The Kidney Donor Profile Index (KDPI) of marginal donors allocated by standardized pretransplant donor biopsy assessment: distribution and association with graft outcomes.

Pretransplant donor biopsy (PTDB)-based marginal donor allocation systems to single or dual renal transplantation could increase the use of organs with Kidney Donor Profile Index (KDPI) in the highest range (e.g. >80 or >90), whose discard rate approximates 50% in the United States. To test this hypothesis, we retrospectively calculated the KDPI and analyzed the outcomes of 442 marginal kidney transplants (340 single transplants: 278 with a PTDB Remuzzi score<4 [median KDPI: 87; interquartile range (IQR): 78-94] and 62 with a score=4 [median KDPI: 87; IQR: 76-93]; 102 dual transplants [median KDPI: 93; IQR: 86-96]) and 248 single standard transplant controls (median KDPI: 36; IQR: 18-51). PTDB-based allocation of marginal grafts led to a limited discard rate of 15% for kidneys with KDPI of 80-90 and of 37% for kidneys with a KDPI of 91-100. Although 1-year estimated GFRs were significantly lower in recipients of marginal kidneys (-9.3, -17.9 and -18.8 mL/min, for dual transplants, single kidneys with PTDB score<4 and =4, respectively; p<0.001), graft survival (median follow-up 3.3 years) was similar between marginal and standard kidney transplants (hazard ratio: 1.20 [95% confidence interval: 0.80-1.79; p=0.38]). In conclusion, PTDB-based allocation allows the safe transplantation of kidneys with KDPI in the highest range that may otherwise be discarded.

Recent progress in the pathophysiology and treatment of FSGS recurrence.

Focal segmental glomerulosclerosis (FSGS) is a glomerular disease characterized by proteinuria, frequent progression to end-stage renal disease, and recurrence after kidney transplantation in ∼25% of patients, which negatively impacts long-term allograft survival. Experimental studies suggest that abnormalities in T and, possibly, B cells may represent one initial pathogenic trigger, leading to podocyte injury and progressive loss. New data also support the existence of circulating permeability factors able to damage the podocytes, but no single molecule has been consistently identified as the causal pathogenic element in FSGS recurrence. Unfortunately, major progress from mechanistic studies has not translated into substantial advancements in patient treatment, with plasmapheresis (PP) and high doses of cyclosporine (CsA) remaining the mainstays of therapy. Despite consistent experimental and clinical evidence that treatment of proteinuria slows renal function decline in proteinuric nephropathies, maximal use of antiproteinuric agents such as renin angiotensin system antagonists is not routine in the management of FSGS recurrence. More recently, encouraging results have been reported with anti-CD20 depleting antibody rituximab, but further studies are needed to establish its safety/efficacy profile.

Eosinophils are not required for the induction and maintenance of an alloantibody response.

Eosinophil-produced cytokines have been shown to participate in the maintenance of antigen-specific plasma cells (PC) in bone marrow (BM), suggesting that eosinophils are required in the development and/or maintenance of alloantibody responses posttransplant. To test this hypothesis, we sensitized eosinophil-deficient ΔdblGATA1 mice and wild-type (WT) control mice with allogeneic splenocytes or with allogeneic heart grafts and compared the kinetics and titers of serum donor-specific antibodies (DSA), as well as BM and spleen CD130 + B220 low PC populations between groups. Spleen cells from naïve ΔdblGATA1 BALB/c mice contained higher percentages of PC than WT without detectable differences in BM PCs. After sensitization with allogeneic splenocytes, BALB/c ΔdblGATA1 mice contained fewer BM PCs but more splenic PCs compared to controls. These differences were associated with modestly lower titers of serum DSA 4 and 12 weeks after sensitization but secondary immunizations induced similar increases in both groups. Moreover, the kinetics and strength of DSA did not differ in WT and ΔdblGATA1 BALB/c mice transplanted with B6 cardiac allografts, nor did they differ in transplanted ΔdblGATA1 and WT mice on a B6 background. Therefore, eosinophils are not required for alloantibody formation or maintenance in mice and are thus unlikely to be effective targets for antibody desensitization.

Immunosuppressive effects of the traditional Chinese herb Qu Mai on human alloreactive T cells.

Current therapies for transplant rejection are suboptimally effective. In an effort to discover novel immunosuppressants we used cytokine ELISPOT and ELISAs to screen extracts from 53 traditional Chinese herbs for their ability to suppress human alloreactive T cells. We identified a dichloromethane-soluble fraction (Qu Mai fraction AD [QMAD]) of Qu Mai (Dianthus superbus) as a candidate. High-performance liquid chromatography (HPLC) analysis of QMAD revealed three dominant peaks, each with a MW ~600 Daltons and distinct from cyclosporine and rapamycin. When we added QMAD to human mixed lymphocyte cultures, we observed dose-dependent inhibition of proliferation and IFNγ production, by naïve and memory alloreactive T cells, and observed an increased frequency of Foxp3(+) CD4(+) T cells. To address whether QMAD induces regulatory T cells we added QMAD to anti-CD3/CD28-stimulated naïve CD4 T cells and observed a dose-dependent upregulation of Foxp3 associated with new suppressive capacity. Mechanistically, QMAD did not induce T cell IL-10 or TGFß but blocked T cell AKT phosphorylation, a key signaling nexus required for T cell proliferation and expansion, that simultaneously prevents Foxp3 transcription. Our findings provide novel insight into the antiinflammatory effects of one traditional Chinese herb, and support the need for continued isolation, characterization and testing of QMAD-derived components as immune suppressants for transplant rejection.

Immune cell-derived C3a and C5a costimulate human T cell alloimmunity.

Emerging evidence indicates that complement provides costimulatory signals for murine T cells but whether complement impacts human T cells remains unclear. We observed production of complement activation products C3a and C5a during in vitro cultures of human T cells responding to allogeneic dendritic cells (DC). Both partners expressed the receptors for C3a (C3aR) and C5a (C5aR) and C3aR- and C5aR-antagonists inhibited T cell proliferation. Recombinant C3a/C5a promoted CD4(+) T cell expansion, bypassed the inhibitory effects of CTLA4-Ig, and induced AKT phosphorylation, the latter biochemically linking C3aR/C5aR to known T cell signaling pathways. Lowering DC C3a/C5a production by siRNA knockdown of DC C3 reduced T cell alloresponses. Conversely downregulating DC expression of the complement regulatory protein decay-accelerating factor increased immune cell C3a/C5a and augmented T cell proliferation, identifying antigen presenting cells as the dominant complement source. Pharmacological C5aR blockade reduced graft versus host disease (GVHD) scores, prolonged survival, and inhibited T cell responses in NOD scid γc(null) mouse recipients of human peripheral blood mononuclear cells, verifying that the mechanisms apply in vivo. Together our findings unequivocally document that immune cell-derived complement impacts human T cell immunity and provide the foundation for future studies targeting C3aR/C5aR as treatments of GVHD and organ transplant rejection in humans.

Trends in immune cell function assay and donor-specific HLA antibodies in kidney transplantation: A 3-year prospective study.

The immune cell function assay (ICFA) and de novo anti-donor-specific HLA antibodies (DSA) have been proposed as assays for immune monitoring in renal transplantation, but longitudinal studies examining the modification of both parameters over time and their relation with clinical events are lacking. We prospectively measured longitudinal changes in ICFA and DSA levels in 55 kidney transplant recipients over 3-year follow-up (534 visits) and analyzed their relation with the risk of developing acute rejections or infections. Seven patients (12.7%) developed biopsy-proven acute rejection, and 20 (36.4%) developed viral infections. At 3 years posttransplant, 28% of the patients had developed de novo DSA. ICFA levels peaked at 1-2 months posttransplant (p = 0.005) and leveled off thereafter. They were not associated with the risk of acute rejections, viral infections or development of de novo DSA. Instead, the incidence of de novo DSA was higher in patients who previously had viral infections (adjusted-odds ratio of de novo DSA associated with prior infections: 6.03 [95% CI, 1.64-22.06; p = 0.007]). Our prospective, longitudinal study does not support using ICFA to quantify the immune risk in kidney transplantation. Further studies are needed to confirm the relationship between viral infections and the subsequent development of de novo DSA.

Thrice-weekly in-center nocturnal hemodialysis: an effective strategy to optimize chronic dialysis therapy.

OBJECTIVES: Daily nocturnal hemodialysis (NHD) has been proposed as a valuable strategy to improve outcomes for patients on conventional hemodialysis (CHD), but it is burdened by high costs and logistic issues. Thrice NHD might represent a more affordable approach to improve hemodialysis patient outcome. METHODS: Here we retrospectively analyzed the data on blood pressure, body weight, and hematochemical parameters in a cohort of 7 patients (mean age 50.4-/+11.0 years, duration of CHD 14.3-/+11.5 years) who registered in the NHD program at the dialysis unit of Ospedali Riuniti, Bergamo, Italy. Data for the 2 first years of NHD were compared with those of the last year on CHD. RESULTS: At 2 years after start of NHD, we found a significant decrease in systolic (149.4-/+16.6 vs. 128.4+/-26.0 mm Hg, p<0.001) and diastolic (87.7-/+11.1 vs. 79.6-/+16.7 mm Hg, p<0.05) blood pressure, along with a significant reduction in the use of per-patient antihypertensive agents (1.17-/+1.19 vs. 0.47-/+0.89, p<0.05 and an increase in dry body weight (61.4-/+21.8 vs. 67.1-/+16.4 kg, p<0.001). Moreover, patients had a significant reduction in phosphate levels (6.2-/+2.4 vs. 5.4-/+3.0 mg/dL, p<0.01). The procedure was safe and well tolerated and did not require extra cost for ad hoc facilities. CONCLUSION: NHD is an effective approach to optimize chronic dialysis therapy.

[Hemolytic uremic syndrome]. / La sindrome emolitico uremica.

Hemolytic uremic syndrome (HUS) is a disease characterized by non immune hemolytic anemia, low platelet count and renal impairment. In children, the disease is most commonly triggered by Shiga-like toxin (Stx)-producing Escherichia coli (Stx-E. Coli): however, renal function recovers in up to 70% of patients. Plasma infusion or exchange reduces mortality and the risk of end-stage renal disease (ESRD) in adult patients. Non-Shiga toxin-associated HUS (non-Stx-HUS), accounting for only 5-10% of all disease cases, can be sporadic or familial. Collectively, non-Stx-HUS forms have a poor outcome. Up to 50% of cases progress to ESRD or have irreversible brain damage, and 25% can die during the acute phase of the disease. Genetic studies have recently documented that the familial form is associated with genetic abnormalities of complement regulatory proteins, and evidence is now emerging that similar genetic alterations can predispose to sporadic cases of non-Stx-HUS as well. Mutations of genes encoding for factor H, a glycoprotein that plays an important role in the regulation of the alternative pathway of complement and for MCP, a widely expressed transmembrane glycoprotein with an inhibitory role of activated C3, are reported in familial HUS. These mutations are more likely to predispose rather than to cause the disease directly.