Outcomes of Transplanting Deceased-Donor Kidneys between Elderly Donors and Recipients

Rate of acceptance of deceased-donor kidneys decreases with donor age despite the growing number of aged transplant candidates on the waiting list. In the Eurotransplant Senior Program, HLA-unmatched kidneys from deceased donors aged ≥65 yr are transplanted regionally into recipients aged ≥65 yr. Because we have become more willing to accept kidneys from donors aged ≥75 yr than previous years, we performed a retrospective analysis of this subgroup. Kidneys were accepted from donors aged ≥75 yr provided a normal creatinine on admission to the hospital, a Cockcroft-Gault creatinine clearance >80 ml/min, and an absence of comorbidities. We compared outcomes of kidneys from donors aged ≥75 yr with both younger-donor kidneys transplanted in the Eurotransplant Senior Program and with younger-donor HLA-matched kidneys transplanted into recipients ≥60 yr. There were no differences in 5-yr graft and patient survival or rate of delayed graft function between groups. Graft function, measured by creatinine and creatinine clearance, differed without pattern at only three of 12 time points during 5 yr of follow-up. In conclusion, our data suggest that kidneys from deceased donors aged ≥75 yr can be transplanted safely into recipients aged ≥65 yr if similar donor criteria and local allocation practices are used.Kidney transplantations (KTX) are beneficial also for old recipients.^1,2 Because the number of aged kidney donors is constantly rising^3,4 and donor shortage is the limiting factor for a timely transplant, Eurotransplant initiated the Eurotransplant Senior Program (ESP) in 1999. In this program, kidneys from deceased donors aged ≥65 are allocated according to waiting time and blood group compatibility without HLA matching to recipients ≥65. Because susceptibility to damage through cold ischemic time increases with donor age, transport time is kept short by local allocation.^5,6 Donors of the age of the ESP are defined as expanded criteria donors (ECD), and kidneys were found to have a 1.7 times higher risk for graft failure compared with normal donors, and >50% of kidneys from deceased donors aged ≥60 are discarded in the United States.^7,8 Discarding these donor kidneys is despite an increasing number of old patients on the waiting list⁹ and the findings of some authors who could show that kidneys refused because of donor age were successfully transplanted in other centers. Also, ECD kidneys were transplanted successfully into recipients aged ≥40.^10,11Our department has taken part in the ESP since its start in 1999.¹² Our center criteria for acceptance of kidneys from ESP donors include absence of comorbidities (uncontrolled arterial hypertension, diabetes, proteinuria), creatinine on admission to the hospital in the normal range, and creatinine clearance (Cockcroft-Gault) of >80 ml/min. Because we observed an increasing number of donors aged ≥75 accepted into this program and because no publication on this subgroup of “very old for old” KTX exists, we performed a retrospective, single-center analysis.During the studied period, kidneys from 48 deceased donors aged ≥75 yr were allocated locally to our center by Eurotransplant (mean number of offers per year 5.3 [0 to 12]). Fifteen (31%) donors fulfilled the inclusion criteria. We transplanted 18 kidneys into 18 recipients aged ≥65 yr (study group [“very old for old”]). Control group 1 were recipients in the ESP who received donor kidneys aged 65 to 74 yr (“old for old”; n = 73), control group 2 were recipients who were ≥60 and received a kidney from a donor in the usually applied Eurotransplant kidney allocation system (ETKAS), which also includes HLA matching (“ETKAS for old”; n = 30).The surgical technique was extraperitoneal with intermittent ureteral stenting of the antirefluxive ureteral implantation, immunosuppression consisted of a standardized triple therapy (calcineurin inhibitor, mycophenolate mofetil, corticosteroids) with dosage reduction over time. Selected patients received an induction therapy with an IL receptor antibody. Rejections were treated by pulsed methylprednisolone bolus therapy, followed by conversion to tacrolimus and/or treatment with ATG in steroid-resistant cases. Delayed graft function (DGF) was defined as the need for dialysis in the first week after KTX. Data for the study were retrieved from our computer database, which stores all patient data, including the follow-up visits, in an electronic patient record system.For demographic data, see

The impact of bleeding history,von Willebrand factor and PFA–100® on the diagnosis of type 1 von Willebrand disease: results from the European study MCMDM‐1VWD

The relationships between the Platelet Function Analyzer (PFA)‐100 and von Willebrand factor (VWF) levels and bleeding score (BS) were evaluated within a multicentre project on Molecular and Clinical Markers for the Diagnosis and Management of type 1 von Willebrand disease (MCMDM‐1VWD). PFA‐100 closure time, either with epinephrine (EPI) or adenosine diphosphate (ADP)‐cartridges, was measured in 107 index cases, 105 affected and 71 unaffected family members, and 79 healthy controls. By regression analysis VWF levels were strongly related to both closure times, with a non‐linear progression. In a multiple stepwise regression model, age‐ and sex‐adjusted PFA‐100 ADP and VWF ristocetin cofactor activity (VWF:RCo) were independently associated with BS. Most of the variation of BS was predicted by PFA‐100 ADP and VWF:RCo alone. In the subgroup of patients with subtle abnormalities of the multimeric pattern, VWF was invariably reduced and closure time prolonged in almost all of them. Neither PFA‐100 ADP nor EPI closure times appeared to significantly improve the diagnostic capability of VWF antigen (VWF:Ag) measurement. Thus, in an unselected population a normal PFA‐100 would be useful to exclude VWD, but whether it could replace the more specific VWF assay in patients with significant mucocutaneous bleeding symptoms remains to be investigated prospectively.     

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

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.     

Improved tumor targeting of anti-epidermal growth factor receptor Nanobodies through albumin binding: taking advantage of modular Nanobody technology

The approximately 15-kDa variable domains of camelid heavy-chain-only antibodies (called Nanobodies) can easily be formatted as multivalent or multispecific single-chain proteins. Because of fast excretion, however, they are less suitable for therapy of cancer. In this study, we aimed for improved tumor targeting of a bivalent anti-epidermal growth factor receptor (EGFR) Nanobody (alphaEGFR-alphaEGFR) by fusion to a Nanobody unit binding to albumin (alphaAlb). Biodistributions of alphaEGFR-alphaEGFR, alphaEGFR-alphaEGFR-alphaAlb ( approximately 50 kDa), alphaTNF-alphaTNF-alphaAlb (control, binding tumor necrosis factor-alpha), and the approximately 150-kDa anti-EGFR antibody cetuximab were compared in A431 xenograft-bearing mice. The proteins were radiolabeled with (177)Lu to facilitate quantification. Tumor uptake of (177)Lu-alphaEGFR-alphaEGFR decreased from 5.0 +/- 1.4 to 1.1 +/- 0.1 %ID/g between 6 and 72 h after injection. Due to its rapid blood clearance, tumor-to-blood ratios >80 were obtained within 6 h after injection. Blood clearance became dramatically slower and tumor uptake became significantly higher by introduction of alphaAlb. Blood levels of alphaEGFR-alphaEGFR-alphaAlb were 21.2 +/- 2.5, 11.9 +/- 0.6, and 4.0 +/- 1.4 and tumor levels were 19.4 +/- 5.5, 35.2 +/- 7.5, and 28.0 +/- 6.8 %ID/g at 6, 24, and 72 h after injection, respectively. Tumor uptake was at least as high as for cetuximab (15.5 +/- 3.9, 27.1 +/- 7.9, and 25.6 +/- 6.1 %ID/g) and significantly higher than for alphaTNF-alphaTNF-alphaAlb. alphaEGFR-alphaEGFR-alphaAlb showed faster and deeper tumor penetration than cetuximab. These data show that simple fusion of alphaEGFR and alphaAlb building blocks results in a bifunctional Nanobody format, which seems more favorable for therapy as far as pharmacokinetics and tumor deposition are concerned.     

Steroid- and calcineurin inhibitor free immunosuppression in kidney transplantation: state of the art and future developments

Owing to the increasing disparity of organ demand and organ supply the search for optimal immunosuppressive strategies has become a central issue in kidney transplantation (KTX). In the focus today are modifications of the use of calcineurin-inhibitors (CNIs, Cyclosporine A/Tacrolimus) and steroids, as they are nephrotoxic and promote cardiovascular risk factors like arterial hypertension, hyperlipidemia and diabetes mellitus. These modifications can either be withdrawal or avoidance of these substances in combination with new and/or established immunosuppressants. Because about half of all KTXs are performed by or with the help of urologists’ knowledge of modern immunosuppressive regimens is crucial also for urologists. We performed a literature research (PubMed, DIMDI, medline) for CNI- and steroid-sparing protocols and studies to elucidate their influence on graft-function and graft- and patient-survival. New substances and actual studies were also evaluated. Several published reports on CNI- and steroid-sparing protocols after KTX exist, including withdrawal, reduction or avoidance. The time of reduction seems to be crucial: an initially increased immune response should be counterbalanced by an initially intensified immunosuppression. Therefore, late steroid withdrawal seems to be safer than early withdrawal especially in Cyclosporine-based immunosuppression. Steroid avoidance also seems feasible on a CNI based regimen, especially in context with induction therapy. Withdrawal or avoidance of CNIs seems feasible with mycophenolate acid and/or induction therapy with IL 2-receptor antibodies as co-immunosuppressants. This is of interest in grafts with deteriorating function or from donors with extended criteria. Also, CNI- and steroid-free immunosuppression can be successfully performed with new immunosuppressants but results are yet premature. CNI- and/or steroid reduction, withdrawal or even avoidance is feasible. As long-term graft function is the goal of KTX and as more kidneys from donors with extended criteria are transplanted “tailored immunosuppression” will replace standards in the future.     

AICD treatment in 2004--state of the art

Primary and secondary prevention of sudden cardiac death is not sufficiently assured by medication. The (automatic) implantable cardioverter/defibrillator ((A)ICD) is able to terminate life-threatening arrhythmias (ventricular fibrillation/flutter, ventricular tachycardia) reliably. The identification and care of risk patients is of crucial importance. Initially, only survived resuscitation for ventricular fibrillation or ventricular tachycardia was regarded as a confirmed indication. Several studies (CABG patch, MADIT, MADIT II, MUSTT, DINAMIT, CAT AMIOVIRT, DEFINITE, COMPANION, SCD-HeFT) have examined the prophylactic indication for ICD therapy in risk groups. Patients with chronic state after myocardial infarction with markedly impaired left ventricular function and/or spontaneous, non-sustained ventricular tachycardia have been documented to benefit. Patients with moderately severe or severe heart failure also profit from ICD implantation, where appropriate in combination with cardiac resynchronization therapy in conduction disorders. There is divergent data on dilated cardiomyopathy. ICD is not indicated in patients with acute infarctions or undergoing elective bypass surgery.     

Glaucomatous optic disc hemorrhages on confocal scanning laser tomographic images

PURPOSE: To evaluate the detectability of glaucomatous optic disc hemorrhages by confocal scanning laser tomography. METHODS: The study included 73 eyes of 63 patients, who consecutively showed optic disc hemorrhages on 15 degrees color optic disc photographs taken at baseline or during follow-up examinations and for whom confocal scanning laser tomographic images were additionally available. Of the total number of 92 observed hemorrhages, 51 hemorrhages extended into the parapapillary region and 41 hemorrhages were restricted to the intrapapillary region. The scanning laser tomographic images were searched for the disc hemorrhages already seen on the conventional disc photographs. RESULTS: Using the reflectivity images, 29 (32%) hemorrhages were detected on the scanning laser tomographs. None of the hemorrhages restricted to the intrapapillary region could be seen on the scanning laser tomographs. By evaluating each of the 32 single images of the scanning laser tomographic image series, 44 (48%) of the hemorrhages were identified on at least one single image. The detectability of disc hemorrhages on the scanning laser tomographs depended significantly on their extension into the parapapillary region or their intrapapillary location. Detectability of disc bleedings was statistically independent of the disc quadrant where the hemorrhage was located, width of the bleeding, size of the optic disc, neuroretinal rim, parapapillary atrophy, and type of glaucoma. CONCLUSIONS: Confocal scanning laser tomography is not very suitable for detection or documentation of optic disc hemorrhages in patients with glaucoma.     

<Superscript>124</Superscript>I-L19-SIP for immuno-PET imaging of tumour vasculature and guidance of <Superscript>131</Superscript>I-L19-SIP radioimmunotherapy

Purpose  The human monoclonal antibody (MAb) fragment L19-SIP is directed against extra domain B (ED-B) of fibronectin, a marker of tumour angiogenesis. A clinical radioimmunotherapy (RIT) trial with ¹³¹I-L19-SIP was recently started. In the present study, after GMP production of ¹²⁴I and efficient production of ¹²⁴I-L19-SIP, we aimed to demonstrate the suitability of ¹²⁴I-L19-SIP immuno-PET for imaging of angiogenesis at early-stage tumour development and as a scouting procedure prior to clinical ¹³¹I-L19-SIP RIT. Methods   ¹²⁴I was produced in a GMP compliant way via ¹²⁴Te(p,n)¹²⁴I reaction and using a TERIMO™ module for radioiodine separation. L19-SIP was radioiodinated by using a modified version of the IODO-GEN method. The biodistribution of coinjected ¹²⁴I- and ¹³¹I-L19-SIP was compared in FaDu xenograft-bearing nude mice, while ¹²⁴I PET images were obtained from mice with tumours of <50 to ∼700 mm³. Results   ¹²⁴I was produced highly pure with an average yield of 15.4 ± 0.5 MBq/μAh, while separation yield was ∼90% efficient with <0.5% loss of TeO₂. Overall labelling efficiency, radiochemical purity and immunoreactive fraction were for ¹²⁴I-L19-SIP: ∼80 , 99.9 and >90%, respectively. Tumour uptake was 7.3 ± 2.1, 10.8 ± 1.5, 7.8 ± 1.4, 5.3 ± 0.6 and 3.1 ± 0.4%ID/g at 3, 6, 24, 48 and 72 h p.i., resulting in increased tumour to blood ratios ranging from 6.0 at 24 h to 45.9 at 72 h p.i.. Fully concordant labelling and biodistribution results were obtained with ¹²⁴I- and ¹³¹I-L19-SIP. Immuno-PET with ¹²⁴I-L19-SIP using a high-resolution research tomograph PET scanner revealed clear delineation of the tumours as small as 50 mm³ and no adverse uptake in other organs. Conclusions   ¹²⁴I-MAb conjugates for clinical immuno-PET can be efficiently produced. Immuno-PET with ¹²⁴I-L19-SIP appeared qualified for sensitive imaging of tumour neovasculature and for predicting ¹³¹I-L19-SIP biodistribution. Bernard M. Tijink and Lars R. Perk contributed equally to this article.     

Characterization of VWF gene conversions causing von Willebrand disease

We previously reported that von Willebrand Factor gene (VWF) conversions are a relatively frequent cause of von Willebrand disease (VWD), however, their molecular pathomechanisms resulting in variant phenotypes is largely unknown. Here, we characterized VWF conversions harbouring missense and synonymous mutations, through generating a series of mutant constructs followed by transient expression in 293 cells, and qualitative and quantitative analysis of recombinant VWF (rVWF). The characterization of mutant rVWF showed the critical roles of synonymous variants in the pathogenicity of VWF conversions. The gene conversion variants p.Val1229Gly, p.Asn1231Thr, p.Asn1231Ser and p.Ala1464Pro in the absence of synonymous p.Ser1263= and p.Gln1449= showed minimal effect on rVWF synthesis and activity. Interestingly, a construct including the synonymous variants displayed significantly low rVWF expression and activity. The variant p.Pro1266Leu showed gain of rVWF function toward glycoprotein Ibα; surprisingly, this function was significantly abolished in the presence of gene conversion variants p.Val1229Gly-p.Asn1231Thr. Taken together, our expression studies suggest that synonymous variants in the combination of other gene conversion variants suppress the protein expression, possibly due to defective primary mRNA structure or processing. The variants p.Val1229Gly-p.Asn1231Thr affected the VWF gain of function caused by variant p.Pro1266Leu, probably due to conformational changes in VWF.