ABO Incompatible High-Titer Renal Transplantation without Splenectomy or Anti-CD20 Treatment

Most successful protocols for renal transplantation across ABO incompatible (ABOi) barriers have utilized splenectomy as part of the pre-conditioning process. We recently described successful ABOi transplantation using anti-CD20 monoclonal antibody in lieu of splenectomy. In the current study, we hypothesized that plasmapheresis (PP) and low dose CMV hyper-immunoglobulin (CMVIg) alone would be sufficient to achieve successful engraftment of ABOi kidneys. We describe four blood type incompatible patients who received live donor renal transplants from A1 (two patients), A2 (one patient), and B (one patient) donors. All patients started with antihuman globulin (AHG) phase titers of 64 or higher and were pre-conditioned with PP/CMVIg but not splenectomy or anti-CD20. All 4 patients underwent successful transplantation and have a mean current serum creatinine of 1.1 (range: 0.9-1.2). There were no episodes of antibody mediated rejection. Rapid allograft accommodation may limit the need for long-term antibody suppression provided by splenectomy or anti-CD20, thereby eliminating the added infectious risk of these modalities and removing another disincentive to ABOi transplantation.     

Infectious complications associated with the use of rituximab for ABO-incompatible and positive cross-match renal transplant recipients

Immunosuppressive protocols for ABO-incompatible (ABOI) and positive cross-match (PCM) solid organ transplant (SOT) recipients have included the use of rituximab (RTX). Infectious complications (IC) have been reported after the use of RTX for other indications, but have not been well studied in the SOT population. We performed a retrospective review of IC occurring within six months of ABOI and PCM renal transplantation (RT) in recipients receiving RTX. Medical records were reviewed for bloodstream, lung, gastrointestinal tract, allograft, or soft tissue infection. Between July 2001 and December 2004, 34 ABOI or PCM RT were performed at University of Illinois at Chicago, 25 of which received RTX with plasmapheresis and antithymocyte globulin (ATG) (eight ABOI and 17 PCM). Among the RTX recipients, the rate of IC was 48% compared with 11% among historical controls who did not receive RTX (p = 0.107). There were 21 episodes of IC in 13 patients including skin and soft tissue infection (8), bloodstream infection (5), esophagitis (3), peritonitis (3), pneumonia (1), and colitis (1). There was no difference in the rate of rejection, graft survival or patient survival between the two groups. These data suggest that there is a trend toward an increased rate of IC with RTX therapy in ABOI and PCM RT recipients.     

Comparison of Clinical Outcome between High and Low Baseline Anti-ABO Antibody Titers in ABO-Incompatible Kidney Transplantation

High baseline anti-ABO antibody titer is still an important obstacle for successful ABO-incompatible kidney transplantation (ABO IKT). This study aims to investigate the clinical outcome of ABO IKT in patients with a high baseline titer in comparison with patients with a low baseline titer. Fourteen patients who received ABO IKT at our center were classified as the high-titer group (≥1:256, n = 8) or the low-titer group (≤1:128, n = 6). We used a protocol composed of rituximab, plasmapheresis, and intravenous immunoglobulin (RTX/PP/IVIG). We compared the intensity of preparation, complications, and clinical outcome between the two groups. The high-titer group required more sessions of pretransplant (10.5 ± 3.5 vs. 6.0 ± 1.3 times, p = 0.01) and posttransplant (1.6 ± 1.8 vs. 0 ± 0 times) PP/IVIG than the low-titer group did. All patients from both groups showed immediate recovery of graft function. The antibody titer and allograft function in the high-titer group were stable and did not differ significantly from those of the low-titer group up to 1 year after kidney transplantation. There was no antibody-mediated rejection in either group during follow-up, but three cases of acute cellular rejection developed in the high-titer group. The high-titer group showed two cases of opportunistic viral infection (herpes gingivitis and cytomegalovirus viremia) and one case of graft loss due to postoperative bleeding. ABO IKT can be safely performed even in patients with a high baseline anti-ABO antibody titer, but the risk for infection and bleeding should be considered before transplantation.     

Experiences and problems pre-operative anti-CD20 monoclonal antibody infusion therapy with splenectomy and plasma exchange for ABO-incompatible living-donor liver transplantation

BACKGROUND: ABO-incompatible living-donor liver transplantation (LDLT) requires a reduction of the anti-ABO antibody titer to <16 before transplantation, which is usually achieved by pre-operative plasma exchange (PE) or double-filtration plasmapheresis. ABO-incompatible transplantations have been performed after a splenectomy with heavy drug immunosupression plus B-cell-specific drugs. Here, we evaluated a pre-transplantation infusion protocol with an anti-CD20 monoclonal antibody (rituximab) for ABO-incompatible LDLT. METHODS: Between March 2002 and December 2005, 73 adult patients underwent LDLT without retransplantation in our institution. Among these cases, 57 were ABO-identical, 11 were ABO-compatible and five were ABO-incompatible. The rituximab infusion protocol consisted of a weekly infusion of rituximab (375 mg/m(2)) for three wk, which was administered to three of the five ABO-incompatible LDLT patients. All three patients underwent a pre-operative PE, as well as a splenectomy during the operation. A triple immunosuppression protocol of tacrolimus, low-dose steroids and mycophenolate mofetil (1500 mg/d) was administered post-operatively. In addition, the patients received a continuous intra-arterial infusion of prostaglandin E(1) and methylprednisolone, and a continuous intra-portal infusion of a protease inhibitor for three and two wk after transplantation, respectively. RESULTS: After the first rituximab infusion, the peripheral blood CD19(+) B cell count rapidly decreased to <1%. All three patients treated with rituximab subsequently received an ABO-incompatible LDLT, with donor/recipient blood groups of B/O, A(1)/B and A(1)/O. In two cases, the ABO-antibody level transiently increased post-operatively, then decreased and remained low. Rituximab infusion therapy did not develop any direct side effect except for mild allergic reaction to the first infusion, but post-operatively all three patients suffered a cytomegalovirus and were successfully treated with ganciclovir, and one patient had a MRSA-positive intra-abdominal abscess. Two patients are currently alive at 20 and 18 months respectively, and show normal graft-liver function. But one patient died of sepsis because of intra-abdominal abscess. CONCLUSIONS: Although the protocol of rituximab administration is a conventional and safe regimen with no major side effects, the development of a new protocol is needed for prevention of the infection with bone suppression.     

ABO Incompatible Kidney Transplantations Without Splenectomy, Using Antigen-Specific Immunoadsorption and Rituximab

ABO incompatible kidney transplantations have previously only been performed after several preoperative sessions of plasmapheresis and splenectomy, with the conventional triple-drug immunosuppressive protocol being reinforced with antilymphocyte globulin and B-cell-specific drugs, such as cyclophosphamide or deoxyspergualine. We have designed a protocol without splenectomy, based on antigen-specific immunoadsorption, rituximab and a conventional triple-drug immunosuppressive protocol. The protocol calls for a 10-day pretransplantation conditioning period, starting with one dosage of rituximab and followed by full dose tacrolimus, mycophenolate mofetil and prednisolone. Antigen-specific immunoadsorption was performed on pretransplantation days -6, -5, -2 and -1. After the last session, 0.5 g/kg of intravenous immunoglobulin (IVIG) was administered. Postoperatively, three more apheresis sessions were given every third day. Furthermore, if there was a significant increase in the antibody titers, extra sessions were considered. Eleven patients have received transplants with this protocol. The ABO antibodies were readily removed by the antigen-specific immunoadsorption and were kept at a low level post-transplantation by further adsorptions. There were no side effects and all patients have normal renal transplant function. We conclude that after an infusion each of rituximab and IVIG, and antigen-specific immunoadsorption; blood group-incompatible renal transplantations can be performed with excellent results using standard immunosuppression and no splenectomy.     

A Phase I/II Randomized Open-Label Multicenter Trial of Efalizumab, a Humanized Anti-CD11a, Anti-LFA-1 in Renal Transplantation

Leukocyte function associated antigen-1 (LFA-1) has a multifaceted role in the immune response, including adhesion and trafficking of leukocytes, stabilizing the immune synapse of the MHC-TCR complex and providing costimulation signals. Monoclonal antibodies to the CD11a chain of LFA-1 have been seen to result in effective immunosuppression in experimental models. Efalizumab, a humanized IgG1 anti-CD11a, is approved for use in psoriasis and may provide effective immunosuppression in organ transplantation. Thirty-eight patients undergoing their first living donor or deceased renal transplant were randomized to receive efalizumab 0.5 or 2 mg/kg weekly subcutaneously for 12 weeks. Patients were maintained on full dose cyclosporine, mycophenolate mofetil and steroids or half dose cyclosporine, sirolimus and prednisone. At 6 months following transplant patient survival was 97% and graft survival was 95%. Clinical biopsy-proven acute rejection in the first 6 months after transplantation was confirmed in 4 of 38 patients (11%). Three patients (8%) developed post transplant lymphoproliferative disease, all treated with the higher dose efalizumab and full dose cyclosporine. The two doses of efalizumab resulted in comparable saturation and modulation of CD11a. This phase II trial suggests that efalizumab may warrant further investigation in transplantation.     

Mycophenolate Mofetil and Sirolimus Combination in Renal Transplantation

Mycophenolate mofetil (MMF) and sirolimus (SRL) are potent non-nephrotoxic xenobiotic immunosuppressants. Their complementary properties may provide the rationale for their combination in induction and maintenance regimens. MMF, a reversible inhibitor of inosin monophosphate dehydrogenase (IMPDH) acts as an antiproliferative drug; and SRL, an mTOR (mammalian target of rapamycin) inhibitor, inhibits cell proliferation driven by growth factors. Early experiences with the use of the SRL, MMF and steroid combination yielded insufficient prophylaxis of acute rejection. However, the introduction of induction therapy with mono- or polyclonal antilymphocyte antibodies to the SRL-MMF and steroid combination brings an efficient acute rejection prophylaxis, while improving renal function and/or reducing of chronic allograft nephropathy (CAN). However, adverse events related to the use of this drug combination (mainly haematological and surgery-related) result in a high rate of discontinuations in some trials, which may hamper the potential benefits of this calcineurin-inhibitor (CNI)-free strategy. Also, currently under investigation is whether in long-term immunosuppression, in MMF-treated patients, CNIs can be replaced by SRL to avoid and/or halt progression of chronic nephropathy and to improve graft survival. However, some authors reported a high proportion of patients with oral ulcers and proteinuria after switching to SRL. In short, refining the use of MMF and SRL may provide a better risk/benefit ratio to pave the way towards non-nephrotoxic immunosuppression.     

Combination Prophylaxis with Ganciclovir and Cytomegalovirus (CMV) Immune Globulin After Lung Transplantation: Effective CMV Prevention Following Daclizumab Induction

Despite the serious direct and indirect deleterious effects caused by cytomegalovirus (CMV), the optimal prophylactic strategy remains unknown. We sought to determine whether combination prophylaxis using intravenous ganciclovir (GCV) and CMV-IVIG reduced the incidence of CMV compared to GCV alone. Donor CMV positive/recipient negative (D+/R-) patients received GCV (6 weeks i.v. + 6 weeks oral) and CMV-IVIG (every 2 weeks for 7 doses), while R+ patients received GCV (2 weeks i.v. + 4 weeks oral) and CMV-IVIG (every 2 weeks for 3 doses). The group receiving combination prophylaxis (GpA) was compared to a historical, case-controlled group receiving GCV alone (GpB). Groups were matched by CMV donor/recipient serology, pretransplant diagnosis, age, and sex in reverse chronological order. Cyclosporine, azathioprine, and prednisone were used in both groups. Additionally, GpA received daclizumab induction therapy. Groups were compared as to the incidence of CMV disease, CMV infection, and acute rejection (AR). In GpA, 38 patients were evaluable and matched to 48 patients in GpB. Three GpA patients (8%) (2 D+/R-) developed CMV disease vs. 16 patients (33%) in GpB, p = 0.0077, Fisher's exact. There was also a trend toward a delay in CMV onset (148 days in GpA vs. 92 days in GpB, p = 0.07, Mann-Whitney). CMV infection did not occur in GpA, and one case occurred in GpB. There was no difference in the incidence of AR (66% in GpA vs. 79% in GpB, p = 0.22, Fisher's exact) or the need for cytolytic therapy between groups. Despite the use of daclizumab induction therapy, combination prophylaxis with GCV and CMV-IVIG reduced the incidence and probably delayed the onset of CMV infection compared to GCV alone. Longer follow-up will be needed to evaluate the impact of combination therapy on the incidence of bronchiolitis obliterans syndrome (BOS).     

Acute Renal Disease, as Defined by the RIFLE Criteria, Post-Liver Transplantation

Acute renal failure (ARF) can complicate up to 60% of orthotopic liver transplants (OLT). The RIFLE criteria were developed to provide a consensus definition for acute renal disease in critically ill patients. Using the RIFLE criteria, we aimed to determine the incidence and risk factors for ARF and acute renal injury (ARI), and to evaluate the link with the outcomes, patient survival and length of hospital stay. Three hundred patients, who received 359 OLTs, were retrospectively analyzed. ARI and ARF occurred post 11.1 and 25.7% of OLTs, respectively. By multivariate analysis, ARI was associated with pre-OLT hypertension and alcoholic liver disease and ARF with higher pre-OLT creatinine, inotrope and aminoglycoside use. ARF, but not ARI, had an impact on 30-day and 1-year patient survival and longer length of hospital stay. ARI and ARF, as defined by the RIFLE criteria, are common complications of OLT, with distinct risk factors and ARF has serious clinical consequences. The development of a consensus definition is a welcome advance, however these criteria do need to be validated in large studies in a wide variety of patient populations.     

Combination Treatment With Plasmapheresis and Rituximab for Recurrent Focal Segmental Glomerulosclerosis After Renal Transplantation

Therapy for recurrent focal segmental glomerulosclerosis (FSGS) in the renal allograft is largely based on case reports. The use of plasmapheresis alone (based on its effectiveness in children) appears less effective in adults, reaching a response rate of <40%. Recently, rituximab, an anti‐CD20 monoclonal chimeric antibody, showed promising results as rescue therapy in plasmapheresis‐resistant recurrent FSGS. However, following rituximab administration, response is variable, often slow and consequently overlooked. We report a series of four cases of recurrent FSGS following renal transplantation successfully treated with a combination of plasmapheresis and rituximab. Complete remission of proteinuria occurred in two and partial remission in the other two patients whereas renal function improved or remained stable. During treatment and the follow‐up period (18–60 months) no severe infectious complications were observed. Our data suggest that the combination of plasmapheresis and rituximab is an acceptable treatment in patients with post‐transplantation recurrent FSGS.     

C4d and C3d Staining in Biopsies of ABO- and HLA-Incompatible Renal Allografts: Correlation with Histologic Findings

Biopsies of ABO-incompatible and positive crossmatch (HLA-incompatible) renal allografts were retrospectively examined to compare results of C4d and C3d staining, and the correlation between such staining and histologic findings suggestive of antibody-mediated rejection (AMR). A total of 75 biopsies (55 protocol, 17 for graft dysfunction, 3 for other indications) of 24 ABO-incompatible grafts and 244 biopsies (103 protocol, 129 for graft dysfunction, 12 for other indications) of 66 HLA-incompatible grafts were examined; all were stained for C4d and approximately 40% for C3d. In ABO-incompatible grafts, 80% of protocol biopsies and 59% performed for graft dysfunction showed C4d staining in peritubular capillaries (PTC); this staining was not correlated with neutrophil margination in PTC. In HLA-incompatible grafts, PTC C4d was present in 26% of protocol biopsies and 60% of biopsies for graft dysfunction; 92% of biopsies with >1+ (0-4+ scale), diffuse PTC C4d had > or =1+ margination and/or thrombotic microangiopathy (TMA), compared with 12% of C4d-negative biopsies. C3d was somewhat more predictive of margination than C4d in ABO-incompatible, but not HLA-incompatible, grafts. In summary, while PTC C4d deposition indicates probable AMR in biopsies of HLA-incompatible grafts, including protocol biopsies, there is no histologic evidence that C4d deposition is correlated with injury in most ABO-incompatible grafts.     

Rituximab, an Anti-CD20 Monoclonal Antibody: History and Mechanism of Action

Rituximab, chimeric anti-human CD20, is approved for treatment of B-cell lymphoma in adults. It is being used experimentally in other various immune-related diseases such as immune thrombocytopenic purpura, systemic lupus erythematosus, myasthenia gravis and rheumatoid arthritis. In transplant recipients, it is used for treatment of post-transplant lymphoproliferative disease, to anecdotally reduce pre-formed anti-HLA and anti-ABO antibodies and for the prevention and treatment of acute rejection. This article primarily reviews the science behind rituximab: its history, pharmacokinetics and potential mechanism of action. A need for controlled clinical trials is clearly indicated before the widespread use of this drug in transplant.     

Bone Health in Children and Adolescents After Renal Transplantation

The basis for lifelong bone health is established in childhood and adolescence. Whereas pediatric renal transplant (RTx) patients are at risk for impaired bone mass gain and fractures, scarce data on this subject are available. We performed a cross‐sectional and longitudinal study of bone health in a national cohort of 106 pediatric RTx patients (median age, 12.6 yr; median follow‐up, 5.1 yr after RTx). The patients underwent clinical evaluation, DXA for BMD, and spinal imaging for vertebral fractures. In longitudinal analysis, the median lumbar spine BMD Z‐score was lowest (median, ?1.0) at 1 yr postoperatively but increased to a peak value of ?0.2 at 5 yr. In boys, the lumbar spine BMD Z‐score increased also during puberty but decreased in girls. In cross‐sectional analysis, the lumbar spine, hip, and whole body BMD Z‐scores were < ?2 SD in 4%, 6%, and 6% of the patients, respectively. Sixteen percent had sustained peripheral fractures, and 8% had vertebral fractures. Female sex and age >15 yr (OR, 56.26; 95% CI, 5.17–611.82; p = 0.0007) as well as high plasma PTH levels (OR, 4.03; 95% CI, 1.37–11.85; p = 0.009) were significant predictors for low BMD. Three‐year cumulative glucocorticoid dose, outside the immediate post‐RTx years, was not associated with BMD parameters. The observed BMD results were satisfactory. However, the high (8%) prevalence of vertebral fractures warrants careful evaluation of bone health in these patients.     

Extent and Severity of Coronary Disease and Mortality in Patients with End-Stage Renal Failure Evaluated for Renal Transplantation

The purpose of this study is to explore the relationship between coronary artery disease (CAD), transplantation status and subsequent mortality in end-stage renal disease (ESRD) patients undergoing evaluation for renal transplantation. Two hundred fifty-three ESRD patients at high risk for CAD underwent coronary angiography as part of a renal transplant evaluation. The cohort was divided into three groups: Group 1 (n = 127) had no vessels with ≥50% stenosis, Group 2 (n = 56) had one vessel with ≥50% stenosis and Group 3 (n = 70) had two or more vessels with ≥50% stenosis. Long-term survival was determined; median follow-up was 3.3 years. The baseline characteristics were similar except for older age and higher proportion of diabetes mellitus, dyslipidemia and peripheral vascular disease in Groups 2 and 3 patients as compared to Group 1. Survival was worse in Group 3 compared to Group 1 (p < 0.0001). Each of the three subgroups had better survival with renal transplantation than those who did not undergo transplantation (p < 0.0001). Although the degree of CAD is related to subsequent mortality, transplantation is associated with better survival regardless of the extent and severity of CAD. Thus, the presence of CAD should not exclude ESRD patients from consideration for this therapy.     

Early Low-Grade Proteinuria: Causes, Short-Term Evolution and Long-Term Consequences in Renal Transplantation

Proteinuria 1 year after transplantation is associated with poor renal outcome. It is unclear whether low-grade (<1 g/24 h) proteinuria earlier after transplantation and its short-term change affect long-term graft survival. The effects of proteinuria and its change on long-term graft survival were retrospectively assessed in 484 renal transplant recipients. One- and 3-month proteinuria correlated with donor age, donor cardiovascular death, prolonged cold and warm ischemia times and acute rejection. One- and 3-month proteinuria (per 0.1 g/24 h, hazard ratio (HR): 1.07 and 1.15, p<0.0001)-especially low-grade proteinuria (HR: 1.20 and 1.26, p<0.0001)-were powerful, independent predictors of graft loss. Its short-term reduction correlated with arterial pressure (AP) (the lower the 3-month diastolic and 12-month systolic AP, the lower the risk of increasing proteinuria during 1-3 months and 3-12 months periods, respectively: Odds ratio (OR) per 10 MmHg: 0.78, p=0.01 and 0.85, respectively, p=0.02), and was associated with decreased long-term graft loss (per 0.1 g/24 h: HR: 0.88 and 0.98, respectively, p<0.0001), independently of initial proteinuria. Early low-grade proteinuria due to pre-transplant renal lesions, ischemia-reperfusion and immunologic injuries is a potent predictor of graft loss. Short-term reduction in proteinuria is associated with improved long-term graft survival.     

Blood Tacrolimus Levels and Calcineurin Phosphatase Activity Early after Renal Transplantation

The toxicity of tacrolimus (FK) despite therapeutic levels (trough) has led us to investigate its relationship with the inhibition of calcineurin (CaN) in recently transplanted renal patients. Twenty-one patients taking FK had blood drawn on day 3 and 14 at 0,1,2,3,4 and 6h. CaN activity was measured by its ability to cleave 32P from a previously radiolabeled phosphorylated 19-amino acid peptide. Radioactivity was quantitated and results were converted to units CaN. FK concentration was measured simultaneously. Maximal suppression of CaN occurred after 2h on both days. Unlike FK levels, CaN activity returned to predose levels by 6h. Comparing mean CaN activity at time 0 with each subsequent time showed statistical significance at hours 1, 2 and 3 on each day. Comparing mean FK concentrations, similarly, revealed statistical significance at all hours. Area under CaN activity curve (AUCCaN) vs. mean FK levels failed to show significance. However, comparing AUCCaN with mean CaN activity was significant throughout. CaN capacity at time 0 and 6h (day 14) resulted in the best estimate of CaN inhibition. Prior to steady-state (day 3), the best estimate occurred at 2h. No single FK concentration seemed to be a reliable indicator of CaN inhibition.     

ABO-incompatible live donor renal transplantation using blood group A/B carbohydrate antigen immunoadsorption and anti-CD20 antibody treatment

BACKGROUND: Blood group ABO-incompatible live donor (LD) renal transplantation may provide a significant source of organs. We report the results of our first 14 cases of ABO-incompatible LD renal transplantation using specific anti-A/B antibody (Ab) immunoadsorption (IA) and anti-CD20 monoclonal Ab (mAb) treatment. PATIENTS AND TREATMENT PROTOCOL: Recipients were blood group O (n = 12), A (n = 1) and B (n = 1). Donors were A1 (n = 2), A2 (n = 3), A2B (n = 1) and B (n = 8), and all were secretor positive. Anti-human leukocyte antigen (HLA) Ab panel reactivity was negative in all recipients except one. All recipients were pre-treated with 3 to 6 IA sessions, using A or B carbohydrate antigen columns, until their anti-A1/B RBC panel indirect antiglobulin test (IAT) titers were < or =8. CDC crossmatch was negative in all cases. Recipients received preoperative mycophenolic acid, and steroids/tacrolimus were started at transplantation. No splenectomy was performed. Eight recipients received one dose of anti-CD20 mAb (rituximab, 375 mg/m2) pre-operatively and 11 recipients had postoperative protocol IA. RESULTS: In the initial protocol, anti-CD20 mAbs were used only for recipients receiving A1 grafts. One B graft (HLA-identical donor, 84% panel reactivity) was lost in a severe anti-B Ab-mediated acute rejection. Subsequently, the protocol included anti-CD20 for recipients of both A1 and B grafts and postoperative protocol IA to all recipients. The subsequent 10 grafts had excellent function, giving a total graft survival of 13/14 (observation range 2 to 41 months). At 1 yr, mean serum creatinine was 113 micromol/l (n = 8) and mean glomerular filtration rate was 55 ml/min/1.73 m2 (range 24 to 77). In the remaining five cases, with less than 1 yr follow up, mean serum creatinine was 145 micromol/l at 2 to 9 months follow up. Pre-IA anti-A/B titers were in the range of 2 to 32 (NaCl technique) and 16 to 512 (IAT). More than 90 IA sessions were performed in 14 recipients without any significant side effects. Recipient anti-A/B titers returned after transplantation to pre-IA levels or slightly lower. Postoperative renal biopsies were performed in 10 patients. In the 13 patients with long-term function, one patient experienced cellular rejection (Banff IIB) at 3 months without anti-B titer rise. This rejection was concomitant with low tacrolimus plasma levels and was easily reversed by steroids. In 8 of 10 cases, C4d staining was positive in peritubular capillaries. CONCLUSION: Blood group ABO-incompatible LD renal transplantation using A and B carbohydrate-specific IA and anti-CD20 mAbs has excellent graft survival and function.     

Pharmacokinetics and Pharmacodynamics of Cinacalcet in Patients with Hyperparathyroidism After Renal Transplantation

Cinacalcet is a calcimimetic drug for the treatment of secondary hyperparathyroidism (HPT). In a sequential open-label study, ten patients with persistent HPT after renal transplantation received first 30 and then 60 mg oral cinacalcet once daily over 2 weeks each. Cinacalcet steady state oral clearance was 131.1 ± 20.9 l/h and 92.8 ± 9.5 l/h (mean ± SE) after 30 and 60 mg, respectively. Cinacalcet and parathyroid hormone (PTH) concentrations showed an inverse correlation and were fitted to a simple E_max model (E_max= 80% reduction vs. baseline, EC₅₀= 13 ng/mL). A once daily administration of cinacalcet lowered serum calcium over 24 h without fluctuations. The 8-h fractional urinary excretion of calcium was increased after 60 mg cinacalcet (baseline 0.85 ± 0.17%, 30 mg 1.53 ± 0.35%, 60 mg 1.92 ± 0.37%). Renal function remained stable. Cinacalcet pharmacokinetics and pharmacodynamics showed a pronounced interindividual variability. We conclude that the once daily administration of cinacalcet in patients with secondary HPT after renal transplantation effectively reduced iPTH and serum calcium. The transient calciuria could potentially favor nephrocalcinosis and reduce bone mineral density, suggesting that higher doses of cinacalcet need to be used with caution in renal transplant recipients with severe persistent hyperparathyroidism.