Sotrastaurin, a novel small molecule inhibiting protein kinase C: first clinical results in renal-transplant recipients.

Sotrastaurin, a novel protein-kinase-C inhibitor, blocks early T-cell activation. In this 12-month, Phase II study, de novo renal-transplant patients were randomized to sotrastaurin (200 mg b.i.d.) + standard-exposure tacrolimus (SET) or reduced-exposure tacrolimus (RET) (SET: n = 76; RET: n = 66), or control (SET + mycophenolic acid [MPA, 720 mg b.i.d.]; n = 74). In both sotrastaurin groups, patients were converted from tacrolimus to MPA after Month 3, achieving calcineurin inhibitor-free immunosuppression. The primary endpoint was composite efficacy failure (treated biopsy-proven acute rejection, graft loss, death or loss to follow-up). The key secondary endpoint was glomerular filtration rate (GFR). Composite efficacy failure rates were: 4.1%, 5.4% and 1.5% at Month 3 (preconversion) and 7.8%, 44.8% and 34.1% at study end in the control, sotrastaurin + SET and sotrastaurin + RET groups, respectively; these results led to premature study discontinuation. Median GFR at Month 6 was: 57.0, 53.0 and 60.0 mL/min/1.73 m(2), respectively. Study-drug discontinuations due to adverse events occurred in 16.2%, 18.4% and 12.1%, respectively. Leukopenia and neutropenia occurred more frequently preconversion in control versus sotrastaurin groups: 13.7%, 5.6%, and 4.6%; and 11.1%, 4.3% and 3.1%, respectively. The initial sotrastaurin + tacrolimus regimen was efficacious and well tolerated but the postconversion sotrastaurin + MPA regimen showed inadequate efficacy. Longer-term evaluation of sotrastaurin + tacrolimus is warranted.

Clinical significance of a positive flow crossmatch on the outcomes of cadaveric renal transplants.

Pretransplantation crossmatching is an integral part of kidney transplantation. Flow cytometric crossmatch (FCXM) is more sensitive than complement-dependent cytotoxic crossmatch (CDC-XM). However, the clinical significance of positive FCXM with negative CDC-XM is controversial. We evaluated FCXM in 455 consecutive deceased donor renal transplants. All had a negative CDC-XM. There were 341 T-cell and B-cell FCXM negative and 38 T-cell and B-cell positive. There was a higher percentage of retransplantations and HLA mismatches (26.3% vs 8.2%, P= .002 and 2.45 vs 1.99, P= .02, respectively) in the FCXM-positive group compared with the FCXM-negative group; 65.8% of the FCXM-positive patients had rejection compared with 49.3% of the FCXM-negative patients (odds ratio [OR]=1.89, P= .06). FCXM-positive patients had a higher incidence of vascular rejection (28.9% vs 12.6%, OR=2.68, P= .008). One- and 5-year graft survivals were 84% and 66% in the FCXM-positive group vs 90% and 75% in the FCXM-negative group. Censoring for patient death, 1- and 5-year graft survivals were 84% and 73% in the FCXM-positive group vs 94% and 82% in the FCXM-negative group. There was no difference in renal function between the 2 groups. In conclusion, a positive T-cell and B-cell FCXM transplant with a negative CDC-XM is associated with a higher incidence of rejection, twice the risk of vascular rejection, and a trend toward poorer graft survival.

Efficacy of early biopsy in kidney allograft recipients with delayed graft function.

It is accepted that kidney transplants that display delayed graft function (DGF) show poorer survival and function, particularly when an acute rejection episode (ARE) occurs. A diagnostic biopsy to establish the reason for DGF, or acknowledge an ARE, even if borderline, can improve short- and long-term graft survivals. From January 2002 to September 2006 we retrospectively evaluated 358 kidney transplant recipients. We performed a biopsy to evaluate the cause of DGF in all patients who required dialysis, or had serum creatinine levels that increased, remained unchanged, or decreased less than 10% per day on three consecutive days during the first week after transplantation. An ARE was found in 18.8% (n = 19) of the biopsies. Early biopsy for patients with DGF is a safe method that allows uncovering of an ARE that would otherwise be undetected. The immediate recognition and treatment of rejection episodes can certainly increase long-term survival and function of renal transplants.

Cyst infection in renal allograft recipients with adult polycystic kidney disease: the diagnostic value of labeled leukocyte scanning: case reports.

Occult infection following renal transplantation is a common diagnostic problem facing nephrologists and transplant surgeons. Patients with adult polycystic kidney disease (APKD) are prone to recurrent infections in their native kidneys and this can present with little if any localizing signs. Conventional radiological imaging with computed tomography or ultrasonography has a low sensitivity and specificity in such patients due to anatomic distortion and poor native renal function, and therefore identifying the source of sepsis can be difficult. Two cases are presented where patients with APKD who had received kidney transplants were investigated unsuccessfully for occult sepsis. White cell-labeled scanning identified the location of the infection in the patients' native polycystic kidney in both cases, allowing targeted treatment in the form of native nephrectomy. White cell-labeled scanning has an important role in the investigation of occult infection in renal allograft recipients with APKD.

Polar nephrectomy in a transplanted kidney: a case report.

After renal transplantation, infarction of the lower pole may be observed. We report an unusual case of lower pole infarction and perforation of the lower calyx due to thrombosis of a lower polar artery. This was managed successfully with partial nephrectomy (nephron-sparing surgery).

Cytokine gene polymorphisms predict acute graft rejection following renal transplantation.

BACKGROUND: The proinflammatory cytokine tumor necrosis factor-alpha (TNF-alpha) has been implicated in the pathogenesis of acute rejection, while animal models suggest a role for interleukin-10 (IL-10) in promoting graft survival. It has also been shown that polymorphisms in the TNFA gene promoter (position -308) and in the IL-10 gene promoter (position -1082) correlate with differential production of these cytokines in vitro. The aim of this study was to determine whether TNF-alpha and IL-10 gene polymorphisms influence the incidence and severity of acute rejection in the first six months following renal transplantation. METHODS: The cytokine genotypes of 115 consecutive first cadaveric kidney allograft recipients and their donors were screened. The rejection episodes (REs) were defined clinically and confirmed histologically where possible and further classified according to severity (RS), namely steroid-resistant or responsive REs. The genotypes were then correlated with the REs and RS. RESULTS: The recipient TNF-alpha high producer genotype and IL-10 high producer genotype were significantly associated with multiple REs (>/=2) in human leukocyte antigen (HLA)-DR mismatched transplants (P = 0.0047 and P = 0.045, respectively), whereas only the TNF-alpha high producer genotype was associated with steroid-resistant REs (P = 0.025). When recipient cytokines were analyzed together, the TNF-alpha high/IL-10 high producer genotype had the worst prognosis, whereas TNF-alpha low/IL-10 low producer genotype was protective. CONCLUSIONS: We conclude that recipient TNF-alpha and IL-10 gene polymorphisms are determinants of REs and RS following kidney transplantation. Routine screening of these gene polymorphisms may have a clinical role in identifying patients at risk of multiple REs and severe rejections.

Factors influencing kidney transplantation in Manchester, UK: 1989-1996.

The Manchester renal transplant center has the highest single center activity in the UK at present and has managed to achieve high posttransplant survival rates. We believe that this success is due to a combination of factors including a conservative approach to patient management; changes in clinical practice are only made after the evidence base has been established. This center is committed to the philosophy of prolonged survival of all transplanted kidneys. We believe that transplanting kidneys into clinically high-risk patients is not the best use of available resources.