Desensitization Protocol in Recipients of Deceased Kidney Donor With Donor-Specific Antibody-Low Titers.

BACKGROUND: Kidney transplantation is the better option for end-stage renal disease (ESRD), but for patients with human leukocyte antigen (HLA) sensitization, the wait times are significantly longer than for patients without antibodies. Many desensitization protocols have been described involving strong immunosuppression, the use of apheresis, and B-cell-modulating therapies. We have designed a desensitization protocol from day 0 for deceased donor kidney transplantation. Our aim was to present our initial experience with five kidney transplant patients. METHODS: All patients had a negative complement-dependent cytotoxicity cross-match. The desensitization protocol included five to seven doses of thymoglobulin (1.25 mg/kg) and three sessions of plasmapheresis (PP) within the first week after transplantation, with intravenous immunoglobulin (500 mg/kg) after each PP session and one dose of rituximab on day 8. The presence of donor-specific antibodies (DSA) was analyzed by use of Luminex technology; levels between 1000 and 3000 mean fluorescence intensity were considered for desensitization. RESULTS: The median age was 44 years and median renal replacement therapy time was 9 years. All recipients presented 1 to 3 DSA specificities. There were no severe side effects related to PP, infusion of intravenous immunoglobulin, or rituximab. The median follow-up period was 19.3 months. Median serum creatinine level at last follow-up was 1.7 mg/dL. A kidney biopsy was performed in all patients. Graft and patient survival was 100%. CONCLUSIONS: Until now, few data are available concerning whether HLA-incompatible kidney transplantation after desensitization would benefit patients with ERSD. The desensitization strategy using the combination of PP, low doses of intravenous immunoglobulin, and rituximab at our center resulted in a satisfactory clinical outcome.

Safety and efficacy of induction treatment with low thymoglobulin doses in kidney transplantation from expanded-criteria donors.

BACKGROUND: Induction treatment has been recommended as part of the initial immunosuppressive regimen in kidney transplantation, and antithymocyte globulin is one of the drugs used for it, but at usual dosage it has been related to an increase of infectious and neoplastic complications. Our aim was to analyze the safety and efficacy of induction treatment with low doses of antithymocyte globulin, compared to basiliximab. METHODS: In this retrospective cohort study of 321 kidney transplant patients with a minimum follow-up of 2 years, 162 were treated with low doses of antithymocyte globulin (1.25 mg/kg, every other day) and 159 with basiliximab. Mean follow-up was 76.6 ± 37.51 months (range, 24-187 mo) and was similar for the 2 groups. RESULTS: Mean number of antithymocyte globulin doses was 1.89 ± 0.32 mg/kg (range, 1-3). The globulin group received a higher proportion of kidneys from donors >70 years old (25.3% vs 13.8%; P = .010) and donors with higher creatinine levels (1.01 ± 0.62 vs 0.86 ± 0.28 mg/dL; P = .006). The basiliximab group presented a higher incidence of acute rejection (22.1% vs 9.1%; P = .010). Cytomegalovirus disease was more frequent in the globulin group (18.6% vs 8.1%; P = .011) without an increase of infectious hospitalizations. Graft (P = .214) and patient (P = .533) survivals were similar. CONCLUSIONS: Induction with low doses of antithymocyte globulin resulted in a lower incidence of acute rejection with graft and patient survivals similar to that obtained with basiliximab induction, in spite of a worse donor profile. CMV disease was more frequent with antithymocyte globulin, without an increase of infectious hospitalizations or cancer development, in long-term follow-up.

Pretransplant donor-specific HLA antibodies detected by single antigen bead flow cytometry: risk factors and outcomes after kidney transplantation.

BACKGROUND: The clinical significance of pretransplant donor-specific antibodies (pre-Tx DSAs) detected by single antigen bead flow cytometry (SAB-FC) remains unclear. Our aim was to investigate the impact that pre-Tx DSAs detected by SAB-FC have on the early and late clinical outcomes. PATIENTS AND METHODS: We retrospectively tested stored frozen pre-Tx sera from 222 deceased-donor kidney transplants performed between November 1997 and November 2006. All patients had a negative complement-dependent cytotoxicity (CDC) cross-match with the donor. Median follow up was 5.1 years. RESULTS: Twenty-two (10%) patients had pre-Tx HLA antibodies detected by CDC. Pre-Tx HLA antibodies were detected using SAB-FC in the sera of 46 (20.7%) patients; 36 (16.2%) of them presented pre-Tx DSAs, 18 had class I antibodies, 9 class II, and 9 patients presented both classes. Mean pre-Tx DSA class I/II was 2360/1972 (MFI) mean fluorescence index in non CDC-sensitized patients. Pre-Tx DSAs were associated with female sex, retransplants, and pretransplant transfusions. Patients with Pre-Tx DSAs more than 1000 MFI and negative CDC screening presented a higher percentage of delayed graft function (61.1% versus 38.9%), more episodes of acute vascular rejection (33.3% versus 13.7%), and chronic rejection as the cause of allograft failure (22.2% versus 9.7%) compared with non-pre-Tx DSAs patients. Five-year allograft survival was significantly worse in patients with pre-Tx DSA (68.5% versus 82%, P = .006) and in patients with pre-Tx DSA class II more than 1000 MFI (43% versus 82%, P = .009). We didn't find differences in patient survival. DISCUSSION: Pre-Tx DSAs detected by SAB-FC were more frequent in female recipients, and they were associated with acute vascular and chronic rejection and a poorer graft outcome.

Donor-specific HLA antibodies: risk factors and outcomes after kidney transplantation.

BACKGROUND: Anti-human leukocyte antigen antibodies (HLA Abs) have been associated with reduced kidney allograft survival. Our aim was to analyze the prevalence and impact on allograft function of donor-specific HLA antibodies (DSA) among a cohort of kidney transplant recipients. PATIENTS AND METHODS: The 321 recipients had received deceased-donor kidneys followed for a median of 70 ± 43 months. We performed a cross-sectional analysis of the presence of HLA Abs with the use of Luminex technology. RESULTS: Fifty patients (15.6%) displayed HLA Abs after transplantation including 21 (6.7%) as de novo HLA Abs. Eight patients (2.5%) developed DSA, and 42 (13%) showed no DSA. We compared 3 groups of patients: with DSA, without DSA, and without HLA sensitization. The DSA patients were younger (P = .03) with a higher percentage of men (P = .00), and having received less frequent induction treatment with basiliximab or thymoglobulin (P = .02). Patients without DSA revealed a higher percentage of pretransplantation HLA sensitization (P = .00), more pretransplantation transfusions (P = .08), and more frequent retransplantations (P = .00). The incidence of acute rejections was higher for DSA patients (P = .02) than for the other 2 groups, behaving as an independent risk factor (relative risk, 4.7; 95% confidence interval, 1.1-18.8; P = .03). Graft survival at 5 years was lower among patients with compared to those without HLA Abs (P = .00). CONCLUSIONS: HLA donor-specific sensitization, an uncommon situation in our study, was associated with younger male recipients and less induction treatment. An acute rejection episode was an independent risk factor for the development of DSA; therefore, we think that monitoring of HLA Abs should be included in evaluation of the early postransplantation period.

Delayed graft function after renal transplantation: an unresolved problem.

Unlike other areas in renal transplantation, delayed graft function (DGF) remains an apparently unavoidable complication owing to the characteristics of current donors. The aim of this study was to analyze risk factors for DGF in relation to graft and patient survivals. We retrospectively analyzed 507 renal transplant recipients with a median follow-up of 74.83 ± 45.06 months. DGF, which occurred among 189 patients (36.8%) was defined as requirement for dialysis within the first week after transplantation. Donor (P = .000) and recipient (P = .000) age were greater in the DGF group without differences in recipient or donor gender, HLA sensitization, or dialysis time before transplantation. Donor factors as the cause of death associated with DGF were secondary cerebrovascular stroke (P = .002) and hypertensive history (P = .000). Recipient characteristics associated therewith were higher body mass index (P = .000), smoking habit (P = .003), ischemic cardiopathy (P = .01), and dyslipidemia (P = .05). Moreover, the DGF group showed longer cold ischemia (P = .01) and vascular anastomosis (P = .02) times. On multivariate analysis, recipient age (P = .00) and smoking habit (P = .01) together with a donor history of hypertension (P = .02) were independent risk factors for DGF. No differences were observed in acute rejection incidence (P = .07) with worse renal function during follow-up (P < .05). Graft (81% vs 88%; P = .00) and patient (89% vs 95%; P = .00) survivals at 5 years were lower among the DGF group. In conclusion, DGF which was associated with factors related to the donor, the recipient, and the surgical times, produced worse graft and patient survivals. Shortening the cold ischemia time seems to be a modifiable variable to reduce DGF.

Vitamin D deficiency in a renal transplant population: safe repletion with moderate doses of calcidiol.

BACKGROUND: Deficits of vitamin D are a common finding in the general population, especially among patients with chronic kidney disease. However, there are not much data about its prevalence after renal transplantation. Our aim was to analyze the calcidiol status among a cohort of kidney transplant recipients, in a region of Spain with a high number of annual sunshine hours, as well as the effects of supplementation with oral calcidiol. PATIENTS AND METHODS: We included 110 kidney transplant recipients in a retrospective observational study. Measurements of 25-hydroxyvitamin D (25OHD), calcium, phosphate, intact parathyroid hormone (iPTH), serum creatinine and albumin, 24-hour microalbuminuria, and proteinuria were performed at the same time. Patients were classified based on their serum 25OHD levels: normal (>30 ng/mL); insufficiency (16-30 ng/mL); and deficiency (<16 ng/mL). In a second analysis, we included 63 patients with 25OHD<30 ng/mL with adjusted calcium levels below 10.2 mg/dL for treatment with oral calcidiol to approach target levels of 30 to 40 ng/mL. Mineral metabolism parameters were monitored at baseline as well as 6 and 12 months after beginning treatment. RESULTS: Insufficient or deficient 25OHD levels were present in 106/110 patients (96.3%); they were normal in just four patients (3.6%). Patients with calcidiol deficiency were older. We observed no differences in sex, posttransplant follow up, serum calcium, phosphate, iPTH, glomerular filtration rate, or 24- hour albuminuria or proteinuria. The 63 patients treated with oral calcidiol received a mean dose of 8044±4087 IU/wk at baseline. The 61.3% of them with deficient 25OHD levels at baseline decreased to 2.1% at 6 months and 7.5% at 12 months after treatment. No significant changes in calcium, phosphate or iPTH were observed during the treatment. CONCLUSIONS: Deficits of 25 OHD was frequent after renal transplantation but improved safely with moderate doses of oral calcidiol without negative secondary effects.

Very low-grade proteinuria at 3 months posttransplantation is an earlier marker of graft survival.

Proteinuria is an early finding that appears in the first 3 months after transplantation in half of patients. Frequently, it is very low grade (VLP; <0.5 g/24 h). The aim of this study was to analyze the risk factors and prognostic significance of VLP at 3 months posttransplantation, which was maintained for the first year among our renal recipients. We compared 141 patients (39.7%) who showed VLP with 214 patients (60.3%) without proteinuria. VLP was associated with older recipients (P = .002), HLA incompatibilities (P = .001), older donors (P = .000), nontraumatic cause of brain death (P = .033) and previous hypertension (P = .030), tacrolimus (P = .000) and induction treatment with Thymoglobulin (P = .018) or anti-CD25 monoclonal antibodies (P = .000), as well as delayed graft function (DGF; P = .000). VLP patients showed worse renal function (P < .05) and greater requirement for antihypertensive drugs (P = .001). Multivariate analysis confirmed the impact of donor age, HLA incompatibilities, DGF, and tacrolimus treatment to predict the presence of VLP. Graft (P = .0019) and patient (P = .0146) survivals were lower among the VLP group. Cox analysis showed that VLP (RR: 2.047; P = .018) and DGF (RR: 2.062; P = .0017) were independently associated with reduced graft survival. The positive predictive value of VLP on graft survival was low. In conclusion, VLP was related to increasing acceptance of marginal donors, DGF, and worse renal function. Proteinuria was a noninvasive, readily determined parameter which was related to reduced graft and patient survivals, so renoprotective measures are mandatory from the early stages after transplantation.

Use of basiliximab induction in low-immunological risk renal transplant recipients receiving tacrolimus-based immunosuppression.

Basiliximab induction treatment has been shown to reduce the incidence of acute rejection episodes without the secondary side effects observed with antilymphocyte polyclonal antibodies. We analyzed our experience with basiliximab induction associated with tacrolimus-based immunosuppression among low-immunological risk renal transplant recipients. We retrospectively analyzed 55 renal transplantation patients of low inmunological risk who received organs from donors younger than 55 years. We compared a group of 21 patients (38.9%; group 1) treated with basiliximab (Simulect, Novartis, Basel, Switzerland) with 33 patients (61.1%; group 2) without induction. The patient groups did not differ in recipient age (46.39 +/- 11.1 in group 1 vs 41.82 +/- 11.02 years in group 2; P = .25), donor age (36.71 +/- 14.72 vs 35.09 +/- 14.63 years; P = .69), or recipient and donor gender. No differences were observed in dose or tacrolimus levels during follow-up. The incidences of delayed graft function (DGF; 28.6% vs 28.1%; P = .97) and of acute rejection episodes (9.5% vs 15.6%; P = .52) were similar in both groups. Serum creatinine and proteinuria levels (P > .05) and hospital admissions due to infections (36.4 vs 35.7%; P = .97) were also similar in both groups. At 1 year graft survival rates were 92% and 96% (P = .97) in groups 1 and 2, respectively. Considering our findings and the costs of basiliximab treatment, we conclude that routine administration of basiliximab cannot be justified in young, low-immunological risk transplant recipients undergoing tacrolimus-based immunosuppression.

Induction treatment with low-dose thymoglobulin or basiliximab in renal transplants from older donors.

Transplantation of kidneys from older donors is followed by an increase in delayed graft function (DGF) and acute rejection episodes (ARE). In these circumstances, induction treatment, whether with antithymocyte globulin or with interleukin-2 receptor blockers, may delay the introduction of calcineurin inhibitors (CNI) with effective prevention of ARE. We examined the efficacy and safety of induction treatment with 2 low doses of thymoglobulin compared with 2 doses of basiliximab. A group of 27 patients were treated with thymoglobulin and another 36 with basiliximab. CNI introduction was delayed until day 3 posttransplantation. The thymoglobulin group received 2 doses of 1.25 mg/kg on alternate days and the basiliximab group 2 doses of 20 mg. A trend to a lower incidence of DGF was observed in the thymoglobulin group (33% vs 55.6%; P = .08), with lower levels of serum creatinine on days 7 (P = .02) and 14 (P = .02) posttransplantation. No patient in the thymoglobulin group experienced ARE, but 11 patients (30.6%) in the basiliximab group did (P < .001), and 5 needed rescue treatment with thymoglobulin. We found no differences in the incidence of cytomegalovirus (CMV) disease (P = .945), admission due to infections (P = .274), or neoplasia (P = .340), or differences in graft (P = .69) and patient (P = .21) survivals at 1 and 3 years. Low-dose thymoglobulin was more effective at preventing DGF and ARE in renal transplant recipients of organs from older donors, with no differences in infectious complications or graft and patient survivals.