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AbstractChronic allograft nephropathy is a major cause of progressive renal failure in renal transplant recipients. Its etiology is multifactorial and may include both immunologic and nonimmunologic causes. In this observational cohort study we set out to see if calcineurin inhibitor withdrawal would reduce the likelihood of graft loss. Methods: One hundred and five renal transplant recipients with impaired kidney function (mean serum creatinine 3.0 ± 0.1 mg/dl) and biopsy-proven chronic allograft nephropathy had the dose of their calcineurin inhibitors, cyclosporine (CSA), or tacrolimus (FK), reduced or discontinued with either the addition of, or continuation of mycophenolate mofetil and low-dose corticosteroids. This intervention occurred at a mean of 29.0 ± 2.7 months after transplantation. Follow-up after intervention was 54.3 ± 4.1 months in the reduced CSA group (n = 64), 41.6 ± 3.2 months in the reduced FK group (n = 28), and 75.5 ± 6.7 months in the calcineurin inhibitor withdrawal group (n = 13). Results: There were 24 graft failures in the reduced CSA group, 9 graft failures in the reduced FK group, and 1 graft lost in the calcineurin inhibitor withdrawal group. The unadjusted relative risk for graft failure in the CSA and FK groups combined (confidence interval 1.05–31.6), was 4.07 using the calcineurin inhibitor withdrawal group as the reference, p = 0.05. A Cox proportional hazards model adjusting for baseline covariates including age, gender, race, type of transplant, delayed graft function, baseline blood pressure and random serum glucose and cholesterol demonstrated that only calcineurin inhibitor dose reduction but not withdrawal, older age, delayed graft function, higher serum creatinine at the time of intervention , and higher diastolic blood pressure and serum glucose, correlated with graft loss. Only 6 of the 105 patients developed Banff grade acute rejection. All responded to steroid therapy. We conclude that although this observational cohort study may have a selection bias, late calcineurin inhibitor withdrawal in patients with chronic allograft nephropathy and impaired kidney function appears safe and durable as a treatment strategy to reduce the likelihood of graft failure.Copyright © 2004 S. Karger AG, Basel

The morphological features of polyoma virus disease (PVDz) in 571 concurrent urine and biopsy samples from 413 patients are described. In 54 patients PV was found in both biopsy and urine samples. Histologically, PV presented as: (a) mild, viral cytopathic/cytolytic changes, with absent or minimal inflammation involving isolated tubules; (b) moderate and severe, cytopathic/cytolytic changes associated with patchy or diffuse tubulo-interstitial inflammation and atrophy; (c) advanced, graft sclerosis with rare or absent viral cytopathic changes, indistinguishable from chronic allograft nephropathy. Histological progression from mild to moderate or severe disease was seen in 28 patients. The mean post-transplantation time at diagnosis was similar in patients with mild or moderate-severe renal involvement (1.05 and 1.3 years, respectively). All patients presented with similarly increased values of serum creatinine (mean 1.35 mg/dL). There was strong correlation between the number of PV infected cells in urine and the concurrent biopsies (p = 0.0001). In 13 patients PV was found only in urine; of these, two developed PVDz later. The positive predictive value of a positive urine was 90%, the negative predictive value of a negative urine was 99% and the accuracy of the test was 97%. We conclude that urine cytology is useful to evaluate renal transplant patients with PV reactivation because sloughed tubular cells are found in urine and positive urine samples are a consistent manifestation of PV renal involvement.

Recurrent autoimmunity destroys nonobese diabetic (NOD) islet isografts, but whether recurrent autoimmunity contributes to islet graft destruction in immunocompetent allogeneic recipients is unknown. In the NOD, a single dose of streptozocin prevents or delays primary autoimmunity, allowing the detection of alloimmunity alone in chemically diabetic hosts (streptozocin-NOD) to be compared to the combined effects of autoimmunity and alloimmunity in spontaneously diabetic NODs (autoimmune-NOD). Islets were isolated from prediabetic NOD (H-2K^dD^b), nonobese resistant (NOR) (H-2K^dD^b), Balb/cByJ (H-2^d) and B10.BR (H-2^k) donors and transplanted to either the renal subcapsule or the intraportal site in autoimmune-NODs or streptozocin-NODs. MHC-matched NOR islets had indefinite graft survival in streptozocin-NODs. However, NOR islets showed graft loss at 12.6 ± 3.2 days in renal subcapsule and at 6.8 ± 0.1 days in intraportal site of autoimmune-NODs. Partially MHC-matched Balb/cByJ islet grafts failed significantly sooner in autoimmune-NODs than in streptozocin-NODs (p < 0.005). Fully MHC-mismatched B10.BR islet grafts also failed sooner in autoimmune-NODs, but the difference did not reach significance (p < 0.06). Although the streptozocin-NOD was functionally tolerant of MHC-matched NOR islets, NOR islets transplanted into autoimmune-NODs failed sooner than NOD islets in both renal subcapsule (12.6 ± 3.2 days vs. 26.4 ± 10.5 days, p = 0.009) and intraportal sites (6.8 ± 0.1 days vs. 11.5 ± 1.7 days, p = 0.014). In the autoimmune-NODs, the intraportal site consistently showed shorter graft survival than the renal subcapsule site (NOD: p = 0.009, NOR: p = 0.014, Balb/cByJ: p = 0.008, B10.BR: p = 0.032). In conclusion, autoimmune processes facilitate the alloimmune response to minor and major histocompatibility antigens and accelerate graft destruction. The same autoimmune processes are more pronounced in the intraportal site.

Background: Nitric oxide (NO) regulates a variety of cellular functions. One mechanism by which NO may exert its influence is through formation of S-nitrosothiols at critical thiol residues in protein-active sites, including those of nuclear protein transcription factors. Methods: NF-@kB p50 and AP-1 c-jun were S-nitrosylated in the presence of acidic NaNO"2. Wild-type protein and protein subjected to nitrosylating conditions in the absence of NaNO"2 served as controls. Confirmatory evidence for S-nitrosothiol bond formation was obtained by ultraviolet-visible spectrophotometry with the absorption maximum for S-NO bonds at ~320 to 360 nm. With consensus oligonucleotide probes, gel-shift analysis was used to examine DNA binding characteristics. Results: In the case of NF-@kB p50, S-nitrosylation resulted in significantly decreased DNA binding. In contrast, S-nitrosylation did not alter c-jun DNA binding. The S-nitrosylating conditions themselves did not alter p50 or c-jun DNA binding. Quantitative analysis was performed according to the Scatchard plot technique to generate the respective dissociation constants. S-nitrosylated p50 was associated with a fourfold greater dissociation constant than that of the wild-type p50. Conclusions: S-nitrosylation of transcription factors may be one mechanism by which NO may selectively regulate gene transcription. (Surgery 1998;124:137-42.)

Five months after a cadaveric renal transplant a 69-year-old man was admitted with caval, iliac, and renal allograft vein thrombosis that occurred in the setting of a previously placed caval filter. The patient's urine output and renal function deteriorated rapidly. Thrombolytic therapy with urokinase was begun, and lysis of the thrombus occurred in 72 hours. The patient's renal function returned to baseline, and the transplant was salvaged. Moreover lower extremity venous patency and valvular function were maintained. We report the case and review the literature on thrombolytic therapy for renal allograft vein and lower extremity deep venous thrombosis. (J VASC SURG 1995;21:691-6.)

The clinical and pathological features of acute pancreas allograft rejection and involvement of the graft by posttransplantation lymphoproliferative disorders (PTLD) overlap. Because the treatment is diametrically opposite in these two types of lesions, an accurate diagnosis is essential. The histological features in pancreas allograft needle biopsy specimens (n = 7) and pancreatectomies (n = 4) from four patients with Epstein-Barr virus (EBV)-related PTLD were compared with the material from 14 patients who did not develop PTLD after 12 to 58 months of follow-up and whose biopsy specimens (n = 10) and pancreatectomies (n - 10) showed rejection-related heavy or atypical inflammatory infiltrates. Features typical of rejection included most (>75%) being of mixed small and large, activated-appearing T lymphocytes, a smaller component of mature plasma cells, and variable numbers of eosinophils. Cytologically atypical cells were always a minority (<10%). The inflammation involved the septal spaces with proportional involvement of the exocrine tissue, veins, ducts, and arteries. The inflammation was particularly targeted against the acini and was associated with acinar cell damage. Features characteristic of PTLD were nodular and expansile infiltrates, composed of a significant proportion of atypical, plasmacytoid B cells (40% to 70% of the infiltrate); Reed-Sternberg-like cells were noted in two patients. The infiltrates involved the parenchyma randomly with no apparent affinity for the acinar tissue. Extensive infiltration of the peripancreatic soft tissues was common. Arterial walls were not involved in PTLD unless there was concurrent acute vascular rejection. Features identified in both conditions were foci of necrosis and infiltration of venous walls with associated endotheliitis. Samples with concurrent PTLD and acute rejection showed combinations of these features. In situ hybridization for EBER (Epstein-Barr-encoded RNAs) was positive only in the samples from patients with PTLD. Based on the assessment of morphological differences and the selective use of relatively simple ancillary techniques, PTLD can be correctly diagnosed even in small tissue samples such as needle biopsy specimens. An early diagnosis will lead to the appropriate treatment.

Background. Recurrent autoimmune @b-cell destruction may contribute to the poor results of clinical islet transplantation. Pancreas transplants from diabetes-resistant BB rats (BB-DR) are uniformly successful in autoimmune diabetic BB rats (BB-Ac), but isolated islets are destroyed, despite immunosuppression. In this study we tested the hypothesis that whole pancreas transplants abrogate autoimmunity by passive transfer to the host of an autoregulatory T-cell subset. Methods. BB-Ac rats served as recipients of BB-DR or Wistar Furth (WF) pancreas or islet transplants. Two cohorts of islet transplants included 50 or 100x10^6 peripancreatic lymph node cells (LNCs). Recipients were monitored for recurrent diabetes and subjected to fluorescence-activated cell sorter analysis of peripheral blood lymphocytes after 200 days by using monoclonal antibodies to class I, CD4, CD8, RT6.2, and RT6.1. Results. BB-DR pancreas transplants replete the RT6.1^+ T-cell subset in BB-Ac rats, whereas BB-DR islet transplants, which are susceptible to recurrent autoimmunity, do not. Addition of 100x10^6 LNC results in repletion of RT6.1 to the same degree as the whole pancreas and leads to complete protection of the islets. WF pancreas transplants result in the appearance of RT6.2^+ T cells in BB-Ac recipients, an RT allele that BB rats lack. Conclusions. BB-Ac rat recipients of whole pancreatic or islets plus LNCs transplants become chimeric for a donor T-cell population that prevents recurrent autoimmune diabetes. Deliberate inclusion of donor lymphoid cells with clinical islet transplants may be beneficial.

Background. A major impediment to kidney transplantation is the current shortage of donor organs. Currently approximately 22,500 candidates are awaiting kidney transplantation, while the number of donors remains stable at approximately 3500 each year in the United States. Alternative approaches to traditional organ donor selection are necessary. In this setting we hypothesized that kidneys with reduced nephron mass from adult donors may provide satisfactory renal function if both donor kidneys are placed into a single recipient. Methods. Eighteen paired adult renal allografts were transplanted into nine adult recipients (DUAL). Recipient graft outcome variables were examined and compared with outcomes from single kidneys transplanted from randomly selected ''ideal'' donors younger than 50 years of age (CONT<50) and ''expanded'' donors older than 60 years of age (CONT>60) who underwent transplantation at our center. Results. Six-month serum creatinine levels in the three groups, DUAL (n=9), CONT<50 (n=20), and CONT>60 (n=12), were 1.6+/-0.3, 2.3+/-0.3 and 4.1+/-0.9 mg/dl, respectively, (p<0.0001) between CONT > 60 and the other two groups. Mean estimated creatinine clearance (ml/min/1.73 m^2) was 43.2+/-3.4, 62.5+/-5.4, and 24.5+/-5.3 (p<0.02). Graft and patient survival at last follow-up in DUAL was 100% compared with 95% in CONT < 50 and 75% graft and 83% patient survival in CONT > 60. Delayed graft function occurred in one of nine patients (11%) in DUAL group compared with 4 of 20 (20%) in CONT < 50 group and 6 of 12 (50%) in CONT > 60 group. Mean follow-up of patients in DUAL group was 6.6 months (range, 2 to 14 months). Conclusions. Double adult kidney transplants (DUAL) are associated with acceptable short-term graft function, graft survival, and patient survival when compared with transplanted kidneys from an ideal donor group (CONT < 50). Double renal allografts are a preferred use for donor kidneys with suboptimal nephron mass. Long-term follow-up is required to validate further the proposed approach.