Chronic renal failure in Kuwaiti children: an eight-year experience

Over an 8-year period (January 1996 to December 2003), a total of 171 patients below the age of 15 years were diagnosed with chronic renal failure. The mean incidence rate of CRF in Kuwaiti children was found to be 38.2 per million children per year, with a peak incidence of 55 per million children per year. While the mean age at diagnosis was 33±12 months (range: 1 month to 15 years), the male:female ratio was 2.7:1. Etiological factors for chronic renal failure included congenital urological malformation (61.9%), chronic glomerulopathies (5.2%), hereditary nephropathies (21%), multi-system disease (0.5%), chronic pyelonephritis (without VUR) (4.6%), tumors (0.6%), ischemic renal disease (1.1%) and unknown etiology (1.7%). Thirty percent of patients reached end-stage renal disease within a mean of 18 months following diagnosis. The overall mortality before reaching ESRD was reported to be 4%. Kuwait has one of the highest incidence and prevalence rates of CRF in children. It is likely that genetic and hereditary factors are the cause of these high rates.     

Inhibition of the chemokine receptor CXCR2 prevents kidney graft function deterioration due to ischemia/reperfusion

BACKGROUND: Ischemia/reperfusion (I/R) injury after organ transplantation is a major cause of delayed graft function. Following I/R, locally produced CXC chemokines attract and activate granulocytes, which in turn promote graft damage. METHODS: We examined the involvement of granulocyte recruitment via the CXCR2 pathway in a rat model of 4 hours cold ischemia followed by kidney transplantation. Serum creatinine and intragraft granulocyte infiltration were monitored in the early phase posttransplant. A CXCR2 inhibitor, repertaxin, was given to recipients before transplantation (at -24 hours or -8 hours or -2 hours), immediately before reperfusion and 2 hours later. RESULTS: An increase of granulocyte chemoattractant CINC-1/interleukin-8 (IL-8) mRNA expression after I/R both in syngeneic and allogeneic transplantation was associated with a marked infiltration of granulocytes in renal tissue. In syngeneic transplantation, Lewis rats given 15 mg/kg repertaxin 24 hours before surgery had granulocyte graft infiltration and serum creatinine levels significantly reduced in respect to vehicle-treated animals. Intermediate effects were observed with 5 mg/kg, whereas the dose of 30 mg/kg had toxic effects. We found that reducing the pretreatment time to 8 hours before surgery was still effective. Prevention of granulocyte infiltration and serum creatinine increase was also obtained in allogeneic transplantation, when Brown Norway recipients of Lewis kidneys were given 15 mg/kg repertaxin starting 8 hours before surgery. CONCLUSION: Repertaxin treatment of the recipient animal was effective in preventing granulocyte infiltration and renal function impairment both in syngeneic and in allogeneic settings. The possibility to modulate I/R injury in this rat model opens new perspectives for preventing posttransplant delayed graft function in humans.     

Pretransplant donor peripheral blood mononuclear cells infusion induces transplantation tolerance by generating regulatory T cells

BACKGROUND: It was suggested that maintenance of tolerance to organ transplantation may depend on the formation of T regulatory cells. METHODS: Lewis (LW) rats were made tolerant to a Brown Norway kidney by pretransplant donor peripheral blood mononuclear cells (PBMC) infusion. At greater than 90 days after transplantation, lymph node cells (LN) and graft-infiltrating leukocytes (GIL) alloreactivity was tested in mixed lymphocyte reaction (MLR), coculture, and transwell experiments. GIL phenotype was analyzed by FACS. mRNA expression of cytokines and other markers was analyzed on CD4+ T cells from LN. The tolerogenic potential of tolerant cells in vivo was evaluated by adoptive transfer. RESULTS: Tolerant LN cells showed a reduced proliferation against donor stimulators but a normal anti-third-party alloreactivity. In coculture, these cells inhibited antidonor but not antithird-party reactivity of na?ve LN cells. Interleukin (IL)-10 and FasL mRNA expression was up-regulated in tolerant CD4+ T cells, but an anti-IL-10 monoclonal antibody (mAb) only partially reversed their inhibitory effect. Immunoregulatory activity was concentrated in the CD4+ CD25+ T-cell subset. In a transwell system, tolerant T cells inhibited a na?ve MLR to a lesser extent than in a standard coculture. Regulatory cells transferred tolerance after infusion into na?ve LW recipients. CD4+ T cells isolated from tolerized grafts were hyporesponsive to donor stimulators and suppressed a na?ve MLR against donor antigens. CONCLUSIONS: Donor-specific regulatory T cells play a role in tolerance induction by donor PBMC infusion. Regulatory activity is concentrated in the CD4+ CD25+ subset and requires cell-to-cell contact. Regulatory CD4+ T cells accumulate in tolerized kidney grafts where they could exert a protective function against host immune response.     

Impact of cyclosporine 2-h level and mycophenolate mofetil dose on clinical outcomes in de novo heart transplant patients receiving anti-thymocyte globulin induction

BACKGROUND: Cyclosporine (CsA) 2-h post-dose level (C2) correlates better than trough levels (C0) with the area under the curve. We evaluated the clinical impact of C2 and mycophenolate mofetil (MMF) dose in adult heart transplant patients receiving anti-thymocyte globulin (ATG) induction. METHODS: Two immunosuppressive strategies were sequentially evaluated. In Group 1 (13 patients), simultaneous C0/C2 (ng/mL) were analyzed. CsA dose monitoring was initially based on C0 : <3 months: 200-300, 4-6 months: 150-250, 6-9 months: 100-200, and on C2 thereafter (as in Group 2). In Group 2 (nine patients), C2 monitoring was implemented: <3 months: 600-800, 4-6 months: 500-700, >6 months: 400-600. All patients received ATG induction, corticosteroids, and MMF (1.0 g b.i.d. in Group 1 and 1.5 g b.i.d. in Group 2). RESULTS: Patients in Group 2 received higher MMF doses during the first trimester. C2 at 1, 3, 6, 12, 24, and 36 months was, respectively, 1199 +/- 476, 1202 +/- 587, 999 +/- 467, 664 +/- 203, 593 +/- 208, and 561 +/- 147 in Group 1, and 809 +/- 160 (p = 0.02), 644 +/- 178 (p = 0.003), 664 +/- 169 (p = 0.02), 616 +/- 221, 464 +/- 234, and 451 +/- 165 in Group 2. The incidence of acute rejection (grade > or =3A) at 6, 12, 24, and 36 months was, respectively, 38.5, 38.5, 46, and 54% in Group 1, and 11, 44, 56, and 56% in Group 2 (p = NS). At 3 months, the creatinine clearance was 25% lower in Group 1. Thereafter, renal function remained stable in both groups. CONCLUSION: Our results suggest that heart transplant patients receiving ATG induction may experience similar outcomes with either a higher C2 and a lower MMF dose or a lower C2 and a higher MMF dose. These results could be considered to design prospective studies to optimize C2 monitoring, to reduce the incidence of acute rejection without increasing the risk of renal dysfunction.     

Emergency craniotomy for intraparenchymal massive hematoma after embolization of supratentorial arteriovenous malformations

OBJECTIVE: We sought to evaluate the efficacy of emergency craniotomy for patients with massive hematoma secondary to endovascular embolization of supratentorial arteriovenous malformations (AVMs) and to investigate relevant factors affecting outcome. METHODS: Within the past 15 years, 605 patients with intracranial AVMs have undergone 1066 endovascular embolizations at our institution. Of these, 24 patients experienced intracranial hemorrhage during or after the procedure. Fourteen patients were demonstrated to have massive intraparenchymal hematomas and deteriorated to a comatose state (Glasgow Come Scale score < or =6). Twelve patients underwent craniotomy within 170 minutes of being diagnosed with intraparenchymal hemorrhage. The surgical procedures performed were hematoma evacuation with total (6 patients) or partial (2 patients) resection of the AVM or hematoma evacuation only (4 patients). The clinical records of these 12 patients were analyzed retrospectively. RESULTS: Nine patients recovered to a favorable condition (good recovery, four patients; moderately disabled, five patients), one patient remained in a persistent vegetative state, and two patients died. The interval between hemorrhage and emergency craniotomy was significantly shorter in patients with favorable outcomes than in those with poor clinical outcomes. Advanced age and a larger volume of intraoperative blood loss were the factors relevant to poor outcome. Temporal lobe location of the AVM and incomplete embolization tended to correlate to poor clinical outcome, but this correlation was not statistically significant. The sizes of the AVM and the hematoma did not correlate to patient outcome. There was no difference in outcomes with regard to the surgical procedure performed. CONCLUSION: In patients with massive postembolization hematomas, emergency craniotomy should be performed as soon as possible to achieve a favorable outcome. Cooperation among interventional neuroradiologists, intensive care physicians, and neurosurgeons is essential to manage AVM patients with critical postembolization hemorrhage. There is no need to persist in performing simultaneous total resection of the AVM at the emergency craniotomy.     

Clonidine as an adjuvant to intrathecal local anesthetics for surgery: systematic review of randomized trials

BACKGROUND AND OBJECTIVES: Clonidine is added to intrathecal local anesthetics to improve intraoperative analgesia and to increase the duration of sensory and motor block. The aim of this systematic review is to quantify beneficial and harmful effects of clonidine when used as an adjuvant to intrathecal local anesthetics for surgery. METHODS: We included data from 22 randomized trials (1,445 patients) testing a large variety of doses of clonidine, added to intrathecal bupivacaine, mepivacaine, prilocaine, or tetracaine. RESULTS: Clonidine 15 to 150 microg prolonged in a linear, dose-dependent manner, the time to 2 segment regression (range of means, 14 to 75 minutes) and the time to regression to L2 (range of means, 11 to 128 minutes). The time to first analgesic request (median 101 minutes, range 35 to 310) and of motor block (median 47 minutes, range 6 to 131) was prolonged without evidence of dose-responsiveness. Time to achieve complete sensory or motor block, and extent of cephalic spread remained unchanged. There were fewer episodes of intraoperative pain with clonidine (relative risk, 0.24; 95% confidence interval [CI], 0.09-0.64; number needed to treat, 13) but more episodes of arterial hypotension (relative risk, 1.81; 95% CI 1.44-2.28; number needed to harm, 8) without evidence of dose-responsiveness. The risk of bradycardia was unchanged. CONCLUSIONS: This study may serve as a rational basis to help clinicians decide whether or not to combine clonidine with an intrathecal local anesthetic for surgery. The optimal dose of clonidine, however, remains unknown.     

Mycophenolic acid concentrations in long-term heart transplant patients: relationship with calcineurin antagonists and acute rejection

BACKGROUND: When used in conjunction with steroids and cyclosporin, mycophenolate mofetil (MMF) has been shown to significantly reduce mortality and incidence of rejection in the first year after heart transplantation. It also appears that in this early post-transplantation period, the monitoring of immunosuppressive therapies may be warranted. The current study was undertaken to determine if such monitoring is still useful more than 1 yr after heart transplantation. METHODS: Twenty-six patients who had survived the first year after orthotopic heart transplantation and had been on MMF therapy for more than 3 months were prospectively followed. At the time of their routine endomyocardial biopsy blood samples were taken to monitor immunosuppressive therapy. Most patients had two samples taken, on average 109 d apart. RESULTS: There were 22 episodes of asymptomatic rejection documented on a total of 48 biopsies. Of these, only two were of ISHLT (International Society for Heart and Lung Transplantation) grade 3A the remainder being of ISHLT grades 1 or 2. There was no relation between immunosuppressive regimen (tacrolimus and MMF or cyclosporin and MMF) and rejection. There was no relation between monitored immunosuppressive levels and rejection. Patients with the combination of MMF and tacrolimus had significantly higher plasma mycophenolic acid levels despite significantly lower daily MMF dose. CONCLUSION: There does not appear to be a benefit in continued monitoring of plasma mycophenolic acid levels beyond the first year of heart transplantation. There were significant differences in plasma mycophenolic acid levels depending on the type of calcineurin inhibitor concomitantly used.     

Calcineurin inhibitor substitution with sirolimus vs. reduced-dose calcineurin inhibitor plus sirolimus is associated with improved renal dysfunction in heart transplant patients

Heart transplant (HTx) patients are at risk of developing renal dysfunction. Sirolimus has been used as an alternative for calcineurin inhibitors (CNI) in transplant patients with renal dysfunction. Recent data suggest that the combination of sirolimus with a CNI is associated with a deterioration of renal function in renal transplant patients. The purpose of the present study was to compare the effect on the creatinine clearance (CrCl) of heart transplant (HTx) patients with renal dysfunction (RD) on CNI-based sirolimus-free regimens of conversion to either reduced-dose CNI plus sirolimus or outright substitution of CNI with sirolimus. We retrospectively identified 29 treatment switches for 26 patients with RD defined as a decline in the CrCl > 25% post-HTx. Treatment switches were divided into two groups. Group 1 included 13 switches in 13 patients (four women, nine men, age 62 +/- 10 yr) in whom sirolimus replaced CNI. Group 2 included 16 switches in 15 patients [two women, 13 men (one man underwent two such switches), age 61 +/- 9 yr] in whom CNI dose was reduced and sirolimus was added. Two men appear in both groups. Average follow-up was 10.4 +/- 3.2 months. Overall mortality, rejection, and side-effects rates were comparable between groups. At 12-months post-switch, the mean CrCl had increased from 48 +/- 15 at time of treatment switch to 56 +/- 22 mL/min in group 1 and decreased from 53 +/- 19 to 47 +/- 17 mL/min in group 2 (p = 0.02). In conclusion, substitution of CNI with sirolimus provided improved renal recovery compared with lower-dose CNI plus sirolimus in HTx patients with renal dysfunction.