Magdalena Krajewska

The impact of non-HLA antibodies directed against endothelin-1 type A receptors (ETAR) on early renal transplant outcomes.

BACKGROUND Non-HLA antibodies (Abs) targeting vascular receptors are considered to have an influence on renal transplant injury. Anti-endothelin-1 type A receptor (anti-ETAR) antibodies were associated with cellular and antibody-mediated rejection and early onset of vasculopathy in heart transplant patients but their role in renal transplantation remains unclear. The aim of our study was to assess the incidence and importance of anti-ETAR antibodies and their impact on renal transplant during the first year observation. METHODS We evaluated the presence of anti-ETAR antibodies in 116 consecutive renal transplant recipients in pre- and post-transplant screening (before and in 1st, 3rd, 6th, 12th month after transplantation). Additionally, we assessed the presence of anti-HLA antibodies. Anti-ETAR antibodies were assayed by ELISA. The diagnosis of acute rejection was based on the Banff criteria. RESULTS Anti-ETAR antibodies were observed in 55 (47.4%) of the analyzed recipients before transplantation. The function of renal transplant was significantly worse in the anti-ETAR(+) group compared to the anti-ETAR(-) group during the first post-transplant year. One month after transplantation the serum creatinine in anti-ETAR (+) patients (pts) was 1.86±0.8mg/dl and 1.51±0.5 in anti-ETAR(-) pts (p=0.009). Twelve months after transplantation the difference between the groups was still observed 1.70±0.7 vs. 1.40±0.4 (p=0.04). Biopsy proven acute rejection was recognized in 8/55 (14.5%) in ETAR(+) and 9/61 (14.8%) in ETAR(-) patients but cases with mild to severe intimal arteritis (v1-v3) were more often observed in patients with the presence of anti-ETAR Abs 4/55 (7.2%) comparing with 1/61 (1.6%) in anti-ETAR(-) patients. The anti-ETAR antibody levels varied at different measurement intervals during the one-year follow-up. CONCLUSIONS The presence of anti-ETAR antibodies is associated with a worse renal transplant function during the first 12months after transplantation. Including anti-ETAR antibodies in the diagnostics of renal transplant recipient immune status should be considered to provide comprehensive assessment of humoral alloimmunity.

Outcome of Autogenous Fistula Construction in Hemodialyzed Patients Over 75 Years of Age

Background: There are controversies regarding the feasibility of autogenous vascular access creation in elderly hemodialysis (HD) patients. The aim of this retrospective study was to evaluate the results of creating different types of autogenous arteriovenous fistulas (AVFs) in a consecutive series of HD patients over 75 years of age. Methods: The analysis was performed in 131 patients (65 females, 66 males, average age 79.1 ± 3.6 years) in whom the creation of an autogenous AVF was considered within a 6-year period (February 1998 to February 2004). Among them, 26.7%were diabetics, 66.3% had hypertension, 30.7% were smokers, and 35.6% were obese. Patient survival and primary and secondary AVF patency were assessed. Results: The survival rates for patients were 94, 88, 66, and 45% at 6 months and at 1, 3, and 5 years, respectively. Successful autogenous AVF formation was finally achieved in 107 patients (81.6%): in 99 patients in the forearm and in 8in the upper arm. A Kaplan-Meier analysis showed primary AVF patency rates of: 74 ± 4.3% (± SE) at 1 month; 70 ± 4.7% at 6 months; 59 ± 4.9% at 1 year; 59 ± 4.9% at 2 years; 59± 4.9% at 3 years; 59 ± 4.9% at 4 years, and 58 ± 4.9% at 5 years. The secondary patency rates were: 95 ± 2.0; 92 ± 2.2; 84 ± 3.3; 79 ± 4.0; 72 ± 4.3; 71 ± 4.4, and 69 ± 4.5% in the corresponding periods, respectively. All postoperative complications in 10 patients were treated surgically, if applicable, without endovascular techniques. Conclusions: By exploiting all suitable types of autogenous AVF it is possible to establish the best form of vascular access even in the majority of elderly patients.

The Impact of De Novo Donor-specific Anti-Human Leukocyte Antigen Antibodies on 5-Year Renal Transplant Outcome

Numerous studies have shown that circulating donor-specific antibodies targeting human leukocyte antigen (HLA) are associated with accelerated renal transplant failure, but many patients with these antibodies have good graft function. The aim of our study was to investigate the long-term graft function and survival in patients with de novo post-transplant donor-specific anti-HLA antibodies (DSA). Our prospective study included 78 consecutive recipients with a negative crossmatch before transplantation. Recipient serum samples were assayed for DSA in week 2 and 1, 3, 6, 9, 12 months after transplantation using a complement-dependent lymphocytotoxic technique with donor lymphocytes. Additionally, patients with DSA and stable renal function in the first year were tested with a more sensitive flow-panel-reactive antibody. DSA were present in 34 (44%) of our patients during the first 12 months after transplantation. Biopsy-proved acute rejection occurred in 11 DSA-positive and 10 DSA-negative patients. Seven DSA-positive patients had antibody-mediated rejection and no DSA-negative ones developed humoral rejection. The serum creatinine level in DSA-positive patients was significantly higher (2.48 vs 1.43 mg/dL) in year 5. The 13 (38%) DSA-positive patients with good graft function in month 12 were stable during a 5-year follow-up: their serum creatinine was 1.46 ± 0.4 in year 1 and 1.56 ± 0.4 mg/dL in year 5 and nobody lost their allograft. One- and 5- year graft survivals were appropriately 85% and 59% in DSA-positive patients compared to 93% and 93% in DSA-negative patients. To sum up, post-transplant DSA had a significant influence on kidney function and graft survival but in 38% of patients the presence of DSA did not decrease a 5-year renal function. A good renal allograft function in the presence of DSA in the first year after transplantation and cessation of their production in the subsequent years may be a good prognostic marker for a long-term allograft function and survival.

Non-HLA antibodies: angiotensin II type 1 receptor (anti-AT1R) and endothelin-1 type A receptor (anti-ETAR) are associated with renal allograft injury and graft loss.

INTRODUCTION Non-HLA antibodies specific for angiotensin II type 1 receptor (anti-AT1R) and endothelin-1 type A receptor (anti-ETAR) of vascular cells activate signaling pathways leading to cell proliferation and vascular injury. The aim of this study was to evaluate the impact of non-HLA antibodies on kidney allograft morphology and function in patients who underwent a kidney biopsy due to renal function impairment. PATIENTS AND METHODS The study included 65 consecutive renal transplant patients who were evaluated for the presence of non-HLA and anti-HLA antibodies at the time of transplant biopsy. Results of pre-transplant CDC cross-match were negative. A kidney allograft biopsy was performed between 6 days and 13 years (42 ± 49 months) after transplantation, and the diagnosis was made on the basis of the Banff criteria. The level >9 U/L of anti-AT1R and anti-ETAR antibodies was considered high. RESULTS A high level of non-HLA antibodies (anti-AT1R and/or anti-ETAR) was found in 7 (10.7%) of 65 patients at the time of biopsy. Graft loss in the non-HLA-positive patients was significantly higher (71% in non-HLA-positive cases after 7.8 ± 2.6 months vs 11% after 6 months in non-HLA-negative cases [P = .00099]). In these non-HLA-positive patients, the mean anti-AT1R level was 15.3 ± 9.4 U/L and the mean anti-ETAR level was 13.8 ± 8.6 U/L. In only 2 of these patients were anti-HLA antibodies additionally detected: anti-class I in 1 and anti-class II in both patients. The mean serum creatinine level was 2.34 ± 0.6 mg/dL at the time of biopsy. Results of an early biopsy revealed acute vascular rejection (Banff grade IIB). Chronic allograft injury was found (grading cg1-3, cv1-2, ci1-2, ct1-2) in the remaining 6 patients. C4d was present in 3 of 7 patients. CONCLUSIONS High levels of anti-AT1R and/or anti-ETAR antibodies were associated with morphological and functional allograft injury and graft loss in these study patients. Non-HLA antibodies can be helpful in assessing the risk of graft failure.

The increased risk of post-transplant diabetes mellitus in peritoneal dialysis-treated kidney allograft recipients

BACKGROUND Post-transplant diabetes mellitus (PTDM) is a common metabolic complication in kidney allograft recipients, significantly contributing to the elevated cardiovascular morbidity after renal transplantation and increased risk of chronic transplant dysfunction. The aim of the present investigation was to evaluate the factors influencing PTDM development. Under particular consideration were the elements, existing before the transplantation, especially the modality of dialysis treatment significance, i.e. haemodialysis (HD) versus peritoneal dialysis (PD). METHODS Three hundred and seventy-seven consecutive outpatients who underwent renal transplantation (RTx) in our institution between January 2003 and December 2005 were analysed. PTDM was diagnosed according to the current American Diabetic Association/World Health Organization criteria. Statistical inference was conducted by means of univariate methods (one factor versus PTDM) and multivariate methods in frames of generalized linear model. RESULTS In the study group, 72 patients (23.4%) developed PTDM after RTx (55 HD and 17 PD patients). PTDM incidence at 3, 6 and 12 months was 15.9%, 22.1% and 23.4%, respectively. The mean interval from transplantation to the onset of PTDM was 3.08 ± 2.73 months. In univariate analysis, the factors associated with the elevated risk of PTDM appearance were older recipient age, positive family history of diabetes, hypertensive nephropathy as end-stage renal disease cause, higher body mass index at transplantation, treatment by PD, and the graft from an older donor. In multivariate verification, statistical significance remained: older recipient age (P < 0.001), positive family history of diabetes (P = 0.002), and treatment by PD (P = 0.007). CONCLUSIONS Treatment by PD appears to be a possible novel factor, not yet reported, which may increase the risk of PTDM development.

Concurrent Infection of the Urinary Tract with Encephalitozoon cuniculi and Enterocytozoon bieneusi in a Renal Transplant Recipient

ABSTRACT A urinary tract coinfection, caused by Encephalitozoon cuniculi genotype II and Enterocytozoon bieneusi genotype D, was identified in an HIV-seronegative renal transplant recipient kept under lifelong immunosuppression. To our knowledge, this is the first report describing concurrent infection with these two microsporidia species in organ transplant recipients.

A program of physical rehabilitation during hemodialysis sessions improves the fitness of dialysis patients.

Aim: The aim of the present study was to evaluate the influence of cycle exercise during hemodialysis (HD) on patients’ physical proficiency, muscle strength, quality of life and selected laboratory parameters. Patients and Methods: In a group of 29 (15 female, 14 male) HD patients (age 64.2 ± 13.1 years), 3 months of cycle training during dialysis sessions was performed. The following data were analyzed: strength of lower extremities (six-minute walk test, isokinetic knee extension, flexion peak torque), nutrition parameters (albumin, BMI), inflammation intensity (CRP, IL-6), and quality of life (SF-36v2). Results: In the six-minute walk test, the increase in walk velocity was 4% (3.56 km/h before and 3.73 km/h after cycle training; p < 0.01). At angular velocity (AV) of 60°/s, extension peak torque in the knee joint rose by 7% and at AV of 300°/s by 4% (p = 0.04). Flexion peak torque at AV of 180°/s increased by 13% (p = 0.0005). The program does not influence nutrition or inflammation parameters. No complications directly related to exercise were observed. Conclusion: Cycle exercise during dialysis is safe even in older HD patients with multiple comorbidities. It results in a significant increase in general patient walking ability and in a gain in lower extremity muscle strength.

Extracorporeal photopheresis as an antirejection prophylaxis in kidney transplant recipients: preliminary results.

Extracorporeal photopheresis (ECP) is considered a promising immunomodulatory therapy of acute allograft rejection in organ transplantation and graft-versus-host disease. Our aim was to investigate the biological responses of 10 patients who underwent kidney transplantation with ECP as prophylactic treatment. They received conventional immunosuppressive therapy plus ECP immediately after transplantation: 12 to 16 applications over the course of 2.5 months. ECP procedures were performed using an automated system for leukocyte separation and photoactivation with methoxsalen. All recipients were followed by estimated glomerular filtration rate (eGFR) and peripheral T, B, natural killer, T-regulatory (Treg) and dendritic cells (DC) counts and phenotypes. An acute rejection episode appeared in one control group recipient. The ECP group showed a positive trend to an higher GFR at months 3 (53±11 vs 47.1±9; P=.17) and 6 (67.5±10 vs 53.6±3; P=.03, Wilcoxon test). An increased percentage of Treg (CD3+ CD4+ CD25+) among the total CD3 cell count (4.9%±1% to 9.4%±15%) as well as inducible Treg (CD3+ CD8+ CD28-) was observed among CD3 cells (3.3%±3% to 11.8%±8%, P=.025) within 3 months of ECP treatment. A significant difference in the percentage of Treg was noted at month 3 (completed ECP) between the ECP and the control groups (9.4%±15% vs 3%±1%; P=.01). Addition of ECP to standard immunosuppression was associated with a significantly higher GFR at 6 months and with a significant increase in natural Treg among CD3 cells.

Pretransplantation Cellular Alloreactivity Is Predictive of Acute Graft Rejection and 1-Year Graft Function in Kidney Transplant Recipients

OBJECTIVE To study cellular alloimmunity in kidney allograft recipients using an interferon-gamma enzyme-linked immunosorbent spot assay (ELISPOT). MATERIAL AND METHODS Donor splenocyte peripheral blood mononuclear cells were obtained during kidney recovery in 53 kidney recipients including 11 with positive panel-reactive antibodies pretransplantation. For ELISPOT data analysis, the spot number, size, and intensity were calculated, reflecting the volume of cytokine secretion at the single-cell level. Results were recalculated as the ratio of the values observed for donor-stimulated to unstimulated recipient cells corrected for residual donor activity. RESULTS Significantly greater pretransplantation donor-stimulated activity was observed in recipients who experienced an acute rejection episode (ARE) within 1 year (P < .05). Mean change in spot number, size, and intensity in patients without or with AREs was 0.99 vs 3.33, 1.60 vs 6.05, and 1.40 vs 6.31, respectively. The assessed parameters were prognostic of high risk of ARE: 1.5-fold increase in spot number (ARE incidence, 52% vs 9%), 2.5-fold increase in spot size (ARE incidence, 53% vs 13%), and 2.7-fold increase in spot intensity (ARE incidence, 52% vs 9%). The 3 parameters correlated with 1-year serum creatinine concentration (P < .05). In 14 recipients, AREs could have been predicted in 11 using pretransplantation ELISPOT results, and in only 2 on the basis of panel-reactive antibodies. CONCLUSION The ELISPOT-determined capacity of donor-induced reactivity observed in recipient cells obtained just before transplantation is predictive of risk of graft rejection and 1-year allograft function.

A new technique for autogenous brachiobasilic upper arm transposition for vascular access for hemodialysis.

Purpose Conventional brachiobasilic fistula creation consists of the mobilization and preparation of the brachial part of the basilic vein along its whole length, the vein transposition on the anterior surface of the arm and anastomosis using the brachial artery. In case of late thrombosis, the reparation of such a fistula is almost impossible. Methods To avoid total vein clotting in the case of thrombosis we decided to prepare only a short part of the vein in our method and not to mobilize the other part of the vein. The brachiobasilic fistula with our modification was performed as a two-stage procedure in 18 patients (8 females and 10 males), aged from 37–78 yrs (60 ± 13.6 yrs). Results In two patients early thrombosis occurred. The reparation procedure was not performed in two patients (the first patient died due to pneumonia; the second patient did not give his permission for further intervention). In 16 patients brachiobasilic fistula creation was successful. Late thrombotic complications occurred in three patients (in the 3rd, 8th and 12th months). A new successful fistula, a few centimeters proximally to the original one, was performed in 2 patients 24hr and in 1 patient 48hr after fistula clotting. On the following day after the procedure the fistula was ready to be used. The primary, assisted primary and cumulative secondary patency rates after 12 months of follow-up were 74, 89 and 100%, respectively. Conclusion In comparison with standard brachiobasilic techniques our method offers the possibility of a reparation procedure in the case of late thrombosis, which could improve the long-term patency of brachiobasilic fistulas. However, a prospective controlled study is necessary to establish if this new technique is superior to the traditional surgical procedure.