Anti-C1s monoclonal antibody BIVV009 in late antibody-mediated kidney allograft rejection-results from a first-in-patient phase 1 trial.

The classical pathway (CP) of complement may contribute to the pathogenesis of antibody-mediated rejection (ABMR). Selective CP blockade may be a promising strategy to counteract rejection. The objective of this first-in-patient phase 1b trial was to evaluate the safety/tolerability and CP-blocking potential of 4 weekly doses (60 mg/kg) of the anti-C1s antibody BIVV009 in complement-mediated disorders. Here we describe the results in a cohort of 10 stable kidney transplant recipients (median of 4.3 years posttransplantation) with late active ABMR and features of CP activation, such as capillary C4d or complement-fixing donor-specific antibodies (DSA). During 7 weeks follow-up, no severe adverse events were reported, and BIVV009 profoundly inhibited overall and DSA-triggered CP activation in serum. Five of 8 C4d-positive recipients turned C4d-negative in 5-week follow-up biopsies, while another 2 recipients showed a substantial decrease in C4d scores. There was, however, no change in microcirculation inflammation, gene expression patterns, DSA levels, or kidney function. In conclusion, we demonstrate that BIVV009 effectively blocks alloantibody-triggered CP activation, even though short-course treatment had no effect on indices of activity in late ABMR. This initial trial provides a valuable basis for future studies designed to clarify the therapeutic value of CP blockade in transplantation. ClinicalTrials.gov NCT#02502903.

Regulatory T Cells Promote Natural Killer Cell Education in Mixed Chimeras.

Therapeutic administration of regulatory T cells (Tregs) leads to engraftment of conventional doses of allogeneic bone marrow (BM) in nonirradiated recipient mice conditioned with costimulation blockade and mammalian target of rapamycin inhibition. The mode of action responsible for this Treg effect is poorly understood but may encompass the control of costimulation blockade-resistant natural killer (NK) cells. We show that transient NK cell depletion at the time of BM transplantation led to BM engraftment and persistent chimerism without Treg transfer but failed to induce skin graft tolerance. In contrast, the permanent absence of anti-donor NK reactivity in mice grafted with F1 BM was associated with both chimerism and tolerance comparable to Treg therapy, implying that NK cell tolerization is a critical mechanism of Treg therapy. Indeed, NK cells of Treg-treated BM recipients reshaped their receptor repertoire in the presence of donor MHC in a manner suggesting attenuated donor reactivity. These results indicate that adoptively transferred Tregs prevent BM rejection, at least in part, by suppressing NK cells and promote tolerance by regulating the appearance of NK cells expressing activating receptors to donor class I MHC.

Effect of the Anti-C1s Humanized Antibody TNT009 and Its Parental Mouse Variant TNT003 on HLA Antibody-Induced Complement Activation-A Preclinical In Vitro Study.

The classic pathway (CP) of complement is believed to significantly contribute to alloantibody-mediated transplant injury, and targeted complement inhibition is currently considered to be a promising approach for preventing rejection. Here, we investigated the mode of action and efficacy of the humanized anti-C1s monoclonal antibody TNT009 and its parental mouse variant, TNT003, in preclinical in vitro models of HLA antibody-triggered CP activation. In flow cytometric assays, we measured the attachment of C1 subcomponents and C4/C3 split products (C4b/d, C3b/d) to HLA antigen-coated flow beads or HLA-mismatched aortic endothelial cells and splenic lymphocytes. Anti-C1s antibodies profoundly inhibited C3 activation at concentrations >20 µg/mL, in both solid phase and cellular assays. While C4 activation was also prevented, this was not the case for C1 subcomponent attachment. Analysis of serum samples obtained from 68 sensitized transplant candidates revealed that the potency of inhibition was related to the extent of baseline CP activation. This study demonstrates that anti-C1s antibodies TNT009 and TNT003 are highly effective in blocking HLA antibody-triggered complement activation downstream of C1. Our results provide the foundation for clinical studies designed to investigate the potential of TNT009 in the treatment or prevention of complement-mediated tissue injury in sensitized transplant recipients.

The Immunosuppressive Effect of CTLA4 Immunoglobulin Is Dependent on Regulatory T Cells at Low But Not High Doses.

B7.1/2-targeted costimulation blockade (CTLA4 immunoglobulin [CTLA4-Ig]) is available for immunosuppression after kidney transplantation, but its potentially detrimental impact on regulatory T cells (Tregs) is of concern. We investigated the effects of CTLA4-Ig monotherapy in a fully mismatched heart transplant model (BALB/c onto C57BL/6). CTLA4-Ig was injected chronically (on days 0, 4, 14, and 28 and every 4 weeks thereafter) in dosing regimens paralleling clinical use, shown per mouse: low dose (LD), 0.25 mg (≈10 mg/kg body weight); high dose (HD), 1.25 mg (≈50 mg/kg body weight); and very high dose (VHD), 6.25 mg (≈250 mg/kg body weight). Chronic CTLA4-Ig therapy showed dose-dependent efficacy, with the LD regimen prolonging graft survival and with the HD and VHD regimens leading to >95% long-term graft survival and preserved histology. CTLA4-Ig's effect was immunosuppressive rather than tolerogenic because treatment cessation after ≈3 mo led to rejection. FoxP3-positive Tregs were reduced in naïve mice to a similar degree, independent of the CTLA4-Ig dose, but recovered to normal values in heart recipients under chronic CTLA4-Ig therapy. Treg depletion (anti-CD25) resulted in an impaired outcome under LD therapy but had no detectable effect under HD therapy. Consequently, the immunosuppressive effect of partially effective LD CTLA4-Ig therapy is impaired when Tregs are removed, whereas CTLA4-Ig monotherapy at higher doses effectively maintains graft survival independent of Tregs.

Exogenous Lipocalin 2 Ameliorates Acute Rejection in a Mouse Model of Renal Transplantation.

Lipocalin 2 (Lcn2) is rapidly produced by damaged nephron epithelia and is one of the most promising new markers of renal injury, delayed graft function and acute allograft rejection (AR); however, the functional importance of Lcn2 in renal transplantation is largely unknown. To understand the role of Lcn2 in renal AR, kidneys from Balb/c mice were transplanted into C57Bl/6 mice and vice versa and analyzed for morphological and physiological outcomes of AR at posttransplantation days 3, 5, and 7. The allografts showed a steady increase in intensity of interstitial infiltration, tubulitis and periarterial aggregation of lymphocytes associated with a substantial elevation in serum levels of creatinine, urea and Lcn2. Perioperative administration of recombinant Lcn2:siderophore:Fe complex (rLcn2) to recipients resulted in functional and morphological amelioration of the allograft at day 7 almost as efficiently as daily immunosuppression with cyclosporine A (CsA). No significant differences were observed in various donor-recipient combinations (C57Bl/6 wild-type and Lcn2(-/-) , Balb/c donors and recipients). Histochemical analyses of the allografts showed reduced cell death in recipients treated with rLcn2 or CsA. These results demonstrate that Lcn2 plays an important role in reducing the extent of kidney AR and indicate the therapeutic potential of Lcn2 in transplantation.

Banff Initiative for Quality Assurance in Transplantation (BIFQUIT): reproducibility of polyomavirus immunohistochemistry in kidney allografts.

Immunohistochemistry (IHC) is the gold standard for diagnosing (positive vs. negative) polyomavirus BK (BKV) nephropathy and has the potential for disease staging based on staining intensity and quantification of infected cells. This multicenter trial evaluated the reproducibility of BKV IHC among 81 pathologists at 60 institutions. Participants stained tissue microarray slides and scored them for staining intensity and percentage of positive nuclei. Staining protocol details and evaluation scores were collected online. Slides were returned for centralized panel re-evaluation and kappa statistics were calculated. Individual assessment of staining intensity and percentage was more reproducible than combined scoring. Inter-institutional reproducibility was moderate for staining intensity (κ = 0.49) and percentage (κ = 0.42), fair for combined (κ = 0.25) and best for simple positive/negative scoring (κ = 0.78). Inter-observer reproducibility was substantial for intensity (κ = 0.74), percentage (κ = 0.66), positive/negative (κ = 0.78) and moderate for combined scoring (κ = 0.43). Inter-laboratory reproducibility was fair for intensity (κ = 0.37), percentage (κ = 0.40) and combined (κ = 0.24), but substantial for positive/negative scoring (κ = 0.67). BKV RNA copies/cell correlated with staining intensity (r = 0.56) and percentage (r = 0.62). These results indicate that BKV IHC is reproducible between observers but scoring should be simplified to a single-feature schema. Standardization of tissue processing and staining protocols would further improve inter-laboratory reproducibility.

Banff initiative for quality assurance in transplantation (BIFQUIT): reproducibility of C4d immunohistochemistry in kidney allografts.

Detection of C4d is crucial for diagnosing antibody-mediated-rejection. We conducted a multicenter trial to assess the reproducibility for C4d immunohistochemistry on paraffin tissue. Unstained slides from a tissue microarray (TMA) comprising 44 kidney allograft specimens representing a full analytical spectrum for C4d were distributed to 73 institutions. Participants stained TMA slides using local protocols and evaluated their slides following the Banff C4d schema. Local staining details and evaluation scores were collected online. Stained slides were returned for centralized panel re-evaluation. Kappa statistics were used to determine reproducibility. Poor interinstitutional reproducibility was observed (kappa 0.17), which was equally due to limitations in interobserver (kappa 0.44) and interlaboratory reproducibility (kappa 0.46). Depending on the cut-off, reproducibility could be improved by omitting C4d grading and only considering ± calls. Heat-induced epitope recovery (pH 6-7, 20-30 min, citrate buffer) with polyclonal antibody incubation (<1:80, >40 min) appeared as best practice. The BIFQUIT trial results indicated that C4d staining on paraffin sections varies considerably between laboratories. Refinement of the current Banff C4d scoring schema and harmonization of tissue processing and staining protocols is necessary to achieve acceptable reproducibility.

Peritransplant immunoadsorption for positive crossmatch deceased donor kidney transplantation.

Various desensitization protocols were shown to enable successful living donor kidney transplantation across a positive complement-dependent cytotoxicity crossmatch (CDCXM). Positive crossmatch transplantation, however, is less well established for deceased donor transplantation. We report a cohort of 68 deceased donor renal allograft recipients who, on the basis of broad sensitization (lymphocytotoxic panel reactivity ≥40%), were subjected to a protocol of peritransplant immunoadsorption (IA). Treatment consisted of a single session of immediate pretransplant IA (protein A) followed by posttransplant IA and antilymphocyte antibody therapy. Twenty-one patients had a positive CDCXM, which could be rendered negative by pretransplant apheresis. Solid phase HLA antibody detection revealed preformed donor-specific antibodies (DSA) in all 21 CDCXM-positive and in 30 CDCXM-negative recipients. At 5 years, overall graft survival, death-censored graft survival and patient survival were 63%, 76% and 87%, respectively, without any differences between CDCXM-positive, CDCXM-negative/DSA-positive and CDCXM-negative/DSA-negative recipients. Furthermore, groups did not differ regarding rates of antibody-mediated rejection (24% vs. 30% vs. 24%, p = 0.84), cellular rejection (14% vs. 23% vs. 18%, p = 0.7) or allograft function (median 5-year serum creatinine: 1.3 vs. 1.8 vs. 1.7 mg/dL, p = 0.62). Our results suggest that peritransplant IA is an effective strategy for rapid desensitization in deceased donor transplantation.

Banff '09 meeting report: antibody mediated graft deterioration and implementation of Banff working groups.

The 10th Banff Conference on Allograft Pathology was held in Banff, Canada from August 9 to 14, 2009. A total of 263 transplant clinicians, pathologists, surgeons, immunologists and researchers discussed several aspects of solid organ transplants with a special focus on antibody mediated graft injury. The willingness of the Banff process to adapt continuously in response to new research and improve potential weaknesses, led to the implementation of six working groups on the following areas: isolated v-lesion, fibrosis scoring, glomerular lesions, molecular pathology, polyomavirus nephropathy and quality assurance. Banff working groups will conduct multicenter trials to evaluate the clinical relevance, practical feasibility and reproducibility of potential changes to the Banff classification. There were also sessions on quality improvement in biopsy reading and utilization of virtual microscopy for maintaining competence in transplant biopsy interpretation. In addition, compelling molecular research data led to the discussion of incorporation of omics-technologies and discovery of new tissue markers with the goal of combining histopathology and molecular parameters within the Banff working classification in the near future.

Posttransplant HLA alloreactivity in stable kidney transplant recipients-incidences and impact on long-term allograft outcomes.

Humoral alloreactivity is well established to predict adverse allograft outcomes. However, in some recipients, alloantibodies may also occur in the absence of graft dysfunction. We evaluated if and how often complement- and noncomplement-fixing alloantibodies are detectable in stable recipients and whether, in this context, they affect long-term outcomes. Sera obtained from 164 kidney transplant recipients at 2, 6 and 12 months were evaluated by FlowPRA screening and single-antigen testing for detection of IgG- or C4d-fixing HLA panel reactivity and donor-specific antibodies (DSA). Applying stringent criteria, we selected 34 patients with an uneventful 1-year course (no graft dysfunction or rejection) and excellent graft function at 12 months [estimated glomerular filtration rate (eGFR) >or=60 mL/min and proteinuria

In vitro detection of C4d-fixing HLA alloantibodies: associations with capillary C4d deposition in kidney allografts.

Capillary C4d deposition is a valuable marker of antibody-mediated rejection (AMR). In this analysis, flow cytometric detection of alloantibody-triggered C4d deposition to HLA antigen-coated microparticles ([C4d]FlowPRA) was evaluated for its value as a marker for C4d deposition in renal allografts. For comparative analysis, 105 first renal biopsies performed for graft dysfunction and an equal number of concurrent sera were subjected to immunohistochemistry and [C4d] plus standard [IgG]FlowPRA, respectively. C4d deposition/fixation was detected in 17 biopsies and, applying [C4d]FlowPRA HLA class I and II screening, also in a small number of corresponding sera (N = 20). IgG reactivity detected by standard [IgG]FlowPRA was more frequent (49% of sera). Comparing [C4d]FlowPRA screening with capillary C4d staining, we found a high level of specificity (0.92 [95% confidence interval: 0.86-0.98]), which far exceeded that calculated for [IgG]FlowPRA (0.60 [0.50-0.70]). [IgG]FlowPRA screening, however, turned out to be superior in terms of sensitivity (0.94 [0.83-1.05] vs. 0.76 [0.56-0.97] calculated for C4d-fixing panel reactivity). Remarkably, posttransplant single antigen testing for identification of complement-fixing donor-specific alloreactivities failed to improve the predictive value of FlowPRA-based serology. In conclusion, our results suggest that detection of complement-fixing HLA panel reactivity could provide a specific tool for monitoring of C4d-positive AMR.

Banff 07 classification of renal allograft pathology: updates and future directions.

The 9th Banff Conference on Allograft Pathology was held in La Coruna, Spain on June 23-29, 2007. A total of 235 pathologists, clinicians and scientists met to address unsolved issues in transplantation and adapt the Banff schema for renal allograft rejection in response to emerging data and technologies. The outcome of the consensus discussions on renal pathology is provided in this article. Major updates from the 2007 Banff Conference were: inclusion of peritubular capillaritis grading, C4d scoring, interpretation of C4d deposition without morphological evidence of active rejection, application of the Banff criteria to zero-time and protocol biopsies and introduction of a new scoring for total interstitial inflammation (ti-score). In addition, emerging research data led to the establishment of collaborative working groups addressing issues like isolated 'v' lesion and incorporation of omics-technologies, paving the way for future combination of graft biopsy and molecular parameters within the Banff process.

The source matters: no impact of the CCL2/MCP-1-1-2518G polymorphism of the donor on renal allograft outcome during the first year after transplantation.

Chemokines are involved in the recruitment of inflammatory cells to vascularized allografts. The chemokine CCL2/MCP-1 is expressed during allograft dysfunction, which is associated with the recruitment of inflammatory cells. Both intrinsic renal cells (donor origin) as well as infiltrating inflammatory cells (recipient origin) can be a source of CCL2/MCP-1. We previously demonstrated that the recipient MCP-1-2518G polymorphism is associated with increased CCL2/MCP-1 production by inflammatory cells and decreased renal allograft survival. We evaluated the impact of the MCP-1-2518G polymorphism in donor cells on renal allograft outcomes. We enrolled 252 recipients of kidney allografts in this retrospective study who had received grafts from 152 cadaveric donors. The CCL2/MCP-1 genotype was assessed using genomic DNA isolated from cryopreserved donor splenocytes. Outcome parameters studied were acute biopsy proven rejection (Banff criteria), serum creatinine, and glomerular filtration rate (GFR) at 1 year after transplantation, allograft loss, and death. MCP-1-2518 genotypes were in HW equilibrium. A/A was present in 125 (49.6%), A/G in 107 (42.5%), and G/G in 20 (7.9%) donor kidneys. There were no significant differences in the number of rejection episodes, the number of allograft losses, serum creatinine, GFR, or overall survival 1 year after transplantation. In contrast with the detrimental effect of the CCL2/MCP-1 polymorphism of the recipient, the CCL2/MCP-1 polymorphism of the donor has no impact on the allograft outcome during the first year after transplantation. The impact on the long-term outcomes needs further evaluation.

[The role of endothelial cells in allograft rejection]. / Die Rolle von Endothelzellen in der Transplantatabstossung.

Endothelial cells (EC) are crucially involved in allograft rejection. They are prime targets of alloreactivity but also key players in the recruitment and extravasation of immune cells. These mechanisms also become clear in allograft biopsies with antibody-mediated complement deposition on EC and associated intracapillary accumulation of immune cells. HLA molecules are the most prominent targets of alloantibodies in AB0 compatible transplantation. Clinically relevant antibodies against other antigens such as MICA (MHC class I-related chain A) or the angiotensin II Type-1 receptor could also be convincingly demonstrated. The lack of generally available diagnostic tests for such non-HLA antibodies hampers their introduction into clinical practice. Alloantibodies undoubtedly cause allograft rejection. However, our knowledge of the molecular mechanisms underlying graft dysfunction in antibody-mediated rejection (AMR) is still fragmentary. Activation of EC by anti-endothelial cell antibodies was demonstrated in several experimental systems. Recent animal studies employing immune cell deficient transplant recipients or in-vitro assays, however, failed to demonstrate an immediate response of EC upon antibody binding and complement activation. It might therefore be considered that direct antibody- or complement-mediated EC damage is not necessarily the leading event in acute AMR. Antibody- and/or complement-induced recruitment of immune cells might rather be of crucial importance at least in the early phases of AMR.

Glomerular permselectivity in proteinuric patients after kidney transplantation.

To characterize the defect in glomerular permselectivity responsible for proteinuria after renal transplantation, we studied 10 patients with moderate proteinuria (median 0.37 g/d, range 0.20-0.79), 16 patients with the nephrotic syndrome (6.73 g/d, 3.9-14.6), 8 living related donor transplant recipients without any history of rejection (median proteinuria 0.26 g/d, 0.06-0.58), and 12 healthy volunteers. The fractional clearance of neutral dextrans > 54 A was significantly higher in nephrotic patients, demonstrating a defect in glomerular size selectivity. Using a log-normal model of glomerular pore size distribution, r*(5%) and r*(1%), indices for the presence of large pores, were increased in the nephrotic patients. The fractional clearance of negatively charged dextran sulfate was significantly higher in all patient groups, indicating a loss of glomerular charge selectivity. Biopsy findings showed more prominent glomerular lesions in the nephrotic group compared with the moderately proteinuric group. We conclude that mild proteinuria late after renal transplantation is associated with a defect in glomerular charge selectivity. The development of nephrotic range proteinuria is associated also with a defect of glomerular size selectivity, which correlates with prominent glomerular pathology.

VEGF(165) mediates glomerular endothelial repair.

VEGF(165), the most abundant isoform in man, is an angiogenic cytokine that also regulates vascular permeability. Its function in the renal glomerulus, where it is expressed in visceral epithelial and mesangial cells, is unknown. To assess the role of VEGF(165) in glomerular disease, we administered a novel antagonist - a high-affinity, nuclease-resistant RNA aptamer coupled to 40-kDa polyethylene glycol (PEG) - to normal rats and to rats with mesangioproliferative nephritis, passive Heymann nephritis (PHN), or puromycin aminonucleoside nephrosis (PAN). In normal rats, antagonism of VEGF(165) for 21 days failed to induce glomerular pathology or proteinuria. In rats with mesangioproliferative nephritis, the VEGF(165) aptamer (but not a sequence-scrambled control RNA or PEG alone) led to a reduction of glomerular endothelial regeneration and an increase in endothelial cell death, provoking an 8-fold increase in the frequency of glomerular microaneurysms by day 6. In contrast, early leukocyte influx and the proliferation, activation, and matrix accumulation of mesangial cells were not affected in these rats. In rats with PHN or PAN, administration of the VEGF(165) aptamer did not influence the course of proteinuria using various dosages and administration routes. These data identify VEGF(165) as a factor of central importance for endothelial cell survival and repair in glomerular disease, and point to a potentially novel way to influence the course of glomerular diseases characterized by endothelial cell damage, such as various glomerulonephritides, thrombotic microangiopathies, or renal transplant rejection.

The original Gerstmann-Sträussler-Scheinker family of Austria: divergent clinicopathological phenotypes but constant PrP genotype.

We present new data on the original Austrian kindred with Gerstmann-Sträussler-Scheinker disease (GSS) which encompasses currently 221 members in 9 generations. The mode of inheritance is autosomal dominant. Predominant clinical features are slowly progressive ataxia and late impairment of higher cerebral functions. In contrast, a recent case with proven P102L mutation of the PRNP gene had rapidly developing dementia and severe cortical damage indistinguishable from the clinicopathological phenotype of Creutzfeldt-Jakob disease (CJD). PRNP codon 129 was homozygous for methionine in both the historic and recent cases. Neuropathology confirms spongiosis of variable degree and numerous protease resistant/prion protein (PrP) amyloid plaques scattered throughout most of the brain as constant features in this family. Some amyloid deposits are surrounded by dystrophic neurites with accumulation of phosphorylated neurofilaments and abnormal organelles, reminiscent of Alzheimer-type plaques. Severe telencephalic damage and a synaptic-type fine granular immunoreactivity in laminar distribution in the cortex with anti-PrP after hydrated autoclaving of sections were seen only in the recent patient. In conclusion, factors in addition to the PRNP genotype at codons 102 and 129 must play a role in determining clinicopathological characteristics of this inherited brain amyloidosis.

The long-term effect of simultaneous heart and kidney transplantation on native renal function.

BACKGROUND: It is unclear whether patients with heart failure and renal insufficiency should receive a simultaneous heart and kidney transplant or whether a single heart transplantation is sufficient to restore native renal function. METHODS: We analyzed the renal plasma flow and glomerular filtration of the native and transplant kidneys in eight patients long term after simultaneous heart and kidney transplantation using a dynamic MAG3 radioisotope scan and serum creatinine determinations. All subjects had been hemodialysis dependent before transplantation. Seven patients suffered from an intrinsic renal disease that were diabetic nephropathy in three cases, small fibrotic kidneys of undetermined origin in two cases, one lupus nephritis, and cyclosporine nephrotoxicity in one patient who had a previous heart transplant. In one patient renal insufficiency was considered to be solely due to renal hypoperfusion because no intrinsic renal disease could be detected. RESULTS: All patients were on cyclosporine-based triple immunosuppression, transplanted for 4 to 10 years, exhibited cardiac ejection fractions of more than 50% and had normal serum creatinine values. Radioisotopic scan showed no function of the native kidneys in all seven patients with intrinsic renal disease but exhibited normal function of the native kidneys as well as the renal transplant in the patient without intrinsic kidney disease before transplantation. CONCLUSIONS: These data suggest that a simultaneous heart and kidney transplantation is necessary in patients with cardiomyopathy and renal insufficiency due to primary kidney disease, but not in those with hemodynamically mediated renal failure, even if an immunosuppressive regimen with calcineurin inhibitors is used.

The contribution of adhesion molecule expression in donor kidney biopsies to early allograft dysfunction.

BACKGROUND: Renal allograft rejection is associated with the expression of adhesion molecules on vascular endothelial and tubular epithelial cells. METHODS: To assess whether the number of cell adhesion molecules expressed in donor kidneys can predict early rejection or delayed graft function, kidney biopsies from 20 living and 53 cadaveric kidney donors were obtained before engraftment into the recipients and the expression of the cell adhesion molecules intercellular adhesion molecule 1 (ICAM-1), vascular cell adhesion molecule 1 (VCAM-1), and endothelial leukocyte adhesion molecule (E-selectin) were determined by immunohistochemistry. RESULTS: All biopsies from living donors showed significantly lower expression of ICAM-1 and VCAM-1 compared to biopsies from cadaveric donors. There was no difference in the expression of adhesion molecules on tubular cells between transplants with primary function compared to allografts with early rejection in living donated kidneys (ICAM-1: 2+/-8 vs. 3+/-8%; VCAM-1: 9+/-7 vs. 1+/-1%), as well as in cadaveric kidneys (ICAM-1: 38+/-29 vs. 39+/-38%; VCAM-1: 55+/-27 vs. 48+/-29%). The expression of ICAM-1 molecules on tubular cells was determined to be a predictor for the occurrence of delayed graft function in cadaveric kidneys (ICAM-1: 65+/-24* vs. 38+/-29% delayed graft versus primary graft function). No delayed graft function occurred in recipients of living donated kidneys. CONCLUSIONS: These data suggest that adhesion molecule expression in donor biopsies is not a predictor for early allograft rejection, but can be used as a marker for the development of postischemic acute renal allograft failure.

Posttransplant hemolytic uremic syndrome in adult retransplanted kidney graft recipients: advantage of FK506 therapy?

BACKGROUND: Posttransplant hemolytic uremic syndrome (pHUS) is a rare but severe disorder that confers a poor prognosis on an allograft due to thrombotic microangiopathy. Immunosuppression with cyclosporine (CsA) is implicated as a significant risk factor for the development of pHUS. In early reports, it was hypothesized that immunosuppression with FK506 (tacrolimus) would avoid the development of pHUS. However, this initially supposed beneficial effect remains controversial, because pHUS associated with tacrolimus therapy has been published in some later case reports. This article aims to further evaluate FK506 with respect to the development and resolution of pHUS. METHODS: We describe the course of seven adult kidney graft recipients with pHUS, treated with FK506 either as initial immunosuppression for retransplantation or after discontinuation of CsA for resolution of pHUS. Work-up for pHUS was initiated when certain clinical features, such as hemolytic anemia, thrombocytopenia, and deterioration of graft function, were found. The diagnosis was confirmed by histologic examination of a renal allograft biopsy specimen (thrombotic microangiopathy). With the onset of pHUS, additional plasma exchange was performed in all patients. RESULTS: Two patients suffered from end-stage renal disease due to primary HUS and had a history of recurrent pHUS in previous renal transplants. In both patients, the attempt to regraft was only made because of the early optimistic reports using FK506. Despite initial FK506 therapy, both recipients developed pHUS again, leading to loss of graft function. Two additional kidney graft recipients with primary renal failure other than HUS also received FK506 as initial immunosuppression. One of them (loss of the first kidney graft due to CsA-induced pHUS) was successfully treated with FK506 for his second renal transplant. The other recipient, a patient in whom de novo pHUS had occurred in the first graft despite initial therapy with FK506, was treated with CsA for his second graft and again developed pHUS. The latter process, however, could be reversed by a switch to steroids and azathioprine. In all three patients regrafted for reasons other than pHUS, development of de novo pHUS was treated by CsA withdrawal and a switch to FK506; this approach was effective in two patients. CONCLUSION: Our results demonstrate that three of seven renal allograft recipients benefited from FK506 therapy for prevention or resolution of pHUS. Treatment or prophylaxis with FK506 can be considered advantageous in some patients with de novo pHUS, but FK506 fails to prevent recurrent pHUS in patients with primary HUS.