multiple myeloma ( mm ) is a b - cell neoplasia which is characterized by an malignant proliferation of aberrant plasma cells in the bone marrow . renal impairment and bone resorption are among the most important consequences of this disease [ 1 - 3 ] . novel treatment options are urgently needed and are being developed [ 4 - 6 ] . in mm malignant plasma cells usually produce excessive amounts of monoclonal proteins , which may involve intact immunoglobulins or serum free light chains ( sflc ) or both . in a study of 1027 patients with newly diagnosed mm , kyle et al . sflc play a crucial role in mm induced renal damage and are probably the most important cause of renal failure in these patients . in healthy individuals production of sflc this " physiologic " amount of sflc gets rapidly cleared and degraded by the kidneys . however , sflc production in mm can reach 30 g / day exceeding the clearance capacity of the kidneys . sflc are normally transported to the interstitium of the kidney via specific receptors in the proximal tubule . overload of these receptors by excessive amounts of sflc results in an overflow of them to the distal tubule . sflc entering the distal tubule usually bind to uromucoid ( tamm - horsfall protein ) and form casts , which obstruct tubular fluid flow , leading to disruption of the basement membrane and interstitial damage [ 8 - 12 ] . the amount of sflc necessary to cause renal impairment has recently been studied by nowrouisan et al . . the median serum concentration associated with overflow proteinuria and hence tubular damage were 113 mg / l for kappa and 278 mg / l for lambda light chain , respectively . thus , this level corresponds to a daily production of light chains about 5 g. reduction of sflc levels therefore represents a potential strategy to improve renal function in acute renal failure in mm . in this regard prompt initiation of an effective chemotherapy protocol is a precondition for success , but additional supportive treatment options are increasingly discussed in this regard . studies were initiated to investigate the use of plasma exchange in patients with mm and acute renal failure but failed to show any significant benefit on renal function . in the present manuscript we report on a new type of renal replacement therapy ( rrt ) , namely rrt using a protein leaking membrane . protein leaking membranes are characterized by an increased pore size of the dialyzer membrane promoting the elimination of middle sized molecules such as sflc . these membranes were initially developed to improve the clearance capacity for inflammatory mediators in critically ill septic patients . particularly one hemofilter , the hco1100 has been extensively studied in the regard . in this paper we analyzed the efficacy of the protein leaking membrane hco1100 to eliminate sflc in kappa light chain mm patients with acute renal failure necessitating rrt . the elimination capacity of the hco1100 was studied in the hemodialysis and hemodiafiltration mode and was compared to standard hemodialysis procedures as well as to plasma exchange . four consecutive patients with kappa light chain mm were included in this study . all patients necessitated rrt due to acute renal failure . baseline laboratory evaluation included blood creatinine , estimated creatinine clearance ( mdrd formula ) , urea , acid base and electrolyte household . before and after each renal replacement session sflc levels were measured using latex - enhanced nephelometric immunoassays ( the binding site , schwetzingen , germany ) adapted to the bn prospec nephelometer ( dade - behring , eschborn , germany ) . l for the sflc lambda assay with control sera ( n = 10 ) provided by the binding site . hemodialysis and hemodiafiltration procedures were performed with a dialysis device allowing the online preparation of ultrapure hemofiltration replacement fluids if required ( ak200s , gambro dialysatoren gmbh , hechingen , germany ) . polyamide high flux hemofilter ( polyflux 140h , polyflux 210h , steam sterilized , gambro dialysatoren gmbh , hechingen , germany ) were used for standard hemodialysis . for standard hemodiafiltration membrane specifications for the high flux hemofilter polyflux 140h ( pf 140h ) and polyflux 210h ( pf 210h ) are as follows : effective surface area 1.4 qm for pf 140h and 2.1 qm for pf 210h , wall thickness 50 m , inner diameter 215 m , membrane pore size ~ 5 nm , ultrafiltration coefficient 60 ( ml / h , mmhg ) for pf 140h and 85 ( ml / h , mmhg ) for pf 210h , cut off point 30 - 40 kd , sieving coefficient for vitamin b12 ( molecular weight 1.35 kd ) and inulin ( molecular weight 5.20 kd ) 1.0 , for 2 microglobulin ( molecular weight 11.8 kd ) 0.7 . for rrt ( either hemodialysis or hemodiafiltration ) with the protein leaking membrane a newly designed high cut off hemofilter , the polyamide hco 1100 hemofilter ( hco 1100 , effective surface area 1.1 qm , steam sterilized , gambro corporate research , hechingen , germany ) was used . the high cut off hemofilter is characterized by an increased pore diameter of ~10 nm with a membrane thickness of 50 m and an internal diameter of 215 m . the in vivo cut off point of the membrane is approximately 60 - 80 kd . the hemofilter has been designed to increase the in - vivo permeability for substances in the molecular weight range up to 60 kd . basic features of this new hemofilter have been recently described [ 18 - 21 ] . whenever the protein leaking membrane was applied regular controls of plasma albumin and total protein were performed ( pre - and post dialysis ) . in case of high transmembrane protein losses a balanced substitution of human albumin was uniformly set at 200 ml / h , dialysate flow rate was 500 ml / min . the ultrafiltration rate was based on the individual fluid balance of the patients . in a subgroup of patients sflc kappa - clearances in the initial phase ( 10 min after start of treatment ) and at the end of therapy were calculated as follows : clearance ( ml / min ) = dialysate concentration of flc / inlet serum concentration of flc  dialysate flow rate . a roller blood pump device was used for plasma exchange ( bsm 22 , gambro hospal germany ) . a standard plasmafilter ( gambro pf 2000n , gambro , lund , sweden ) was chosen . 2500 ml of fresh frozen plasma were given in exchange during a 2.5 h session . paired data were compared using the wilcoxon rank sum test , unpaired data by the mann - whitney - u - test . patient 1 was a 73-year - old male who had previously received 6 cycles of chemotherapy with melphalan and prednisolone . at the time of admission he had acute renal failure with a creatinine level of 11.3 mg / dl ( egfr 5 ml / min ) . chemotherapy with adriamycin and dexamethasone was initiated . in order to reduce the amount of sflc two treatment sessions of plasma exchange were performed ( figure 1 ) . for uremia control rrt had to be started . six sessions of high flux hemodialysis ( figure 2 ) with a median ultrafiltration rate of 1680 ml ( range 900 - 2600 ml ) per session were applied . reduction rate ( % ) of sflc kappa with hemodialysis using the high flux membrane pf 140h . patient 2 was a 70-year - old female who had developed mm induced acute renal failure with a creatinine of 3.4 mg / dl and an estimated gfr of 14 ml / min at hospital admission . the patient was treated with hemodialysis thrice weekly using a standard high flux hemofilter as well as the protein leaking membrane on day 15 , 18 and 25 ( figure 3 ) . reduction rate ( % ) of sflc kappa with hemodialysis using the protein leaking membrane hco1100 . patient 3 was a 61-year - old woman with a long known history of light chain mm disease . previously , this patient had been treated with various chemotherapy protocols , including high - dose chemotherapy with autologous stem cell transplantation , thalidomide and dexamethasone , bortezomib , lenalidomide and dexamethasone . she was admitted to the hospital due to mm induced acute renal failure . at admission creatinine was 5.4 mg / dl ( egfr 9 ml / min ) . treatment was started with three sessions of hemodialysis using the protein leaking membrane ( figure 4 ) . the hemodialysis procedures were followed by 5 sessions of hemodiafiltration using the same hemofilter ( figure 5 ) . after hemodiafiltration 4 sessions of standard hemodialysis using a standard hemofilter ( pf 140h , gambro ) were performed ( figure 4 ) . reduction rate ( % ) of sflc kappa with hemodiafiltration applying the hco 1100 and pf210h hemofilter . although chemotherapy was promptly initiated , the patient developed progressive disease with an increase of sflc kappa from 5740 mg / a detailed sequence of the hemofilters used in this patient is given in figures 4 and 5 . this previously untreated patient was admitted to our hospital due to hypercalcaemia of 3.7 mmol / l and acute renal failure with a creatinine of 5.3 mg / dl ( egfr 12 ml / min ) . a total of 9 hemodialysis sessions with a median ultrafiltration rate of 415 ml ( range 0 - 1500 ml ) were performed . simultaneously furthermore the patient received 7 sessions of hemodiafiltration ( hc1100 ) with a median ultrafiltration of 550 ml ( range 0 - 1500 ml ) ( figure 7 ) . our data reveal that hemodiafiltration with the protein leaking membrane hco 1100 was superior to all other extracorporeal replacement strategies in eliminating sflc from circulating blood ( figure 8) . with the protein leaking membrane hco 1100 a median reduction rate of 40.8% ( range 13.9% -66.4% ) was achieved during hemodiafiltration and 23.7% ( range -32.9% -55.8% ) during hemodialysis ( p = 0.017 ) ( figure 8) . eliminating the extremes ( there were two protein leaking membrane hemodialysis sessions were the sflc increased during dialysis , probably due to an highly active disease ) significance still remained in favor for the hemodiafiltration mode ( p = 0.04 ) . of interest , the percentage decline of sflc kappa during plasma exchange was only 14.5% and 9.9% , respectively ( figure 1 ) . in the same patient high flux hemodialysis achieved a median reduction rate of 21.4% ( range -7.4% -32.7% , figure 2 ) . box - whiskers - plot : summary of median sflc kappa reduction rates by different renal replacement strategies . the median overall reduction rate for conventional high flux hemodialysis was 21.2% ( range -7,5% 41.5% ) . comparing the small ( pf 140h ) versus the large surface area membrane ( pf 210h ) revealed a slight , but statistically not significant advantage in favor for the large surface area membrane ( p = 0.66 ) . nevertheless , a significant difference was found between standard high flux hemodiafiltration ( pf 210h ) and hemodialysis ( pf 210h ) , in favor for the hemodiafiltration mode ( p = 0.005 ) ( figure 8) . in parallel best clearance rates were achieved during hemodiafiltration with the protein leaking membrane followed by hemodialysis with the protein leaking membrane . maximum clearances were achieved in the initial phase of the treatment with values reaching up to 25 ml / min during hco 1100 compared to 5 ml / min during conventional therapy ( pf 210h ) . however , even when the protein leaking membrane was used clearance rates declined to around 10 ml / min at 4 hours . blood pressure drops were equally distributed between standard high flux treatments and treatments performed with the protein leaking membrane . median albumin values before and after treatment with the protein leaking membrane were 3.3 ( range 3.1 - 3.7 ) and 3.4 ( range 3.3 - 3.89 ) , respectively . patient 1 was a 73-year - old male who had previously received 6 cycles of chemotherapy with melphalan and prednisolone . at the time of admission he had acute renal failure with a creatinine level of 11.3 mg / dl ( egfr 5 ml / min ) . chemotherapy with adriamycin and dexamethasone was initiated . in order to reduce the amount of sflc two treatment sessions of plasma exchange were performed ( figure 1 ) . for uremia control rrt had to be started . six sessions of high flux hemodialysis ( figure 2 ) with a median ultrafiltration rate of 1680 ml ( range 900 - 2600 ml ) per session were applied . reduction rate ( % ) of sflc kappa with hemodialysis using the high flux membrane pf 140h . patient 2 was a 70-year - old female who had developed mm induced acute renal failure with a creatinine of 3.4 mg / dl and an estimated gfr of 14 ml / min at hospital admission . the patient was treated with hemodialysis thrice weekly using a standard high flux hemofilter as well as the protein leaking membrane on day 15 , 18 and 25 ( figure 3 ) . reduction rate ( % ) of sflc kappa with hemodialysis using the protein leaking membrane hco1100 . patient 3 was a 61-year - old woman with a long known history of light chain mm disease . previously , this patient had been treated with various chemotherapy protocols , including high - dose chemotherapy with autologous stem cell transplantation , thalidomide and dexamethasone , bortezomib , lenalidomide and dexamethasone . she was admitted to the hospital due to mm induced acute renal failure . at admission creatinine was 5.4 mg / dl ( egfr 9 ml / min ) . treatment was started with three sessions of hemodialysis using the protein leaking membrane ( figure 4 ) . the hemodialysis procedures were followed by 5 sessions of hemodiafiltration using the same hemofilter ( figure 5 ) . after hemodiafiltration 4 sessions of standard hemodialysis using a standard hemofilter ( pf 140h , gambro ) were performed ( figure 4 ) . reduction rate ( % ) of sflc kappa with hemodiafiltration applying the hco 1100 and pf210h hemofilter . although chemotherapy was promptly initiated , the patient developed progressive disease with an increase of sflc kappa from 5740 mg / a detailed sequence of the hemofilters used in this patient is given in figures 4 and 5 . this previously untreated patient was admitted to our hospital due to hypercalcaemia of 3.7 mmol / l and acute renal failure with a creatinine of 5.3 mg / dl ( egfr 12 ml / min ) . a total of 9 hemodialysis sessions with a median ultrafiltration rate of 415 ml ( range 0 - 1500 ml ) were performed . simultaneously furthermore the patient received 7 sessions of hemodiafiltration ( hc1100 ) with a median ultrafiltration of 550 ml ( range 0 - 1500 ml ) ( figure 7 ) . our data reveal that hemodiafiltration with the protein leaking membrane hco 1100 was superior to all other extracorporeal replacement strategies in eliminating sflc from circulating blood ( figure 8) . with the protein leaking membrane hco 1100 a median reduction rate of 40.8% ( range 13.9% -66.4% ) was achieved during hemodiafiltration and 23.7% ( range -32.9% -55.8% ) during hemodialysis ( p = 0.017 ) ( figure 8) . eliminating the extremes ( there were two protein leaking membrane hemodialysis sessions were the sflc increased during dialysis , probably due to an highly active disease ) significance still remained in favor for the hemodiafiltration mode ( p = 0.04 ) . of interest , lowest sflc kappa elimination rates were achieved with plasma exchange . the percentage decline of sflc kappa during plasma exchange was only 14.5% and 9.9% , respectively ( figure 1 ) . in the same patient high flux hemodialysis achieved a median reduction rate of 21.4% ( range -7.4% -32.7% , figure 2 ) . box - whiskers - plot : summary of median sflc kappa reduction rates by different renal replacement strategies . the median overall reduction rate for conventional high flux hemodialysis was 21.2% ( range -7,5% 41.5% ) . comparing the small ( pf 140h ) versus the large surface area membrane ( pf 210h ) revealed a slight , but statistically not significant advantage in favor for the large surface area membrane ( p = 0.66 ) . nevertheless , a significant difference was found between standard high flux hemodiafiltration ( pf 210h ) and hemodialysis ( pf 210h ) , in favor for the hemodiafiltration mode ( p = 0.005 ) ( figure 8) . in parallel best clearance rates were achieved during hemodiafiltration with the protein leaking membrane followed by hemodialysis with the protein leaking membrane . maximum clearances were achieved in the initial phase of the treatment with values reaching up to 25 ml / min during hco 1100 compared to 5 ml / min during conventional therapy ( pf 210h ) . however , even when the protein leaking membrane was used clearance rates declined to around 10 ml / min at 4 hours . blood pressure drops were equally distributed between standard high flux treatments and treatments performed with the protein leaking membrane . median albumin values before and after treatment with the protein leaking membrane were 3.3 ( range 3.1 - 3.7 ) and 3.4 ( range 3.3 - 3.89 ) , respectively . in this study we analyzed different modes of extracorporeal elimination techniques for reducing sflc kappa in patients with kappa light chain mm associated nephropathy requiring dialysis . we compared a novel type of hemofilter , a so - called protein leaking membrane , applied in a hemodialysis and hemodiafiltration mode to standard procedures such as high flux hemodialysis and hemodiafiltration as well as plasma exchange . we found a superiority in favor for the protein leaking membrane particularly when applied in the hemodiafiltration mode . high flux hemofilters , particularly high flux membranes with a large surface area reached surprisingly good reduction rates for sflc kappa . however , when the clearance rates were analyzed , a significant advantage in favor for the protein leaking membrane was found . up to 10 fold higher clearance rates were achieved with the protein leaking membrane compared to the high flux hemofilter ( pf 210h ) . they are normally cleared in 2 - 4 hours at 40% of the glomerular filtration rate . however , removal may be significantly prolonged in patients with renal failure and can reach up to 2 - 3 days in mm patients in complete renal failure . free light chains are distributed in similar concentrations in serum , extra - vascular compartment and in tissue edema fluid . the intra - vascular compartment probably contains only 15 - 20% of the total amount . thus , redistribution from the interstitium into the vascular compartment occurs which makes a long extracorporeal treatment session necessary for an effective removal of sflc . clark et al . studied the effects of plasma exchange on clinical course of mm patients . they performed 5 to 7 plasma exchanges in their patients and found that it did not reduce a composite outcome of death , dialysis dependence , or glomerular filtration rate at 6 months . however , they initiated the study before the routine availability of the immunoglobulin free light chain assay , thus sflc were not investigated and subgroup analyses for light chain diseases could not be performed . very recently , cserti and co - workers studied sflc concentration in two patients and found that plasma exchange failed to effectively lower sflc levels . plasma exchange was performed using a continuous - flow cell separator . in our study plasma exchange the plasma exchange volume was 2.5 l , which is a standard dose for plasma exchange . based on this finding and having in mind the results from clark and co - workers we decided not to proceed with plasma exchange in light chain mm since the low serum reduction rates do not compensate for the potential risks ( allergic reaction , infections etc ) . hemodialysis with newly designed protein leaking membranes may represent an alternative strategy to clear sflc more effectively . due to an increased pore size of these membranes the elimination of middle sized molecules including sflc is eased . very recently hutchison and co - workers studied the impact of different protein leaking membranes on the capacity to clear sflc . excellent clearance rates for both kappa and lambda light chains were reported which translated in a significant removal of sflc in light chain mm patients with acute renal failure . , we analyzed the gambro hco 1100 membrane in the hemodialysis and hemodiafiltration mode extending the results of hutchison and co - workers . the maximum reduction rate for sflc kappa was 66% which is line with the data reported by hutchison . interestingly , we observed a high variability in the inter - and intra - patient reduction rate for sflc kappa during hco 1100 rrt which is best explained by a variable activity status of the underlying disease . while patient 2 and 4 had a more or less constant sflc kappa reduction rate of around 25 to 30% over time ( indicating a stable disease activity ) , patient 3 showed an increase in sflc kappa on day 1 of the first cycle of chemotherapy with adriamycin and dexamethasone from 4320 mg / l before starting hco 1100 dialysis to 5740 values increased even further in the dialysis free interval and reached 9739 mg / l on the consecutive dialysis day ( predialysis value ) . the missing fall in sflc kappa can be clearly interpreted as a sign of rapid disease progression . a switch in chemotherapy to bortezomib a highly effective chemotherapy is a precondition for treating mm associated nephropathy and must be initiated simultaneously to the rrt . after the first cycle of chemotherapy with adriamycin and dexamethasone sflc decreased from 6270 mg / l ( day1 ) to 3500 mg / l ( day14 ) , but then increased up to 6450 mg / l ( day 28 ) again . thus , we changed the regimen to bortezomib and dexamethasone . at day 16 after starting this chemotherapy regime sflc dropped to 48.8 mg / l . here , a combination of an effective chemotherapy and hemodialysis led to a very good result . importantly , the observed rebound phenomenon after rrt also results from the distribution of sflc into the different body compartments . only around 20% of the total amount of sflc are found in circulating blood whereas 80% lay in the so called " third compartment " . redistribution processes have to take place before these " trapped " sflc can be eliminated . hence , sustained elimination procedures are required . rrt with some protein leaking membranes can lead to substantial transmembrane protein losses particularly when used on a extended daily base as propagated by hutchison et al . . however , in our study population a severe protein depletion was not observed . in conclusion , extracorporeal elimination strategies with the protein leaking membrane hco 1100 may be a new and promising adjuvant treatment strategy for patients with sflc nephropathy requiring dialysis . hemodiafiltration and to lesser extend also hemodialysis with the hco 1100 hemofilter are able to eliminate substantial amounts of sflc kappa in mm patients . however , a rebound phenomenon is observed which not only demands a prolonged and repeated treatment strategy but also an effective chemotherapy protocol as a precondition for renal recovery .
multiple myeloma ( mm ) is a malignancy with excessive production of monoclonal proteins . at disease presentation 30% of mm patients 
 have significant renal impairment which may progress to renal failure requiring dialysis . besides chemotherapy extracorporeal elimination procedures such as plasma exchange have been applied as adjuvant strategies to eliminate free light chains from circulating blood , however the efficacy was poor with older techniques . 
 we report about a highly efficient method to eliminate serum free light chain ( sflc ) using a newly designed protein leaking membrane in patients suffering from sflc induced acute renal failure . the protein leaking membrane ( hco 1100 ) 
 is characterized by increased pore size facilitating elimination of middle molecules such as sflc kappa ( 22.5 kd ) . 
 the hco 1100 membrane was applied in a hemodialysis and hemodiafiltration mode and compared to standard procedures ( high flux hemodialysis , hemodiafiltration and plasma exchange ) . 
 hemodiafiltration with the protein leaking membrane hco 1100 was superior to all other extracorporeal replacement strategies in eliminating sflc - kappa from circulating blood . a median blood reduction rate of 40.8% ( range 13.9% - 66.4% ) was achieved during hemodiafiltration . 
 the corresponding peak clearance rate was 25 ml / min . 
 importantly , the poorest elimination rate was achieved by plasma exchange followed by standard high flux hemodialysis . 
 extracorporeal elimination strategies with the protein leaking membrane hco 1100 may be a promising adjuvant treatment strategy for patients with sflc nephropathy requiring dialysis . 
 hemodiafiltration and to lesser extend also hemodialysis with the hco 1100 hemofilter are able to eliminate substantial amounts of sflc kappa in mm patients .