Renal survival in pediatric patients with IgA nephropathy.
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Adolescent↗
Biomedical subjects
Robert J Wyatt
Publications and source records attributed to Robert J Wyatt.
Five years' experience with thymoglobulin induction in a pediatric renal transplant population.
Antibody induction therapy is used in the majority of pediatric patients undergoing renal transplantation. Our center has previously reported short-term outcomes with TMG as induction therapy. We now present our experience over the last five yr. Patients received TMG intra- and post-operatively at a dose of 1.5 mg/kg/day. The dose was decreased to 0.75 mg/kg/day or held dependent on the patient's WBC and platelet counts. Post-transplant immunosuppression also included corticosteroids, MMF, and either TAC or CSA. Patient and graft survival, number of acute rejection episodes, creatinine clearance, incidence and type of infections, and trough levels of calcineurin inhibitor drugs were monitored during the follow-up period. Thirty-four renal transplants were performed in 33 pediatric patients ranging in age from 1.7 to 17.8 yr. Seventeen rejection episodes occurred during the time of follow-up with three patients having more than one episode, but only three episodes occurred within the first year after transplantation. Three patients had graft loss in the first week after transplantation from primary non-function (1) or technical failure/thrombosis (2). Graft losses occurred in seven additional patients during the time of follow-up with the first loss occurring at 17.7 months. Among patients with functional grafts at one wk after transplant, graft survival at one and three yr was 100% and 73% respectively. There were no patient deaths. There were no cases of post-transplant lymphoproliferative disease or other malignancy. One patient had symptomatic CMV disease. TMG is safe and effective as induction therapy in pediatric renal transplant patients. Late graft loss remains a challenge in the pediatric patient population, particularly in adolescents.
Adolescent↗
Predominance of nocturnal hypertension in pediatric renal allograft recipients.
Hypertension is common in children with end-stage renal disease who have undergone renal transplantation. We performed ambulatory blood pressure monitoring (ABPM) in renal allograft recipients who were on stable maintenance immunosuppressive medications and were more than six months post-transplant. Echocardiographic measurement of left ventricular mass index (LVMI) was obtained at the time of ABPM. Twenty-nine children with a mean age of 14.8 yr (8-18 yr) were evaluated 4.3 yr (0.6-12.8 yr) after deceased donor (n = 13) or living donor (n = 16) transplantation. BP levels were higher during sleep compared with when awake using the 95th percentile to standardize mean BP for each period: mean BP was expressed as a standard deviation score (SDS) for each time period, awake vs. sleep: systolic (s) BP SDS were 0.43 +/- 1.3 vs. 1.29 +/- 1.2 (p < 0.001) and diastolic (d) BP SDS were 0.04 +/- 1.3 vs. 1.34 +/- 1.2 (p < 0.001). Significant differences between awake and sleep BP were also confirmed using the mean BP for each period expressed as a BPI. Hypertension (HTN) during sleep was more common than awake HTN. Based upon BPI, 21% had sHTN when awake compared with 48% during sleep and 7% had dHTN when awake compared with 41% during sleep (p < 0.05). Based upon mean BP load, 38% had sHTN when awake compared with 55% during sleep and 21% demonstrated dHTN when awake compared with 52% during sleep (p < 0.05). Left ventricular mass (LVM) was abnormally increased in six of 17 children (35%); LVM was not correlated with BP. Children prescribed angiotensin converting enzyme inhibitors or angiotensin II receptor blockers (ACEi/ARB) had significantly lower systolic BP compared with those on calcium channel blocking agents (CCB). Mean sSDS was -0.11 +/- 1.1 in those children on ACEi/ARB compared with 1.6 +/- 1.2 in those on CCB (p = 0.02): sSDS during sleep was significantly lower in the ACEi/ARB group compared with CCB (0.70 +/- 1.1 vs. 2.0 +/- 1.1, p = 0.04). Isolated nocturnal HTN is more common than daytime HTN among clinically stable pediatric renal allograft recipients. Detection and treatment of nocturnal HTN in pediatric allograft recipients could potentially affect graft survival.
Adolescent↗
Sirolimus pharmacokinetics in pediatric renal transplant recipients receiving calcineurin inhibitor co-therapy.
We have previously reported sirolimus (SRL) pharmacokinetics (PK) in pediatric renal transplant recipients on a calcineurin inhibitor (CNI)-free protocol. We now report pediatric SRL PK in pediatric renal transplant patients receiving SRL + CNI. SRL was dosed to achieve target trough levels between 10 and 20 ng/mL. We performed 49 SRL PK profiles in pediatric renal transplant recipients receiving SRL in combination with either cyclosporine (CsA; 25 profiles), or tacrolimus (TCL; 24 profiles). Ten of the SRL + TCL profiles were obtained from children receiving SRL on a b.i.d. dosing regimen. All other SRL profiles were q.d. regimens. We calculated, the maximum concentration (C(max)), AUC, apparent clearance (aCL; dose/AUC) for dose in mg/m(2), and mean residence time (MRT). SRL levels were measured at 6 and 7 time points for b.i.d. and q.d. dosing, respectively. Regression analysis of SRL trough values vs. AUC showed good correlation in the SRL q.d. + CsA, SRL q.d. + TCL, and SRL b.i.d. + TCL groups (r(2) = 0.95, 0.68, and 0.44, respectively). SRL aCL corrected for body surface area was higher in children aged 0-5 yr receiving SRL with either CsA or TCL. SRL dosing schedule should be tailored to each patient. Higher SRL aCL may be present in younger children when administered with CNI.
Adolescent↗
C1q nephropathy: features at presentation and outcome.
The study population comprised all 20 patients followed since 1990 through December 2004 at the Le Bonheur Children's Medical Center with diagnosis of C1q nephropathy (55% boys; 60% African Americans). All were aged under 18 years at biopsy (mean 11.2 years, 65% aged 11 or over); the youngest presented at age 10 months and progressed to end-stage renal disease at 14 months. None had clinical or laboratory features of systemic lupus erythematosis or membranoproliferative glomerulonephritis. Clinical features assessed at diagnosis were age, gender, blood pressure, history of macroscopic hematuria, urinary protein to creatinine ratio, serum creatinine, estimated glomerular filtration rate, renal histology, and pattern for immunofluorescent reactants. At the time of biopsy 40% had nephrotic syndrome and 30% nephrotic range proteinuria without nephrotic syndrome. Three patients with nephrotic syndrome also had chronic renal insufficiency at diagnosis. The most common histological feature was focal segmental glomerulosclerosis in 40%, but 30% had minimal change lesion. Four patients, all with nephrotic syndrome at diagnosis, progressed to end-stage renal disease. Of the 12 patients not presenting with nephrotic syndrome, none had chronic renal insufficiency at last follow-up. Kidney survival was 94% and 78% at 1 and 5 years, respectively, in all patients and 88% and 49% in those presenting with nephrotic syndrome.
Adolescent↗
Glomerulonephritis.
GN in the adolescent requires prompt diagnosis. When even mild degrees of renal insufficiency are documented, immediate referral to a nephrologist is necessary to ensure that serious conditions, such as RPGN, are correctly diagnosed and aggressively managed. In an adolescent with macroscopic hematuria, the demonstration of dysmorphic RBCs, RBC casts, and proteinuria indicates that the bleeding is of glomerular origin. Physicians caring for adolescents with chronic GN should have a basic understanding of the specific disorders. They may be involved in blood pressure monitoring and should be aware of the potential side effects of the antihypertensive and immunosuppressive medications used in patients with GN.
Acute Disease↗
Purpura followed by proteinuria in a 7-year-old girl.
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Angiotensin-Converting Enzyme Inhibitors↗
IgA1-containing immune complexes in IgA nephropathy differentially affect proliferation of mesangial cells.
BACKGROUND: Sera of patients with IgA nephropathy (IgAN) contain circulating immune complexes (CIC) composed of galactose-deficient IgA1 complexed with antiglycan antibodies. The role of these CIC in the pathogenesis of IgAN is not known. METHODS: We studied how proliferation of cultured mesangial cells (MC) is affected by CIC prepared from sera of IgAN patients and healthy control subjects using size-exclusion chromatography. CIC-containing fractions were added to serum-starved MC in culture, and cell proliferation was measured using (3)H-thymidine incorporation. The results were confirmed by staining MC using an antibody against proliferating cell nuclear antigen. RESULTS: The incubation of starved MC with serum fractions with M(r) 800 to 900 kD, rich with galactose-deficient IgA1, stimulated proliferation, while fractions with smaller complexes were inhibitory. Furthermore, CIC-containing larger molecular mass fractions isolated from serum of an IgAN patient collected during an episode of macroscopic hematuria stimulated MC proliferation more than CIC obtained during a subsequent quiescent phase. To examine the role of IgA, we removed IgA1 from serum before fractionation. The resultant IgA1-depleted fractions were devoid of stimulatory IgA-CIC. Sera of IgAN patients were also fractionated after addition of desialylated galactose-deficient polymeric IgA1 to form additional immune complexes. Supplementation with a small quantity of this IgA1 increased cellular proliferation in assays using serum fractions of M(r)>/=800 to 900 kD; uncomplexed IgA1 did not affect MC proliferation significantly. In contrast, supplementation with a larger quantity of this IgA1 inhibited cellular proliferation in assays using serum fractions of M(r) 700 to 800 kD. CONCLUSION: Overall, these findings suggest that CIC containing aberrantly glycosylated IgA1 affect proliferation of MC in vitro and, thus, likely play a role in the pathogenesis of IgAN.
Adult↗
A randomized controlled trial of mycophenolate mofetil in patients with IgA nephropathy [ISRCTN62574616].
BACKGROUND: IgAN is the most common type of glomerulonephritis in the world. Between 15 and 40 percent of adults and children diagnosed with IgAN eventually progress to ESRD. Despite the need for effective treatment strategies, very few RCTs for IgAN have been performed. The most effective therapies for IgAN appear to be corticosteroids, ACEi, and FOS that contain a high concentration of omega 3 fatty acids. While ACEi and FOS are generally well tolerated with minimal side effects, the use of high dose steroids over a long course of therapy is often associated with significant morbidity. OBJECTIVE OF THE STUDY: The objective of the study is to test the hypothesis that treatment with the immunosuppressive agent, MMF, will lead to significant and sustained improvement in urinary protein excretion in patients with IgAN who have been pre-treated (and continue to be treated) with ACEi and FOS compared to a placebo control group of patients receiving comparable doses of ACEi and FOS without MMF. DESIGN: After a three month treatment period with the ACEi, lisinopril and the FOS, Omacor, 100 (2 x 50) patients with IgAN and a urinary P/C ratio > or = 0.6 (males) and > or = 0.8 (females) and an estGFR > or = 40 ml/min/1.73 m2 will be randomized to treatment with either MMF or placebo for one year. All patients will be followed off study drug for a second year, but will continue treatment with lisinopril and Omacor for the two year duration of the study. The primary outcome measure of change in urine P/C ratio will be assessed at the end of years one and two.
Angiotensin-Converting Enzyme Inhibitors↗
Pediatric IgA nephropathies: clinical aspects and therapeutic approaches.
The pediatric IgA nephropathies are IgA nephrothapy (Berger's Disease) and Henoch-Schönlein purpura nephritis. Both conditions are reviewed in detail with respect to epidemiology, clinical features, outcome, prognostic markers, and therapeutic approaches. For both conditions variable disease severity and outcome along with the lack of conclusive evidence for efficacy of treatment based on randomized clinical trials makes it difficult to make strong recommendations regarding therapy.
Child↗
Racial disparities in renal transplantation in children.
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Adolescent↗
Short-term outcomes of Thymoglobulin induction in pediatric renal transplant recipients.
No data are currently available that describe the clinical outcomes associated with Thymoglobulin (rabbit polyclonal anti-thymocyte globulin) induction in pediatric renal transplant recipients. We report the outcomes of 17 pediatric renal transplant recipients (mean age 10.1+/-5.2 years) transplanted between 1 August 1999 and 31 July 2001. Eleven patients (65%) were Caucasian and 6 (35%) were African-American. Eleven (65%) recipients received cadaveric allografts. Two patients (12%) were second allograft recipients. One patient had primary allograft non-function secondary to vascular thrombosis. Two patients (12%) had delayed allograft function. Immunosuppression consisted of Thymoglobulin induction (mean number of doses 6+/-1.7) with tacrolimus (62%) or cyclosporine A (38%), mycophenolate mofetil, and prednisone. One year post transplant, patient and graft survival was 100% and 93%, respectively. No acute rejection episodes occurred during the first 6 months after transplantation in any of the recipients. Additionally, no rejection episode occurred among the 14 patients followed for 1 year after transplant. The incidences of asymptomatic cytomegalovirus (CMV) and Epstein-Barr virus (EBV) seroconversion at 1 year in seronegative recipients with a seropositive donor were 100% of 4 patients and 0% of 4 patients, respectively. No symptomatic CMV or EBV infections and no post-transplant lymphoproliferative disease have occurred in any patient. These short-term data suggest that Thymogobulin induction is safe and effective in combination with triple immunosuppressive therapy for preventing early rejection in pediatric renal transplant recipients.
Acute Disease↗
Angiotensin-converting enzyme genotype and outcome in pediatric IgA nephropathy.
Angiotensin-converting enzyme (ACE) I/D polymorphism has been implicated as a genetic marker for progression of glomerular disease. Studies of ACE genotypes in adults with IgA nephropathy (IgAN) have yielded conflicting results. We performed ACE genotyping on 79 patients with IgAN diagnosed prior to age 18 years who had either progressed to end-stage renal disease (ESRD) or are now more than 5 years post biopsy. Mean follow-up was 14.8 years for those with normal renal function. Forty-three (54.4%) subjects had normal renal function and a normal urinalysis at last evaluation. Sixteen (20%) progressed to ESRD and 1 has chronic renal insufficiency. Kaplan-Meier survival curves for progression to ESRD did not differ significantly for the ACE DD, ID, and II genotype groups (P=0.095, log-rank test). By univariate analysis, presence of hypertension and degree of proteinuria at diagnosis, and unfavorable histology but not ACE genotype, was significantly associated with progression to ESRD. In the Cox proportional hazards model that included grade of proteinuria, the ACE D allele was a significant independent predictor of outcome with a hazard ratio of 2.37 (P=0.031). Our data, while inconclusive, suggest that the ACE D allele may associate with poor outcome in pediatric IgAN.
Adolescent↗