The effects of the DASH dietary pattern on clinical outcomes and quality of life in adults with uncontrolled asthma: Design and methods of the ALOHA Trial.

BACKGROUND: Poor diet quality is an important risk factor for increased asthma prevalence and poor asthma control. To address the question of whether adults with asthma can benefit from following a healthy diet, this trial will test the efficacy and mechanisms of action of a behavioral intervention promoting the Dietary Approaches to Stop Hypertension (DASH) dietary pattern with sodium reduction among patients with uncontrolled asthma. METHODS: In this 2-arm randomized clinical trial, 320 racially/ethnically and socioeconomically diverse adults with uncontrolled asthma on standard controller therapy will be randomized to either a control or an intervention group and assessed at baseline, 3, 6 and 12 months. Control and intervention participants will receive education on lung health, asthma, and other general health topics; additionally, the intervention group will receive DASH behavioral counseling over 12 months. The primary hypothesis is that the DASH behavioral intervention, compared with the education-only control, will lead to significantly more participants with minimum clinically important improvement (responders) in asthma-specific quality of life at 12 months. Secondary hypotheses will test the intervention effects on other asthma (e.g., asthma control, lung function) and non-asthma outcomes (e.g., quality of life). Additionally, therapeutic (e.g., short chain fatty acids, cytokines) and nutritional biomarkers (e.g., dietary inflammatory index, carotenoids) will be assessed to understand the mechanisms of the intervention effect. CONCLUSION: This trial can substantially advance asthma care by providing rigorous evidence on the benefits of a behavioral dietary intervention and mechanistic insights into the role of diet quality in asthma. CLINICALTRIALS: gov #: NCT05251402.

A peripheral blood diagnostic test for acute rejection in renal transplantation.

Monitoring of renal graft status through peripheral blood (PB) rather than invasive biopsy is important as it will lessen the risk of infection and other stresses, while reducing the costs of rejection diagnosis. Blood gene biomarker panels were discovered by microarrays at a single center and subsequently validated and cross-validated by QPCR in the NIH SNSO1 randomized study from 12 US pediatric transplant programs. A total of 367 unique human PB samples, each paired with a graft biopsy for centralized, blinded phenotype classification, were analyzed (115 acute rejection (AR), 180 stable and 72 other causes of graft injury). Of the differentially expressed genes by microarray, Q-PCR analysis of a five gene-set (DUSP1, PBEF1, PSEN1, MAPK9 and NKTR) classified AR with high accuracy. A logistic regression model was built on independent training-set (n = 47) and validated on independent test-set (n = 198)samples, discriminating AR from STA with 91% sensitivity and 94% specificity and AR from all other non-AR phenotypes with 91% sensitivity and 90% specificity. The 5-gene set can diagnose AR potentially avoiding the need for invasive renal biopsy. These data support the conduct of a prospective study to validate the clinical predictive utility of this diagnostic tool.

Subclinical inflammation and chronic renal allograft injury in a randomized trial on steroid avoidance in pediatric kidney transplantation.

Steroid avoidance is safe and effective in children receiving kidney transplants in terms of graft function and survival, but the effects on allograft histology are unknown. In this multicenter trial, 130 pediatric renal transplant recipients were randomized to steroid-free (SF; n = 60) or steroid-based (SB; n = 70) immunosuppression, and underwent renal allograft biopsies at the time of graft dysfunction and per protocol at implantation and 6, 12 and 24 months after transplantation. Clinical follow-up was 3 years posttransplant. Subclinical acute rejection was present in 10.6% SF versus 11.3% SB biopsies at 6 months (p = 0.91), 0% SF versus 4.3% SB biopsies at 1 year (p = 0.21) and 0% versus 4.8% at 2 years (p = 0.20). Clinical acute rejection was present in 13.3% SF and 11.4% SB patients by 1 year (p = 0.74) and in 16.7% SF and 17.1% SB patients by 3 years (p = 0.94) after transplantation. The cumulative incidence of antibody-mediated rejection was 6.7% in SF and 2.9% in SB by 3 years after transplantation (p = 0.30). There was a significant increase in chronic histological damage over time (p < 0.001), without difference between SF and SB patients. Smaller recipient size and higher donor age were the main risk factors for chronic histological injury in posttransplant biopsies.

Complete steroid avoidance is effective and safe in children with renal transplants: a multicenter randomized trial with three-year follow-up.

To determine whether steroid avoidance in pediatric kidney transplantation is safe and efficacious, a randomized, multicenter trial was performed in 12 pediatric kidney transplant centers. One hundred thirty children receiving primary kidney transplants were randomized to steroid-free (SF) or steroid-based (SB) immunosuppression, with concomitant tacrolimus, mycophenolate and standard dose daclizumab (SB group) or extended dose daclizumab (SF group). Follow-up was 3 years posttransplant. Standardized height Z-score change after 3 years follow-up was -0.99 ± 2.20 in SF versus -0.93 ± 1.11 in SB; p = 0.825. In subgroup analysis, recipients under 5 years of age showed improved linear growth with SF compared to SB treatment (change in standardized height Z-score at 3 years -0.43 ± 1.15 vs. -1.07 ± 1.14; p = 0.019). There were no differences in the rates of biopsy-proven acute rejection at 3 years after transplantation (16.7% in SF vs. 17.1% in SB; p = 0.94). Patient survival was 100% in both arms; graft survival was 95% in the SF and 90% in the SB arms (p = 0.30) at 3 years follow-up. Over the 3 year follow-up period, the SF group showed lower systolic BP (p = 0.017) and lower cholesterol levels (p = 0.034). In conclusion, complete steroid avoidance is safe and effective in unsensitized children receiving primary kidney transplants.

A randomized double-blind, placebo controlled trial of steroid withdrawal after pediatric renal transplantation.

In an effort to reduce rejection, extend allograft survival and minimize complications, we hypothesized that robust immunosuppression during the first 6 months after transplantation would allow for the safe withdrawal of steroids. A total of 274 pediatric subjects were enrolled and received an anti-CD25 antibody, sirolimus, calcineurin inhibitor and steroids. At 6 months after transplantation, subjects were randomized to steroid withdrawal (n=73) versus continued low-dose steroids (n=59). This study was stopped prior to target enrollment because of the incidence of post-transplant lymphoproliferative disorder. At the time of study termination, 132 subjects had been randomized and were available for analysis. At 18 months after transplantation, there was no difference in the standardized height z score; however, the standardized height velocity was greater in the steroid withdrawal group compared to the control group (p=0.033). There were no differences in acute rejection episodes between treatment groups. The 3-year allograft survival rate was 84.5% in the control group and 98.6% in the steroid withdrawal group (p=0.002). The immunosuppressive protocol utilized in this study allowed for the withdrawal of steroids without an increased risk of rejection or allograft loss. However, the complications associated with the use of this immunosuppressive protocol were too high to recommend its routine use in pediatric patients.

Should pediatric patients wait for HLA-DR-matched renal transplants?

Graft survival rates from deceased donors aged 35 years or less among all primary pediatric kidney transplant recipients in the United States between 1996 and 2004 were retrospectively examined to determine the effect of HLA-DR mismatches on graft survival. Zero HLA-DR-mismatched kidneys had statistically comparable 5-year graft survival (71%), to 1-DR-mismatched kidneys (69%) and 2-DR-mismatched kidneys (71%). When compared to donors less than 35 years of age, the relative rate of allograft failure was 1.32 (p = 0.0326) for donor age greater than or equal to age 35. There was no statistical increase in the odds of developing a panel-reactive antibody (PRA) greater than 30% at the time of second waitlisting, based upon the degree of HLA-A, -B or -DR mismatch of the first transplant, nor was there a 'dose effect' when more HLA antigens were mismatched between the donor and recipient. Therefore, pediatric transplant programs should utilize the recently implemented Organ Procurement and Transplantation Network's (OPTN)allocation policy, which prioritizes pediatric recipients to receive kidneys from deceased donors less than 35 years of age, and should not turn down such kidney offers to wait for a better HLA-DR-matched kidney.

Incidence of PTLD in pediatric renal transplant recipients receiving basiliximab, calcineurin inhibitor, sirolimus and steroids.

Pediatric renal transplant recipients were enrolled in a multicenter, randomized, double-blind trial of steroid withdrawal. Subjects received basiliximab, calcineurin inhibitor, sirolimus and steroids. Of 274 subjects enrolled, 19 (6.9%) subjects developed posttransplant lymphoproliferative disorder (PTLD). The relative hazard (RH) for PTLD was 5.3-fold higher in children aged < or =5 versus those >12 years (p = 0.0017). EBV seronegative subjects had a 4.7-fold higher RH compared to EBV positive subjects (p = 0.02). Among EBV donor+/recipient- (D+/R-) subjects, the RH increased by 6.1-fold (p = 0.0001). In a multivariate model, risk factors included recipient age < or =5 years (RH 3.2, 95% CI: 1.1-9.6, p = 0.034) and EBV D+/R- status (RH 7.7, 95% CI: 1.6-35.9, p = 0.010). Of 19 patients with PTLD, 17 are alive with functioning grafts and 2 lost their grafts, 1 of whom subsequently died of recurrent PTLD. This 'robust' immunosuppression protocol was associated with low rejection rates but an unacceptably high incidence of PTLD. The combination of basiliximab, calcineurin inhibitor, sirolimus and steroids resulted in over-immunosuppression in a high-risk pediatric population and we do not recommend its use. Future studies must include routine viral monitoring to permit early identification of viral activity and a protocol driven reduction of immunosuppression aimed at avoiding complications.

Decreased risk of renal allograft thrombosis associated with interleukin-2 receptor antagonists: a report of the NAPRTCS.

Graft thrombosis is the most common cause of first year graft failure in pediatric renal transplantation. The North American Pediatric Renal Transplant Cooperative Study (NAPRTCS) database was analyzed for cases of graft failure due to thrombosis among patients transplanted from 1998 to 2004. The impact of interleukin-2 (IL-2) receptor antagonists as induction therapy was determined. There were a total of 51 graft failures due to thrombosis among the 2750 reported renal transplants (1.85%) (95% CI (1.39%, 2.41%)). This represents the most common cause of graft loss during the first year post-transplant accounting for 35% of first year losses and 18% of all graft losses. The incidence of thrombosis among patients who received IL-2 receptor antibodies was 1.07% (12/1126) compared to 2.40% (39/1624) among patients who did not (OR 0.44, 95% CI 0.23, 0.84, p = 0.014). Use of IL-2 receptor blockade was the only significant prognostic factor in a multivariate model with previously identified risk factors. Analysis of NAPRTCS data found that the use of IL-2 receptor antibodies as induction therapy is associated with a significantly decreased risk of graft failure due to thrombosis. This provocative finding requires further investigation to determine whether thrombotic failure can be decreased by this therapeutic strategy.

Short sirolimus half-life in pediatric renal transplant recipients on a calcineurin inhibitor-free protocol.

Immunosuppression with SRL may provide an opportunity to avoid long-term exposure to the nephrotoxicity of CNI. Thus, we have initiated an experimental protocol of IL-2r antibody induction, prednisone, MMF and SRL in pediatric renal transplant recipients (median age 15.5 yr, IQR 8.5, range 1.3-21.7). The recipients were treated with daclizumab every 2 wk for the first 2 months, prednisone on a tapering schedule, MMF at 1200 mg/m(2)/day and SRL given b.i.d. The SRL was dosed to achieve defined target whole blood 12-h trough levels. We performed 24 SRL PK profiles in 13 stable pediatric renal transplant recipients at 1 and 3 months post-transplant. Half-life (T(1/2)) and terminal T(1/2) were 9.7 (7.1-24.6) and 10.8 (4.4-95.2) hours (median, range) respectively at month 1, and were 9.6 (5-17.8) and 12.1 (4.7-71.0) hours respectively at month 3. SRL trough levels correlated with AUC (r(2) = 0.84, p < 0.001). There was no relationship between SRL and mycophenolic acid (MPA) AUC values (r(2) = 0.04). During the first 3 months post-transplant only one patient experienced severe neutropenia and another patient had subclinical (histologic) evidence of a mild acute rejection episode with no change in renal function. We conclude that the T(1/2) of SRL in pediatric renal transplant recipients not treated with CNI is much shorter than what has been reported for adults, due to rapid metabolism. We conclude that children require SRL dosing every 12 h, higher doses and frequent drug monitoring to achieve target SRL concentrations.

Is a 1-CM margin necessary during nephron-sparing surgery for renal cell carcinoma?

OBJECTIVES: To determine whether a 1-cm margin is necessary for cancer control during nephron-sparing surgery (NSS) for renal cell carcinoma (RCC). METHODS: A retrospective review of 67 patients who underwent NSS for RCC between 1990 and 2000 was conducted. The data collected included patient demographics, tumor size and location, histologic type and grade, margin status (positive or negative), and the shortest distance of normal parenchyma (in millimeters) around the tumor in the final pathologic specimen. Recurrence was determined from the clinical follow-up, which included physical examination, ultrasonography or computed tomography, and various laboratory tests. RESULTS: Fifty-five cases were performed open and 12 laparoscopically. The mean follow-up was 60 months (range 5 to 124). The mean tumor size was 3.0 cm (range 0.9 to 11.0). Seven patients were found to have a positive margin; 1 died of metastatic RCC, 1 was alive with systemic recurrence, and 5 had no evidence of disease. Of 11 patients with a negative margin distance of less than 1 mm, 9 were recurrence free, 1 had simultaneous local and pulmonary relapse, and the other had pulmonary recurrence only. The remainder of the study patients (n = 49) had negative margins greater than 1 mm, and all were alive without evidence of disease at the last follow-up. CONCLUSIONS: This review questions the necessity of a 1-cm margin to prevent recurrence after NSS for RCC. Additional studies to determine the optimal margin distance should be conducted.

Single-center analysis of early recurrence of nephrotic syndrome following renal transplantation in children.

Recurrence of nephrotic syndrome (NS) after transplantation (Tx) occurs in 20-50% of renal transplant recipients, with a median time to recurrence of 14 days and a 50% rate of graft loss. We performed a retrospective analysis of 22 pediatric patients with NS who received renal transplants at the Children's Hospital, Boston, between 1982 and 1999. During the first 14 days following Tx, 13 (59%) patients developed clinical recurrent nephrotic syndrome (RNS). RNS developed in 50% of living donor recipients and in 70% of cadaveric donor recipients (p= non-significant). Seven of the 13 patients with RNS were treated with plasmapheresis, while six received standard immunosuppressive induction therapy only. Two of the seven treated patients and one of the six untreated patients lost their grafts to RNS, yielding a total RNS graft loss rate of 23%. However, patients with RNS who achieved remission had significantly higher cumulative graft survival at 5 yr than did RNS patients who did not achieve remission (p< 0.001). Overall cumulative graft survival at 5 yr was not significantly different between the two groups: 67% in those with non-recurrent nephrotic syndrome (NRNS) vs. 64% in those with RNS, p= non-significant. We conclude that successful reversal of early RNS improves long-term graft survival in pediatric RNS. Multi-center studies are sorely needed to develop novel, less toxic therapies for native and recurrent NS.

Bladder rupture after blunt trauma: guidelines for diagnostic imaging.

PURPOSE: The purpose of this study was to establish guidelines for diagnostic imaging for bladder rupture in the blunt trauma victim with multiple injuries, in whom the delay caused by unnecessary testing can hamper the trauma surgeon and threaten outcome. METHODS: We undertook chart review (1995-1999) of patients with blunt trauma and bladder rupture at our four institutions and performed focused literature review of retrospective series. RESULTS: Of our 53 patients identified, all had gross hematuria and 85% had pelvic fracture. Literature review revealed similar rates. CONCLUSION: The classic combination of pelvic fracture and gross hematuria constitutes an absolute indication for immediate cystography in blunt trauma victims. Existing data do not support lower urinary tract imaging in all patients with either pelvic fracture or hematuria alone. Clinical indicators of bladder rupture may be used to identify atypical patients at higher risk. Patients with isolated hematuria and no physical signs of lower urinary tract injury may be spared the morbidity, time, and expense of immediate cystographic evaluation.

Ureteral substitution with a stapled neoureter: a simplified Boari flap.

PURPOSE: We evaluate a new technique that will quickly and easily replace a long segment of ureter by creating a tapered neoureter (Boari flap) with bladder wall and absorbable staples. MATERIALS AND METHODS: A neoureter was created in 14 pigs with native bladder and 75 mm. Polysorb gastrointestinal anastomosis staplers (U. S. Surgical, Norwalk, Connecticut). Urine culture and serum creatinine were obtained before neoureter creation. Neoureter length and time to construct were recorded. At 6 weeks serum creatinine was repeated, and ureteral stent removed with evaluation of the staple lines for stones and residual staples. At 4 months intravenous pyelogram, cystogram and serum creatinine were obtained before necropsy. The bladder, neoureter and kidneys were examined grossly and histologically for hydronephrosis, staples, stones and stenosis. RESULTS: Mean neoureter length was 13.4 cm. and mean time to construct was 15 minutes. Laboratory results were unremarkable. Of the 14 pigs 2 died of pneumonia before stent removal, and at autopsy neither had evidence of hydronephrosis nor anastomotic stricture. In the remaining 12 pigs there was no evidence of residual staples or stone formation with mucosa covering the staple line at cystoscopy and necropsy. Successful neoureter substitution was performed in 9 pigs with no gross or histological changes. There were 3 pigs that had evidence of hydronephrosis with histological findings of chronic pyelonephritis and 2 of them appeared atrophic compared to the contralateral kidney. CONCLUSIONS: Our study demonstrates a new technique for ureteral substitution with bladder and absorbable staples that may be performed quickly and easily. Furthermore, we show that absorbable staples can be safely incorporated into the urinary tract with minimal worry about encrustation or calculus formation.

Management of pediatric postrenal transplantation infections.

Infections are the leading cause of hospitalization and death after renal transplantation in children. Various agents are implicated in posttransplantation infections. Viral infections due to the cytomegalovirus and Epstein-Barr virus have assumed greater importance as other infections such as pneumocystis pneumonia have come under control. Multiple factors contribute to the difficulty in the prevention, diagnosis, and treatment of pediatric postrenal transplantation infections. Prevention of infections by adequate preparation before transplantation and the use of chemoprophylaxis should be made a priority. An aggressive approach to diagnosis is required when investigating fever in children. It is hoped that the use of more specific immunosuppressive agents that block only the alloactivated T cells and leave the rest of the immune response intact may result in a reduction in the number and frequency of infections.

Hounsfield unit density in the determination of urinary stone composition.

OBJECTIVES: Noncontrast computed tomography (NCCT) has emerged as the diagnostic study of choice in the evaluation of acute flank pain. Recent in vitro studies have suggested that NCCT can be used to predict the composition of urinary stones on the basis of differences in radiodensity (measured in Hounsfield units, HUs). We sought to determine whether the analysis of in vivo urinary stones seen on NCCT could predict their composition. METHODS: Between March 1997 and August 1999, 100 pure stones from patients seen at the Wilford Hall Medical Center in San Antonio, Texas were submitted for analysis. All had been visualized by NCCT before stone passage or retrieval. A General Electric High-Speed Advantage CT scanner evaluated most of these patients by a "flank pain protocol" (ie, helical technique with breath-holding at 120 kV, 200 mA with 5 mm collimation). Each scan was interpreted by one of two staff radiologists who measured the HUs for each stone. A statistical comparison was made between the stone composition and radiodensity. To allow for subsequently observed increases in radiodensity with increasing stone size regardless of composition, the HU value was divided by each stone's largest transverse diameter in millimeters to give the HU density. A statistical comparison was then made between stone composition and HU density. RESULTS: No significant difference was noted between the HU values of calcium oxalate and calcium phosphate stones, and thus they were analyzed collectively as "calcium stones." When the HU values of calcium (n = 87), uric acid (n = 7), struvite (n = 4), and cystine (n = 2) stones were compared, the overlap of ranges precluded accurate identification, and the mean HU values were not significantly different from one another. There was less overlap noted when comparing the HU densities of the stones studied, and no noncalcium stone had an HU density greater than 76 HU/mm. Using one-way analysis of variance, significant differences were noted between the mean HU density of calcium (105 +/- 43) and uric acid (50 +/- 24) stones (P = 0.006). A trend toward significance was found between the mean HU density of the calcium and struvite stones (53 +/- 28, P = 0.073). No significant differences were found among the other stones. CONCLUSIONS: HU density compared with the HU value alone better characterized differences in radiodensities among urinary stones; calcium stones can be distinguished from uric acid stones on the basis of this value. However, neither the HU density nor the mean HU value was able to identify urinary stones in vivo.

Correlation of cystoscopic impression with histologic diagnosis of biopsy specimens of the bladder.

There is a paucity of information in the contemporary literature that would permit assessment of the urologist's ability to endoscopically discriminate between benign and malignant lesions of the bladder or to predict the grade and stage of papillary neoplasms. This prospective study evaluates the correlation between cystoscopic impression of urothelial lesions and final histologic diagnoses. Sixty-four patients with 68 urothelial abnormalities requiring formal biopsy or endoscopic resection were evaluated prospectively. At the time of endoscopy, treating urologists completed questionnaires documenting the surgeon's endoscopic impression of disease type and extent and performed standard biopsy or resection of all suspicious lesions. Specimens were submitted for routine histopathologic analysis, and the results were correlated with the questionnaire data. Endoscopic evaluation correctly discriminated between dysplastic/malignant and benign/reactive lesions in this study with a sensitivity of 100%, specificity of 100%, and positive and negative predictive values of 100%. Urologists could not readily distinguish between low- and high-grade papillary urothelial lesions and were frequently unable to determine if a tumor was invasive, particularly if the degree of invasion was microscopic. Endoscopic impression at the time of bladder biopsy or resection is accurate and discriminates between the presence and absence of cancer. Endoscopic impression alone is a relatively poor staging tool with respect to extent of invasive disease and must be coupled with careful histopathologic analysis of biopsy material, bimanual examination when appropriate, and axial imaging for complete assessment of a given tumor.