Publications by authors named "Joke I Roodnat"

49 Publications

Risk of post-transplant cardiovascular events in kidney transplant recipients with preexisting aortoiliac stenosis.

Clin Transplant 2022 Jan 9;36(1):e14515. Epub 2021 Nov 9.

Erasmus MC Transplant Institute, Division HPB and Transplant Surgery, Department of Surgery, Erasmus MC, University Medical Center, Rotterdam, The Netherlands.

Prediction of the risk of cardiovascular events (CVE's) is important to optimize outcomes after kidney transplantation. Aortoiliac stenosis is frequently observed during pre-transplant screening. We hypothesized that these patients are at higher risk of post-transplant CVE's due to the joint underlying atherosclerotic disease. Therefore, we aimed to assess whether aortoiliac stenosis was associated with post-transplant CVE's. This retrospective, single-center cohort study included adult kidney transplant recipients, transplanted between 2000 and 2016, with contrast-enhanced imaging available. Aortoiliac stenosis was classified according to the Trans-Atlantic Inter-Society Consensus (TASC) II classification and was defined as significant in case of ≥50% lumen narrowing. The primary outcome was CVE-free survival. Eighty-nine of 367 patients had significant aortoiliac stenosis and were found to have worse CVE-free survival (median CVE-free survival: stenosis 4.5 years (95% confidence interval (CI) 2.8-6.2), controls 8.9 years (95% CI 6.8-11.0); log-rank test P < .001). TASC II C and D lesions were independent risk factors for a post-transplant CVE with a hazard ratio of 2.15 (95% CI 1.05-4.38) and 6.56 (95% CI 2.74-15.70), respectively. Thus, kidney transplant recipients with TASC II C and D aortoiliac stenosis require extensive cardiovascular risk management pre-, peri,- and post-transplantation.
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http://dx.doi.org/10.1111/ctr.14515DOI Listing
January 2022

To screen or not to screen? The development of a prediction model for aorto-iliac stenosis in kidney transplant candidates.

Transpl Int 2021 Nov 12;34(11):2371-2381. Epub 2021 Sep 12.

Division of HPB and Transplant Surgery, Department of Surgery, Erasmus MC Transplant Institute, Erasmus MC University Medical Center, Rotterdam, The Netherlands.

Screening for aorto-iliac stenosis is important in kidney transplant candidates as its presence affects pre-transplantation decisions regarding side of implantation and the need for an additional vascular procedure. Reliable imaging techniques to identify this condition require contrast fluid, which can be harmful in these patients. To guide patient selection for these imaging techniques, we aimed to develop a prediction model for the presence of aorto-iliac stenosis. Patients with contrast-enhanced imaging available in the pre-transplant screening between January 1st, 2000 and December 31st, 2018 were included. A prediction model was developed using multivariable logistic regression analysis and internally validated using bootstrap resampling. Model performance was assessed with the concordance index and calibration slope. Three hundred and seventy-three patients were included, 90 patients (24.1%) had imaging-proven aorto-iliac stenosis. Our final model included age, smoking, peripheral arterial disease, coronary artery disease, a previous transplant, intermittent claudication and the presence of a femoral artery murmur. The model yielded excellent discrimination (optimism-corrected concordance index: 0.83) and calibration (optimism-corrected calibration slope: 0.91). In conclusion, this prediction model can guide the development of standardized protocols to decide which patients should receive vascular screening to identify aorto-iliac stenosis. External validation is needed before this model can be implemented in patient care.
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http://dx.doi.org/10.1111/tri.14013DOI Listing
November 2021

Alemtuzumab as Second-Line Treatment for Late Antibody-Mediated Rejection of Transplanted Kidneys.

Transplant Proc 2021 Sep 8;53(7):2206-2211. Epub 2021 Aug 8.

Nephrology and Transplantation, Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands.

Whether the anti-CD52 monoclonal antibody alemtuzumab can be an effective treatment option for late antibody-mediated rejection (ABMR) is not known. In a single-center pilot study, 12 patients with late ABMR were given 30 mg subcutaneous alemtuzumab.Median time from transplantation to biopsy was 22 months with 10 of 12 recipients fulfilling criteria for the histologic diagnosis chronic-active ABMR. The estimated glomerular filtration rate (eGFR) loss before diagnosis was 1.2 mL/min/mo with graft loss (eGFR <15 mL/min) expected to occur within 2 years in 11 of 12 cases. All recipients showed no or an inadequate response to initial treatment with steroids and intravenous immunoglobulin. eGFR at time of alemtuzumab administration was 35 mL/min/1.73 m (IQR, 30-42) and stabilized or improved in 10 of 12 recipients within 12 months. Proteinuria was stable in the year after alemtuzumab. At 3-year follow-up, the death-censored graft survival was 68% (uncensored graft survival was 58%). Five cases of 10 cases that could be evaluated at 3-year follow-up had stable eGFR (on average 44 mL/min at 12 months and 42 mL/min at 36 months). Alemtuzumab was generally well tolerated and only 2 cases of opportunistic infections were noted. One case of symptomatic parvovirus B infection and 1 case of BK viral infection occurred, which both cleared at follow-up. In conclusion, alemtuzumab may be of value as a second-line treatment for late ABMR with rapid loss of eGFR.
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http://dx.doi.org/10.1016/j.transproceed.2021.07.005DOI Listing
September 2021

Herpes Zoster in Solid Organ Transplantation: Incidence and Risk Factors.

Front Immunol 2021 18;12:645718. Epub 2021 Mar 18.

Department of Internal Medicine-Nephrology and Transplantation, Erasmus MC, University Medical Centre Rotterdam, Rotterdam, Netherlands.

Background: Studies on herpes zoster (HZ) incidence in solid organ transplant (SOT) recipients report widely varying numbers. We investigated HZ incidence, severity, and risk factors in recipients of four different SOTs, with a follow-up time of 6-14 years.

Methods: Records of 1,033 transplant recipients after first heart (HTx: n = 211), lung (LuTx: n = 121), liver (LiTx: n = 258) and kidney (KTx: n = 443) transplantation between 2000 and 2014 were analyzed for VZV-PCR, clinical signs of HZ, and complications.

Results: HZ was diagnosed in 108 of 1,033 patients (10.5%): 36 HTx, 17 LuTx, 15 LiTx, and 40 KTx recipients. Overall HZ incidence rate after HTx (30.7 cases/1,000 person-years (PY)), LuTx (38.8 cases/1,000 PY), LiTx (22.7 cases/1,000 PY) and KTx (14.5 cases/1,000 PY) was significantly higher than in the general 50-70 year population. Multivariable analysis demonstrated age ≥50 years at transplantation (p = 0.038, RR 1.536), type of organ transplant (overall p = 0.002; LuTx p = 0.393; RR 1.314; LiTx p = 0.011, RR 0.444; KTx p = 0.034, RR 0.575), CMV prophylaxis (p = 0.043, RR 0.631) and type of anti-rejection therapy (overall p = 0.020; methylprednisolone p = 0.008, RR 0.475; r-ATG p = 0.64, RR1.194) as significant risk factors. Complications occurred in 33 of 108 (31%) patients (39% of HTx, 47% of LuTx, 20% of LiTx, 20% of KTx): post-herpetic neuralgia, disseminated disease, and cranial nerve involvement.

Conclusion: HZ incidence and severity in SOT recipients are most pronounced after heart and lung transplantation, in older patients, and when CMV prophylaxis is lacking.
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http://dx.doi.org/10.3389/fimmu.2021.645718DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8012754PMC
September 2021

Delayed graft function and rejection are risk factors for cytomegalovirus breakthrough infection in kidney transplant recipients.

Pharmacol Res 2021 05 17;167:105565. Epub 2021 Mar 17.

Department of Clinical Pharmacy and Toxicology, Leiden University Medical Center, Postbus 9600, 2300 RC Leiden, The Netherlands.

Breakthrough cytomegalovirus (CMV) disease during valganciclovir prophylaxis is rare but may cause significant morbidity and even mortality. In order to identify patients at increased risk the incidence of CMV disease was studied in a large population of renal transplant recipients who underwent a kidney transplantation in the Radboud University Medical Center between 2004 and 2015 (n = 1300). CMV disease occurred in 31/1300 patients. Multivariate binary linear regression analysis showed that delayed graft function (DGF) (p = 0.018) and rejection (p = 0.001) significantly and independently increased the risk of CMV disease, whereas CMV status did not. Valganciclovir prophylaxis was prescribed to 281/1300 (21.6%) high-risk patients (defined as CMV IgG-seronegative recipients receiving a kidney from a CMV IgG-seropositive donor (D+/R-)). Of these 281 patients, 51 suffered from DGF (18%). The incidence of breakthrough CMV disease in D + /R- patients with DGF was much higher than in those with immediate function (6/51 (11.8%) vs 2/230, (0.9%), p = 0.0006 Fisher's exact test), despite valganciclovir prophylaxis. This higher incidence of CMV disease could not be explained by a higher incidence of rejection (and associated anti-rejection treatment) in patients with DGF. D + /R- patients with DGF are at increased risk of developing CMV disease despite valganciclovir prophylaxis. These findings suggest that underexposure to ganciclovir occurs in patients with DGF. Prospective studies evaluating the added value of therapeutic drug monitoring to achieve target ganciclovir concentrations in patients with DGF are needed.
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http://dx.doi.org/10.1016/j.phrs.2021.105565DOI Listing
May 2021

Clinical outcome of kidney transplantation after bariatric surgery: A single-center, retrospective cohort study.

Clin Transplant 2021 03 9;35(3):e14208. Epub 2021 Jan 9.

Division of HPB and Transplant Surgery, Department of Surgery, Erasmus Medical Center, Rotterdam, The Netherlands.

Patients with class II and III obesity and end-stage renal disease are often ineligible for kidney transplantation (KTx) due to increased postoperative complications and technically challenging surgery. Bariatric surgery (BS) can be an effective solution for KTx candidates who are considered inoperable. The aim of this study is to evaluate outcomes of KTx after BS and to compare the outcomes to obese recipients (BMI ≥ 35 kg/m ) without BS. This retrospective, single-center study included patients who received KTx after BS between January 1994 and December 2018. The primary outcome was postoperative complications. The secondary outcomes were graft and patient survival. In total, 156 patients were included, of whom 23 underwent BS prior to KTx. There were no significant differences in postoperative complications. After a median follow-up of 5.1 years, death-censored graft survival, uncensored graft survival, and patient survival were similar to controls (log rank test p = .845, .659, and .704, respectively). Dialysis pre-transplantation (Hazard Ratio (HR) 2.55; 95%CI 1.03-6.34, p = .043) and diabetes (HR 2.41; 95%CI 1.11-5.22, p = .027) were independent risk factors for all-cause mortality. A kidney from a deceased donor was an independent risk factor for death-censored graft loss (HR 1.98; 95%CI 1.04-3.79, p = .038). Patients who received a KTx after BS have similar outcomes as obese transplant recipients.
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http://dx.doi.org/10.1111/ctr.14208DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8047925PMC
March 2021

Comparison of Alemtuzumab and Anti-thymocyte Globulin Treatment for Acute Kidney Allograft Rejection.

Front Immunol 2020 3;11:1332. Epub 2020 Jul 3.

Division of Nephrology and Transplantation, Department of Internal Medicine, Erasmus MC, University Medical Center, Rotterdam, Netherlands.

Rabbit anti-thymocyte globulin (rATG) is currently the treatment of choice for glucocorticoid-resistant, recurrent, or severe acute allograft rejection (AR). However, rATG is associated with severe infusion-related side effects. Alemtuzumab is incidentally given to kidney transplant recipients as treatment for AR. In the current study, the outcomes of patients treated with alemtuzumab for AR were compared with that of patients treated with rATG for AR. The patient-, allograft-, and infection-free survival and adverse events of 116 alemtuzumab-treated patients were compared with those of 108 patients treated with rATG for AR. Propensity scores were used to control for differences between the two groups. Patient- and allograft survival of patients treated with either alemtuzumab or rATG were not different [hazard ratio (HR) 1.14, 95%-confidence interval (CI) 0.48-2.69, = 0.77, and HR 0.82, 95%-CI 0.45-1.5, = 0.52, respectively). Infection-free survival after alemtuzumab treatment was superior compared with that of rATG-treated patients (HR 0.41, 95%-CI 0.25-0.68, < 0.002). Infusion-related adverse events occurred less frequently after alemtuzumab treatment. Alemtuzumab therapy may therefore be an alternative therapy for glucocorticoid-resistant, recurrent, or severe acute kidney transplant rejection.
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http://dx.doi.org/10.3389/fimmu.2020.01332DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7350932PMC
April 2021

Creating Options for Difficult-to-match Kidney Transplant Candidates.

Transplantation 2021 01;105(1):240-248

Department of Internal Medicine, Erasmus Medical Centre, Rotterdam, The Netherlands.

Background: Most transplantation centers recognize a small patient population that unsuccessfully participates in all available, both living and deceased donor, transplantation programs for many years: the difficult-to-match patients. This population consists of highly immunized and/or ABO blood group O or B patients.

Methods: To improve their chances, Computerized Integration of Alternative Transplantation programs (CIAT) were developed to integrate kidney paired donation, altruistic/unspecified donation, and ABO and HLA desensitization. To compare CIAT with reality, a simulation was performed, including all patients, donors, and pairs who participated in our programs in 2015-2016. Criteria for inclusion as difficult-to-match, selected-highly immunized (sHI) patient were as follows: virtual panel reactive antibody >85% and participating for 2 years in Eurotransplant Acceptable Mismatch program. sHI patients were given priority, and ABO blood group incompatible (ABOi) and/or HLA incompatible (HLAi) matching with donor-specific antigen-mean fluorescence intensity (MFI) <8000 were allowed. For long-waiting blood group O or B patients, ABOi matches were allowed.

Results: In reality, 90 alternative program transplantations were carried out: 73 compatible, 16 ABOi, and 1 both ABOi and HLAi combination. Simulation with CIAT resulted in 95 hypothetical transplantations: 83 compatible (including 1 sHI) and 5 ABOi combinations. Eight sHI patients were matched: 1 compatible, 6 HLAi with donor-specific antigen-MFI <8000 (1 also ABOi), and 1 ABOi match. Six/eight combinations for sHI patients were complement-dependent cytotoxicity cross-match negative.

Conclusions: CIAT led to 8 times more matches for difficult-to-match sHI patients. This offers them better chances because of a more favorable MFI profile against the new donor. Besides, more ABO compatible matches were found for ABOi couples, while total number of transplantations was not hampered. Prioritizing difficult-to-match patients improves their chances without affecting the chances of regular patients.
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http://dx.doi.org/10.1097/TP.0000000000003203DOI Listing
January 2021

The prognosis of kidney transplant recipients with aorto-iliac calcification: a systematic review and meta-analysis.

Transpl Int 2020 05 4;33(5):483-496. Epub 2020 Mar 4.

Division of HPB and Transplant Surgery, Department of Surgery, Erasmus MC University Medical Center, Rotterdam, The Netherlands.

The prognosis of kidney transplant recipients (KTR) with vascular calcification (VC) in the aorto-iliac arteries is unclear. We performed a systematic review and meta-analysis to investigate their survival outcomes. Studies from January 1st, 2000 until March 5th, 2019 were included. Outcomes for meta-analysis were patient survival, (death-censored) graft survival and delayed graft function (DGF). Twenty-one studies were identified, eight provided data for meta-analysis. KTR with VC had a significantly increased mortality risk [1-year: risk ratio (RR) 2.19 (1.39-3.44), 5-year: RR 2.28 (1.86-2.79)]. The risk of 1-year graft loss was three times higher in recipients with VC [RR 3.15 (1.30-7.64)]. The risk of graft loss censored for death [1-year: RR 2.26 (0.58-2.73), 3-year: RR 2.19 (0.49-9.82)] and the risk of DGF (RR 1.24, 95% CI 0.98-1.58) were not statistically different. The quality of the evidence was rated as very low. To conclude, the presence of VC was associated with an increased mortality risk and risk of graft loss. In this small sample size, no statistical significant association between VC and DGF or risk of death-censored graft loss could be demonstrated. For interpretation of the outcomes, the quality and sample size of the evidence should be taken into consideration.
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http://dx.doi.org/10.1111/tri.13592DOI Listing
May 2020

Living Donor Kidney Transplantation Should Be Promoted Among "Elderly" Patients.

Transplant Direct 2019 Oct 27;5(10):e496. Epub 2019 Sep 27.

Department of Internal Medicine, Section of Nephrology and Transplantation, Rotterdam Transplant Group, Erasmus MC, Rotterdam, the Netherlands.

Age criteria for kidney transplantation have been liberalized over the years resulting in more waitlisted elderly patients. What are the prospects of elderly patients on the waiting list?

Methods: Between 2000 and 2013, 2622 patients had been waitlisted. Waiting time was defined as the period between dialysis onset and being delisted. Patients were categorized according to age upon listing: <25; 25-44; 45-54; 55-64; and >64 years. Furthermore, the influence of ABO blood type and panel reactive antibodies on outflow patterns was studied.

Results: At the end of observation (November 2017), 1957 (75%) patients had been transplanted, 333 (13%) had been delisted without a transplantation, 271 (10%) had died, and 61 (2%) were still waiting. When comparing the age categories, outflow patterns were completely different. The percentage of patients transplanted decreased with increasing age, while the percentage of patients that had been delisted or had died increased with increasing age, especially in the population without living donor. Within 6 years, 93% of the population <25 years had received a (primarily living) donor kidney. In the populations >55 years, 39% received a living donor kidney, while >50% of patients without a living donor had been delisted/died. Multivariable analysis showed that the influence of age, ABO blood type, and panel reactive antibodies on outflow patterns was significant, but the magnitude of the influence of the latter 2 was only modest compared with that of age.

Conclusions: "Elderly" (not only >64 y but even 55-64 y) received a living donor kidney transplantation less often. Moreover, they cannot bear the waiting time for a deceased donor kidney, resulting in delisting without a transplant in more than half the population of patients without a living donor. Promoting living donor kidney transplantation is the only modification that improves transplantation and decreases delisting/death on the waiting list in this population.
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http://dx.doi.org/10.1097/TXD.0000000000000940DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6791595PMC
October 2019

Systematic Surgical Assessment of Deceased-Donor Kidneys as a Predictor of Short-Term Transplant Outcomes.

Eur Surg Res 2019 3;60(3-4):97-105. Epub 2019 Sep 3.

Division of Transplant Surgery, Department of Surgery, Erasmus MC, Rotterdam, The Netherlands.

Background: Short-term kidney graft dysfunction is correlated with complications and it is associated with a decreased long-term survival; therefore, a scoring system to predict short-term renal transplant outcomes is warranted.

Aim: The aim of this study is to quantify the impression of the organ procurement surgeon in correlation with the following kidney transplant outcomes: immediate graft function (IGF), delayed graft function (DGF), and primary nonfunction (PNF). Results are compared to factors associated with the 1-year outcome.

Methods: A regional prospective pilot study was performed using deceased-donor organ assessment forms to be filled out by procurement surgeons after procurement. Data were gathered on kidney temperature, perfusion, anatomy, atherosclerosis, and overall quality.

Results: Included were 90 donors who donated 178 kidneys, 166 of which were transplanted. Variables that were significantly more prevalent in the DGF-or-PNF group (n = 65) are: large kidney size (length, p = 0.008; width, p = 0.036), poor perfusion quality (p = 0.037), lower diuresis (p = 0.039), fewer hypotensive episodes (p = 0.003), and donation-after-circulatory-death donors (p = 0.017). Multivariable analysis showed that perfusion quality and kidney width significantly predicted the short-term outcome. However multivariable analysis of long-term outcomes showed that the first measured donor creatinine, kidney donor risk index, IGF vs. DGF+PNG, and kidney length predicted outcomes.

Conclusions: Results show that short-term graft function and 1-year graft function indeed are influenced by different variables. DGF and PNF occur more frequently in kidneys with poor perfusion and in larger kidneys. A plausible explanation for this is that these kidneys might be insufficiently washed out, or even congested, which may predispose to DGF. These kidneys would probably benefit most from reconditioning strategies, such as machine perfusion. A scoring system including these variables might aid in decision-making towards allocation and potential reconditioning strategies.
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http://dx.doi.org/10.1159/000501602DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6878746PMC
March 2020

Oxalate deposition in renal allograft biopsies within 3 months after transplantation is associated with allograft dysfunction.

PLoS One 2019 16;14(4):e0214940. Epub 2019 Apr 16.

Rotterdam Transplant Group, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands.

Background: Calcium oxalate (CaOx) deposition in the kidney may lead to loss of native renal function but little is known about the prevalence and role of CaOx deposition in transplanted kidneys.

Methods: In patients transplanted in 2014 and 2015, all for-cause renal allograft biopsies obtained within 3 months post-transplantation were retrospectively investigated for CaOx deposition. Additionally, all preimplantation renal biopsies obtained in 2000 and 2001 were studied.

Results: In 2014 and 2015, 388 patients were transplanted, of whom 149 had at least one for-cause renal biopsy. Twenty-six (17%) patients had CaOx deposition. In the population with CaOx deposition: Patients had significantly more often been treated with dialysis before transplantation (89 vs. 64%; p = 0.011); delayed graft function occurred more frequently (42 vs. 23%; p = 0.038); and the eGFR at the time of first biopsy was significantly worse (21 vs. 29 ml/min/1.73m2; p = 0.037). In a multivariate logistic regression analysis, eGFR at the time of first biopsy (OR 0.958, 95%-Cl: 0.924-0.993, p = 0.019), dialysis before transplantation (OR 4.868, 95%-Cl: 1.128-21.003, p = 0.034) and the time of first biopsy after transplantation (OR 1.037, 95%-Cl: 1.013-1.062, p = 0.002) were independently associated with CaOx deposition. Graft survival censored for death was significantly worse in patients with CaOx deposition (p = 0.018). In only 1 of 106 preimplantation biopsies CaOx deposition was found (0.94%).

Conclusion: CaOx deposition appears to be primarily recipient-derived and is frequently observed in for-cause renal allograft biopsies obtained within 3 months post-transplantation. It is associated with inferior renal function at the time of biopsy and worse graft survival.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0214940PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6467373PMC
December 2019

Impact of Aortoiliac Stenosis on Graft and Patient Survival in Kidney Transplant Recipients Using the TASC II Classification.

Transplantation 2019 10;103(10):2164-2172

Division of HPB and Transplant Surgery, Department of Surgery, Erasmus MC University Medical Center, Rotterdam, The Netherlands.

Background: Patients with end-stage renal disease and aortoiliac stenosis are often considered ineligible for kidney transplantation, although kidney transplantation has been acknowledged as the best therapy for end-stage renal disease. The clinical outcomes of kidney transplantation in patients with aortoiliac stenosis are not well-studied. This study aimed to assess the impact of aortoiliac stenosis on graft and patient survival.

Methods: This retrospective, single-center study included kidney transplant recipients transplanted between January 1, 2000, and December 31, 2016, who received contrast-enhanced imaging. Patients with aortoiliac stenosis were classified using the Trans-Atlantic Inter-Society Consensus (TASC) II classification and categorized as having TASC II A/B lesions or having TASC II C/D lesions. Patients without aortoiliac stenosis were functioning as controls.

Results: A total number of 374 patients was included in this study (n = 88 with TASC II lesions, n = 286 as controls). Death-censored graft survival was similar to the controls. Patient and uncensored graft survival was decreased in patients with TASC II C/D lesions (log-rank test P < 0.001). Patients with TASC II C/D lesions had a higher risk of 90-day mortality (hazard ratio, 3.96; 95% confidence interval, 1.12-14.04). In multivariable analysis, having a TASC II C/D lesion was an independent risk factor for mortality (hazard ratio, 3.25; 95% confidence interval, 1.87-5.67; P < 0.001). Having any TASC II lesion was not a risk factor for graft loss (overall P = 0.282).

Conclusions: Kidney transplantation in patients with TASC II A/B is feasible and safe without increased risk of perioperative mortality. TASC II C/D decreases patient survival. Death-censored graft survival is unaffected.
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http://dx.doi.org/10.1097/TP.0000000000002635DOI Listing
October 2019

The Efficacy of Rabbit Anti-Thymocyte Globulin for Acute Kidney Transplant Rejection in Patients Using Calcineurin Inhibitor and Mycophenolate Mofetil-Based Immunosuppressive Therapy.

Ann Transplant 2018 Aug 17;23:577-590. Epub 2018 Aug 17.

Department of Internal Medicine, Division of Nephrology and Transplantation, Erasmus MC, University Medical Center Rotterdam, Rotterdam Transplant Group, Rotterdam, Netherlands.

BACKGROUND T cell depleting antibody therapy with rabbit anti-thymocyte globulin (rATG) is the treatment of choice for glucocorticoid-resistant acute kidney allograft rejection (AR) and is used as first-line therapy in severe AR. Almost all studies investigating the effectiveness of rATG for this indication were conducted at the time when cyclosporine A and azathioprine were the standard of care. Here, the long-term outcome of rATG for AR in patients using the current standard immunosuppressive therapy (i.e., tacrolimus and mycophenolate mofetil) is described. MATERIAL AND METHODS Between 2002 to 2012, 108 patients were treated with rATG for AR. Data on kidney function in the year following rATG and long-term outcomes were collected. RESULTS Overall survival after rATG was comparable to overall survival of all kidney transplantation patients (P=0.10). Serum creatinine 1 year after rATG was 179 µmol/L (interquartile range (IQR) 136-234 µmol/L) and was comparable to baseline serum creatinine (P=0.22). Early AR showed better allograft survival than late AR (P=0.0007). In addition, 1 year after AR, serum creatinine was lower in early AR (157 mol/L; IQR 131-203) compared to late AR (216 mol/L; IQR 165-269; P<0.05). The Banff grade of rejection, kidney function at the moment of rejection, and reason for rATG (severe or glucocorticoid resistant AR) did not influence the allograft survival. CONCLUSIONS Treatment of AR with rATG is effective in patients using current standard immunosuppressive therapy, even in patients with poor allograft function. Early identification of AR followed by T cell depleting treatment leads to better allograft outcomes.
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http://dx.doi.org/10.12659/AOT.909646DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6248318PMC
August 2018

Antegrade Balloon Dilatation as a Treatment Option for Posttransplant Ureteral Strictures: Case Series of 50 Patients.

Exp Clin Transplant 2018 Apr;16(2):150-155

From the Department of of Surgery, Division of Transplant Surgery, Erasmus University Medical Center, Rotterdam, The Netherlands.

Objectives: The aim of this study was to investigate the effects of antegrade balloon dilatation on ureteral strictures that developed after kidney transplant.

Materials And Methods: The hospital databases of the Erasmus Medical Center (Rotterdam, The Netherlands) and the Academic Medical Center (Amsterdam, The Netherlands) were retrospectively screened for patients who underwent balloon dilatation after kidney transplant. Balloon dilatation was technically successful whenever it was able to pass the strictured segment with the guidewire followed by balloon inflation; the procedure was clinically successful if no further interventions (for example, surgical revision of the ureteroneocystostomy or prolonged double J placement) were necessary.

Results: Fifty patients (2.4%) of 2075 kidney transplant recipients underwent antegrade balloon dilatation because of urinary outflow obstruction. Median time between transplant and balloon dilatation was 3 months (range, 0-139 mo). In 43 patients (86%), balloon dilatation was technically successful. In the remaining 7 patients (14%), it was impossible to pass the strictured segment with the guidewire. In 20 of 43 patients (47%) having a technically successful procedure, the procedure was also clinically successful, with median follow-up after balloon dilatation of 35.5 months (range, 0-102 mo). We did not identify any patient or stricture characteristic that influenced the outcome of treatment.

Conclusions: Balloon dilatation is a good option for ureter stricture treatment after kidney transplant as it is minimal invasive and can prevent surgical exploration in almost 50% of cases.
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April 2018

A Successful Approach to Kidney Transplantation in Patients With Enteric (Secondary) Hyperoxaluria.

Transplant Direct 2017 Dec 8;3(12):e331. Epub 2017 Nov 8.

Division of Nephrology and Transplantation, Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands.

Background: Enteric hyperoxaluria due to malabsorption may cause chronic oxalate nephropathy and lead to end-stage renal disease. Kidney transplantation is challenging given the risk of recurrent calcium-oxalate deposition and nephrolithiasis.

Methods: We established a protocol to reduce plasma oxalic acid levels peritransplantation based on reduced intake and increased removal of oxalate. The outcomes of 10 kidney transplantation patients using this protocol are reported.

Results: Five patients received a living donor kidney and had immediate graft function. Five received a deceased donor kidney and had immediate (n = 1) or delayed graft function (n = 4). In patients with delayed graft function, the protocol was prolonged after transplantation. In 3 patients, our protocol was reinstituted because of late complications affecting graft function. One patient with high-output stoma and relatively low oxalate levels had lost her first kidney transplant because of recurrent oxalate depositions but now receives intravenous fluid at home on a routine basis 3 times per week to prevent dehydration. Patients are currently between 3 and 32 months after transplantation and all have a stable estimated glomerular filtration rate (mean, 51 ± 21 mL/min per 1.73 m). In 4 of 8 patients who underwent for cause biopsies after transplantation oxalate depositions were found.

Conclusions: This is the first systematic description of kidney transplantation in a cohort of patients with enteric hyperoxaluria. Common complications after kidney transplantation impact long-term transplant function in these patients. With our protocol, kidney transplantation outcomes were favorable in this population with unfavorable transplantation prospects and even previous unsuccessful transplants.
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http://dx.doi.org/10.1097/TXD.0000000000000748DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5828694PMC
December 2017

A high intrapatient variability in tacrolimus exposure is associated with poor long-term outcome of kidney transplantation.

Transpl Int 2016 Nov 28;29(11):1158-1167. Epub 2016 Jun 28.

Department of Internal Medicine, Erasmus MC, University Medical Centre, Rotterdam, The Netherlands.

Tacrolimus is a critical dose drug with a considerable intrapatient variability (IPV) in its pharmacokinetics. We investigated whether a high IPV in tacrolimus exposure is associated with adverse long-term renal transplantation outcomes. Tacrolimus IPV was calculated from predose concentrations measured between 6 and 12 months post-transplantation of 808 renal transplant recipients (RTRs) transplanted between 2000 and 2010. One hundred and eighty-eight (23.3%) patients reached the composite end point consisting of graft loss, late biopsy-proven rejection, transplant glomerulopathy, or doubling of serum creatinine concentration between month 12 and the last follow-up. The cumulative incidence of the composite end point was significantly higher in patients with high IPV than in patients with low IPV (hazard ratio: 1.41, 95% CI: 1.06-1.89; P = 0.019). After the adjustment for several factors, the higher incidence of the composite end point for RTRs with a high IPV remained statistically significant (hazard ratio: 1.42, 95% CI: 1.06-1.90; P = 0.019). Younger recipient age at transplantation, previous transplantation, worse graft function (at month 6 post-transplantation), and low mean tacrolimus concentration at 1 year post-transplantation were additional predictors for worse long-term transplant outcome. A high tacrolimus IPV is an independent risk factor for adverse kidney transplant outcomes that can be used as an easy monitoring tool to help identify high-risk RTRs.
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http://dx.doi.org/10.1111/tri.12798DOI Listing
November 2016

Increased risk of graft failure and mortality in Dutch recipients receiving an expanded criteria donor kidney transplant.

Transpl Int 2017 Jan;30(1):14-28

Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, The Netherlands.

Survival of expanded criteria donor (ECD) kidneys and their recipients has not been thoroughly evaluated in Europe. Therefore, we compared the outcome of ECD and non-ECD kidney transplantations in a Dutch cohort, stratifying by age and diabetes. In all first Dutch kidney transplants in recipients ≥18 years between 1995 and 2005, both relative risks (hazard ratios, HR) and adjusted absolute risk differences (RD) for ECD kidney transplantation were analysed. In 3062 transplantations [recipient age 49.0 (12.8) years; 20% ECD], ECD kidney transplantation was associated with graft failure including death [HR 1.62 (1.44-1.82)]. The adjusted HR was lower in recipients ≥60 years of age [1.32 (1.07-1.63)] than in recipients 40-59 years [1.71 (1.44-2.02) P = 0.12 for comparison with ≥60 years] and recipients 18-39 years [1.92 (1.42-2.62) P = 0.03 for comparison with ≥60 years]. RDs showed a similar pattern. In diabetics, the risks for graft failure and death were higher than in the nondiabetics. ECD kidney grafts have a poorer prognosis than non-ECD grafts, especially in younger recipients (<60 years), and diabetic recipients. Further studies and ethical discussions should reveal whether ECD kidneys should preferentially be allocated to specific subgroups, such as elderly and nondiabetic individuals.
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http://dx.doi.org/10.1111/tri.12863DOI Listing
January 2017

An Acute Cellular Rejection With Detrimental Outcome Occurring Under Belatacept-Based Immunosuppressive Therapy: An Immunological Analysis.

Transplantation 2016 05;100(5):1111-9

1 Department of Internal Medicine, Section Transplantation and Nephrology, Erasmus MC, University Medical Center, Rotterdam, the Netherlands. 2 Department of Clinical Genetics, Erasmus MC, University Medical Center, Rotterdam, the Netherlands. 3 Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, Leiden, the Netherlands. 4 Department of Pathology, Erasmus MC, University Medical Center, Rotterdam, the Netherlands.

Background: Belatacept has been associated with an increased acute rejection rate after kidney transplantation. This case report sheds light on the possible immunological mechanisms underlying this phenomenon by analyzing the immunological mechanisms in patient serum, peripheral blood mononuclear cells, rejected kidney tissue, and graft infiltrating cells.

Methods: A 61-year-old woman treated with belatacept, who received her first kidney transplant from her husband was admitted with an acute, vascular rejection 56 days after transplantation which necessitated a transplantectomy. Histology and immunohistochemistry were performed on biopsy and explant tissue. CD86 expression on peripheral monocytes was assessed. Using Ficoll density methods, peripheral blood, and graft infiltrating lymphocytes were isolated and phenotyped.

Results: The explant showed a vascular rejection (Banff ACR grade III) and a perivascular infiltrate mostly consisting of T cells. No evidence for antibody-mediated rejection was found. In contrast to the peripheral blood monocytes, CD86 was still expressed by part of the mononuclear cells in the explant.Isolated graft cells were mostly CCR7-CD45RO+ effector memory CD4 and CD8 T cells (60-70%). CD28-positive as CD28-negative T cells were present in the explant, showing a great IFN-γ production capacity and expressing granzyme B.

Conclusions: We postulate that this glucocorticoid-resistant cellular rejection occurring under belatacept was predominantly mediated by cytotoxic memory T cells, which are less susceptible to costimulatory blockade by belatacept, or resulted from incomplete CD80/86 blockade at the tissue level.
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http://dx.doi.org/10.1097/TP.0000000000001004DOI Listing
May 2016

A High Comorbidity Score Should Not be a Contraindication for Kidney Transplantation.

Transplantation 2016 Feb;100(2):400-6

1 Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands. 2 Department of General Surgery, Erasmus Medical Center, Rotterdam, The Netherlands.

Background: Currently, potential kidney transplant patients more often suffer from comorbidities. The Charlson Comorbidity Index (CCI) was developed in 1987 and is the most used comorbidity score. We questioned to what extent number and severity of comorbidities interfere with graft and patient survival. Besides, we wondered whether the CCI was best to study the influence of comorbidity in kidney transplant patients.

Methods: In our center, 1728 transplants were performed between 2000 and 2013. There were 0.8% cases with missing values. Nine pretransplant comorbidity covariates were defined: cardiovascular disease, cerebrovascular accident, peripheral vascular disease, diabetes mellitus, liver disease, lung disease, malignancy, other organ transplantation, and human immunodeficiency virus positivity. The CCI used was unadjusted for recipient age. The Rotterdam Comorbidity in Kidney Transplantation score was developed, and its influence was compared to the CCI. Kaplan-Meier analysis and multivariable Cox proportional hazards analysis, corrected for variables with a known significant influence, were performed.

Results: We noted 325 graft failures and 215 deaths. The only comorbidity covariate that significantly influenced graft failure censored for death was peripheral vascular disease. Patient death was significantly influenced by cardiovascular disease, other organ transplantation, and the total comorbidity scores. Model fit was best with the Rotterdam Comorbidity in Kidney Transplantation score compared to separate comorbidity covariates and the CCI. In the population with the highest comorbidity score, 50% survived more than 10 years.

Conclusions: Despite the negative influence of comorbidity, patient survival after transplantation is remarkably good. This means that even patients with extensive comorbidity should be considered for transplantation.
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http://dx.doi.org/10.1097/TP.0000000000000973DOI Listing
February 2016

Alternative Living Kidney Donation Programs Boost Genetically Unrelated Donation.

J Transplant 2015 2;2015:748102. Epub 2015 Sep 2.

Department of Internal Medicine, Erasmus MC, s-Gravendijkwal 230, 3015 CE Rotterdam, Netherlands.

Donor-recipient ABO and/or HLA incompatibility used to lead to donor decline. Development of alternative transplantation programs enabled transplantation of incompatible couples. How did that influence couple characteristics? Between 2000 and 2014, 1232 living donor transplantations have been performed. In conventional and ABO-incompatible transplantation the willing donor becomes an actual donor for the intended recipient. In kidney-exchange and domino-donation the donor donates indirectly to the intended recipient. The relationship between the donor and intended recipient was studied. There were 935 conventional and 297 alternative program transplantations. There were 66 ABO-incompatible, 68 domino-paired, 62 kidney-exchange, and 104 altruistic donor transplantations. Waiting list recipients (n = 101) were excluded as they did not bring a living donor. 1131 couples remained of whom 196 participated in alternative programs. Genetically unrelated donors (486) were primarily partners. Genetically related donors (645) were siblings, parents, children, and others. Compared to genetically related couples, almost three times as many genetically unrelated couples were incompatible and participated in alternative programs (P < 0.001). 62% of couples were genetically related in the conventional donation program versus 32% in alternative programs (P < 0.001). Patient and graft survival were not significantly different between recipient programs. Alternative donation programs increase the number of transplantations by enabling genetically unrelated donors to donate.
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http://dx.doi.org/10.1155/2015/748102DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4572426PMC
September 2015

Conversion from twice-daily to once-daily tacrolimus does not reduce intrapatient variability in tacrolimus exposure.

Ther Drug Monit 2015 Apr;37(2):262-9

*Department of Hospital Pharmacy, Clinical Pharmacology Unit; and †Department of Internal Medicine, Division of Nephrology and Renal Transplantation, Erasmus MC, University Medical Center, Rotterdam, The Netherlands.

Background: Intrapatient variability (IPV) in tacrolimus exposure is associated with renal allograft failure. The aim of this study was to investigate whether conversion from the twice-daily tacrolimus formulation (Tac-TD) to a once-daily formulation (Tac-OD) leads to a lower IPV in tacrolimus exposure.

Methods: Two hundred forty-seven stable renal transplant recipients were converted from Tac-TD to Tac-OD (Advagraf) on a 1:1-mg total daily dose basis. After conversion, patients were followed for 12 months and tacrolimus predose whole-blood concentrations (C0), serum creatinine, estimated glomerular filtration rate, and proteinuria were measured. These parameters were compared with those collected at all outpatient visits in the 12-month period (±3 months) before conversion (Tac-TD period). The IPV was calculated based on the dose-adjusted tacrolimus C0.

Results: The Tac-OD formulation provided an excellent graft survival (100%), a low acute rejection rate (0.8%), and good tolerability. Renal function remained stable: estimated glomerular filtration rate 48 (16-90) versus 46 (12-90) mL/min (P = 0.15) before and after conversion, respectively. After conversion to Tac-OD, mean C0 was significantly lower, decreasing from 5.7 ± 1.5 to 5.0 ± 1.5 ng/mL, corresponding to a 12% reduction (P < 0.01). Both drugs had similar IPVs (Tac-TD: 17.3% ± 1.6% versus Tac-OD: 16.4% ± 1.6%, P = 0.31).

Conclusions: Although conversion from Tac-TD to Tac-OD significantly reduces tacrolimus exposure as measured by C0 and seems safe, it does not reduce IPV in tacrolimus exposure.
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http://dx.doi.org/10.1097/FTD.0000000000000136DOI Listing
April 2015

Understanding the influence of ethnicity and socioeconomic factors on graft and patient survival after kidney transplantation.

Transplantation 2014 Nov;98(9):974-8

1 Department of Internal Medicine, Erasmus Medical Center Rotterdam, Rotterdam, The Netherlands. 2 Department of General Surgery, Erasmus Medical Center Rotterdam, Rotterdam, The Netherlands. 3 Address correspondence to: Mirjam Laging, M.Sc., Erasmus Medical Center, Room D408, PO Box 2040, 3000 CA Rotterdam, The Netherlands.

Background: Studies on the influence of socioeconomic factors and ethnicity on the results of kidney transplantation have led to various outcomes. In this study, we analyzed the influence of a combination of these factors on graft and patient survival in a population of kidney transplant recipients.

Methods: This retrospective study included all 1,338 patients who received a kidney transplant between 2000 and 2011 (825 living, 513 deceased donor transplantations). Both clinical and socioeconomic variables were studied. Clinical variables were recipient age, gender, ethnicity, original disease, maximum and current panel reactive antibodies, ABO blood type, retransplants, pretreatment, time on dialysis, comorbidity, transplant year, total number of HLA mismatches, donor type (living or deceased), age and gender, and calcineurin inhibitor treatment. Each recipient's postal code was linked to a postal code area information database to extract information on housing value, income, percentage non-Europeans in the area, and urbanization level.

Results: In multivariable analysis, graft survival censored for death was significantly influenced by recipient age, maximum panel reactive antibodies, HLA mismatches, donor type, donor age, and calcineurin inhibitor treatment. Patient survival was significantly influenced by recipient age, comorbidity, transplant year, and donor type. Socioeconomic factors and ethnicity did not have a significant influence on graft and patient survival.

Conclusions: Though ethnicity and socioeconomic factors do not influence survival after kidney transplantation, the favorable influence of living donor type is of paramount importance. As non-Europeans and patients with unfavorable socioeconomic variables less often receive a living donor kidney transplant, their survival may be unfavorable after all.
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http://dx.doi.org/10.1097/TP.0000000000000164DOI Listing
November 2014

Independent risk factors for urological complications after deceased donor kidney transplantation.

PLoS One 2014 7;9(3):e91211. Epub 2014 Mar 7.

Department of Surgery, Division of Transplant Surgery, Erasmus MC, University Medical Center, Rotterdam, the Netherlands.

Urological complications after kidney transplantation are mostly related to the ureteroneocystostomy, often requiring interventions with additional costs, morbidity and mortality. Our aim was to assess risk factors for urological complications in deceased donor kidney transplantation. Between January 2000 and December 2011, 566 kidney transplantations were performed with deceased donor kidneys. Recipients were divided in a group with, and a group without urological complications, defined as the need for a percutaneous nephrostomy catheter or surgical revision of the ureteroneocystostomy. Univariate and multivariate analyses were performed. Univariate analysis showed increased number of male donors (p = 0.041), male recipients (p = 0.002), pre-emptively transplanted recipients (p = 0.007), and arterial reconstructions (p = 0.004) in the group with urological complications. Less urological complications occurred in recipients on hemodialysis (p = 0.005). More overall surgical interventions (p<0.001), surgical site infections (p = 0.042), urinary tract infections (p<0.001) and lymphoceles (p<0.001) occurred in the group with urological complications. Multivariate analysis showed that male recipients (p = 0.010) and arterial reconstructions (p = 0.019) were independent risk factors. No difference was found between both groups in patient or graft survival. In conclusion, recipient male gender and arterial reconstruction are independent risk factors for urological complications after deceased donor kidney transplantation. Nevertheless, graft and recipient survival is not different between both groups.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0091211PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3946700PMC
February 2015

15-year follow-up of a multicenter, randomized, calcineurin inhibitor withdrawal study in kidney transplantation.

Transplantation 2014 Jul;98(1):47-53

1 Department of Internal Medicine, Erasmus Medical Centre Rotterdam, The Netherlands. 2 Department of Nephrology, Radboud University Medical Centre, Nijmegen, The Netherlands. 3 Department of Internal Medicine, Albert Schweitzer Hospital, Dordrecht, The Netherlands. 4 Dutch Transplantation Foundation, Leiden, The Netherlands. 5 Department of Nephrology University Medical Centre, Utrecht, The Netherlands. 6 Address correspondence to: J. I. Roodnat, M.D., Ph.D., Erasmus Medical Centre, Room D427, PO box 2040, 3000CA Rotterdam, The Netherlands.

Background: Calcineurin inhibitors (CNIs) are essential immunosuppressive drugs after renal transplantation. Because of nephrotoxicity, withdrawal has been a challenge since their introduction.

Methods: A randomized multicenter trial included 212 kidney patients transplanted between 1997 and 1999. All patients were initially treated with mycophenolate mofetil (MMF), cyclosporine A (CsA), and prednisone (pred). At 6 months after transplantation, 63 patients were randomized for MMF/pred, 76 for MMF/CsA, and 73 for MMF/CsA/pred. Within 18 months after randomization 23 patients experienced a rejection episode: MMF/pred (27.0%), MMF/CsA (6.8%) and MMF/CsA/pred (1.4%) (P<0.001).

Results: During 15 years of follow-up, 73 patients died with a functioning graft, and 43 patients lost their graft. Ninety-six were alive with a functioning graft. Intention-to-treat analysis did not show a significant difference in patient and graft survival. In multivariate analysis, death-censored graft survival was significantly associated with serum creatinine at 6 months after transplantation and maximum PRA but not with the randomization group. CNI withdrawal did not result in a reduced incidence of or death by malignancy or cardiovascular disease. Death-censored graft survival was significantly worse in those patients randomized for CNI withdrawal that had to be reverted to CNI. Independent of randomization group, compared with no rejection, death-censored graft survival was significantly worse in 23 patients with acute rejection after randomization.

Conclusion: Fifteen years after conversion to a CNI free regimen, there was no benefit regarding graft and patient survival or regarding prevalence of or death by comorbidities. However, rejection shortly after CNI withdrawal was associated with decreased graft survival.
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http://dx.doi.org/10.1097/01.TP.0000442774.46133.71DOI Listing
July 2014

Transplantation results of completely HLA-mismatched living and completely HLA-matched deceased-donor kidneys are comparable.

Transplantation 2014 Feb;97(3):330-6

1 Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands. 2 Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, Leiden, The Netherlands. 3 Department of General Surgery, Erasmus Medical Center, Rotterdam, The Netherlands. 4 Address correspondence to: Mirjam Laging, M.Sc., Department of Internal Medicine, Erasmus Medical Center, Room D408, P.O. Box 2040, 3000 CA Rotterdam, The Netherlands.

Background: Human leukocyte antigen (HLA) mismatches are known to influence graft survival in deceased-donor kidney transplantation. We studied the effect of HLA mismatches in a population of recipients of deceased-donor or living-donor kidney transplantations.

Methods: All 1998 transplantations performed in our center between 1990 and 2011 were included in this retrospective cohort study. Four different multivariable Cox proportional hazard analyses were performed with HLA mismatches as continuous variable, as categorical variable (total number of HLA mismatches), as binary variable (zero vs. nonzero HLA mismatches), and HLA-A, -B, and -DR mismatches included separately.

Results: Nine hundred ninety-one patients received a deceased-donor kidney and 1007 received a living-donor kidney. In multivariable Cox analysis, HLA mismatches, recipient age, current panel-reactive antibodies, transplant year, donor age, calcineurin inhibitor treatment, and donor type were found to have a significant and independent influence on the risk of graft failure, censored for death. Variables representing the total number of HLA-A, -B, and -DR mismatches had a significant and comparable influence in all analyses.

Conclusions: The influence of HLA mismatches on death-censored graft survival holds true for both deceased- and living-donor kidney transplantation. However, the relative risk of death-censored graft failure of a 2-2-2 mismatched living-donor kidney is comparable with that of a 0-0-0 mismatched deceased-donor kidney.
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http://dx.doi.org/10.1097/01.TP.0000435703.61642.43DOI Listing
February 2014

Genetic variants of FOXP3 influence graft survival in kidney transplant patients.

Hum Immunol 2013 Jun 28;74(6):751-7. Epub 2013 Feb 28.

Department of Internal Medicine, Transplantation Laboratory, Erasmus University Medical Center, Rotterdam, The Netherlands.

FOXP3(+) regulatory T cells (Treg) play a role in controlling alloreactivity. It has been shown that short (GT)n dinucleotide repeats (≤(GT)15; S) in the promoter region of the FOXP3 gene enhance the promoter activity when compared to long (GT)n repeats (≥(GT)16; L). The present study retrospectively investigated the influence of this (GT)n FOXP3 gene polymorphism on renal allograft survival. A total of 599 consecutive first-time kidney transplant patients (median follow-up time 7.7 years) were subdivided according to their FOXP3 genotype into the S-genotype group (SG) and the L-genotype group (LG). The SG was superior to the LG in both general graft survival censored for death (logrank test, p=0.013) and graft survival following acute rejection (p=0.021). Multivariate analysis defined the (GT)n FOXP3 dinucleotide repeat polymorphism as an independent factor and confirmed an advantage for the SG in renal allograft survival (HR=0.67, 95% CI 0.48-0.94, p=0.02). This gene association study identified a beneficial effect of FOXP3 genetic variants on graft survival in kidney transplant patients.
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http://dx.doi.org/10.1016/j.humimm.2013.02.008DOI Listing
June 2013

Long-term outcome of kidney transplantation in patients with a urinary conduit: a case-control study.

Int Urol Nephrol 2013 Apr 14;45(2):405-11. Epub 2013 Feb 14.

Department of Surgery, Division of Transplant Surgery, Erasmus MC, University Medical Center, H-822 k, PO BOX 2040, 3000 CA, Rotterdam, The Netherlands.

Purpose: To study the short- and long-term outcomes of kidney transplantation in patients with a bladder augmentation or urinary diversion compared to patients with a kidney transplantation in a normal functional bladder.

Patients And Methods: Between January 2000 and March 2011, 13 patients received 16 grafts into a reconstructed urinary tract. We performed a retrospective case-control study and matched each patient to 4 controls for donor and recipient gender and year of transplantation.

Results: Short- and long-term complications of kidney transplantation occurred in 12 patients, varying from urinary tract infections to medical hospitalization with or without surgical or radiological intervention. In 5 patients, a percutaneous nephrostomy (PCN) was placed followed by surgical re-intervention. In three patients, the grafts failed as a result of chronic rejection and were re-transplanted. There was no graft loss as a result of surgical complications or the reconstructed urinary tract. One-year patient and graft survival was 100 %. After five years, all patients were alive and seven of nine grafts (77.8 %) were functioning. Mean follow-up time was 4.3 years. Among the controls, 55 grafts were transplanted in 52 patients. Ten patients received a PCN. Five patients needed surgical re-intervention. In three patients, transplantectomy was performed for ongoing rejection. Three patients were re-transplanted. One patient had a failing graft 7.5 years post-transplantation and became dialysis dependent.

Conclusion: Kidney transplantation in patients with a reconstructed urinary tract has an increased complication rate. Nevertheless, the long-term results are comparable to patients with a normal urinary bladder.
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http://dx.doi.org/10.1007/s11255-013-0395-1DOI Listing
April 2013

Living donor kidney transplantation among ethnic minorities in the Netherlands: a model for breaking the hurdles.

Patient Educ Couns 2013 Jan 30;90(1):118-24. Epub 2012 Aug 30.

Erasmus MC, Department of Medical Psychology, Rotterdam, The Netherlands.

Objective: Despite living donor kidney transplantation (LDKT) being the optimal treatment option for patients with end-stage renal disease, we observed a significant inequality in the number of LDKT performed between patients of Dutch versus non-Dutch descent. We conducted a focus group study to explore modifiable hurdles to LDKT.

Methods: Focus group discussions and in-depth interviews were conducted among 50 end-stage renal patients. Analyses were conducted according to 'grounded theory' using Atlas.ti.

Results: We found nearly all patients to be in favor of LDKT (96%). However, multiple factors played a role in considering LDKT. Four potentially modifiable hurdles were derived: (1) inadequate patient education, (2) impeding cognitions and emotions, (3) restrictive social influences, and (4) suboptimal communication. With regard to solutions, we found that our patients were open to home-based group education on renal replacement therapy options (88% in favor).

Conclusion: The study highlights the need for sensitivity and awareness of the influence of cultural factors on decision-making when discussing living donation with culturally diverse populations.

Practice Implications: Since the majority of our patients were open to a tailored group education in their own homes, we see this as an opportunity to address factors that influence equality in access to LDKT.
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http://dx.doi.org/10.1016/j.pec.2012.08.004DOI Listing
January 2013

The functional polymorphism Ala258Ser in the innate receptor gene ficolin-2 in the donor predicts improved renal transplant outcome.

Transplantation 2012 Sep;94(5):478-85

Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, Leiden, the Netherlands.

Background: Innate immunity plays a role in controlling adaptive immune responses.

Methods: We investigated the clinical relevance of single nucleotide polymorphisms in 22 genes encoding innate, secreted, and signaling pattern recognition receptors in a total of 520 donor-recipient pairs of postmortem, human leukocyte antigen-DR-compatible kidney transplantations. Associations with rejection incidence were tested in an a priori randomized training set and validation set.

Results: Polymorphisms in TLR-3 (rs3775296) in the recipients and in ficolin-2 (rs7851696; Ala258Ser) and C1qR1 (rs7492) in the donors showed the strongest association with severe rejection. In multivariate analysis, presence of the ficolin-2 Ala258Ser variant in the donor predicted lower incidence of severe rejection (odds ratio=0.3; 95% confidence interval, 0.1-0.9; P=0.024) and of graft loss (hazard ratio=0.5; 95% confidence interval, 0.2-1.0; P=0.046) independently of clinical risk factors. Ficolin-2 messenger RNA expression was detected in pretransplantation biopsies from 69 donor grafts. Serum and tissue ficolin-2 levels were unaffected by genotype. Ficolin-2 protein, which bound to dying cells, was detected in donor kidneys in a passenger leukocyte-like pattern. Indeed, monocytes, monocyte-derived macrophages, and peripheral blood mononuclear cells expressed ficolin-2. Donor grafts with the ficolin-2 Ala258Ser variant contained significantly elevated expression of interleukin 6, having ascribed cytoprotective effects. It has been described that Ala258Ser leads to increased binding capacity of ficolin-2 to N-acetylglucosamine.

Conclusions: Presence of the ficolin-2 Ala258Ser polymorphism in the donor independently predicts improved graft outcome. Based on mechanistic data, we propose that this functional polymorphism leads to more efficient handling of injured cells by phagocytozing cells, resulting in decreased intragraft exposure to danger signals and dampened alloimmune responses.
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http://dx.doi.org/10.1097/TP.0b013e31825c5967DOI Listing
September 2012
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