kidney transplantation is the treatment of choice for patients who suffer end - stage renal disease ( esrd ) .
survival and quality of life in renal transplant recipients are more than in dialysis patients ( 1 , 2 ) .
unfortunately , organ availability for kidney transplantation is restricted by the growing number of patients waiting for this treatment ( 3 ) .
additionally , several complications occur after kidney transplantation , including surgical complications ( e.g. fluid collections , urinoma , lymphocele , hematoma , and abscess ) , incisional hernia , acute kidney injury , infections and allograft rejection ( 4 ) . among these complications ,
the management of acute rejection is very important , because each rejection that is not controlled will destroy the allograft and increase patient s morbidity and mortality ( 2 ) .
there are two international classications for acute allograft rejection : t cell - mediated acute rejection and antibody - mediated acute rejection ( amr ) .
t cell - mediated acute rejection was more studied than amr over the past several years .
the use of potent immunosuppressive agents has greatly reduced the rate of acute cellular rejection .
consequently , the 1-year graft survival has significantly improved , following kidney transplantation . in recent years ,
acute and chronic amr are playing serious roles in kidney allograft loss and are considered as important causes that limit long - term outcomes of kidney transplantation ( 2 , 5 , 6 ) . within the few days after kidney transplantation , early acute amr occurs in transplant recipients with anti - hla or donor specific antibodies ( dsa ) ( 7 ) . rejection phenotypes and outcomes are more complex in clinical practice than in the theory .
rejection can be diagnosed by renal biopsy findings , such as c4d deposition in the peritubular capillaries and histological features of inammation , allograft dysfunction , and serologic evidence of circulating antibodies ( 2 ) . despite signicant advances in recent years
several differential diagnoses have to be considered when amr is suspicious , which include acute ischemic injury , acute calcineurin inhibitor ( cni ) toxicity , infections and thrombotic microangiopathy ( tma ) .
the tma is always the most important differential diagnosis of amr ( 8) . the gold standard for exact diagnosis is renal biopsy ( 9 ) ; however , in many patients , performing kidney biopsy is not feasible due to the patient s low platelet count and lack of personal satisfaction . in these situations ,
this study was designed to assess the efficacy of routine treatment of amr / tma in iranian kidney transplant recipients , comprising of plasmapheresis and intravenous immunoglobulin ( ivig ) .
this 1-year cross - sectional study was performed at the kidney transplantation ward of imam - khomeini hospital complex , affiliated to tehran university of medical sciences , tehran , iran from 1st january 2014 .
all kidney transplant recipients , who were administered plasmapheresis and ivig to treat definite or suggested amr or tma , were assessed .
all patients in this transplant ward receive rabbit antithymocyte globulin ( ratg ) , as induction therapy , with a cumulative dose of at least 6 mg / kg .
they are also administered methylprednisolone 500 mg on the transplantation day and 250 and 125 mg on the next two days after transplantation , which is continued with oral prednisolone 1
mg / kg / day , with rapid taper down during the next days , to reach the dose of 5 mg / day after month one from transplantation .
they also receive a cni ( mostly tacrolimus ) and mycophenolate mofetil as maintenance immunosuppressive regimen .
all patients receive intravenous ganciclovir / oral valganciclovir , oral co - trimoxazole and clotrimazole for routine viral , pneumocystis pneumonia , and fungal prophylaxis .
patients demographic and clinical data ( sex , age , weight , height , cause of esrd ) , laboratory findings ( including serum creatinine and urea concentrations , urine volume , serum electrolytes , complete blood counts and serum lactate dehydrogenase ( ldh ) concentration ) , were gathered in designed forms .
the study protocol was approved by local ethics committee of tehran university of medical sciences , tehran , iran .
all patients or their representatives provided their informed consent and were assured that their information will be published anonymously .
this 1-year cross - sectional study was performed at the kidney transplantation ward of imam - khomeini hospital complex , affiliated to tehran university of medical sciences , tehran , iran from 1st january 2014 .
all kidney transplant recipients , who were administered plasmapheresis and ivig to treat definite or suggested amr or tma , were assessed .
all patients in this transplant ward receive rabbit antithymocyte globulin ( ratg ) , as induction therapy , with a cumulative dose of at least 6 mg / kg .
they are also administered methylprednisolone 500 mg on the transplantation day and 250 and 125 mg on the next two days after transplantation , which is continued with oral prednisolone 1 mg / kg / day , with rapid taper down during the next days , to reach the dose of 5 mg / day after month one from transplantation .
they also receive a cni ( mostly tacrolimus ) and mycophenolate mofetil as maintenance immunosuppressive regimen .
all patients receive intravenous ganciclovir / oral valganciclovir , oral co - trimoxazole and clotrimazole for routine viral , pneumocystis pneumonia , and fungal prophylaxis .
patients demographic and clinical data ( sex , age , weight , height , cause of esrd ) , laboratory findings ( including serum creatinine and urea concentrations , urine volume , serum electrolytes , complete blood counts and serum lactate dehydrogenase ( ldh ) concentration ) , were gathered in designed forms .
the study protocol was approved by local ethics committee of tehran university of medical sciences , tehran , iran .
all patients or their representatives provided their informed consent and were assured that their information will be published anonymously .
five kidney transplant patients were treated for suspicious / definite amr or tma during the year 2014 at this center .
the patient s.t . , a 56-year - old female , with a history of esrd with undiagnosed cause , was admitted in february 2014 for a second renal transplantation . she had a history of renal transplant with hyperacute rejection 6 years ago .
her creatinine was decreased from 5.6 to 0.9 mg / dl , within 5 days after transplantation ; however , on day 6 after transplantation , her urine output was significantly decreased and her serum creatinine level rose .
our concern regarded the tma and possibility of acute rejection , although we were unable to perform allograft biopsy , because of her low platelet count .
g / kg ideal body weight , for 5 days , which is equal to approximately 460 mg / kg / day .
concomitant with ivig therapy , plasmapheresis was performed daily for four sessions and thereafter , every other day , for three sessions .
the ivig doses were infused after plasmapheresis treatment . due to lack of improvement in kidney function and platelet count , tacrolimus was stopped 16 days after transplantation .
treatment with plasmapheresis and ivig was not effective in this patient and therefore was discontinued .
due to uncontrolled fever and patient s illness , nephrectomy was performed in her case .
, a 15-year - old male , with a history of esrd of unknown origin , was admitted in may 2014 for preemptive kidney transplantation from a 14-year - old deceased male .
although his diethylene triamine pentacaetic acid ( dtpa ) radionuclide scan suggested acute rejection , renal biopsy could not be performed .
plasmapheresis and high - dose of ivig ( 2 g / kg ) were prescribed 2 days after transplantation .
he was treated with plasmapheresis for 9 consecutive days and his ivig was divided to these 9 days after each plasmapheresis session ( i.e. about 222 mg / kg after each plasmapheresis ) .
he was discharged from the hospital with a serum creatinine level similar to his pretransplant value .
, a 40-year - old male , with a history of esrd with undetermined origin , was admitted in june 2014 .
his maintenance regimen included tacrolimus , mycophenolate mofetil and prednisolone . during the first few days he showed good allograft functioning . however , 3 days after transplantation , serum ldh level increased and platelet count decreased significantly .
four days after plasmapheresis initiation , ldh decreased and platelet count increased . at day 18 from transplantation , his serum creatinine concentration increased from 1.5 mg / dl to 1.9 and 2.4 mg / dl , during two days . therefore , his plasmapheresis was continued additionally for four sessions every other day and 1.5 g / kg of ivig was divided to four doses ( 375 mg / kg each ) on the days that patient did not undergo plasmapheresis . after this treatment , his creatinine
, a 44-year - old male with a history of esrd with undetermined origin , was admitted in september 2014 and received the kidney from a 37-year - old deceased female .
his first renal biopsy , which was performed 5 days after transplantation , showed c4d deposition in peritubular capillaries .
plasmapheresis was performed daily for 5 days and every other day , for five additional sessions .
the ivig with a cumulative dose of 2.1 g / kg was administered during 8 consecutive days ( i.e. about 263 mg / kg each day ) , starting the day before plasmapheresis initiation . however , there was no improvement in his renal function .
the second biopsy that was done 11 days after transplantation revealed necrosis and vascular congestion , associated with amr . because of no improvement in his renal function
, the third biopsy was done on day 16 after transplantation and showed more than 90% glomerular necrosis .
, a 57-year - old female with a history of esrd because of autosomal dominant polycystic kidney disease , was admitted in october 2014 .
the biopsy was performed at day 12 , showing glomerular basement membrane thickening and subendothelial widening that was compatible with tma .
after that , platelet count decreased from 100000 to 39000 cells / microliter and serum ldh level increased . therefore , she received methylprednisolone pulses for 3 days .
she received a cumulative dose of 2.3 g / kg ivig during 4 consecutive days ( i.e. about 383 mg / kg at each doses ) , started with plasmapheresis treatment .
plasmapheresis was performed for a cumulative 15 sessions , six of which were daily and the others every 2 - 3 days .
the patient s general condition was deteriorated and despite nephrectomy and antibiotic therapy , the patient unfortunately expired in a sepsis tableau .
the patient s.t . , a 56-year - old female , with a history of esrd with undiagnosed cause , was admitted in february 2014 for a second renal transplantation .
her creatinine was decreased from 5.6 to 0.9 mg / dl , within 5 days after transplantation ; however , on day 6 after transplantation , her urine output was significantly decreased and her serum creatinine level rose .
our concern regarded the tma and possibility of acute rejection , although we were unable to perform allograft biopsy , because of her low platelet count .
two days later , she received ivig , with a cumulative dose of 2.3 g / kg ideal body weight , for 5 days , which is equal to approximately 460 mg / kg / day .
concomitant with ivig therapy , plasmapheresis was performed daily for four sessions and thereafter , every other day , for three sessions .
the ivig doses were infused after plasmapheresis treatment . due to lack of improvement in kidney function and platelet count ,
treatment with plasmapheresis and ivig was not effective in this patient and therefore was discontinued .
due to uncontrolled fever and patient s illness , nephrectomy was performed in her case .
, a 15-year - old male , with a history of esrd of unknown origin , was admitted in may 2014 for preemptive kidney transplantation from a 14-year - old deceased male .
although his diethylene triamine pentacaetic acid ( dtpa ) radionuclide scan suggested acute rejection , renal biopsy could not be performed .
plasmapheresis and high - dose of ivig ( 2 g / kg ) were prescribed 2 days after transplantation .
he was treated with plasmapheresis for 9 consecutive days and his ivig was divided to these 9 days after each plasmapheresis session ( i.e. about 222 mg / kg after each plasmapheresis ) .
he was discharged from the hospital with a serum creatinine level similar to his pretransplant value .
, a 40-year - old male , with a history of esrd with undetermined origin , was admitted in june 2014 .
his maintenance regimen included tacrolimus , mycophenolate mofetil and prednisolone . during the first few days he showed good allograft functioning . however , 3 days after transplantation , serum ldh level increased and platelet count decreased significantly .
four days after plasmapheresis initiation , ldh decreased and platelet count increased . at day 18 from transplantation ,
his serum creatinine concentration increased from 1.5 mg / dl to 1.9 and 2.4 mg / dl , during two days .
therefore , his plasmapheresis was continued additionally for four sessions every other day and 1.5 g / kg of ivig was divided to four doses ( 375 mg / kg each ) on the days that patient did not undergo plasmapheresis .
after this treatment , his creatinine was decreased to 1.7 mg / dl and relative improvement occurred .
, a 44-year - old male with a history of esrd with undetermined origin , was admitted in september 2014 and received the kidney from a 37-year - old deceased female .
his first renal biopsy , which was performed 5 days after transplantation , showed c4d deposition in peritubular capillaries .
plasmapheresis was performed daily for 5 days and every other day , for five additional sessions . the ivig with a cumulative dose of 2.1 g / kg was administered during 8 consecutive days ( i.e. about 263 mg / kg each day ) , starting the day before plasmapheresis initiation .
the second biopsy that was done 11 days after transplantation revealed necrosis and vascular congestion , associated with amr . because of no improvement in his renal function ,
the third biopsy was done on day 16 after transplantation and showed more than 90% glomerular necrosis .
the patient h.n . , a 57-year - old female with a history of esrd because of autosomal dominant polycystic kidney disease , was admitted in october 2014 .
the biopsy was performed at day 12 , showing glomerular basement membrane thickening and subendothelial widening that was compatible with tma .
after that , platelet count decreased from 100000 to 39000 cells / microliter and serum ldh level increased .
she received a cumulative dose of 2.3 g / kg ivig during 4 consecutive days ( i.e. about 383 mg / kg at each doses ) , started with plasmapheresis treatment .
plasmapheresis was performed for a cumulative 15 sessions , six of which were daily and the others every 2 - 3 days . the patient s general condition was deteriorated and despite nephrectomy and antibiotic therapy , the patient unfortunately expired in a sepsis tableau .
during recent years , the use of effective immunosuppressants resulted in the decrease of the rate of acute cellular rejection .
however , amr has become an important cause of graft loss during the initial weeks to months after transplantation ( 7 ) .
the incidence of acute graft loss in amr is greater than acute cellular rejection ( 7 ) . in patients with high levels of dsa
, the incidence of graft loss in the first month after transplantation may be as high as 40% , while this rate is less than 10% in patients with a negative dsa ( 7 , 10 ) .
early aggressive treatment of amr may be required to prevent graft loss ( 7 ) .
dehydration or elevated blood levels of cnis can also cause an increase in serum creatinine concentration .
although renal biopsy and measurement of the serum dsa are helpful , they are not always readily practical or available in the clinical settings ( 7 ) . performing renal biopsy
therefore , it is indicated to choose a treatment regimen that is helpful for both conditions . during year 2014
, we encountered five patients with suspicious amr or tma at our kidney transplant center .
renal biopsy was performed for two of them , suggesting amr in one patient and tma for the other .
therefore , we treated them with plasmapheresis plus ivig ; however , only one out of these five patients showed response albeit not completely .
the first strategy is to control b - cell activities by removal or dilution of antibodies .
we can use plasmapheresis or immunoadsorption for removal of antibodies . by administration of ivig ,
the second option is to inhibit or deplete of b - cells using antibodies , such as rituximab , that act against cd20 in b - cells surface .
the third way is to reduce t - cells . diminished t - cells can decrease b - cell counts .
inhibitors of t - cell division ( mycophenolate mofetil and steroids ) , inhibitors of il-2 signaling to t - cells ( cnis ) , and t - cell depleting agents such as ratg are three options that decrease t - cells . a fourth target for the managing of amr
antibodies that are produced by plasma cell will become bound to graft and activate complement cascade .
therefore , the fth target that has recently been introduced is the xation of complement , which is activated by antibodies .
eculizumabis , a c5 inhibitor , is an option that reduces the dissemination of the complement cascade , even after antibodies have bound to the graft ( 1 , 6 , 11 ) . despite these various options for amr treatment ,
there is no consensus over which treatment must be selected first in transplanted patients with amr ( 6 - 8 , 11 , 12 ) .
the importance of this issue is more apparent when we could not perform biopsy , as a gold standard for detecting amr . on the other hand , in several situations we could not distinguish between amr and tma , according to the clinical features
therefore , designing a useful treatment strategy that could be used in both amr and tma is very crucial .
nevertheless , the first line of therapy was not indicated by any study ( 7 , 11 ) .
the systematic review conducted by roberts et al . demonstrated that the optimal treatment for amr remains unknown .
they recommended a combination treatment for the management of amr that is associated with multiple pathophysiologic pathways .
this combination includes plasmapheresis , ivig , immunosuppressants , rituximab , bortezumib and eculizumab ( 13 ) . as seen
, this proposed strategy is too expensive to be applied for all patients with definite or possible amr .
the management of tma has also been reviewed in many studies . almost always , plasma exchange is the first line of tma treatment .
the use of corticosteroids is recommended in tma patients with neurological or cardiovascular involvement . with these therapies , there is still a high mortality rate of 10 - 20% and a high relapse rate , of approximately 20 - 50% .
the effectiveness of rituximab in decreasing tma relapse and hospitalization duration has been confirmed in a series of studies ( 14 - 18 ) .
a cohort study that has been performed by westwood et al . revealed that early administration of rituximab for thrombotic thrombocytopenic purpura ( ttp ) ( within 3 days ) was associated with faster remission , fewer plasma exchange sessions and shorter duration of hospital stay ( 14 ) .
the efficacy and safety of rituximab in severe ttp was shown by froissart et al . in adults , who responded poorly to therapeutic plasma exchange .
one - year relapses and hospitalization duration were decreased in patients who were treated with rituximab , compared with historical controls , who were treated with plasmapheresis ( 18 ) . in the present study
, the effectiveness of plasmapheresis and ivig were investigated in iranian kidney transplant recipients , with suspicious / definite amr or tma . assessing donor specific antibody
kidney biopsy is not performed in patients with thrombocytopenia in most iranian kidney transplant wards , due to legal considerations and fear of bleeding and its ominous consequences . due to similar clinical and laboratory features of amr and tma , including increased serum creatinine concentration , decreased urine output and platelet count , and increased serum ldh levels , most clinicians consider both situations when selecting treatment . according to the high cost of rituximab and lack of iranian insurance coverage of rituximab by nephrologist s order , a limited number of patients can afford its cost .
therefore , rituximab can not be easily used as first option in these situations in kidney transplant patients , which determines iranian nephrologists to usually start amr or tma treatment with plasmapheresis plus ivig . applying these therapies in our patients cohort
showed that only one out of five patients ( 20% ) , showed only partial response to these treatments .
the amr and tma were confirmed only in two patients by biopsy ( each in one patient ) . according to the literature
, it seems better to start combination treatments for both amr and tma , with common regimen of plasmapheresis plus ivig , plus rituximab .
almost all patients with tma are at risk of relapse ( 19 , 20 ) . in transplanted patients
we aim to decrease the relapse rate , because each tma episode could result in graft failure ( 20 ) , and rituximab is the required agent ( 14 - 18 ) .
the time of initiation of ivig and plasmapheresis was different between our patients . according to the study by jodele et al .
( 21 ) early plasmapheresis could be effective in ttp patients even with multiorgan damage .
therefore , the early use of plasmapheresis and rituximab are recommended in situation in which it is difficult to distinguish between tma and amr .
however , according to the high cost and lack of insurance coverage of rituximab for kidney transplant recipients , almost none of our patients could benefit from this drug .
another explanation for the high rate of treatment failure in our patients may be the ineffectiveness of ivig , possibly due to its removal by plasmapheresis . in most studies ,
it is recommended to administer ivig with maintenance dose of 100 mg / kg after each plasmapheresis , and when plasmapheresis was stopped , the remaining dose of ivig , to a cumulative dose of 2 g / kg , could be administered once ( 11 ) . in our center , as a routine practice of nephrology attending that has reached to nephrology fellows as well ,
the cumulative dose of 2 g / kg of ivig is divided into 300 - 400 mg / kg after each plasmapheresis . due to daily plasmapheresis within the first few days after amr or tma , this ivig administration approach may result in high amount of ivig withdrawal by plasmapheresis .
the ivig role in the treatment of amr is more complex than just diluting antibodies , as proposed in several studies ( 1 ) .
the ivig may induce b - cell apoptosis and modulates b - cell signaling ( 22 ) .
it also inhibits antibody binding to the allograft and complement activities , by unknown mechanisms ( 23 ) .
therefore , removing high amounts of ivig by plasmapheresis , without its replacement , due to not adding removed ivig to the cumulative dose , may explain our high rate of treatment failure .
due to a series of similarities in clinical and laboratory features of amr and tma in kidney transplant recipients , the unavailability of dsa assessment in iranian laboratories , high risk kidney biopsy in several patients , especially in those with thrombocytopenia , and delayed pathology reports of renal biopsy in several iranian kidney transplant centers , it seems reasonable to start amr and tma management concomitantly , in clinical situations .
it means that it is better to start plasmapheresis with ivig and rituximab . due to the lack of iranian insurance coverage of rituximab by nephrologist
s order and high cost of this drug , most patients are not able to afford its cost . based on these clinical limitations
our suggestion is to reduce ivig dose after each plasmapheresis to 100 mg / kg ( i.e. replacement dose ) to reach the cumulative dose of 2 g / kg . if plasmapheresis treatment is held sooner than the completion of ivig cumulative dose of 2 g / kg , the remaining dose can be administered during one injection .
 background : antibody mediated rejection ( amr ) and thrombotic microangiopathy ( tma ) after kidney transplantation are difficult to differentiate most of the times and both play important roles in kidney allograft loss . 
 common treatment strategies of these two conditions include plasmapheresis , intravenous immunoglobulin ( ivig ) and rituximab.objectives:this study was designed to assess the efficacy of routine treatment of amr / tma in iranian kidney transplant recipients , which comprises of plasmapheresis and ivig.patients and methods : this one - year cross - sectional study was performed in the kidney transplantation ward of imam - khomeini hospital complex , tehran , iran . 
 all kidney transplant recipients who were administered plasmapheresis and ivig to treat definite or suggested amr or tma were assessed clinically and also evaluated on laboratory data.results:during 2014 , we encountered five patients with suspicious amr or tma at our kidney transplant center . 
 renal biopsy was performed for two of them , suggesting amr for one patient and tma for another patient . 
 all patients were treated with plasmapheresis plus ivig . in this center , as a routine practice , the cumulative dose of 2 g / kg of ivig was divided to 300 - 400 mg / kg after each plasmapheresis . 
 only one out of the five patients showed response , albeit not completely.conclusions:due to daily plasmapheresis within the first several days after amr or tma , administering high amounts of the cumulative dose of ivig after plasmapheresis may result in high amounts of ivig withdrawal by plasmapheresis and response failure . 
 our suggestion is to reduce the ivig dose after each plasmapheresis to 100 mg / kg ( i.e. replacement dose ) to reach a cumulative dose of 2 g / kg . if plasmapheresis treatment is initiated sooner than the completion of the ivig cumulative dose of 2 g / kg , the remaining dose can be administered during one injection . 