Fixed low dose versus concentration-controlled initial tacrolimus dosing with reduced target levels in the course after kidney transplantation: results from a prospective randomized controlled non-inferiority trial (Slow & Low study).

Background: Optimal initial tacrolimus dosing and early exposure of tacrolimus after renal transplantation is not well studied. Methods: In this open-label, 6 months, multicenter, randomized controlled, non-inferiority study, we randomly assigned 432 renal allograft recipients to receive basiliximab induction, mycophenolate and steroids and either standard prolonged-release tacrolimus (trough levels: 7-9 ng/ml; Standard Care arm), or an initial 7-day fixed 5 mg/day dose of prolonged-release tacrolimus followed by lower tacrolimus predose levels (trough levels: 5-7 ng/ml; Slow & Low arm). The primary end point was the combined incidence rate of biopsy-proven acute rejections (BPAR; including borderline), graft failure, or death at 6 months with a non-inferiority margin of 12.5%. (EudraCT-Nr: 2013-001770-19. Findings: The combined primary endpoint in the Slow & Low arm was non-inferior compared to the Standard Care arm (22.1% versus 20.7%; difference: 1.4%, 90% CI -5.5% to 8.3%). The overall rate of BPAR including borderlines was similar (Slow & Low 17.4% versus Standard Care 16.6%). Safety parameters such as delayed graft function, kidney function, donor specific HLA-antibodies, infections, or post-transplantation diabetes mellitus did not differ. Interpretation: This is the first study to show that an initial fixed dose of 5 mg per day followed by lower tacrolimus exposure is non-inferior compared to standard tacrolimus therapy and equally efficient and safe within 6 months after renal transplantation. These data suggest that therapeutic drug monitoring for prolonged release tacrolimus can be abandoned until start of the second week after transplantation. Funding: Investigator-initiated trial, financial support by Astellas Pharma GmbH.

Excellent efficacy and beneficial safety during observational 5-year follow-up of rapid steroid withdrawal after renal transplantation (Harmony FU study).

BACKGROUND: We previously reported excellent efficacy and improved safety aspects of rapid steroid withdrawal (RSWD) in the randomized controlled 1-year "Harmony" trial with 587 predominantly deceased-donor kidney transplant recipients randomized either to basiliximab or rabbit antithymocyte globulin induction therapy and compared with standard immunosuppressive therapy consisting of basiliximab, low tacrolimus once daily, mycophenolate mofetil and corticosteroids. METHODS: The 5-year post-trial follow-up (FU) data were obtained in an observational manner at a 3- and a 5-year visit only for those Harmony patients who consented to participate and covered clinical events that occurred from the second year onwards. RESULTS: Biopsy-proven acute rejection and death-censored graft loss rates remained low and independent of RSWD. Rapid steroid withdrawal was an independent positive factor for patient survival (adjusted hazard ratio 0.554, 95% confidence interval 0.314-0.976; P = .041).The reduced incidence of post-transplantation diabetes mellitus in RSWD patients during the original 1-year study period was not compensated by later incidences during FU. Incidences of other important outcome parameters such as opportunistic infections, malignancies, cardiovascular morbidity/risk factors, donor-specific antibody formation or kidney function did not differ during FU period. CONCLUSIONS: With all the limitations of a post-trial FU study, the Harmony FU data confirm excellent efficacy and beneficial safety aspects of RSWD under modern immunosuppressive therapy over the course of 5 years after kidney transplantation in an immunologically low-risk, elderly population of Caucasian kidney transplant recipients. Trial registration: Clinical trial registration number: Investigator Initiated Trial (NCT00724022, FU study DRKS00005786).

Kidney Autotransplantation in a 78-Year-Old Man with Proximal Ureteral Urothelial Carcinoma after Living Donor Nephrectomy.

Six years after living donor nephrectomy to his daughter, the 78-year-old donor presented to the emergency room with anuria for approximately 12 h. Only arterial hypertension, mildly reduced kidney function (eGFR 54 mL/min), and benign prostatic hyperplasia were known as preexisting medical conditions. In sonography, hydronephrosis III° was visible in the right single kidney. Ureterorenoscopy revealed an occlusive tumor in the right proximal ureter, which was treated via double J stent. Biopsy showed focal invasive papillary urothelial carcinoma of G2 high grade. Preoperative staging did not show any signs of lymph node or distant metastases. For therapeutic options, nephroureterectomy with consecutive need for dialysis was discussed versus partial ureteral resection with in situ ureteral reconstruction versus nephroureterectomy with partial ureteral resection and kidney autotransplantation. Eventually, laparoscopic right nephroureterectomy was performed with back-table preparation and tumor resection, followed by ipsilateral autotransplantation. The patient developed postsurgical acute kidney failure due to ischemia/reperfusion with a maximum serum Cr of 5.66 mg/dL (eGFR 10 mL/min), which quickly resolved. The papillary invasive urothelial carcinoma was graded pT1 pTis G2 high grade R0. Regular follow-ups showed no sign for cancer recurrence in computer tomography or cystoscopy; serum Cr was at 1.87 mg/dL (eGFR 53) 12 months after surgery.

Pericardectomy after pericarditis constrictiva led to onset of transplant kidney function after 98 days of anuric kidney graft: a case report.

BACKGROUND: Constrictive pericarditis is easily overlooked and can lead to severe problems in hemodynamics and end-organ perfusion, in our patient leading to 98 days of anuria after living kidney transplantation. This was completely reversible after pericardectomy. CASE PRESENTATION: A 43-year-old female caucasian patient received a living kidney donation from her mother. She had developed end-stage renal disease 2 years prior due to nephrotic syndrome linked to graft-versus-host disease after allogenic stem-cell transplantation for aplastic anemia. The graft showed insufficient function already in the early postoperative phase. Dialysis was paused after surgery, but the patient developed hypervolemia with ascites and edema in the lower extremities. Doppler ultrasonography showed scarce perfusion, with intrarenal arterial waveforms without end-diastolic flow. The venous perfusion profiles showed pulsatile retrograde flow. There was no identifiable reason for a primary vascular perfusion problem on ultrasonography or transplant kidney angiography. Kidney transplant biopsy revealed no rejection but extensive acute tubular necrosis. Three weeks after transplantation, the patient developed an acute anuric graft failure caused by severe cardiac decompensation. Echocardiography revealed a previously unnoticed constrictive pericarditis, which could be confirmed in a cardio computed tomography scan. The constrictive pericarditis had not been apparent on previous x-rays, computed tomography scans, or echocardiographies, including those for transplantation evaluation. Conservative management of the constrictive pericarditis was not successful and the graft remained anuric. Eventually, the patient underwent pericardectomy 16 weeks after kidney transplantation. Shortly after surgery, the graft started urine production again, which significantly increased within a few days. The clearance improved and 2 weeks later, the patient was free from dialysis. CONCLUSIONS: This case illustrates that special attention should be given to the pericardium during transplant evaluation, especially for patients who previously underwent stem-cell transplantations, chemotherapy or radiation.

Accuracy and concordance of measurement methods to assess non-adherence after renal transplantation - a prospective study.

BACKGROUND: Non-adherence (NA) to immunosuppressants (IS) among renal transplant recipients (RTRs) is associated with higher risk of allograft rejection, graft loss, and mortality. A precise measurement of NA is indispensable, although its prevalence differs greatly depending on the respective measurement methods. The objective of this study was to assess the accuracy and concordance of different measurement methods of NA in patients after renal transplantation. DESIGN AND METHODS: This was a single-center prospective observational study. At baseline (T0), NA was measured via physicians' estimates (PE), self-reports (SR), and tacrolimus trough level variability (CV%) in 78 RTRs. A Visual Analogue Scale (VAS, 0-100%) was applied both for SR and PE. In addition, we used BAASIS© for SR and a 5-point Likert scale for PE. NA was measured prospectively via electronic monitoring (EM, VAICA©) during a three month period. Meanwhile, all participants received phone calls in a two week interval (T1-T6) during which SRs were given. RESULTS: Seventy-eight RTRs participated in our study. At t0, NA rates of 6.4%, 28.6%, and 15.4% were found for PE, SR, and CV%, respectively. No correlation was found between these methods. During the study, the percentages of self-reported and electronically monitored adherence remained high, with a minimum mean of 91.2% for the strictest adherence measure (Timing Adherence ±30 min). Our results revealed a moderate to high association between SR and EM. In contrast to PE and CV%, SR significantly predicted electronically monitored adherence. Overall, a decreasing effect of electronically monitored adherence was found for both taking and timing adherence (±2 h, ±30 min) over the course of the study. DISCUSSION: The moderate to high concordance of SR and EM suggests that both methods measure NA equally accurately. SR seems to be a method that can adequately depict electronically monitored NA and may represent a good and economical instrument to assess NA in clinical practice. The increased adherence at the beginning of the study and its subsequent decrease suggests an intervention effect. Surveillance of IS intake via EM with intermittent phone calls could improve adherence on a short-term basis. To establish long-term effects, further research is necessary.

Rabbit-ATG or basiliximab induction for rapid steroid withdrawal after renal transplantation (Harmony): an open-label, multicentre, randomised controlled trial.

BACKGROUND: Standard practice for immunosuppressive therapy after renal transplantation is quadruple therapy using antibody induction, low-dose tacrolimus, mycophenolate mofetil, and corticosteroids. Long-term steroid intake significantly increases cardiovascular risk factors with negative effects on the outcome, especially post-transplantation diabetes associated with morbidity and mortality. In this trial, we examined the efficacy and safety parameters of rapid steroid withdrawal after induction therapy with either rabbit antithymocyte globulin (rabbit ATG) or basiliximab in immunologically low-risk patients during the first year after kidney transplantation. METHODS: In this open-label, multicentre, randomised controlled trial, we randomly assigned renal transplant recipients in a 1:1:1 ratio to receive either basiliximab induction with low-dose tacrolimus, mycophenolate mofetil, and steroid maintenance therapy (arm A), rapid corticosteroid withdrawal on day 8 (arm B), or rapid corticosteroid withdrawal on day 8 after rabbit ATG (arm C). The study was done in 21 centres across Germany. Only participants aged between 18 and 75 years with a low immunological risk who were scheduled to receive a single-organ renal transplant from either a living donor or a deceased donor were considered for enrolment. Patients receiving a second renal transplant were eligible, provided that the first allograft was not lost due to acute rejection within the first year after transplantation. Donor and recipient had to be ABO compatible. Grafts with pre-transplant existing donor-specific human leukocyte antigen (HLA) antibodies were not eligible and the recipients had to have a panel-reactive antibody concentration of 30% or less. Pregnant women and nursing mothers were excluded from the study. The primary endpoint was the incidence of biopsy-proven acute rejection (BPAR) at 12 months. All analyses were done by intention-to-treat. This trial is registered with ClinicalTrials.gov, number NCT00724022. FINDINGS: Between Aug 7, 2008, and Nov 30, 2013, 615 patients were randomly assigned to arm A (206), arm B (189), and arm C (192). BPAR rates were not reduced by rabbit ATG (9·9%) compared with either treatment arm A (11·2%) or B (10·6%; A versus C: p=0·75, B versus C p=0·87). As a secondary endpoint, rapid steroid withdrawal reduced post-transplantation diabetes in arm B to 24% and in arm C to 23% compared with 39% in control arm A (A versus B and C: p=0·0004). Patient survival (94·7% in arm A, 97·4% in arm B, and 96·9% in arm C) and censored graft survival (96·1% in arm A, 96·8% in arm B, and 95·8% in arm C) after 12 months were excellent and equivalent in all arms. Safety parameters such as infections or the incidence of post-transplantation malignancies did not differ between the study arms. INTERPRETATION: Rabbit ATG did not show superiority over basiliximab induction for the prevention of BPAR after rapid steroid withdrawal within 1 year after renal transplantation. Nevertheless, rapid steroid withdrawal after induction therapy for patients with a low immunological risk profile can be achieved without loss of efficacy and is advantageous in regard to post-transplantation diabetes incidence. FUNDING: Investigator Initiated Trial; financial support by Astellas Pharma GmbH, Sanofi, and Roche Pharma AG.

Treatment of antibody-mediated rejection including immunoadsorption during first year after renal transplantation--Clinical results and regulation of endothelial progenitor cells.

OBJECTIVE: Antibody-mediated rejection (AMR) is associated with poor allograft survival. Therefore, effective treatment strategies are required. Extracorporeal strategies are increasingly included in treatment of antibody-mediated rejection to eliminate the detrimental alloantibodies. Yet, other mechanisms contributing to the beneficial effect of apheresis besides the removal of antibodies are under consideration. METHODS: We retrospectively analyzed data of 427 transplant patients from 2006 to 2013 with special focus on occurrence, treatment - always including immunoadsorption - and 12-months outcome of antibody-mediated rejection. Besides, we prospectively monitored how the number and phenotype of endothelial progenitor cells in four patients experiencing antibody-mediated rejection changed during the treatment course of 6-20 sessions of immunoadsorption in comparison to seven patients subjected to immunoadsorption because of preparation for ABO-incompatible transplantation. RESULTS: 24 patients were diagnosed with acute AMR and treated with immunoadsorption resulting in patient and allograft survival of 100% and 87.5%, respectively. In patients with antibody-mediated rejection, the endothelial progenitor cell number after successful immunoadsorption therapy was always transiently decreased and the adhesive and migratory ability improved. This regulation of circulating endothelial precursor cells was not seen in patients undergoing repetitive immunoadsorptions before ABO-incompatible transplantation. CONCLUSION: Combined therapy with immunoadsorption allows a successful treatment of AMR. Treatment seems to be associated with a transient regulation of circulating endothelial precursor cells.

Severe metabolic alkalosis and recurrent acute on chronic kidney injury in a patient with Crohn's disease.

BACKGROUND: Diarrhea is common in patients with Crohn's disease and may be accompanied by acid base disorders, most commonly metabolic acidosis due to intestinal loss of bicarbonate. CASE PRESENTATION: Here, we present a case of severe metabolic alkalosis in a young patient suffering from M. Crohn. The patient had undergone multiple resections of the intestine and suffered from chronic kidney disease. He was now referred to our clinic for recurrent acute kidney injury, the nature of which was pre-renal due to profound volume depletion. Renal failure was associated with marked hypochloremic metabolic alkalosis which only responded to high volume repletion and high dose blockade of gastric hypersecretion. Intestinal failure with stomal fluid losses of up to 5.7 litres per day required port implantation to commence parenteral nutrition. Fluid and electrolyte replacement rapidly improved renal function and acid base homeostasis. CONCLUSIONS: This case highlights the important role of gastrointestinal function to maintain acid base status in patients with Crohn's disease.