Publications by authors named "Klemens Budde"

326 Publications

Does the Side Matter? A Retrospective Cohort Study Comparing Left and Right Pure Laparoscopic Donor Nephrectomies.

Urol Int 2021 Aug 6:1-9. Epub 2021 Aug 6.

Department of Nephrology, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humbold-Universität zu Berlin, Berlin Institute of Health, Berlin, Germany.

Objectives: Right laparoscopic donor nephrectomy (RLDN) is no longer regarded inferior to left LDN (LLDN). However, this knowledge is based on many studies suffering from inherent learning curves, center-specific imbalances, and different laparoscopic techniques.

Methods: Pure LDNs at a high-volume referral center from 2011 to 2016 were retrospectively analyzed. Patient, graft characteristics, outcomes of LDNs, and corresponding open kidney transplantations were compared between LLDN and RLDN including a follow-up.

Results: 160 (78.4%) LLDNs and 44 (21.6%) RLDNs only differed regarding graft characteristics, as more right grafts had multiple veins (34.1 vs. 6.9%, p < 0.001) and worse scintigraphic function (44 vs. 51%, p < 0.001). RLDNs were shorter (201 vs. 220 min, p = 0.032) with longer warm ischemia time (165 vs. 140 s, p < 0.001), but left grafts were transplanted faster (160 vs. 171 min, p = 0.048). Recipients of right kidneys had more postoperative complications (grade 3: 25.6 vs. 11.3%, p = 0.020). At a follow-up of 45 (range 6-79) months, neither the kidney function, nor death-censored graft (5-year: LLDN 89 vs. 92%, p = 0.969) and patient survival (5-year: LLDN 95 vs. 98%, p = 0.747) differed.

Conclusions: Pure LLDN and RLDN can have different outcomes at high-volume centers, especially higher complications for recipients of right grafts. However, long-term function and graft survival are the same irrespective of the chosen side.
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http://dx.doi.org/10.1159/000517882DOI Listing
August 2021

Sirolimus in renal transplant recipients with malignancies in Germany.

Clin Kidney J 2021 Sep 14;14(9):2047-2058. Epub 2020 Dec 14.

Department of Medicine IV, University Hospital of Munich, Munich, Germany.

Background: Renal transplant recipients have an increased cancer risk. The mammalian target of rapamycin inhibitor sirolimus (SRL) has immunosuppressive and antitumour activities but knowledge about its use in recipients with cancer is limited.

Methods: We retrospectively analysed 726 renal allograft recipients converted to SRL from 10 German transplant centres. Patient and graft survival were analysed depending on malignancy status prior to conversion and tumour entity.

Results: Malignancy before conversion to SRL was reported in 230 patients, with 137 patients having skin cancers and 101 having solid cancers. Cancer occurred 4.6 ± 9.4 (median 3.0) years after transplantation. Basal cell carcinoma, squamous cell carcinoma and Bowen's disease were the most prevalent skin cancers, while carcinomas of the kidney, colon and breast were the most prevalent solid cancers before conversion. Patients with prior malignancy were older and had better renal function at conversion compared with patients without a history of cancer. After conversion to SRL, cancer incidence rates (IRs) of all tumours were lower compared with rates before conversion. Cancer IRs after conversion were higher in patients with malignancy before conversion compared with those without. Patient survival was worse in patients with solid cancers compared with patients with skin cancers or without malignancies. Biopsy-proven acute rejections in the first year after conversion were less frequent in patients with malignancy compared with those without. Graft survival and renal function in all cancer types were better than in patients converted to SRL without cancers.

Conclusions: Conversion to SRL in patients with a history of cancer is safe regarding renal function and graft survival, while patient survival is largely dependent on tumour entity.
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http://dx.doi.org/10.1093/ckj/sfaa262DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8406058PMC
September 2021

Low-dose rapamycin does not impair vascular integrity and tubular regeneration after kidney transplantation in rats.

Sci Rep 2021 Aug 11;11(1):16270. Epub 2021 Aug 11.

Department of Nephrology and Critical Care Medicine, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany.

mTOR inhibitors offer advantages after kidney transplantation including antiviral and antitumor activity besides facilitating low calcineurin inhibitor exposure to reduce nephrotoxicity. Concerns about adverse effects due to antiproliferative and antiangiogenic properties have limited their clinical use particularly early after transplantation. Interference with vascular endothelial growth factor (VEGF)-A, important for physiologic functioning of renal endothelial cells and tubular epithelium, has been implicated in detrimental renal effects of mTOR inhibitors. Low doses of Rapamycin (loading dose 3 mg/kg bodyweight, daily doses 1.5 mg/kg bodyweight) were administered in an allogenic rat kidney transplantation model resulting in a mean through concentration of 4.30 ng/mL. Glomerular and peritubular capillaries, tubular cell proliferation, or functional recovery from preservation/reperfusion injury were not compromised in comparison to vehicle treated animals. VEGF-A, VEGF receptor 2, and the co-receptor Neuropilin-1 were upregulated by Rapamycin within 7 days. Rat proximal tubular cells (RPTC) responded in vitro to hypoxia with increased VEGF-A and VEGF-R1 expression that was not suppressed by Rapamycin at therapeutic concentrations. Rapamycin did not impair proliferation of RPTC under hypoxic conditions. Low-dose Rapamycin early posttransplant does not negatively influence the VEGF network crucial for recovery from preservation/reperfusion injury. Enhancement of VEGF signaling peritransplant holds potential to further improve outcomes.
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http://dx.doi.org/10.1038/s41598-021-95790-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8358014PMC
August 2021

Impact of Early Pancreatic Graft Loss on Outcome after Simultaneous Pancreas-Kidney Transplantation (SPKT)-A Landmark Analysis.

J Clin Med 2021 Jul 22;10(15). Epub 2021 Jul 22.

Department of Nephrology and Medical Intensive Care, Charité-Universitätsmedizin Berlin, 10117 Berlin, Germany.

(1) Background: Simultaneous pancreas-kidney transplantation (SPKT) is a standard therapeutic option for patients with diabetes mellitus type I and kidney failure. Early pancreas allograft failure is a complication potentially associated with worse outcomes. (2) Methods: We performed a landmark analysis to assess the impact of early pancreas graft loss within 3 months on mortality and kidney graft survival over 10 years. This retrospective single-center study included 114 adult patients who underwent an SPKT between 2005 and 2018. (3) Results: Pancreas graft survival rate was 85.1% at 3 months. The main causes of early pancreas graft loss were thrombosis (6.1%), necrosis (2.6%), and pancreatitis (2.6%). Early pancreas graft loss was not associated with reduced patient survival ( = 0.168) or major adverse cerebral or cardiovascular events over 10 years ( = 0.741) compared to patients with functioning pancreas, after 3 months. Moreover, kidney graft function ( = 0.494) and survival ( = 0.461) were not significantly influenced by early pancreas graft loss. (4) Conclusion: In this study, using the landmark analysis technique, early pancreas graft loss within 3 months did not significantly impact patient or kidney graft survival over 10 years.
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http://dx.doi.org/10.3390/jcm10153237DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8347953PMC
July 2021

Early Postoperative Basal Insulin Therapy versus Standard of Care for the Prevention of Diabetes Mellitus after Kidney Transplantation: A Multicenter Randomized Trial.

J Am Soc Nephrol 2021 Aug;32(8):2083-2098

Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria

Background: Post-transplantation diabetes mellitus (PTDM) might be preventable.

Methods: This open-label, multicenter randomized trial compared 133 kidney transplant recipients given intermediate-acting insulin isophane for postoperative afternoon glucose ≥140 mg/dl with 130 patients given short-acting insulin for fasting glucose ≥200 mg/dl (control). The primary end point was PTDM (antidiabetic treatment or oral glucose tolerance test-derived 2 hour glucose ≥200 mg/dl) at month 12 post-transplant.

Results: In the intention-to-treat population, PTDM rates at 12 months were 12.2% and 14.7% in treatment versus control groups, respectively (odds ratio [OR], 0.82; 95% confidence interval [95% CI], 0.39 to 1.76) and 13.4% versus 17.4%, respectively, at 24 months (OR, 0.71; 95% CI, 0.34 to 1.49). In the per-protocol population, treatment resulted in reduced odds for PTDM at 12 months (OR, 0.40; 95% CI, 0.16 to 1.01) and 24 months (OR, 0.54; 95% CI, 0.24 to 1.20). After adjustment for polycystic kidney disease, per-protocol ORs for PTDM (treatment versus controls) were 0.21 (95% CI, 0.07 to 0.62) at 12 months and 0.35 (95% CI, 0.14 to 0.87) at 24 months. Significantly more hypoglycemic events (mostly asymptomatic or mildly symptomatic) occurred in the treatment group versus the control group. Within the treatment group, nonadherence to the insulin initiation protocol was associated with significantly higher odds for PTDM at months 12 and 24.

Conclusions: At low overt PTDM incidence, the primary end point in the intention-to-treat population did not differ significantly between treatment and control groups. In the per-protocol analysis, early basal insulin therapy resulted in significantly higher hypoglycemia rates but reduced odds for overt PTDM-a significant reduction after adjustment for baseline differences-suggesting the intervention merits further study. NCT03507829.
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http://dx.doi.org/10.1681/ASN.2021010127DOI Listing
August 2021

Clinicopathologic Features and Risk Factors of Proteinuria in Transplant Glomerulopathy.

Front Med (Lausanne) 2021 2;8:666319. Epub 2021 Jul 2.

Department of Pathology, Charité-Universitätsmedizin Berlin, Berlin, Germany.

Transplant glomerulopathy (TG) is one of the main causes of post-transplant proteinuria (PU). The features and possible risk factors for proteinuria in TG patients are uncertain. We investigated all patients who had biopsy-proven TG from 2000 to 2018 in our center. The clinical and histological data were compared between two groups with or without PU (cut-off = 0.3 g/day). Spearman correlation analysis was used to evaluate the relationship between PU and pathological changes. The risk factors for PU in TG patients were determined by multivariable logistic regression analysis. One hundred and twenty-five (75.76%) of all enrolled 165 TG patients had proteinuria ≥0.3 g/day at the time of biopsy. TG patients' PU level was significantly correlated with Banff lesion score cg (ρ = 0.247, = 0.003), and mm (ρ = 0.257, = 0.012). Systolic blood pressure ≥140 mmHg (OR 2.72, 95% CI 1.04-7.10, = 0.041), diastolic blood pressure ≥90 mmHg (OR 4.84, 95% CI 1.39-16.82, = 0.013), peak PRA ≥5% (OR 6.47, 95% CI 1.67-25.01, = 0.007), positive C4d staining (OR 4.55, 95% CI 1.29-16.11, 0.019), tacrolimus-based regimen (OR 3.5, 95% CI 1.28-9.54, = 0.014), and calcium channel blocker usage (OR 4.38, 95% CI 1.59-12.09, = 0.004) were independent risk factors for PU. Proteinuria is common in TG patients. systolic blood pressure ≥140 mmHg, diastolic blood pressure ≥90 mmHg, peak PRA ≥5%, positive C4d staining, tacrolimus-based regimen, and calcium channel blocker usage are associated with proteinuria in TG patients.
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http://dx.doi.org/10.3389/fmed.2021.666319DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8283120PMC
July 2021

Immunogenicity of COVID-19 Tozinameran Vaccination in Patients on Chronic Dialysis.

Front Immunol 2021 30;12:690698. Epub 2021 Jun 30.

Department of Nephrology and Intensive Care, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany.

Patients with kidney failure have notoriously weak responses to common vaccines. Thus, immunogenicity of novel SARS-CoV-2 vaccines might be impaired in this group. To determine immunogenicity of SARS-CoV-2 vaccination in patients with chronic dialysis, we analyzed the humoral and T-cell response after two doses of mRNA vaccine Tozinameran (BNT162b2 BioNTech/Pfizer). This observational study included 43 patients on dialysis before vaccination with two doses of Tozinameran 21 days apart. Overall, 36 patients completed the observation period until three weeks after the second dose and 32 patients were further analyzed at week 10. Serum samples were analyzed by SARS-CoV-2 specific IgG and IgA antibodies ~1, ~3-4 and ~10 weeks after the second vaccination. In addition, SARS-CoV-2-specific T-cell responses were assessed at ~3-4 weeks by an interferon-gamma release assay (IGRA). Antibody and T cell outcomes at this timepoint were compared to a group of 44 elderly patients not on dialysis, after immunization with Tozinameran. Median age of patients on chronic dialysis was 74.0 years (IQR 66.0, 82.0). The proportion of males was higher (69.4%) than females. Only 20/36 patients (55.6%, 95%CI: 38.29-71.67) developed SARS-CoV-2-IgG antibodies at the first sampling, whereas 32/36 patients (88.9%, 95%CI: 73.00-96.38) demonstrated IgG detection at the second sampling. In a longitudinal follow-up at ~10 weeks after the second dose, the proportion of dialysis patients reactive for anti-SARS-CoV-2-IgG decreased to 27/32 (84.37%, 95%CI: 66.46-94.10) The proportion of anti-SARS-CoV-2 S1 IgA decreased from 33/36 (91.67%; 95%CI: 76.41-97.82) at weeks 3-4 down to 19/32 (59.38; 95%CI: 40.79-75.78). Compared to a cohort of vaccinees with similar age but not on chronic dialysis seroconversion rates and antibody titers were significantly lower. SARS-CoV-2-specific T-cell responses 3 weeks after second vaccination were detected in 21/31 vaccinated dialysis patients (67.7%, 95%CI: 48.53-82.68) compared to 42/44 (93.3%, 95%CI: 76.49-98.84) in controls of similar age. Patients on dialysis demonstrate a delayed, but robust immune response three to four weeks after the second dose, which indicates effective vaccination of this vulnerable group. However, the lower immunogenicity of Tozinameran in these patients needs further attention to develop potential countermeasures such as an additional booster vaccination.
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http://dx.doi.org/10.3389/fimmu.2021.690698DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8284337PMC
July 2021

Advantages of plasmatic CXCL-10 as a prognostic and diagnostic biomarker for the risk of rejection and subclinical rejection in kidney transplantation.

Clin Immunol 2021 08 2;229:108792. Epub 2021 Jul 2.

Pharmacology and Toxicology Section, CDB, IDIBAPS, Hospital Clinic of Barcelona, University of Barcelona, c/Villarroel, 170, 08036 Barcelona, Spain; Biomedical Research Center in Hepatic and Digestive Diseases (CIBERehd), Instituto de Salud Carlos III, c/Sinesio Delgado 4, 28029 Madrid, Spain. Electronic address:

This study evaluate the potential of plasmatic CXCL-10 (pCXCL-10) as a pre&post transplantation prognostic and diagnostic biomarker of T-cell-mediated rejection (TCMR), antibody-mediated rejection (ABMR) and subclinical rejection (SCR) risk in adult kidney recipients considering BKV and CMV infections as possible clinical confounder factors. Twenty-eight of 100 patients included experienced rejection (TCMR:14; ABMR:14); 8 SCR; 13 and 16 were diagnosed with BKV and CMV infection, respectively. Pre-transplantation pCXCL-10 was significantly increased in TCMR and ABMR and post-transplantation in TCMR, ABMR and SCR compared with nonrejectors. All CMV patients showed pCXCL-10 levels above the cutoff values established for rejection whereas the 80% of BKV patients showed pCXCL-10 concentration < 100 pg/mL. pCXCL-10 could improve pre-transplantation patient stratification and immunosuppressive treatment selection according to rejection risk; and after kidney transplantation could be a potential early prognostic biomarker for rejection. Clinical confounding factor in BKV and particularly in CMV patients must be discarded.
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http://dx.doi.org/10.1016/j.clim.2021.108792DOI Listing
August 2021

Anti-interleukin-6 antibody clazakizumab in late antibody-mediated kidney transplant rejection: effect on cytochrome P450 drug metabolism.

Transpl Int 2021 Aug 8;34(8):1542-1552. Epub 2021 Jul 8.

Division of Nephrology and Dialysis, Department of Medicine III, Medical University of Vienna, Vienna, Austria.

Targeting interleukin-6 (IL-6) is a promising strategy to counteract antibody-mediated rejection (ABMR). In inflammatory states, IL-6 antagonism was shown to modulate cytochrome P450 (CYP), but its impact on drug metabolism in ABMR treatment was not addressed so far. We report a sub-study of a phase 2 trial of anti-IL-6 antibody clazakizumab in late ABMR (ClinicalTrials.gov, NCT03444103). Twenty kidney transplant recipients were randomized to clazakizumab versus placebo (4-weekly doses; 12 weeks), followed by a 9-month extension where all recipients received clazakizumab. To study CYP2C19/CYP3A4 metabolism, we administered pantoprazole (20 mg intravenously) at prespecified time points. Dose-adjusted C levels (C /D ratio) of tacrolimus (n = 13) and cyclosporin A (CyA, n = 6) were monitored at 4-weekly intervals. IL-6 and C-reactive protein were not elevated at baseline, the latter was then suppressed to undetectable levels under clazakizumab. IL-6 blockade had no clinically meaningful impact on pantoprazole pharmacokinetics (area under the curve; baseline versus week 52: 3.16 [2.21-7.84] versus 4.22 [1.99-8.18] μg/ml*h, P = 0.36) or calcineurin inhibitor C /D ratios (tacrolimus: 1.49 [1.17-3.20] versus 1.37 [0.98-2.42] ng/ml/mg, P = 0.21; CyA: 0.69 [0.57-0.85] versus 1.08 [0.52-1.38] ng/ml/mg, P = 0.47). We conclude that IL-6 blockade in ABMR - in absence of systemic inflammation - may have no meaningful effect on CYP metabolism.
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http://dx.doi.org/10.1111/tri.13954DOI Listing
August 2021

Impaired humoral immunity to SARS-CoV-2 BNT162b2 vaccine in kidney transplant recipients and dialysis patients.

Sci Immunol 2021 06;6(60)

Department of Rheumatology and Clinical Immunology, Charité Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany.

Patients with kidney failure are at increased risk for SARS-CoV-2 infection making effective vaccinations a critical need. It is not known how well mRNA vaccines induce B and plasma cell responses in dialysis patients (DP) or kidney transplant recipients (KTR) compared to healthy controls (HC). We studied humoral and B cell responses of 35 HC, 44 DP and 40 KTR. Markedly impaired anti-BNT162b2 responses were identified among KTR and DP compared to HC. In DP, the response was delayed (3-4 weeks after boost) and reduced with anti-S1 IgG and IgA positivity in 70.5% and 68.2%, respectively. In contrast, KTR did not develop IgG responses except one patient who had a prior unrecognized infection and developed anti-S1 IgG. The majority of antigen-specific B cells (RBD+) were identified in the plasmablast or post-switch memory B cell compartments in HC, whereas RBD+ B cells were enriched among pre-switch and naïve B cells from DP and KTR. The frequency and absolute number of antigen-specific circulating plasmablasts in the cohort correlated with the Ig response, a characteristic not reported for other vaccinations. In conclusion, these data indicated that immunosuppression resulted in impaired protective immunity after mRNA vaccination, including Ig induction with corresponding generation of plasmablasts and memory B cells. Thus, there is an urgent need to improve vaccination protocols in patients after kidney transplantation or on chronic dialysis.
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http://dx.doi.org/10.1126/sciimmunol.abj1031DOI Listing
June 2021

Impaired humoral and cellular immunity after SARS-CoV-2 BNT162b2 (tozinameran) prime-boost vaccination in kidney transplant recipients.

J Clin Invest 2021 07;131(14)

Department for General and Visceral Surgery and.

Novel mRNA-based vaccines have been proven to be powerful tools in combating the global pandemic caused by SARS-CoV-2, with BNT162b2 (trade name: Comirnaty) efficiently protecting individuals from COVID-19 across a broad age range. Still, it remains largely unknown how renal insufficiency and immunosuppressive medication affect development of vaccine-induced immunity. We therefore comprehensively analyzed humoral and cellular responses in kidney transplant recipients after the standard second vaccination dose. As opposed to all healthy vaccinees and the majority of hemodialysis patients, only 4 of 39 and 1 of 39 transplanted individuals showed IgA and IgG seroconversion at day 8 ± 1 after booster immunization, with minor changes until day 23 ± 5, respectively. Although most transplanted patients mounted spike-specific T helper cell responses, frequencies were significantly reduced compared with those in controls and dialysis patients and this was accompanied by a broad impairment in effector cytokine production, memory differentiation, and activation-related signatures. Spike-specific CD8+ T cell responses were less abundant than their CD4+ counterparts in healthy controls and hemodialysis patients and almost undetectable in transplant patients. Promotion of anti-HLA antibodies or acute rejection was not detected after vaccination. In summary, our data strongly suggest revised vaccination approaches in immunosuppressed patients, including individual immune monitoring for protection of this vulnerable group at risk of developing severe COVID-19.
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http://dx.doi.org/10.1172/JCI150175DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8279581PMC
July 2021

Accuracy of a Novel SARS-CoV-2 Antigen-Detecting Rapid Diagnostic Test from Standardized Self-Collected Anterior Nasal Swabs.

J Clin Med 2021 May 13;10(10). Epub 2021 May 13.

Department of Nephrology and Medical Intensive Care, Charité-Universitätsmedizin Berlin, 10117 Berlin, Germany.

Antigen-detecting rapid diagnostic tests (Ag-RDT) for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) offer new opportunities for the quick and laboratory-independent identification of infected individuals for control of the SARS-CoV-2 pandemic. Despite the potential benefits, nasopharyngeal sample collection is frequently perceived as uncomfortable by patients and requires trained healthcare personnel with protective equipment. Therefore, anterior nasal self-sampling is increasingly recognized as a valuable alternative. We performed a prospective, single-center, point of care validation of an Ag-RDT using a polypropylene absorbent collector for standardized self-collected anterior nasal swabs. Real-time polymerase chain reaction (RT-PCR) from combined oropharyngeal/nasopharyngeal swabs served as a comparator. Primary endpoint was sensitivity of the standardized Ag-RDT in symptomatic patients with medium or high viral concentration (≥1 million RNA copies on RT-PCR for SARS-CoV-2). Between 12 February and 22 March 2021, 388 participants were enrolled. After exclusion of 9 patients for which no PCR result could be obtained, the novel Ag-RDT was evaluated based on 379 participants, of whom 273 were symptomatic and 106 asymptomatic. In 61 samples from symptomatic patients with medium or high viral load (≥1 million RNA copies), the sensitivity of the standardized Ag-RDT was 96.7% (59/61; 95% confidence interval (CI): 88.7-99.6%) for the primary endpoint. In total, 62 positive Ag-RDT results were detected out of 70 RT-PCR positive individuals, yielding an overall sensitivity of 88.6% (95% CI: 78.7-94.9%). Specificity was 99.7% (95% CI: 98.2-100%) in 309 RT-PCR negative individuals. Here, we present a validation of a novel Ag-RDT with a standardized sampling process for anterior nasal self-collection, which meets World Health Organisation (WHO) criteria of ≥80% sensitivity and ≥97% specificity. Although less sensitive than RT-PCR, this assay could be beneficial due to its rapid results, ease of use, and suitability for standardized self-testing.
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http://dx.doi.org/10.3390/jcm10102099DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8153114PMC
May 2021

Undoubtedly, kidney transplant recipients have a higher mortality due to COVID-19 disease compared to the general population.

Transpl Int 2021 05;34(5):769-771

Department of Nephrology and Medical Intensive Care, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany.

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http://dx.doi.org/10.1111/tri.13881DOI Listing
May 2021

Kidney graft function and arterial stiffness in renal transplant recipients.

Acta Biochim Pol 2021 May;68(2):331-339

Medizinische Klinik mit Schwerpunkt Nephrologie und Internistische Intensivmedizin Charité - Universitätsmedizin Berlin, Berlin, Germany.

Introduction: In renal transplant recipients (RTRs), cardiovascular (CV) complications are associated with non-traditional risk factors, such as a decline in graft function, immunosuppressive therapy, time of dialysis before transplantation, inflammation and anemia. Higher value of arterial stiffness is the consequence of risk factors and it can lead to CV events. The aim of this study was the assessment of the arterial stiffness in RTRs with different value of estimated glomerular filtration rate (eGFR) and its correlation with classical and non-classical CV risk factors.

Methods: 344 stable RTRs were enrolled in this study. The arterial stiffness was measured in all participants. The study population was divided in two groups based on the value of eGFR: 201 (≥45 ml/min/1,73 m2) and 143 (<45 ml/min/1,73 m2). Demographic, immunosuppression status, clinical and biochemical information were referred to a single assessment obtained from medical records in the patients' medical files. Vascular stiffness was determined by an automated oscillometric device.

Results: In the group with eGFR<45 ml/min/1.73 m2 there were more patients with cardiovascular diseases (CVD) and the participants were older, in comparison to those with eGFR≥45 ml/min/1.73 m2. Arterial stiffness was significantly higher in the group with worse graft function. The analysis showed a significant correlation between age, cardiovascular disease and all arterial stiffness parameters. In addition, a significant correlation was found between all PWV variables and pulse pressure (PP) and pulsatile stress (PS), in the total population and in groups with eGFR <45 ml/min/1.73 m2 and eGFR≥45 ml/min/1.73 m2. The multivariate analysis showed a significant correlation between age, CVD and baPWV left, baPWV right and cf PWV in the total population. Arterial stiffness did not differ depending on eGFR.

Conclusions: Significant influence of age and CVD on arterial stiffness in RTRs was confirmed and PWV did not differ depending on eGFR. Our findings suggest that PS, as a marker for arterial stiffness, represents an easy and cost-effective tool.
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http://dx.doi.org/10.18388/abp.2020_5595DOI Listing
May 2021

TBase - an Integrated Electronic Health Record and Research Database for Kidney Transplant Recipients.

J Vis Exp 2021 04 13(170). Epub 2021 Apr 13.

Department of Nephrology and Medical Intensive Care, Charité - Universitätsmedizin Berlin;

TBase is an electronic health record (EHR) for kidney transplant recipients (KTR) combining automated data entry of key clinical data (e.g., laboratory values, medical reports, radiology and pathology data) via standardized interfaces with manual data entry during routine treatment (e.g., clinical notes, medication list, and transplantation data). By this means, a comprehensive database for KTR is created with benefits for routine clinical care and research. It enables both easy everyday clinical use and quick access for research questions with highest data quality. This is achieved by the concept of data validation in clinical routine in which clinical users and patients have to rely on correct data for treatment and medication plans and thereby validate and correct the clinical data in their daily practice. This EHR is tailored for the needs of transplant outpatient care and proved its clinical utility for more than 20 years at Charité - Universitätsmedizin Berlin. It facilitates efficient routine work with well-structured, comprehensive long-term data and allows their easy use for clinical research. To this point, its functionality covers automated transmission of routine data via standardized interfaces from different hospital information systems, availability of transplant-specific data, a medication list with an integrated check for drug-drug interactions, and semi-automated generation of medical reports among others. Key elements of the latest reengineering are a robust privacy-by-design concept, modularity, and hence portability into other clinical contexts as well as usability and platform independence enabled by HTML5 (Hypertext Markup Language) based responsive web design. This allows fast and easy scalability into other disease areas and other university hospitals. The comprehensive long-term datasets are the basis for the investigation of Machine Learning algorithms, and the modular structure allows to rapidly implement these into clinical care. Patient reported data and telemedicine services are integrated into TBase in order to meet future needs of the patients. These novel features aim to improve clinical care as well as to create new research options and therapeutic interventions.
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http://dx.doi.org/10.3791/61971DOI Listing
April 2021

Digital Home-Monitoring of Patients after Kidney Transplantation: The MACCS Platform.

J Vis Exp 2021 04 12(170). Epub 2021 Apr 12.

Department of Nephrology and internal intensive Care, Charité Universitätsmedizin Berlin;

The MACCS (Medical Assistant for Chronic Care Service) platform enables secure sharing of key medical information between patients after kidney transplantation and physicians. Patients provide information such as vital signs, well-being, and medication intake via smartphone apps. The information is transferred directly into a database and electronic health record at the kidney transplant center, which is used for routine patient care and research. Physicians can send an updated medication plan and laboratory data directly to the patient app via this secure platform. Other features of the app are medical messages and video consultations. Consequently, the patient is better-informed, and self-management is facilitated. In addition, the transplant center and the patient's local nephrologist automatically exchange notes, medical reports, laboratory values, and medication data via the platform. A telemedicine team reviews all incoming data on a dashboard and takes action, if necessary. Tools to identify patients at risk for complications are under development. The platform exchanges data via a standardized secure interface (Health Level 7 (HL7), Fast Healthcare Interoperability Resources (FHIR)). The standardized data exchange based on HL7 FHIR guarantees interoperability with other eHealth solutions and allows rapid scalability to other chronic diseases. The underlying data protection concept is in concordance with the latest European General Data Protection Regulation. Enrollment started in February 2020, and 131 kidney transplant recipients are actively participating as of July 2020. Two large German health insurance companies are currently funding the telemedicine services of the project. The deployment for other chronic kidney diseases and solid organ transplant recipients is planned. In conclusion, the platform is designed to enable home monitoring and automatic data exchange, empower patients, reduce hospitalizations, and improve adherence, and outcomes after kidney transplantation.
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http://dx.doi.org/10.3791/61899DOI Listing
April 2021

Exploring the Complexity of Death-Censored Kidney Allograft Failure.

J Am Soc Nephrol 2021 Jun 21;32(6):1513-1526. Epub 2021 Apr 21.

Department of Nephrology and Medical Intensive Care, Charité Universitätsmedizin Berlin, Berlin, Germany.

Background: Few studies have thoroughly investigated the causes of kidney graft loss (GL), despite its importance.

Methods: A novel approach assigns each persistent and relevant decline in renal function over the lifetime of a renal allograft to a standardized category, hypothesizing that singular or multiple events finally lead to GL. An adjudication committee of three physicians retrospectively evaluated indication biopsies, laboratory testing, and medical history of all 303 GLs among all 1642 recipients of transplants between January 1, 1997 and December 31, 2017 at a large university hospital to assign primary and/or secondary causes of GL.

Results: In 51.2% of the patients, more than one cause contributed to GL. The most frequent primary or secondary causes leading to graft failure were intercurrent medical events in 36.3% of graft failures followed by T cell-mediated rejection (TCMR) in 34% and antibody-mediated rejection (ABMR) in 30.7%. In 77.9%, a primary cause could be attributed to GL, of which ABMR was most frequent (21.5%). Many causes for GL were identified, and predominant causes for GL varied over time.

Conclusions: GL is often multifactorial and more complex than previously thought.
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http://dx.doi.org/10.1681/ASN.2020081215DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8259637PMC
June 2021

TuberOus SClerosis registry to increAse disease awareness (TOSCA) Post-Authorisation Safety Study of Everolimus in Patients With Tuberous Sclerosis Complex.

Front Neurol 2021 23;12:630378. Epub 2021 Mar 23.

Pediatric Neurology Unit, Department of Paediatrics, UZ Brussel VUB, Brussels, Belgium.

This non-interventional post-authorisation safety study (PASS) assessed the long-term safety of everolimus in patients with tuberous sclerosis complex (TSC) who participated in the TuberOus SClerosis registry to increase disease Awareness (TOSCA) clinical study and received everolimus for the licensed indications in the European Union. The rate of adverse events (AEs), AEs that led to dose adjustments or treatment discontinuation, AEs of potential clinical interest, treatment-related AEs (TRAEs), serious AEs (SAEs), and deaths were documented. One hundred seventy-nine patients were included in the first 5 years of observation; 118 of 179 patients had an AE of any grade, with the most common AEs being stomatitis (7.8%) and headache (7.3%). AEs caused dose adjustments in 56 patients (31.3%) and treatment discontinuation in nine patients (5%). AEs appeared to be more frequent and severe in children. On Tanner staging, all patients displayed signs of age-appropriate sexual maturation. Twenty-two of 106 female (20.8%) patients had menstrual cycle disorders. The most frequent TRAEs were stomatitis (6.7%) and aphthous mouth ulcer (5.6%). SAEs were reported in 54 patients (30.2%); the most frequent SAE was pneumonia (>3% patients; grade 2, 1.1%, and grade 3, 2.8%). Three deaths were reported, all in patients who had discontinued everolimus for more than 28 days, and none were thought to be related to everolimus according to the treating physicians. The PASS sub-study reflects the safety and tolerability of everolimus in the management of TSC in real-world routine clinical practice.
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http://dx.doi.org/10.3389/fneur.2021.630378DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8021912PMC
March 2021

Critical Illness and Systemic Inflammation Are Key Risk Factors of Severe Acute Kidney Injury in Patients With COVID-19.

Kidney Int Rep 2021 Apr 2;6(4):905-915. Epub 2021 Feb 2.

Department of Nephrology and Medical Intensive Care, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany.

Introduction: Acute kidney injury (AKI) is an important complication in COVID-19, but its precise etiology has not fully been elucidated. Insights into AKI mechanisms may be provided by analyzing the temporal associations of clinical parameters reflecting disease processes and AKI development.

Methods: We performed an observational cohort study of 223 consecutive COVID-19 patients treated at 3 sites of a tertiary care referral center to describe the evolvement of severe AKI (Kidney Disease: Improving Global Outcomes stage 3) and identify conditions promoting its development. Descriptive statistics and explanatory multivariable Cox regression modeling with clinical parameters as time-varying covariates were used to identify risk factors of severe AKI.

Results: Severe AKI developed in 70 of 223 patients (31%) with COVID-19, of which 95.7% required kidney replacement therapy. Patients with severe AKI were older, predominantly male, had more comorbidities, and displayed excess mortality. Severe AKI occurred exclusively in intensive care unit patients, and 97.3% of the patients developing severe AKI had respiratory failure. Mechanical ventilation, vasopressor therapy, and inflammatory markers (serum procalcitonin levels and leucocyte count) were independent time-varying risk factors of severe AKI. Increasing inflammatory markers displayed a close temporal association with the development of severe AKI. Sensitivity analysis on risk factors of AKI stage 2 and 3 combined confirmed these findings.

Conclusion: Severe AKI in COVID-19 was tightly coupled with critical illness and systemic inflammation and was not observed in milder disease courses. These findings suggest that traditional systemic AKI mechanisms rather than kidney-specific processes contribute to severe AKI in COVID-19.
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http://dx.doi.org/10.1016/j.ekir.2021.01.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8007085PMC
April 2021

The underestimated burden of monogenic kidney disease in adults waitlisted for kidney transplantation.

Genet Med 2021 07 12;23(7):1219-1224. Epub 2021 Mar 12.

Medizinische Genetik Mainz, Limbach Genetics GmbH, Mainz, Germany.

Purpose: Chronic kidney disease (CKD) is a major health-care burden. Increasing evidence suggests that a considerable proportion of patients are affected by a monogenic kidney disorder.

Methods: In this study, the kidney transplantation waiting list at the Charité was screened for patients with undetermined cause of CKD. By next-generation sequencing (NGS) we targeted all 600 genes described and associated with kidney disease or allied disorders.

Results: In total, 635 patients were investigated. Of these, 245 individuals had a known cause of CKD (38.5%) of which 119 had a proven genetic disease (e.g., ADPKD, Alport). The other 340 patients (53.5%) were classified as undetermined diagnosis, of whom 87 had kidney failure (KF) onset <40 years. To this latter group genetic testing was offered as well as to those patients (n = 29) with focal segmental glomerulosclerosis (FSGS) and all individuals (n = 21) suspicious for thrombotic microangiopathy (TMA) in kidney biopsy. We detected diagnostic variants in 26 of 126 patients (20.6%) of which 14 of 126 (11.1%) were pathogenic or likely pathogenic. In another 12 of 126 (9.5%) patients, variants of unknown significance (VUS) were detected.

Conclusion: Our study demonstrates the diagnostic value of comprehensive genetic testing among patients with undetermined CKD.
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http://dx.doi.org/10.1038/s41436-021-01127-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8257480PMC
July 2021

Personalized Therapy for Mycophenolate: Consensus Report by the International Association of Therapeutic Drug Monitoring and Clinical Toxicology.

Ther Drug Monit 2021 04;43(2):150-200

INSERM, Université de Limoges, Department of Pharmacology and Toxicology, CHU de Limoges, U1248 IPPRITT, Limoges, France.

Abstract: When mycophenolic acid (MPA) was originally marketed for immunosuppressive therapy, fixed doses were recommended by the manufacturer. Awareness of the potential for a more personalized dosing has led to development of methods to estimate MPA area under the curve based on the measurement of drug concentrations in only a few samples. This approach is feasible in the clinical routine and has proven successful in terms of correlation with outcome. However, the search for superior correlates has continued, and numerous studies in search of biomarkers that could better predict the perfect dosage for the individual patient have been published. As it was considered timely for an updated and comprehensive presentation of consensus on the status for personalized treatment with MPA, this report was prepared following an initiative from members of the International Association of Therapeutic Drug Monitoring and Clinical Toxicology (IATDMCT). Topics included are the criteria for analytics, methods to estimate exposure including pharmacometrics, the potential influence of pharmacogenetics, development of biomarkers, and the practical aspects of implementation of target concentration intervention. For selected topics with sufficient evidence, such as the application of limited sampling strategies for MPA area under the curve, graded recommendations on target ranges are presented. To provide a comprehensive review, this report also includes updates on the status of potential biomarkers including those which may be promising but with a low level of evidence. In view of the fact that there are very few new immunosuppressive drugs under development for the transplant field, it is likely that MPA will continue to be prescribed on a large scale in the upcoming years. Discontinuation of therapy due to adverse effects is relatively common, increasing the risk for late rejections, which may contribute to graft loss. Therefore, the continued search for innovative methods to better personalize MPA dosage is warranted.
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http://dx.doi.org/10.1097/FTD.0000000000000871DOI Listing
April 2021

Monitoring of gene expression in tacrolimus-treated de novo renal allograft recipients facilitates individualized immunosuppression: Results of the IMAGEN study.

Br J Clin Pharmacol 2021 Feb 23. Epub 2021 Feb 23.

Institute of Immunology, University Hospital Heidelberg, Heidelberg, Germany.

Aims: Calcineurin inhibitors (CNI) have a small therapeutic window, and drug monitoring is required. Pharmacokinetic monitoring does not correlate sufficiently with clinical outcome. Therefore, the expression of nuclear factor of activated T cells (NFAT)-regulated genes in the peripheral blood has been suggested as a potentially useful immune monitoring tool to optimize CNI therapy. NFAT-regulated gene expression (RGE) was evaluated in renal allograft recipients as predictive biomarker to detect patients at risk of acute rejection or infections.

Methods: NFAT-RGE (interleukin-2, interferon-γ, granular-macrophage colony-stimulating factor) was evaluated by quantitative real-time polymerase chain reaction in whole blood samples at day 7, day 14, month 1, 3, and 6 after transplantation in 64 de novo renal allograft recipients from 3 European centres. Immunosuppression consisted of tacrolimus (Tac), mycophenolic acid, and corticosteroids.

Results: Tac concentrations (C0 and C1.5) correlated inversely with NFAT-RGE (P < .01). NFAT-RGE showed a high interindividual variability (1-61%). Patients with high residual gene expression (NFAT-RGE ≥30%) were at the increased risk of acute rejection in the following months (35 vs. 5%, P = .02), whereas patients with low residual gene expression (NFAT-RGE <30%) showed a higher incidence of viral complications, especially cytomegalovirus and BK virus replication (52.5 vs. 10%, P = .01).

Conclusions: NFAT-RGE was confirmed as a potential noninvasive early predictive biomarker in the immediate post-transplant period to detect patients at risk of acute rejection and infectious complications in Tac-treated renal allograft recipients. Monitoring of NFAT-RGE may provide additional useful information for physicians to achieve individualized Tac treatment.
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http://dx.doi.org/10.1111/bcp.14794DOI Listing
February 2021

STABIL-study: The Course of Therapy, Safety and Pharmacokinetic Parameters of Conversion of Prograf® to Tacrolimus HEXAL®/Crilomus® in Renal Transplant Recipients - an Observational Study in Germany.

Curr Clin Pharmacol 2021 Feb 14. Epub 2021 Feb 14.

Department of Nephrology and Medical Intensive Care, Charité Universitätsmedizin Berlin, Berlin. Germany.

Background/objective: Tacrolimus HEXAL®/Crilomus® is an approved generic immunosuppressant for the prevention and treatment of rejection following renal transplantation. For safe and socioeconomically efficient conversion from the innovator to generic formulation, high-quality data are necessary, in view of the different and country-specific comorbidities and pharmacokinetics in kidney transplant recipients.

Patients And Methods: From 2014 to 2017, we enrolled 32 kidney transplant recipients, receiving newly prescribed Tacrolimus HEXAL®/Crilomus® in 5 German centers. Efficacy and safety data were collected over 6-8 months and retrospectively compared to the period prior to conversion.

Results: The mean tacrolimus trough level was 4.91 ng/mL standard deviation (SD) (SD ±1.7) before and 5.06 ng/mL (SD ±1.97) after conversion. Mean tacrolimus trough concentration-dose-ratio (+/- SD) was 187.1 ng/mL/mg/kg/day (SD 99.2) for the reference and 205.1 ng/mL/mg/kg/day (SD 133) for the generic product, resulting in a non-significant difference of 18.0 ng/mL/mg/kg/day (SD 71.8) (p=0.84, Wilcoxon V=180). Overall, dosing had to be changed in 4 (14.8%) patients. Graft function remained stable and no rejections occurred.

Conclusion: In conclusion, conversion to the generic tacrolimus formulation can be considered safe and feasible in long-term kidney transplant recipients in Germany. As suggested by guidelines, a vigilant therapeutic drug monitoring is recommended to account for possible tacrolimus concentration variability on the individual patient level.
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http://dx.doi.org/10.2174/1574884716666210215102756DOI Listing
February 2021

Tomoelastography for Longitudinal Monitoring of Viscoelasticity Changes in the Liver and in Renal Allografts after Direct-Acting Antiviral Treatment in 15 Kidney Transplant Recipients with Chronic HCV Infection.

J Clin Med 2021 Feb 1;10(3). Epub 2021 Feb 1.

Department of Radiology, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Charitéplatz 1, 10117 Berlin, Germany.

Besides the liver, hepatitis C virus (HCV) infection also affects kidney allografts. The aim of this study was to longitudinally evaluate viscoelasticity changes in the liver and in kidney allografts in kidney transplant recipients (KTRs) with HCV infection after treatment with direct-acting antiviral agents (DAAs). Fifteen KTRs with HCV infection were treated with DAAs (daclatasvir and sofosbuvir) for 3 months and monitored at baseline, end of treatment (EOT), and 3 (FU1) and 12 (FU2) months after EOT. Shear-wave speed (SWS) and loss angle of the complex shear modulus (φ), reflecting stiffness and fluidity, respectively, were reconstructed from multifrequency magnetic resonance elastography data with tomoelastography post-processing. After virus elimination by DAAs, hepatic stiffness and fluidity decreased, while kidney allograft stiffness and fluidity increased compared with baseline (hepatic stiffness change at FU1: -0.14 m/s, < 0.01, and at FU2: -0.11 m/s, < 0.05; fluidity at FU1: -0.05 rad, = 0.04 and unchanged at FU2: = 0.20; kidney allograft stiffness change at FU1: +0.27 m/s, = 0.01, and at FU2: +0.30 m/s, < 0.01; fluidity at FU1 and FU2: +0.06 rad, = 0.02). These results suggest the restoration of mechanically sensitive structures and functions in both organs. Tomoelastography can be used to monitor the therapeutic results of HCV treatment non-invasively on the basis of hepatic and renal viscoelastic parameters.
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http://dx.doi.org/10.3390/jcm10030510DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7867050PMC
February 2021

What happens after graft loss? A large, long-term, single-center observation.

Transpl Int 2021 04 19;34(4):732-742. Epub 2021 Feb 19.

Department of Nephrology and Medical Intensive Care, Charité - Universitätsmedizin Berlin, Berlin, Germany.

The number of patients returning to dialysis after graft failure increases. Surprisingly, little is known about the clinical and immunological outcomes of this cohort. We retrospectively analyzed 254 patients after kidney allograft loss between 1997 and 2017 and report clinical outcomes such as mortality, relisting, retransplantations, transplant nephrectomies, and immunization status. Of the 254 patients, 49% had died 5 years after graft loss, while 27% were relisted, 14% were on dialysis and not relisted, and only 11% were retransplanted 5 years after graft loss. In the complete observational period, 111/254 (43.7%) patients were relisted. Of these, 72.1% of patients were under 55 years of age at time of graft loss and only 13.5% of patients were ≥65 years. Age at graft loss was associated with relisting in a logistic regression analysis. In the complete observational period, 42 patients (16.5%) were retransplanted. Only 4 of those (9.5%) were ≥65 years at time of graft loss. Nephrectomy had no impact on survival, relisting, or development of dnDSA. Patients after allograft loss have a high overall mortality. Immunization contributes to long waiting times. Only a very limited number of patients are retransplanted especially when ≥65 years at time of graft loss.
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http://dx.doi.org/10.1111/tri.13834DOI Listing
April 2021

Early prognostic performance of miR155-5p monitoring for the risk of rejection: Logistic regression with a population pharmacokinetic approach in adult kidney transplant patients.

PLoS One 2021 22;16(1):e0245880. Epub 2021 Jan 22.

Pharmacology and Toxicology Laboratory, Biochemistry and Molecular Genetics, Biomedical Diagnostic Center (CDB), Hospital Clinic of Barcelona, University of Barcelona, Barcelona, Spain.

Previous results from our group and others have shown that urinary pellet expression of miR155-5p and urinary CXCL-10 production could play a key role in the prognosis and diagnosis of acute rejection (AR) in kidney transplantation patients. Here, a logistic regression model was developed using NONMEM to quantify the relationships of miR155-5p urinary expression, CXCL-10 urinary concentration and tacrolimus and mycophenolic acid (MPA) exposure with the probability of AR in adult kidney transplant patients during the early post-transplant period. Owing to the contribution of therapeutic drug monitoring to achieving target exposure, neither tacrolimus nor MPA cumulative exposure was identified as a predictor of AR in the studied population. Even though CXCL-10 urinary concentration showed a trend, its effect on AR was not significant. In contrast, urinary miR155-5p expression was prognostic of clinical outcome. Monitoring miR155-5p urinary pellet expression together with immunosuppressive drug exposure could be very useful during routine clinical practice to identify patients with a potential high risk of rejection at the early stages of the post-transplant period. This early risk assessment would allow for the optimization of treatment and improved prevention of AR.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0245880PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7822507PMC
June 2021

A Randomized Clinical Trial of Anti-IL-6 Antibody Clazakizumab in Late Antibody-Mediated Kidney Transplant Rejection.

J Am Soc Nephrol 2021 03 18;32(3):708-722. Epub 2020 Dec 18.

Division of Nephrology and Dialysis, Department of Medicine III, Medical University of Vienna, Vienna, Austria

Background: Late antibody-mediated rejection (ABMR) is a leading cause of transplant failure. Blocking IL-6 has been proposed as a promising therapeutic strategy.

Methods: We performed a phase 2 randomized pilot trial to evaluate the safety (primary endpoint) and efficacy (secondary endpoint analysis) of the anti-IL-6 antibody clazakizumab in late ABMR. The trial included 20 kidney transplant recipients with donor-specific, antibody-positive ABMR ≥365 days post-transplantation. Patients were randomized 1:1 to receive 25 mg clazakizumab or placebo (4-weekly subcutaneous injections) for 12 weeks (part A), followed by a 40-week open-label extension (part B), during which time all participants received clazakizumab.

Results: Five (25%) patients under active treatment developed serious infectious events, and two (10%) developed diverticular disease complications, leading to trial withdrawal. Those receiving clazakizumab displayed significantly decreased donor-specific antibodies and, on prolonged treatment, modulated rejection-related gene-expression patterns. In 18 patients, allograft biopsies after 51 weeks revealed a negative molecular ABMR score in seven (38.9%), disappearance of capillary C4d deposits in five (27.8%), and resolution of morphologic ABMR activity in four (22.2%). Although proteinuria remained stable, the mean eGFR decline during part A was slower with clazakizumab compared with placebo (-0.96; 95% confidence interval [95% CI], -1.96 to 0.03 versus -2.43; 95% CI, -3.40 to -1.46 ml/min per 1.73 m per month, respectively, =0.04). During part B, the slope of eGFR decline for patients who were switched from placebo to clazakizumab improved and no longer differed significantly from patients initially allocated to clazakizumab.

Conclusions: Although safety data indicate the need for careful patient selection and monitoring, our preliminary efficacy results suggest a potentially beneficial effect of clazakizumab on ABMR activity and progression.
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http://dx.doi.org/10.1681/ASN.2020071106DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7920172PMC
March 2021

A 2020 Banff Antibody-mediatedInjury Working Group examination of international practices for diagnosing antibody-mediated rejection in kidney transplantation - a cohort study.

Transpl Int 2021 03;34(3):488-498

Division of Nephrology/Transplant Nephrology, Johns Hopkins University, Baltimore, MD, USA.

The Banff antibody-mediated rejection (ABMR) classification is vulnerable to misinterpretation, but the reasons are unclear. To better understand this vulnerability, we evaluated how ABMR is diagnosed in practice. To do this, the Banff Antibody-Mediated Injury Workgroup electronically surveyed an international cohort of nephrologists/surgeons (n = 133) and renal pathologists (n = 99). Most providers (97%) responded that they use the Banff ABMR classification at least sometimes, but DSA information is often not readily available. Only 41.1% (55/133) of nephrologists/surgeons and 19.2% (19/99) of pathologists reported that they always have DSA results when the biopsy is available. Additionally, only 19.6% (26/133) of nephrologists/surgeons responded that non-HLA antibody or molecular transcripts are obtained when ABMR histologic features are present but DSA is undetected. Several respondents agreed that histologic features concerning for ABMR in the absence of DSA and/or C4d are not well accounted for in the current classification [31.3% (31/99) pathologists and 37.6% (50/133) nephrologist/surgeons]. The Banff ABMR classification appears widely accepted, but efforts to improve the accessibility of DSA information for the multidisciplinary care team are needed. Further clarity is also needed in Banff ABMR nomenclature to account for the spectrum of ABMR and for histologic features suspicious for ABMR when DSA is absent.
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http://dx.doi.org/10.1111/tri.13813DOI Listing
March 2021

Pan-Genotype Pre-Exposure Prophylaxis (PrEP) Allows Transplantation of HCV-Positive Donor Kidneys to Negative Transplant Recipients.

J Clin Med 2020 Dec 29;10(1). Epub 2020 Dec 29.

Department of Nephrology and Intensive Medical Care, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Charitéplatz 1, 10117 Berlin, Germany.

Transplant candidates are facing incremental mortality risks on the waiting list. Here, we report a novel strategy to expand the donor pool by including hepatitis C seropositive (HCV+) donors. We investigated a pre-exposure prophylactic (PrEP) treatment with direct-acting antivirals (DAA) to allow transplantation for HCV seronegative (HCV-) kidney transplant recipients (KTR) with the aim to prevent HCV infection post transplantation. In this prospective trial, a pan-genotypic PrEP with daclatasvir and sofosbuvir once daily for 12 week was administered at transplantation. The primary endpoint sustained virological negativity (SVN) 12 weeks after the end of PrEP. Seven patients received a transplantation from four HCV+ donors. Accumulated waiting time was 70 ± 31.3 months already. Of note, study subjects underwent transplantation 24.7 ± 16.1 days after given consent. All KTR developed excellent graft function without any rejection episodes. One patient died with a functioning graft due to sepsis 13 months after transplantation. PrEP demonstrated efficacy with no signs of HCV transmission with excellent tolerability. Two out of four HCV+ donors were viremic at the time of explantation. Interestingly, KTR developed HCV antibodies also from non viramic donors. The acceptance of HCV+ donor was safe and reduced waiting time under the protection of PrEP DAA in kidney transplantation.
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http://dx.doi.org/10.3390/jcm10010089DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7796396PMC
December 2020
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