Glycogen synthase kinase 3beta: a novel marker and modulator of inflammatory injury in chronic renal allograft disease.

One key cell-signaling event central to inflammation in kidney diseases, including chronic renal allograft dysfunction or disease (CRAD), is the activation of NF-kappaB, which controls transcription of numerous proinflammatory mediators. Glycogen synthase kinase (GSK) 3beta is an indispensable element of NF-kappaB activation, however, the exact role of GSK3beta in the pathogenesis of inflammatory kidney diseases like CRAD is uncertain and was examined. Immunohistochemistry staining of GSK3beta was weak in normal kidneys, but was markedly induced in inflamed allograft kidneys, with prominent cytoplasmic staining of tubular cells in areas of inflammation. Net GSK3beta activity is regulated by inhibitory phosphorylation of its serine 9 residue, and this occurred in CRAD. Thus, the magnitude of GSK3beta inactivation was inversely correlated with the degree of injury as assessed by Banff criteria. In vitro in cultured human tubular epithelial cells, GSK3beta overexpression augmented, while GSK3beta silencing diminished proinflammatory cellular responses to TNF-alpha stimulation, including NF-kappaB activation and expression of chemokines MCP-1 and RANTES. These inflammatory responses were obliterated by GSK3beta inhibitors. Collectively, GSK3beta plays an important role in mediating proinflammatory NF-kappaB activation and renal inflammation. Suppression of GSK3beta activity might represent a novel therapeutic strategy to treat CRAD.

The utility of 6-month protocol renal biopsy under modern immunosuppression.

BACKGROUND: Protocol biopsies after renal transplantation are useful in detecting subclinical rejection. In earlier studies, the incidence of subclinical rejection was high among renal transplant recipients on a cyclosporine-based immunosuppression. However, recent data show that subclinical rejection is low under tacrolimus-based immunosuppression. This study evaluates the utility of 6-month protocol biopsy in renal transplant recipients under induction with rabbit antithymocyte globulin and maintenance immunosuppression with tacrolimus, mycophenolate mofetil (MMF) and corticosteroids. METHODS: 6-month protocol biopsies on 40 transplant recipients were analyzed for borderline and subclinical rejections. Allograft injury at biopsy was evaluated using the chronic allograft damage index score system (CADI) and was compared with initial scores obtained at implantation. RESULTS: Borderline rejection was detected in 1 out of 40 patients. No case of subclinical rejection was detected at protocol biopsy. In 31 patients with corresponding implantation biopsies, mean CADI score increased from 1.1 +/- 1.4 to 2.8 +/- 2.1 at 6 months despite stable graft function. In the subgroup of patients with a 6-month CADI score of 2 or less (n = 11), graft function remained stable at 12 months post transplant (65.3 +/- 16.9 ml/min/1.73 m2 at 6 months vs. 65.2 +/- 16.7 ml/min/1.73 m2 at 12 months, p = 0.96). In contrast, allograft function declined significantly at 12 months in those with a 6-month CADI score of > 2 (n = 20) (64.3 +/- 13.5 ml/min/1.73 m2 at 6 months vs. 51 +/- 9.8 ml/min/1.73 m2 at 12 months, p = 0.0006). CONCLUSIONS: While the incidence of borderline and subclinical is low under antilymphocyte antibody induction and tacrolimus-based immunosuppression, chronic allograft damage is highly prevalent at 6 months post transplantation. Our findings suggest that protocol biopsies under current immunosuppression may be more useful in the early detection of chronic allograft nephropathy (CAN).

Acute disseminated encephalomyelitis in a renal transplant recipient: a case report.

Acute disseminated encephalomyelitis (ADEM) is an acute demyelinating disorder of the central nervous system, mostly seen in children after viral or bacterial infection and vaccinations. Cases of ADEM, albeit rare, have been reported in renal transplant recipients. The pathophysiology of posttransplant ADEM remains unclear but has been hypothesized to be due to aberrant T-cell reactivity to myelin basic protein triggered by a bacterial or viral infection. We report an unusual case of a 34-year-old white female with ADEM developing 5 years after a living related renal transplant.

Cell mediated immunity (CMI) and post transplant viral infections--role of a functional immune assay to titrate immunosuppression.

Cell mediated immunity (CMI) was assessed by the ImmuKnow assay in 12 patients after kidney transplantation, who presented with viral infection. Treatment included lowering of immunosuppression in all cases and antiviral treatment if indicated. The assay was repeated during the follow up. The ImmuKnow assay at time of presentation of viral infections was 56.8+/-58.2 (range 3-178; median 22) ATP ng/ml. With the clearance of viral infection and lowering of immunosuppression, the assay showed an increase in the level of CMI at 194.5+/-118.9 (range 53-409; median 150) ATP ng/ml. There was viral clearance or stabilization in all cases and there was no incidence of allograft rejection. The ImmuKnow assay of CMI can be used to titrate initial immunosuppression reduction and its subsequent increase, in patients with viral infection after transplantation.

Excess risk of renal allograft loss and early mortality among elderly recipients is associated with poor exercise capacity.

BACKGROUND: Successful renal transplantation in the elderly offers substantial benefits in quality and life expectancy. However, in this group of patients there is an early increased risk of death compared with those remaining on dialysis. MATERIALS AND METHODS: Graft and patient outcomes in 64 older transplant recipients were compared with 338 patients aged 18 - 59 years. We identified potential risk factors that may predict clinical outcomes in older transplant recipients. A log-rank test and Cox regression analyses were performed to assess the impact of various patient characteristics on graft and patient survival. RESULTS: Among older patients, graft survival was 76.6% and 67% at 1 and 3 years, respectively. When graft survival was censored for death with functioning graft, the 1- and 3-year graft survival was 83% and 82%, respectively. Patient survival was 78% and 71% at 1 and 3 years, respectively. These survival rates were significantly lower than those of younger recipients. Pretransplant inactivity, delayed graft function, smoking history and longer waiting time predicted poor graft and patient survival. A history of chronic obstructive pulmonary disease, and peripheral vascular disease also predicted a higher mortality among older recipients. CONCLUSION: Older kidney transplant recipients are at high risk for allograft failure and early death. Poor functional capacity predicts a poor outcome for older patients undergoing renal transplantation. Therefore, careful patient selection is paramount, and every effort should be made to initiate timely interventions aimed at increasing physical activity in those with low fitness level.

Cryptosporidium infection in renal transplant patients.

Cryptosporidium parvum, an intracellular protozoan parasite, is a significant cause of gastrointestinal disease worldwide. Transmission can occur from an infected person, animal or fecally contaminated environment. The clinical manifestations of cryptosporidiosis are dependent on the immunologic state of the host. Infection among immunocompetent hosts results in diarrhea that is typically self-limited. In immunocompromised hosts, however, the infection may be protracted and life-threatening with no reliable antimicrobial therapy. In transplant patients, a course of antimicrobial therapy along with concurrent reduction in immunosuppression optimize immunologic status and may potentially lead to resolution of the infection.

Factors contributing to acute rejection in renal transplantation: the role of noncompliance.

Early episodes of acute rejection after renal transplantation reflect inadequate immunosuppression at a time of heightened immune challenge. Late acute rejection episodes, however, are less likely related to inadequacy of immunosuppression and may be due to patient noncompliance or overzealous weaning of immunosuppression. We evaluated 443 consecutive renal transplant recipients to determine the incidence and etiology of acute rejection. All episodes were confirmed by ultrasound-guided biopsy. The cause of each acute rejection was determined by chart review. Medication compliance was determined by history at the time of admission for biopsy. Over a follow-up period of 42 +/- 22 months, 87 patients (20%) suffered acute rejection. There was a trend toward fewer episodes of acute rejection with thymoglobulin induction and tacrolimus-based immunosuppression. Younger recipients had an increased risk of acute rejection (odds ratio 0.47, range 0.24-0.91, P = .027). Patient noncompliance with immunosuppression was associated with late acute rejection (P = .0002). Acute rejection increased the risk of allograft failure (P < .0001). Modifiable factors, including the choice of immunosuppression, reduce the risk of acute rejection. More importantly, the transplant recipient plays a substantial role in the maintenance of their allograft health through compliance with immunosuppressive drug therapy. Future strategies to improve compliance, including increased vigilance in high-risk patient groups, frequent medication review, and laboratory testing, should be encouraged.

Experience with sirolimus for calcineurin minimization/elimination in pancreas-after-kidney transplantation.

Pancreas after kidney (PAK) transplantation, associated with a persistent elevation in serum creatinine (defined as a >25% increase from baseline), was seen in 7 of 11 (64%) cases maintained on immunosuppressive therapy consisting of tacrolimus, mycophenolate mofetil, and prednisone. Patients were converted to sirolimus as a means of minimizing or eliminating exposure to tacrolimus, the presumed nephrotoxic agent. With the use of sirolimus-based immunosuppression, and with elimination or minimization of tacrolimus, renal function, as measured by serum creatinine, stabilized or improved in all cases.

Suppression of cell-mediated immunity by a donor-transmitted lymphocytic choriomeningitis virus in a kidney transplant recipient.

Infection with lymphocytic choriomeningitis virus (LCMV) in rodents, the primary host, is known to cause suppression of cell-mediated immunity. Serial determinations using a functional cell-mediated immune assay in a kidney transplant recipient with donor-transmitted LCMV also suggested profound suppression of cellular immunity. This suppression persisted in spite of reduction of immunosuppression. With the clearance of the virus there was reconstitution of the cellular immune response.

Preemptive plasmapheresis and recurrence of FSGS in high-risk renal transplant recipients.

Recurrent focal segmental glomerulosclerosis (FSGS) following transplantation is ascribed to the presence of a circulating FSGS permeability factor (FSPF). Plasmapheresis (PP) can induce remission of proteinuria in recurrent FSGS. This study addressed the efficacy of pre-transplant PP in decreasing the incidence of recurrence in high-risk patients. Ten patients at high-risk for FSGS recurrence because of rapid progression to renal failure (n = 4) or prior transplant recurrence of FSGS (n = 6) underwent a course of 8 PP treatments in the peri-operative period. Recurrences were identified by proteinuria >3 g/day and confirmed by biopsy. Seven patients, including all 4 with first grafts and 3 of 6 with prior recurrence, were free of recurrence at follow-up (238-1258 days). Final serum creatinine in 8 patients with functioning kidneys averaged 1.53 mg/dL. FSGS recurred within 3 months in 3 patients, each of whom had lost prior transplants to recurrent FSGS. Two of these progressed to end-stage renal disease (ESRD) and the third has significant renal dysfunction. Based on inclusion criteria, recurrence rates of 60% were expected if no treatment was given. Therefore, PP may decrease the incidence of recurrent FSGS in high-risk patients. Definitive conclusions regarding optimal management can only be drawn from larger, randomized, controlled studies.

Donor-transmitted parvovirus infection in a kidney transplant recipient presenting as pancytopenia and allograft dysfunction.

Parvovirus B19 is a nonenveloped single-stranded DNA virus that commonly causes a benign childhood infection typically manifesting as a "slapped-cheek" rash. In immunodeficient hosts, this infection can cause persistent anemia and occasionally pancytopenia. Recently, direct renal involvement has been reported in renal transplant recipients leading to various forms of glomerulopathy and allograft dysfunction. Most cases are primary infections and are donor transmitted through the transplanted organ. Clinical and virological response to intravenous immunoglobulin (Ig) is usually excellent. We describe a case of donor-transmitted parvovirus infection in a 23-year-old male who received his first cadaver renal transplant. The patient had an uncomplicated postoperative course with immediate graft function. Eight weeks after transplantation, he presented with fever, polyarthralgia, pancytopenia, and allograft dysfunction. Serological studies revealed elevated IgM titers against parvovirus B19. A renal biopsy was performed, which showed no evidence of acute rejection but with moderate degree of tubular damage. Parvovirus B19 viral DNA was detected in the renal tissue via polymerase chain reaction (PCR). The patient received a 10-day course of intravenous Ig (400 mg/kg/day) with excellent response. His blood count normalized and the allograft improved to baseline function. The incidence of parvovirus infection in renal transplant patients is probably underestimated, because patients are not routinely screened for it and anemia and/or pancytopenia in these patients are often ascribed to immunosuppressive drugs. Because this infection is treatable, we conclude that parvovirus B19 infection should be actively considered in transplant patients presenting with pancytopenia and allograft dysfunction.

Rapid communication: L-folinic acid versus folic acid for the treatment of hyperhomocysteinemia in hemodialysis patients.

BACKGROUND: The hyperhomocysteinemia found in most hemodialysis patients is refractory to combined oral B-vitamin supplementation featuring supraphysiological doses of folic acid (FA). We evaluated whether a high-dose L-folinic acid-based regimen provided improved total homocysteine (tHcy)-lowering efficacy in chronic hemodialysis patients, as suggested by a recent uncontrolled report. METHODS: We block-randomized 48 chronic, stable hemodialysis patients based on their screening predialysis tHcy levels, sex, and dialysis center into two groups of 24 subjects treated for 12 weeks with oral FA at 15 mg/day or an equimolar amount (20 mg/day) of oral L-folinic acid (FNA) [L-5-formyltetrahydrofolate]. All 48 subjects also received 50 mg/day of oral vitamin B6 and 1.0 mg/day of oral vitamin B12. RESULTS: The mean percentage (%) reductions (with 95% CIs) in predialysis tHcy were not significantly different [FNA = 22.1% (11.8 to 31.4%), FA = 20.7% (11.7 to 30.5%), P = 0.950 by paired t test]. Final on-treatment values (mean with 95% CI) were as follows: FNA, 15.9 micromol/L (14.0 to 18.0); FA, 16.9 micromol/L (14.8 to 18.8). Moreover, in those subjects with baseline tHcy levels >/=14 micromol/L, neither treatment resulted in "normalization" of tHcy levels (that is, final on-treatment values <12 micromol/L) among a significantly different or clinically meaningful number of patients [FNA = 2 out of 22 (9.1%); FA = 2 out of 24 (8.3%); Fisher's exact test of between groups difference, P = 1.000]. CONCLUSIONS: Relative to high-dose FA, high-dose oral L-folinic acid-based supplementation does not afford improved tHcy-lowering efficacy in hemodialysis patients. The preponderance of hemodialysis patients (that is,> 90%) exhibits mild hyperhomocysteinemia refractory to treatment with either regimen.