Joseph L, Gu X, Hough A, Barlogie B. Renal pathologic spectrum in an autopsy series of patients with plasma cell dyscrasia. Arch Pathol Lab Med 2004;128:875–9 PMID: 15270616
- ↑ 3.0 3.1 Sanders PW, Booker BB, Bishop JB, Cheung HC. Mechanisms of intranephronal proteinaceous cast formation by low molecular weight proteins. J Clin Invest 1990;85:570–6 PMID: 2298921
- ↑ 4.0 4.1 Sanders PW, Booker BB. Pathobiology of cast nephropathy from human Bence Jones proteins. J Clin Invest 1992;89:630-9 PMID: 1737851
- ↑ Basnayake K, Ying WZ, Wang PX, Sanders PW. Immunoglobulin light chains activate tubular epithelial cells through redox signaling. J Am Soc Nephrol 2010;21:1165-73 PMID: 20558542
- ↑ 6.0 6.1 Zucchelli P, Pasquali S, Cagnoli L, Ferrari G. Controlled plasma exchange trial in acute renal failure due to multiple myeloma. Kidney Int 1988;33:1175–80 PMID: 3043077
- ↑ 7.0 7.1 7.2 Clark WF, Stewart AK, Rock GA, Sternbach M, Sutton DM, Barrett BJ, et al. Plasma exchange when myeloma presents as acute renal failure: a randomized, controlled trial. Ann Intern Med 2005;143:777–84 PMID: 16330788
- ↑ Ritz E. Nephrology beyond JASN: Plasma exchange for acute renal failure of myeloma - logical, yet ineffective. J Am Soc Nephrol 2006;17:914–6
- ↑ Takagi K, Kin K, Itoh Y, Enomoto H, Kawai T. Human alpha 1-microglobulin levels in various body fluids. J Clin Pathol 1980;33:786–91 PMID: 6159369
- ↑ 10.0 10.1 10.2 Hutchison CA, Cockwell P, Reid S, Chandler K, Mead GP, Harrison J, et al. Efficient removal of immunoglobulin free light chains by hemodialysis for multiple myeloma: in vitro and in vivo studies. J Am Soc Nephrol 2007;18:886–95 PMID: 17229909
- ↑ Winearls CG. Myeloma kidney. In: Johnson RJ, Feehally J, eds. Comprehensive clinical nephrology. Mosby, 2003
- ↑ Ying WZ, Sanders PW. Mapping the binding domain of immunoglobulin light chains for Tamm-Horsfall protein. Am J Pathol 2001;158:1859–66 PMID: 11337384
- ↑ 13.0 13.1 Johnson WJ, Kyle RA, Pineda AA, O'Brien PC, Holley KE. Treatment of renal failure associated with multiple myeloma. Plasmapheresis, hemodialysis, and chemotherapy. Arch Intern Med 1990;150:863–9 PMID: 2183734
- ↑ 14.0 14.1 Nowrousian MR, Brandhorst D, Sammet C, Kellert M, Daniels R, Schuett P, et al. Serum free light chain analysis and urine immunofixation electrophoresis in patients with multiple myeloma. Clin Cancer Res 2005;11:8706–14 PMID: 16361557
- ↑ Bladé J. Management of renal, hematologic, and infectious complications. In: Malpas JS, Bergsagel DE, Kyle RA, Anderson KC, eds. Myeloma: Biology and management, Saunders, 2004
- ↑ Abdalla SH. Use of Freelite assay to monitor myeloma with renal failure. Haematologica 2007;92:PO1016a
- ↑ 17.0 17.1 Hutchison CA, Plant T, Drayson M, Cockwell P, Kountouri M, Basnayake K, et al. Serum free light chain measurement aids the diagnosis of myeloma in patients with severe renal failure. BMC Nephrol 2008;9:11 PMID: 18808676
- ↑ Leung N, Gertz MA, Zeldenrust SR, Rajkumar SV, Dispenzieri A, Fervenza FC, et al. Improvement of cast nephropathy with plasma exchange depends on the diagnosis and on reduction of serum free light chains. Kidney Int 2008;73:1282-8 PMID: 18385667
- ↑ 19.0 19.1 Cserti C, Haspel R, Stowell C, Dzik W. Light-chain removal by plasmapheresis in myeloma-associated renal failure. Transfusion 2007;47:511–4 PMID: 17319833
- ↑ Pillon L, Sweeting RS, Arora A, Notkin A, Ballard HS, Wieczorek RL, Leung N. Approach to acute renal failure in biopsy proven myeloma cast nephropathy: is there still a role for plasmapheresis? Kidney Int 2008;74:956–61 PMID: 18418353
- ↑ Hutchison C, Basnayake K, Cook M, Bradwell A, Cockwell P. Free light chain removal hemodialysis increases renal recovery rate and improves patient survival in patients with cast nephropathy. Nephrol Dial Transplant 2008;23:S0019a.
- ↑ Hutchison CA, Bevins A, Mead G, Cook M. An international study of high cut-off hemodialysis for the management of myeloma kidney. Blood 2011;118:3974a
- ↑ Bachmann U, Schindler R, Storr M, Kahl A, Joerres A, Sturm I. Combination of bortezomib-based chemotherapy and extracorporeal free light chain removal for treating cast nephropathy in multiple myeloma. Nephrol Dial Transplant 2008;1:106–8
- ↑ Kleeberg L, Morgera S, Jakob C, Hocher B, Schneider M, Peters H, et al. Novel renal replacement strategies for the elimination of serum free light chains in patients with kappa light chain nephropathy. Eur J Med Res 2009;14:47-54 PMID: 19258212
- ↑ Heyne N, Denecke B, Guthoff M, Oehrlein K, Kanz L, Haring HU, Weisel KC. Extracorporeal light chain elimination: high cut-off (HCO) hemodialysis parallel to chemotherapy allows for a high proportion of renal recovery in multiple myeloma patients with dialysis-dependent acute kidney injury. Ann Hematol 2011 PMID: 22170517
- ↑ Testa A, Dejoie T, Lecarrer D, Wratten M, Sereni L, Renaux JL. Reduction of Free Immunoglobulin Light Chains Using Adsorption Properties of Hemodiafiltration with Endogenous Reinfusion. Blood purification 2010;30:34-6 PMID: 20588010
- ↑ Ludwig H, Drach J, Graf H, Lang A, Meran JG. Reversal of acute renal failure by bortezomib-based chemotherapy in patients with multiple myeloma. Haematologica 2007;92:1411–4 PMID: 17768111
- ↑ Kastritis E, Anagnostopoulos A, Roussou M, Gika D, Matsouka C, Barmparousi D, et al. Reversibility of renal failure in newly diagnosed multiple myeloma patients treated with high dose dexamethasone-containing regimens and the impact of novel agents. Haematologica 2007;92:546–9 PMID: 17488666
- ↑ Bergner R, Hoffmann M, Uppenkamp M. Reply. Kastritis E. et al. Reversibility of renal failure in newly diagnosed multiple myeloma patients treated with high dose dexamethasone containing regimes and the impact of novel agents. Haematologica 2008;93:e18–9 PMID: 18166771
- ↑ Chanan-Khan AA, Kaufman JL, Mehta J, Richardson PG, Miller KC, Lonial S, et al. Activity and safety of bortezomib in multiple myeloma patients with advanced renal failure: a multicenter retrospective study. Blood 2007;109:2604–6 PMID: 17138816
- ↑ Li J, Zhou DB, Jiao L, Duan MH, Zhang W, Zhao YQ, Shen T. Bortezomib and dexamethasone therapy for newly diagnosed patients with multiple myeloma complicated by renal impairment. Clin Lymphoma Myeloma 2009;9:394-8 PMID: 19858061
- ↑ Roussou M, Kastritis E, Christoulas D, Migkou M, Gavriatopoulou M, Grapsa I, et al. Reversibility of renal failure in newly diagnosed patients with multiple myeloma and the role of novel agents. Leuk Res;34:1395-7 PMID: 20510452
- ↑ Dimopoulos MA, Roussou M, Gavriatopoulou M, Zagouri F, Migkou M, Matsouka C, et al. Reversibility of renal impairment in patients with multiple myeloma treated with bortezomib-based regimens: identification of predictive factors. Clin Lymphoma Myeloma 2009;9:302-6 PMID: 19717380
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