Freitag, 02.10.2020

14:00 - 15:30

Poster DGfN 2020

Transplantation 1 (P103 - P110; LA24 - LA25)

 
CMV-Komplikationen bei SARS-CoV-2-Infektion nach Nierentransplantation – Behandlung und Immunmonitoring
P103 

J. Mihm, T. Schmidt, D. Fliser, M. Sester, U. Sester; Homburg/Saar

Einleitung: Die Pandemie mit severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) und zugehöriger Erkrankung Covid-19 stellt uns vor ungeahnte Herausforderungen. Infektionen nach Organtransplantation sind gefürchtet aufgrund eines höheren Risikos für schwere Verläufe. Bedingt durch die Immunsuppression (IS) besteht oftmals eine dauerhafte Lymphopenie. Durch die Virusinfektion kann diese ebenfalls induziert werden. Die immunologische Kontrolle latenter Virusinfektionen wie CMV kann gestört sein. Hier wird über die Fälle von zwei Nierentransplantatempfängern mit SARS-CoV-2-Infektion berichtet, die beide aufgrund von CMV-Reaktivierungen behandelt werden mussten. Neben Virus- (PCR) fand ein Immunmonitoring (Blutbild, CMV- und SARS-CoV-2 spezifischer T-Zellen) statt.
Kasuistik: Die erste Patientin (70 J, Nierentransplantation (NTx) vor 4 Jahren bei unklarer Nephropathie, Tacrolimus (Tac), MycophenolatMofetil (MMF), Methylprednisolon (MP)) infizierte sich im März mit SARS-CoV2 mit schwerem Verlauf durch ein acute respiratory distress syndromes, intensivmedizinischer Betreuung mit invasiver Beatmung und Hämodialyse bei akutem reversiblen Transplantatversagen. MMF wurde bei Aufnahme pausiert und Tac im Verlauf. Komplikativ entwickelte sich eine schwere Lymphopenie und CMV-Reaktivierung. Frühzeitig wurde mit Ganciclovir therapiert, im Verlauf auf Valganciclovir umgestellt und beendet. CMV- und SARS-CoV-2-spez. T-Zellen konnten zunächst nachgewiesen werden, jedoch beeinträchtigte die Lymphopenie zunehmend die Diagnostik. Erst nach Kontrolle der SARS-CoV-2-Infektion konnten stabile Frequenzen beider erregerspezifischen T-Zellpopulationen nachgewiesen werden.
Der zweite Patient (52 J, NTx vor 6 Monaten, diabetische Nephropathie, Tac, MMF MP) litt einen Monat vor SARS-CoV-2-Infektion (nachgewiesen in einem Screening, asymptomatisch) an einer CMV-Reaktivierung behandelt mit Valganciclovir. Eine negative CMV-PCR lag vor. Bereits in diesem Stadium zeigte der Patient eine schwere Leukopenie mit führender Neutropenie. CMV-spezifische T-Zellen waren nachweisbar, sodass die hämatotoxische Medikation mit Valganciclovir beendet wurde und die Gabe CMV-spezifischer Immunglobuline erfolgte. MMF wurde unter Steigerung von MP pausiert. SARS-CoV2-spez. T-Zellen konnten noch nicht nachgewiesen werden.
Schlussfolgerung: Anhand dieser beiden Einzelfälle zeigt sich, dass bei immunsupprimierten Patienten nicht nur die direkten Komplikationen durch Covid-19, sondern auch Reaktivierungen latenter Infektionen bedeutsam sind. Ein konsequentes Infektions- und Immunmonitoring ist erforderlich.

 
Assessment of malignant disease after kidney transplantation
P104 

A. Baum, T. H. Lindner, A. Bachmann, A. Weimann, B. Popp, J. Münch, J. Halbritter; Leipzig

Objective: Solid organ transplant recipients are at increased risk for the development of cancer, reducing both graft and patient survival. This risk is mostly attributed to long-term intake of immunosuppressive agents, host factors, such as time on pre-transplant dialysis, and viral oncogene infections. So far, systematic evaluation of cancer prevalence following kidney transplantation (KTx) in Germany is missing. Therefore, our study aims to assess the frequency, distribution, and entity of post-transplant malignancies (PTM) of a single center cohort.
Method: We gathered clinical data from electronic health records and collected current updates on all patients who received a KTx at the University Hospital of Leipzig since 1993. This data was assessed for PTM prevalence and further specifics.
Results: Between 1993 and 2019, a total of 1,035 KTx were performed in 901 patients at the University Hospital Leipzig (female 38.9%). 114 patients were deceased at the time of study initiation.
137 patients (17.9%) of our cohort showed a history of malignant diseases. Among them, malignancy mainly occurred after KTx (14.6%). In only 2.6% neoplasms already existed before KTx, and recurrence was observed in 0.7%. The median time from KTx to PTM was 8.3 years. The average time between the diagnosis of PTM and patients’ death was 1.7 years.
Within the group of patients with PTM, skin cancer represented the most common entity: basalioma 29.1%, squamous cell carcinoma 27.0%, and melanoma 4.4%. Renal cell carcinoma occurred with a frequency of 18.2% including two patients with renal carcinoma of the allograft. Post-transplant lymphoproliferative disease and cancer of the intestine applied to 7.3% and 5.8%, respectively. Less common tumor entities occurred in the prostate, breast, uterus, ovaries, bladder, liver, lung, thyroid, and connective tissue. Almost one-fourth (24.1%) of patients with PTM had more than one tumor manifestation in different organ systems or tissues.
Conclusion: The development of PTM constitutes a devastating condition in the course of KTx and is associated with poor survival rates. In accordance with data from other European transplant centers, non-melanoma skin cancer represents the most common entity of PTM, followed by solid organ tumors of the kidney. Of note, a relevant proportion of patients with PTM developed multiple neoplasms, suggesting the presence of specific oncogenic mechanisms underlying cancer formation, e.g. immunosuppression, viral infections or hereditary factors. Identifying these factors may advance improvement of PTM surveillance strategies in KTx recipients.

 
Tacrolimus toxicity and loss of renal function following heart transplant depend on C/D ratio
P105 

D. Dischl, K. Tippmann, U. Schönermarck, M. Orban, C. Grinninger, U. Wilbert-Lampen, S. Michel, K. Rizas, M. Fischereder; München

Objective: Immunosuppressive therapy with tacrolimus (tac) is a common standard after solid organ transplantation. Significant side effects are especially nephro- and neurotoxicity. To identify patients who are at increased risk of developing nephropathy, Thölking et al. have already established in patients after kidney and liver transplantation, the concentration / dose ratio (C/D ratio) as a meaningful clinical tool. Renal failure after heart transplantation is a major factor in mortality and morbidity. In the present study, the C/D ratio in patients after heart transplantation was evaluated for the first time.
Method: A retrospective monocentric observational study was carried out. The study included 159 patients in the 2007-2018 period who had not received a prior transplant, who had not undergone a combined organ transplant, and who had been taking tac for at least 6 months. The initial immunosuppression therapy consisted of tac (Prograf), mycophenolate mofetil and prednisolone. The statistical analyzes were carried out with Matlab. Ethical approval was obtained by the local ethics committee.
Results: The C/D ratio of all patients was calculated 6 months after the transplantation and the patient population was divided into two groups (fast and slow metabolizers) based on a cut-off value of 1.86 ng / ml / mg.

P105-1

A comparison of both groups after 6 and 12 months showed a significantly reduced ΔGFR of the fast metabolizers. After one year, 75.3% of the fast metabolizers had an eGFR <60 ml / min / 1.73m2, whereas in the group of slow metabolizers only 45.6% had an eGFR <60 ml / min / 1.73m2 (p-value < 0,001).

P105-2

There were no significant differences in terms of rejection rate or all-cause mortality.
Conclusion: The C/D ratio appears to correlate with renal function in heart transplant patients. This could be used as a clinical diagnostic tool to identify fast metabolizers and to monitor and treat them more closely with regard to nephropathy.

 
Gesundheit und Lebensqualität nach Lebendnierenspende. Eine retrospektive Single-Center-Studie.
P106 

J. Lindemann, M. Ruocco, L. S. Schulte-Kemna, R. J. van Erp, M. Kächele, B. Schröppel; Ulm

Hintergrund: In der retrospektiven Untersuchung von 53 Lebendnierenspendern untersuchten wir den langfristigen Einfluss der Nephrektomie auf Fatigue und gesundheitsbezogene Lebensqualität, sowie auf die körperliche Gesundheit.
Methode: Analysiert wurden Patienten die nach Nephrektomie zur Lebendnierenspende betreut wurden. Neben klinischen und demografischen Parameter erfolgte eine einmalige postoperative Befragung von Fatigue (MFI-20) und der gesundheitsbezogenen Lebensqualität (SF-36).
Ergebnisse: 26 (49%) der 53 Lebendnierenspender beantworten die MFI-20 und SF-36 Fragebögen. Das Alter lag bei durchschnittlich 66,3 Jahren, 54% waren weiblich, die Organspende lag im Mittel 10,9 Jahre (Spanne von 2,6 bis 18,6 Jahre) zurück, zwischen den Teilnehmern und Nicht-Teilnehmern an der Befragung bestanden bezüglich Alter, Geschlechterverteilung, Beziehung zum Transplantatempfänger keine Unterschiede.
Im Vergleich mit der Allgemeinbevölkerung schnitt unsere Kohorte in den meisten Dimensionen mit vergleichbarer oder höherer Lebensqualität und niedrigeren Werten für Fatigue ab (Differenzen auf MFI-20-Subskalen zwischen -4,1 und 0,5). Lediglich die Männer maßen niedrigere körperliche Lebensqualität (Tab.1).
 
Tab. 1: Mittelwerte der körperlichen und psychischen Summenskala (KSK/PSK) des SF-36 nach Gesamt-, Geschlechts- und Altersgruppen für die Norm- und Studienkohorte (N/S)

 
  Gesamt Frauen Männer 41-50 Jahre 51-60 Jahre 61-70 Jahre ≥70 Jahre
KSK N 50,2 49,1 51,4 51 47,9 44,8 39,9
KSK S 49,8 53,1 46 56,8 54,5 52,1 45,2
PSK N 51,5 50,7 52,4 51,4 51,2 53,2 52,4
PSK S 57,5 56,7 58,6 58,9 54,9 59,2 58,9


Zusammenfassung: Lebendspender in unserer Kohorte schneiden in den Dimensionen von Lebensqualität und Fatigue im Vergleich mit der Allgemeinbevölkerung und anderen Studienkohorten gleich oder in Teilgruppen sogar besser ab.

 
Ein Screening von donorspezifischen HLA-AK scheint das Transplantatüberleben positiv zu beeinflussen
P107 

J. K. Busch, M. Ziemann, M. Nitschke, I. Derad; Lübeck

Hintergrund: Der Erfolg einer Nierentransplantation (Tx) zeigt sich im Langzeitüberleben und hängt neben anderen Faktoren von der Abwesenheit von HLA-Antikörpern (HLA-AK), insbesondere von donorspezifischen HLA-AK (DSA) ab. Auswirkungen eines frühen Erfassens der DSA durch ein Screening werden untersucht. Die Hypothese wird geprüft, ob das Transplantatüberleben verringert ist in der Gruppe mit de novo DSA versus ohne DSA.
Methode: HLA-AK und DSA im Serum werden regelmäßig post-Tx untersucht (via Luminex und Beadassay). Das Screening erfolgt seit 2010 (alle 6 Monate über zwei Jahre, dann jährlich, lagen DSA vor alle 3 Monate über zwei Jahre, dann alle sechs Monate). 2010 wurde ein Behandlungsprotokoll implementiert, das bei erstmaligem Nachweis von DSA (de novo DSA) empfiehlt (1) die Immunsuppression auf keinen Fall zu reduzieren, (2) eine Abstoßung auszuschließen, bzw. zu behandeln und (3) einen Steroidentzug zu vermeiden. Retrospektiv werden in dieser monozentrischen Kohortenstudie HLA-AK, DSA, Nierenfunktion und Patientendaten erfasst. Das Gesamt- und Transplantüberleben der zwischen 2010 und 2016 Transplantierten wird nach Kaplan-Meier analysiert und für Patienten ohne DSA (DSA-) und Patienten mit donorspezifischen HLA AK (DSA+) im Log-Rank Test verglichen.
Ergebnisse: HLA-AK Befunde lagen bei 503 DSA- Patienten und bei 120 DSA+ Patienten vor. Das mittlere Gesamtüberleben nach 8 Jahren, der zwischen 2010 und 2016 Transplantierten (n= 337) unterschied sich nicht für die zwei Gruppen (p=0,61), auch nicht das Transplantatüberleben (p=0,52).

P107

Die Nierenfunktion unterschied sich nicht in Bezug auf die Kreatinin Clearance, während eine tendenziell höhere Albuminurie bei DSA+ vorlag. Die Basisimmunsuppression und die Veränderung der Immunsuppression im Langzeitverlauf (Tx-Aufenthalt, 1. Jahr, 2-bis 4.Jahr, 5.bis >8.Jahr) und vor DSA-Erstdiagnose werden berichtet und mittels Chi-Quadrat Test verglichen.
Zusammenfassung: Im Gegensatz zu Vorarbeiten1 unterschied sich das Transplantatüberleben nicht für Patienten mit de-novo DSA in unserer Kohorte mit implementiertem HLA-AK Screening. Vor Erstdiagnose der DSA war häufiger ein Steroidentzug erfolgt oder die CNI Zielspiegel wurden nicht erreicht. Möglicherweise kann eine schnelle Intervention bei DSA-Erstdiagnose die langfristige Verschlechterung der Transplantatfunktion beeinflussen. Weitere Studien müssen zeigen, ob sie verzögert oder verhindert werden kann.
1 Loupy et al. 2015 JASN 26(7):1721-1731

 
C-terminal and intact FGF23 in kidney transplant recipients and their associations with graft loss and mortality
P108 

C. Chu, S. Zeng, Y. Xiong, A. Hasan, B. K. Krämer, B. Hocher; Berlin, Potsdam, Mannheim

Objective: Increased fibroblast growth factor 23 (FGF23) is a risk factor for mortality, cardiovascular disease, and progression of chronic kidney disease. Limited data exist comparing the association of either c-terminal FGF23 (cFGF23) or intact FGF23 (iFGF23) in kidney transplant recipients (KTRs) with graft loss and all-cause mortality.
Method: We conducted a prospective observational cohort study in 562 stable kidney transplant recipients. Patients were followed for graft loss and all-cause mortality for a follow-up of 48 months.
Results: During a median follow-up of 48 months, 94 patients had adverse outcome (graft loss or died). Both cFGF23 and iFGF23 concentrations were significantly higher in patients who had adverse outcome than those without adverse outcome (24.59 [11.43-87.82] versus 10.67 [5.99-22.73] pg/ml; p<0.0001 and 45.24 [18.63-159.0] versus 29.04 [15.23-60.65] pg/ml; p=0.002 for cFGF23 and iFGF23, respectively). cFGF23 and iFGF23 measurements correlated well (rho=0.54, p <0.0001). ROC analysis of cFGF23 and iFGF23 yielded AUC of 0.69 (p <0.0001) and 0.61 (p =0.002) for prediction of the composite endpoint, respectively (figure 1).

P108-1

Cox regression analyses adjusted for eGFR, gender, age, time post-transplantation, hemoglobin, albumin, donor’s age, cold ischemia time, serum calcium, serum phosphorus, parathyroid hormone and urinary protein excretion, showed that cFGF23 (HR for one unit increase of log transformed cFGF23: 1.35; 95% CI, 1.03-1.77; p=0.028) but not iFGF23 (HR for one unit increase of log transformed iFGF23: 1.03; 95% CI, 0.81-1.31; p=0.827) was associated with the composite endpoint (figure 2).

P108-2

Conclusion: Elevated cFGF23 levels at baseline are independently associated with an increased risk all-cause mortality or graft loss in KTRs. iFGF23 measurements were not independently associated with the study endpoint. The cFGF23 ELISA might detect bioactive FGF23 fragments that are not detected by the iFGF23 ELISA.

 
Development of de novo donor-specific HLA-antibodies in renal transplant patients depends on CYP3A5 genotype
P109 

J. Friebus-Kardash, E. Nela, B. Moehlendick, F. Heinemann, A. Heinold, A. Kribben, W. Siffert, U. Eisenberger; Essen

Objective: Genetic variations in CYP3A5 as one of the most important enzyme for the tacrolimus metabolism contribute to 50% of the pharmaceutic variability of the drug. The single nucleotide polymorphism of CYP3A5 6986A>G is related to reduced metabolizing activity. Individuals carrying at least one copy of the wild-type allele defined as CYP3A5 expressers have higher tacrolimus clearance and lower through concentrations than homozygous nonexpressers. However, reports on the influence of CYP3A5 genotype on allograft survival and acute rejection after kidney transplantation are controversial. We investigated the link between CYP3A5 polymorphism and renal allograft outcome and incidence of viral and bacterial infections.
Method: A retrospective single center study was performed on 412 kidney transplant patients who were transplanted 2011-2015 and received tacrolimus. We determine the CYP3A5 genotype by polymerase chain reaction and assessed its effect on allograft survival, rejection rate and occurrence of de novo donor-specific antibodies (DSA) as well as risk of infections during the first 5 years after transplantation.
Results: We identified 70 (17%) of 412 patients having the expresser genotype. CYP3A5 expressers had significantly lower concentration-to-dose ratios of tacrolimus than nonexpressers at 2 weeks and at month 1, 3 and 6 posttransplant. CYP3A5 genotype had no impact on clinical outcome such as allograft failure and T-cell mediated as well as antibody-mediated rejection. Indeed, the percentage of patients with de novo anti-HLA antibodies and DSA was significantly increased in the CYP3A5 expresser group. De novo anti-HLA antibody- und DSA-free survival rates were lower in expressers compared with nonexpressers. Additionally, in univariate and multivariate analysis CYP3A5 expresser status was found to be an independent risk factor for de novo DSA development. No differences in infection rates posttransplant between both groups were observed.
Conclusion: CYP3A5 expresser genotype is an independent risk factor for de novo DSA development. Early identification of recipients carrying CYP3A5 expresser genotype following genotype–based dose adjustment of tacrolimus immediately after renal transplantation might be a useful strategy to reduce the risk of de novo DSA production and improve long-term allograft survival.

 
Systemic immune responses in kidney transplantation
P110 

K. Buscher, K. Ley, H. Pavenstädt, S. Reuter; Münster, La Jolla/USA

Objective: Kidney transplantation triggers complex immune responses in the host. Many studies focus on the allograft to define the immunological status. Here we hypothesized that systemic and coordinated immune responses are triggered by the allograft that can be detected in the blood.
Method: We used two independent cohorts of n=8 and n=13 patients with the clinical indication for a graft biopsy. For each patient a multi-omic data set was assembled including serum proteomics (176 proteins), leukocyte mass cytometry, clinical data and histological scoring. Pearson correlation with bootstrapping was applied to find co-regulated multi-omic immune patterns.
Results: We found that leukocytes, cytokines and other proteins form co-regulated immune clusters that are mostly evident in transplanted patients but not in healthy controls. In our data set, 11 identical clusters were found in both patient cohorts comprising 4 to 34 multi-omic parameters. They are  enriched in specific functions such as matrix organization, leukocyte activation, PI3k-Akt signaling, interleukin signaling and humoral responses. The cytokine response is closely linked to the complex leukocyte landscape in the blood, and both correlate with the identified immune clusters. Patient stratification by immune cluster activity predominantly allows to reproduce the histological diagnosis.
Conclusion: Co-regulated multi-omic immune clusters in the blood appear to reflect a systemic immune response that might allow new biomarker strategies and immunomonitoring in kidney transplantation.

 
Identifying the Causes for Kidney Allograft Failure
LA24 

M. Mayrdorfer, L. Liefeldt, K. Wu, B. Rudolph, N. Lachmann, D. Schmidt, W. Düttmann, M. Naik, F. Friedersdorff, F. Halleck, J. Waiser, M. Dürr, K. Budde; Berlin

Objective: Since it has been proposed that several causes can contribute to graft loss (GL), we analyzed transplant (Tx) recipients in our center and attributed a cause to each relevant and persistent decline in renal function, finally leading to GL.
Method: We retrospectively analyzed 1477 Tx, transplanted between 1997 and 2017 in a single center, of which 303 progressed to death-censored GL. An adjudication committee consisting of 3 physicians evaluated biopsies, laboratory data and medical history. Nonreversible decreases in renal function were attributed to primary and secondary Causes.
Results: Overall graft survival for all patients is 93.7% for 1 year, 80% for 5 years and 60.6% for 10 years. The most frequent causes leading to GL were intercurrent medical events in 36.3%, followed by T-cell mediated rejection (TCMR) in 34% and antibody-mediated rejection (ABMR) in 30.7% (table1).

LA24-1

For primary causes, ABMR (21.5%) was the leading cause, followed by medical events (21.1%) and TCMR (12.9%). As expected, we observed an increasing relevance of ABMR in late GL (figure 1). Over 50% of GL had >1 cause.

LA24-2


Conclusion: Analyzing GL, we observed that >50% were multifactorial. Our results show a significant role of TCMR in GL. Additionally, we were able to attribute medical events to GL in 36.3% of Tx and to highlight the role of ABMR in late GL.

 
Lack of desensitization contributes to constant activation of AT1R mediated by agonistic antibodies
LA25 

A. Philippe, R. A. Catar, P. Scheerer, G. Kleinau, M. Szczepek, D. Dragun; Berlin

Objective: Angiotensin II type 1 receptor (AT1R) exhibits multiligand binding abilities and may signal upon either its natural ligand Angiotensin II (AngII) or AT1R-agonistic Immunoglobulin G (AT1R-IgG)-mediated stimulation. Development of high-resolution methods allows now for structural-functional relationship studies of receptor activation. Elucidation of AT1R activation mechanisms could have broad clinical relevance for vascular pathologies in native kidneys and after organ transplantation.
Method: To distinguish activation mediated by the Ang II or agonistic IgG, we developed a three-part GPCR activation assay based on yeasts expressing human AT1R, and mammalian cells for AT1R desensitization assessment and downstream signalling reporter assays. AT1R activation was induced by either its natural ligand or by AT1R-IgG isolated from patients with renal vascular pathology.
Results: Both Ang II and agonistic IgG triggered dose-dependent AT1R activation. AT1R-IgG induced stronger receptor activation than Ang II, stressing their “superagonistic” potency. AT1R antagonist fully blocked Ang II-induced AT1R activation, but only partially AT1R activation mediated by AT1R-IgG. In mammalian cells, both Gq/11 and G12/13 signalling were stronger activated by AT1R-IgG. Constantly high membrane AT1R expression levels showed that antibodies stabilize the presentation of the receptor over time and induced a lack of desensitization of the receptor compared to Ang II. We have successfully created models appreciating AT1R receptor functional plasticity to understand actions of AT1R-IgG antibodies.
Conclusion: Understanding previously unknown molecular mechanisms responsible for AT1R activation based on lack of desensitization explains “superagonistic” activities of AT1R-IgG and explains fast progressive course thereby induced renal vascular pathologies.

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