Donor-specific antibodies create an immunologic barrier to transplantation. Current therapies to modify donor-specific antibodies are limited and ineffective in the most highly HLA-sensitized ...patients. The IgG-degrading enzyme derived from Streptococcus pyogenes (IdeS), an endopeptidase, cleaves human IgG into F(ab')
and Fc fragments inhibiting complement-dependent cytotoxicity and antibody-dependent cellular cytotoxicity, which suggests that IdeS might be useful for desensitization. We report on the combined experience of two independently performed open-label, phase 1-2 trials (conducted in Sweden and the United States) that assessed the efficacy of IdeS with regard to desensitization and transplantation of a kidney from an HLA-incompatible donor.
We administered IdeS to 25 highly HLA-sensitized patients (11 patients in Uppsala or Stockholm, Sweden, and 14 in Los Angeles) before the transplantation of a kidney from an HLA-incompatible donor. Frequent monitoring for adverse events, outcomes, donor-specific antibodies, and renal function was performed, as were renal biopsies. Immunosuppression after transplantation consisted of tacrolimus, mycophenolate mofetil, and glucocorticoids. Patients in the U.S. study also received intravenous immune globulin and rituximab after transplantation to prevent antibody rebound.
Recipients in the U.S. study had a significantly longer cold ischemia time (the time elapsed between procurement of the organ and transplantation), a significantly higher rate of delayed graft function, and significantly higher levels of class I donor-specific antibodies than those in the Swedish study. A total of 38 serious adverse events occurred in 15 patients (5 events were adjudicated as being possibly related to IdeS). At transplantation, total IgG and HLA antibodies were eliminated. A total of 24 of 25 patients had perfusion of allografts after transplantation. Antibody-mediated rejection occurred in 10 patients (7 patients in the U.S. study and 3 in the Swedish study) at 2 weeks to 5 months after transplantation; all these patients had a response to treatment. One graft loss, mediated by non-HLA IgM and IgA antibodies, occurred.
IdeS reduced or eliminated donor-specific antibodies and permitted HLA-incompatible transplantation in 24 of 25 patients. (Funded by Hansa Medical; ClinicalTrials.gov numbers, NCT02224820 , NCT02426684 , and NCT02475551 .).
Background Malignancies in the urinary tract and the kidney graft are quite common after kidney transplantation. In some selected cases tumours develop from donor-derived tissue. Objectives We ...hypothesised that there is a clinical value to investigate donor/recipient origin in urologic malignancies in renal transplant recipients. Methods In this retrospective study, including patients transplanted between the years 1969 and 2014 at Uppsala University Hospital, Sweden, 11 patients with malignancies in urinary tract and 4 patients with malignancies in kidney transplants were investigated. Donor/recipient origin of tumour tissue was analysed by polymerase chain reaction (PCR) of human leucocyte antigen (HLA) genotypes or by fluorescence in situ hybridization (FISH analysis) of sex chromosomes. HLA genotype and sex chromosomes of the tumour were compared to the known HLA genotype and sex chromosomes of recipient and donor. Results Three of ten cancers in the urinary tract and three of four cancers in the kidney transplants were donor-derived. Conclusions We suggest that urologic malignancies in renal transplant recipients can be investigated for transplant origin. In addition to conventional therapy the allograft immune response against these tumours can be valuable to treat donor-derived cancers.
Safety, immunogenicity, pharmacokinetics, and efficacy of the IgG‐degrading enzyme of Streptococcus pyogenes (IdeS imlifidase) were assessed in a single‐center, open‐label ascending‐dose study in ...highly sensitized patients with chronic kidney disease. Eight patients with cytotoxic PRAs (median cytotoxic PRAs of 64%) at enrollment received 1 or 2 intravenous infusions of IdeS on consecutive days (0.12 mg/kg body weight ×2 n = 3; 0.25 mg/kg ×1 n = 3, or 0.25 mg/kg ×2 n = 2). IgG degradation was observed in all subjects after IdeS treatment, with <1% plasma IgG remaining within 48 hours and remaining low up to 7 days. Mean fluorescence intensity values of HLA class I and II reactivity were substantially reduced in all patients, and C1q binding to anti‐HLA was abolished. IdeS also cleaved the IgG‐type B cell receptor on CD19+ memory B cells. Anti‐IdeS antibodies developed 1 week after treatment, peaking at 2 weeks. A few hours after the second IdeS infusion, 1 patient received a deceased donor kidney offer. At enrollment, the patient had a positive serum crossmatch (HLA‐B7), detected by complement‐dependent cytotoxicity, flow cytometry, and multiplex bead assays. After IdeS infusion (0.12 mg/kg ×2) and when the HLA‐incompatible donor (HLA‐B7+) kidney was offered, the HLA antibody profile was negative. The kidney was transplanted successfully.
In highly sensitized patients with chronic kidney disease, the immunoglobulin G–degrading enzyme of Streptococcus pyogenes (imlifidase) degrades plasma IgG efficiently, reduces HLA antibodies substantially, and abolishes C1q binding to anti‐HLA, thus enabling HLA‐incompatible kidney transplantation.
Chronic active antibody-mediated rejection (caAMR) in kidney transplants is associated with irreversible tissue damage and a leading cause of graft loss in the long-term. However, the treatment for ...caAMR remains a challenge to date. Recently, tocilizumab, a recombinant humanized monoclonal antibody directed against the human interleukin-6 (IL-6) receptor, has shown promise in the treatment of caAMR. However, it has not been systematically investigated so far underscoring the need for randomized controlled studies in this area.
The INTERCEPT study is an investigator-driven randomized controlled open-label multi-center trial in kidney transplant recipients to assess the efficacy of tocilizumab in the treatment of biopsy-proven caAMR. A total of 50 recipients with biopsy-proven caAMR at least 12 months after transplantation will be randomized to receive either tocilizumab (n = 25) added to our standard of care (SOC) maintenance treatment or SOC alone (n = 25) for a period of 24 months. Patients will be followed for an additional 12 months after cessation of study medication. After the inclusion biopsies at baseline, protocol kidney graft biopsies will be performed at 12 and 24 months. The sample size calculation assumed a difference of 5 ml/year in slope of estimated glomerular filtration rate (eGFR) between the two groups for 80% power at an alpha of 0.05. The primary endpoint is the slope of eGFR at 24 months after start of treatment. The secondary endpoints include assessment of the following at 12, 24, and 36 months: composite risk score iBox, safety, evolution and characteristics of donor-specific antibodies (DSA), graft histology, proteinuria, kidney function assessed by measured GFR (mGFR), patient- and death-censored graft survival, and patient-reported outcomes that include transplant-specific well-being, adherence to immunosuppressive medications and perceived threat of the risk of graft rejection.
No effective treatment exists for caAMR at present. Based on the hypothesis that inhibition of IL-6 receptor by tocilizumab will reduce antibody production and reduce antibody-mediated damage, our randomized trial has a potential to provide evidence for a novel treatment strategy for caAMR, therewith slowing the decline in graft function in the long-term.
ClinicalTrials.gov NCT04561986. Registered on September 24, 2020.
Surgical excision is the standard treatment for chronic pilonidal disease, but all excisional techniques are associated with tissue loss, risk of wound break down, and chronic healing problems.
The ...aim of the study was to compare sinus excision and primary closure vs a laying open technique in a prospective randomized trial.
Eighty patients were randomly assigned to sinus excision and primary closure (n = 39) or laying open (n = 41). Follow-up was performed 1, 3, and 12 months after surgery.
The main outcome measure was the healing rate after 1 year.
The healing rate was significantly higher after excision and closure than after laying open at 1 month (20 of 39 vs 8 of 41; P = .005) and 3 months (36 of 38 vs 28 of 39; P = .013) after surgery. At follow-up 12 months after surgery no difference was seen in healing rate between the treatment arms (33 of 37 vs 37 of 38; P = .198).
This prospective randomized trial shows that sinus excision and primary closure results in faster healing than laying open does, but there is no difference in healing rate after 1 year. The laying open procedure is minimally invasive with small risks for the patient, and it might therefore be considered more frequently as the first choice of treatment (www.clinicaltrials.gov. Unique identifier: NCT00997048).
Pretreating porcine kidneys with Corline Heparin Conjugate (CHC) during hypothermic machine perfusion (HMP) has been shown to reduce preservation injury and improve early kidney function. In this ...first-in-human phase I study, the safety and tolerability of transplanting CHC-pretreated kidneys were evaluated.
CHC or placebo was added to the preservation solution during HMP of donated kidneys from deceased donors for at least 3 h before transplantation into adult patients. The primary safety endpoint was the number and severity of adverse events (AEs) and serious AEs (SAEs) during the first 30 d after transplantation.
In the first 30 d, 66 AEs were reported in 8 patients who received CHC-pretreated kidneys with 39 AEs in 8 patients who received placebo-pretreated kidneys (
= 0.1 in post hoc analysis). The most common AEs were hypertension (CHC, n = 5; placebo, n = 2) and anemia (CHC, n = 5; placebo, n = 2). Most AEs were assessed as mild (58%) or moderate (39%) and not related to treatment (95%). There were 2 SAEs reported in each group. One SAE, considered possibly related to CHC treatment, was a case of severe postprocedural hemorrhage that required reoperation. No patients needed dialysis. There were no observed rejections and no patient deaths.
Pretreatment of kidneys with CHC before transplantation was considered safe and tolerable. Efficacy studies are now planned to investigate if CHC can reduce early ischemia-reperfusion injury in humans.
Abstract Background Endothelial glycocalyx regulates the endothelial function and plays an active role in maintaining vascular homeostasis. During ischema and reperfusion, the glycocalyx is rapidly ...shed into the blood stream. A Corline heparin conjugate (CHC; Corline systems AB, Uppsala, Sweden) consists of 70 heparin molecules that have the capacity to adhere strongly to biological tissues expressing heparin affinity. We hypothesized that CHC could be used to restore disrupted glycocalyx in vivo in kidneys from brain-dead pigs. Materials and methods Brain death was induced in male landrace pigs ( n = 6) by inflating a balloon catheter in the epidural space until obtaining negative cerebral perfusion. The recovered kidneys ( n = 5 + 5) were perfused by hypothermic machine perfusion using two Lifeport kidney transporters (Organ Recovery Systems, Chicago, IL). CHC (50 mg) (including 25 mg biotinylated CHC) or 50 mg unfractionated heparin (control) was added to the perfusion fluid in the respective machines. In one case, the kidneys were used only for dose escalation of CHC with the same procedure. Results CHC was detected by immunofluorescence and confocal microscopy in the inner surface of the vessel walls. The binding of CHC in the kidney was confirmed indirectly by consumption of CHC from the perfusion fluid. Conclusions In this first attempt, we show that CHC maybe used to coat the vessel walls of perfused kidneys during hypothermic machine perfusion, an approach that could become useful in restoring endothelial glycocalyx of kidneys recovered from deceased donors to protect vascular endothelium and possibly ameliorate ischemia and reperfusion injuries.
Wound complications are the most common surgical complication after kidney allograft transplantation. Total wound rupture exposing the entire kidney is a rare and not well-described event. We present ...a successful treatment of this complication in a patient admitted to our unit. A single-stage procedure was performed combining debridement and reconstruction with a pedicled anterolateral thigh flap and an iliotibial band transferring. A short literature review is performed comparing the different treatment strategies and results.
Abstract Background So far, the ImmuKnow Immune Cell Function Assay (Cylex, Inc., Columbia, MD, USA) has been used to assess risks of infection and rejection in transplant patients. We hypothesized ...that the ImmuKnow assay might be used for mortality screening in transplant patients overall. Methods In the period of February 2007 to December 2009, at the Uppsala University Hospital, 362 patients who received either kidney, kidney + pancreas, kidney + islet cells, liver or liver + kidney allografts were randomly screened using the ImmuKnow assay. All causes of mortality were compared between two groups: patients with at least one ImmuKnow assay below 175 ng/mL and patients with all ImmuKnow assays from 175 ng/mL and above. Subsequently, the frequency of rejection within thirty days of the ImmuKnow assay was compared between these two groups. Results The study included 1031 ImmuKnow assays obtained from the 362 patients. A total of 111 patients had at least one ImmuKnow below 175 ng/mL and 251 patients had all their ImmuKnow assays from 175 ng/mL and above. By January 31st 2010, 16 of 111 patients (14.4%) with at least one ImmuKnow assay below 175 ng/mL were deceased, compared to 13 of 251 patients (5.2%) with all ImmuKnow assays from 175 ng/mL and above ( p = 0.0053, Fisher's exact test). There was no difference in the frequency of rejection between the two groups (19.8% versus 17.5%, p = 0.66). Conclusions In addition to assessing relative risks of infection and rejection in transplant patients, the ImmuKnow assay may be used to identify patients with increased risk of short-term mortality. Transplant patients being highly overimmunosuppressed as assessed by the ImmuKnow assay do not seem to have a lower risk of short-term rejection.
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