Hyperuricemia: an unrecognized risk factor for kidney-related sequelae in children with hemolytic uremic syndrome.

BACKGROUND: Chronic kidney-related sequelae after STEC-HUS occur in 20-40% of patients. Hyperuricemia (HU) may cause acute and chronic toxicity involving the kidneys. We retrospectively assessed if there was an association between the presence of HU during the acute illness and that of kidney-related sequelae in children with STEC-HUS. METHODS: Children with STEC-HUS who had clinical and laboratory data at 2 years of follow-up were included in this case-control study. Univariate and multivariate analyses were performed between patients with (cases) or without (controls) kidney-related sequelae to identify factors associated with outcomes, including different measures of serum uric acid (sUA) (baseline level, peak, and duration of HU). HU was defined as sUA > 8 mg/dL. RESULTS: Of 86 patients included, 77.9% had HU. Patients with sequelae (n = 41) had a higher prevalence of HU (41/41 vs. 26/45, p < 0.01), higher baseline leukocyte count, serum creatinine (sCr), and sUA levels as well as lower sodium than controls. During hospitalization, cases also had higher sCr peak, sUA peak and duration of HU, requirement and duration of dialysis, extrarenal complications, and hypertension. By multivariate analysis, after adjusting for length of dialysis, only duration of HU (p = 0.0005; OR 1.7, 95% CI 1.27-2.36) remained as an independent predictor of sequelae, with a best cutoff of 5.5 days (AUC 0.95, specificity 80%, sensitivity 100%). CONCLUSIONS: The presence of HU is a common finding in children with STEC-HUS and its duration during the acute stage was associated with kidney-related sequelae, regardless of the duration of dialysis. A higher resolution version of the Graphical abstract is available as Supplementary Information.

Effects of losartan and enalapril on serum uric acid and GFR in children with proteinuria.

BACKGROUND: Studies have shown that losartan reduces serum uric acid in adults, unlike angiotensin-converting enzyme inhibitors. A previous study demonstrated that losartan and enalapril had comparable effects on proteinuria in children. METHODS: We conducted a post hoc analysis of results from a prospective trial in which the proteinuria-reducing effects of losartan and enalapril were compared. We have now evaluated (a) the effects of these medications on SUA in 248 children with proteinuria and (b) the correlation between changes in SUA and eGFR. RESULTS: SUA levels after 36 months were found to be increased when compared to baseline in both losartan and enalapril groups. The mean change in SUA from baseline was significantly different at 12 months between 23 hypertensive patients randomised to losartan (3.69% decrease [95% CI 11.31%, 3.93%]) and 24 randomised to enalapril (12.57% increase [95% CI 3.72%, 21.41%]), p = 0.007. This significant difference remained after 24, 30 and 36 months but was observed in the entire group of 248 patients only at 12 months. There was a statistically significant negative correlation between changes in SUA and changes in eGFR at each time point over 36 months. CONCLUSIONS: Losartan may have long-term beneficial effects on SUA and eGFR in children with proteinuria.

Hyperuricosuria, hematuria, and novel bladder images with IgA nephropathy.

Episodic (recurrent) macroscopic hematuria in patients with IgA nephropathy is usually associated with a benign prognosis, although some patients experience a transient fall in glomerular filtration rate during the episodes. We present a 15-year-old girl with mild IgA nephropathy who had multiple episodes of macroscopic hematuria associated with severe but transient decreases in estimated glomerular filtration rate, low levels of serum uric acid, and marked increases in fractional excretion of uric acid. Ultrasound studies showed marked inflammatory changes in the bladder, especially involving the trigone. Cystoscopic findings were consistent with these changes. We hypothesize that the macroscopic hematuria may have resulted, at least in part, from hyperuricosuria causing acute irritation of the bladder mucosa in the trigone area.

Changes in PTGS1 and ALOX12 Gene Expression in Peripheral Blood Mononuclear Cells Are Associated with Changes in Arachidonic Acid, Oxylipins, and Oxylipin/Fatty Acid Ratios in Response to Omega-3 Fatty Acid Supplementation.

INTRODUCTION: There is a high degree of inter-individual variability among people in response to intervention with omega-3 fatty acids (FA), which may partly explain conflicting results on the effectiveness of omega-3 FA for the treatment and prevention of chronic inflammatory diseases. In this study we sought to evaluate whether part of this inter-individual variability in response is related to the regulation of key oxylipin metabolic genes in circulating peripheral blood mononuclear cells (PBMCs). METHODS: Plasma FA and oxylipin profiles from 12 healthy individuals were compared to PBMC gene expression profiles following six weeks of supplementation with fish oil, which delivered 1.9 g/d eicosapentaenoic acid (EPA) and 1.5 g/d docosahexaenoic acid (DHA). Fold changes in gene expression were measured by a quantitative polymerase chain reaction (qPCR). RESULTS: Healthy individuals supplemented with omega-3 FA had differential responses in prostaglandin-endoperoxide synthase 1 (PTGS1), prostaglandin-endoperoxide synthase 2 (PTGS2), arachidonate 12-lipoxygenase (ALOX12), and interleukin 8 (IL-8) gene expression in isolated PBMCs. In those individuals for whom plasma arachidonic acid (ARA) in the phosphatidylethanolamine (PE) lipid class decreased in response to omega-3 intervention, there was a corresponding decrease in gene expression for PTGS1 and ALOX12. Several oxylipin product/FA precursor ratios (e.g. prostaglandin E2 (PGE2)/ARA for PTGS1 and 12-hydroxyeicosatetraenoic acid (12-HETE)/ARA for ALOX12) were also associated with fold change in gene expression, suggesting an association between enzyme activity and gene expression. The fold-change in PTGS1 gene expression was highly positively correlated with ALOX12 gene expression but not with PTGS2, whereas IL-8 and PTGS2 were positively correlated. CONCLUSIONS: The regulation of important oxylipin metabolic genes in PBMCs varied with the extent of change in ARA concentrations in the case of PTGS1 and ALOX12 regulation. PBMC gene expression changes in response to omega-3 supplementation varied among healthy individuals, and were associated with changes in plasma FA and oxylipin composition to different degrees in different individuals. TRIAL REGISTRATION: clinicaltrials.gov NCT01838239.

Randomized controlled trial of mycophenolate mofetil in children, adolescents, and adults with IgA nephropathy.

BACKGROUND: Previous randomized controlled trials evaluating the efficacy of mycophenolate mofetil (MMF) in patients with immunoglobulin A nephropathy (IgAN) have produced varying results. STUDY DESIGN: Double-blind placebo-controlled randomized controlled trial. SETTING & PARTICIPANTS: 52 children, adolescents, and adults with biopsy-proven IgAN in 30 centers in the United States and Canada. Entry criteria: age older than 7 to younger than 70 years; urine protein-creatinine ratio (UPCR), ≥0.6g/g (males) or ≥0.8g/g (females); and estimated glomerular filtration rate ≥ 50mL/min/1.73m(2) (≥40mL/min/1.73m(2) if receiving angiotensin-converting enzyme inhibitor). Mean age, 32±12 (SD) years; 62% men; and 73% white. INTERVENTION: Lisinopril (or losartan) plus a highly purified omega-3 fatty acid (Omacor [Pronova Biocare]) was given to 94 patients for 3 months; 52 of the patients with persistent UPCR≥0.6g/g (males) and ≥0.8g/g (females) were randomly assigned to MMF or placebo (target dose, 25-36mg/kg/d) in addition to lisinopril/losartan plus Omacor. OUTCOMES: Change in UPCR after 6 and 12 months treatment with MMF/placebo and 12 months after the end of treatment. MEASUREMENTS: UPCR measured on 24-hour urine samples. Glomerular filtration rate estimated with the Schwartz (age < 18 years) or Cockcroft-Gault (age ≥ 18 years) formula. RESULTS: 44 patients completed 6 months of treatment with MMF (n=22) or placebo (n=22). The trial was terminated early at the recommendation of the Data Monitoring Committee because of the lack of benefit. No patient achieved a complete remission (UPCR<0.2g/g). Mean UPCRs at randomization and after 6 months were 1.45 (95% CI, 1.16-1.75) and 1.40 (95% CI, 1.09-1.70) for MMF and 1.41 (95% CI, 1.17-1.65) and 1.58 (95% CI, 1.13-2.04) for placebo, respectively. The mean difference in UPCR change between these groups (MMF minus placebo) was -0.22 (95% CI, -0.75 to 0.31; P=0.4). Adverse events were rare apart from nausea (MMF, 8.7%; placebo, 3.7%); one of these MMF patients withdrew. LIMITATIONS: Low patient enrollment and short follow-up. CONCLUSIONS: MMF did not reduce proteinuria significantly in patients with IgAN who had persistent proteinuria after lisinopril/losartan plus Omacor.

Individual variation in lipidomic profiles of healthy subjects in response to omega-3 Fatty acids.

INTRODUCTION: Conflicting findings in both interventional and observational studies have resulted in a lack of consensus on the benefits of ω3 fatty acids in reducing disease risk. This may be due to individual variability in response. We used a multi-platform lipidomic approach to investigate both the consistent and inconsistent responses of individuals comprehensively to a defined ω3 intervention. METHODS: The lipidomic profile including fatty acids, lipid classes, lipoprotein distribution, and oxylipins was examined multi- and uni-variately in 12 healthy subjects pre vs. post six weeks of ω3 fatty acids (1.9 g/d eicosapentaenoic acid [EPA] and 1.5 g/d docosahexaenoic acid [DHA]). RESULTS: Total lipidomic and oxylipin profiles were significantly different pre vs. post treatment across all subjects (p=0.00007 and p=0.00002 respectively). There was a strong correlation between oxylipin profiles and EPA and DHA incorporated into different lipid classes (r(2)=0.93). However, strikingly divergent responses among individuals were also observed. Both ω3 and ω6 fatty acid metabolites displayed a large degree of variation among the subjects. For example, in half of the subjects, two arachidonic acid cyclooxygenase products, prostaglandin E2 (PGE2) and thromboxane B2 (TXB2), and a lipoxygenase product, 12-hydroxyeicosatetraenoic acid (12-HETE) significantly decreased post intervention, whereas in the other half they either did not change or increased. The EPA lipoxygenase metabolite 12-hydroxyeicosapentaenoic acid (12-HEPE) varied among subjects from an 82% decrease to a 5,000% increase. CONCLUSIONS: Our results show that certain defined responses to ω3 fatty acid intervention were consistent across all subjects. However, there was also a high degree of inter-individual variability in certain aspects of lipid metabolism. This lipidomic based phenotyping approach demonstrated that individual responsiveness to ω3 fatty acids is highly variable and measurable, and could be used as a means to assess the effectiveness of ω3 interventions in modifying disease risk and determining metabolic phenotype.

Renal function and proteinuria after successful immunosuppressive therapies in patients with FSGS.

BACKGROUND AND OBJECTIVES: In the FSGS Clinical Trial, 22 cyclosporine-treated and 20 mycophenolate/dexamethasone-treated patients experienced a complete or partial remission after 26 weeks, completed 52 weeks of treatment, and were studied through 78 weeks. Herein, changes in the urine protein/creatinine ratio (UP/C) and estimated GFR (eGFR) throughout the entire study period are defined. DESIGN, SETTING, PARTICIPANTS, AND MEASUREMENTS: The FSGS Clinical Trial, which was conducted from November 2004 to January 2010, enrolled patients aged 2-40 years, with eGFR ≥40 ml/min per 1.73 m(2) and UP/C >1 mg/mg after ≥4 weeks of corticosteroid therapy. Both groups received lisinopril or losartan throughout the study. UP/C and eGFR were measured at 0, 26, 52, and 78 weeks. RESULTS: The median UP/C in the cyclosporine- and mycophenolate/dexamethasone-responsive patients fell by 89.8% and 82.7% at 52 weeks; the fall was largely sustained at 78 weeks (74.7% and 80.3%, respectively). The mean eGFR fell by 19.4% in the cyclosporine group and rose by 7.0% in the mycophenolate mofetil/dexamethasone group at 52 weeks, but subsequently rose by 16.4% and fell by 2.6%, respectively, in the two groups from 52 to 78 weeks. CONCLUSIONS: In this subset of responding FSGS patients, the improvement in UP/C after cyclosporine or mycophenolate/dexamethasone treatment was largely sustained for 6 months after therapy. Reduction in eGFR in the cyclosporine group was improved 6 months after cyclosporine was stopped although the levels were lower than baseline in seven patients who entered the study with decreased eGFR.

Serum oxylipin profiles in IgA nephropathy patients reflect kidney functional alterations.

Immunoglobulin A nephropathy (IgAN) is a leading cause of chronic kidney disease, frequently associated with hypertension and renal inflammation. ω-3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) in fish oil (FO) improve kidney function in animal models, but have inconsistent metabolic effects in humans. Oxylipin profiles in serum from IgAN patients supplemented with either FO or corn oil (CO) placebo were analyzed by liquid chromatography coupled to tandem mass spectrometry. EPA cyclooxygenase and lipoxygenase metabolites, and EPA and DHA epoxides and diols were increased in response to FO supplementation, as were total epoxides and epoxide/diol ratios. Several of these metabolites were drivers of separation as assessed by multivariate analysis of FO patients pre- vs. post-supplementation, including 17,18-dihydroxyeicosatrienoic acid, prostaglandin D3, prostagalandin E3, Resolvin E1, 12-hydroxyeicosapentaenoic acid, and 10(11)-epoxydocosapentaenoic acid. In patients whose proteinuria improved, plasma total oxylipins as well as several hydroxyoctadecadienoic acids, hydroxyeicosatetraenoic acids, and leukotriene B4 metabolites were among the metabolites that were significantly lower than in patients whose proteinuria either did not improve or worsened. These data support the involvement of oxylipins in the inflammatory component of IgAN as well as the potential use of oxylipin profiles as biomarkers and for assessing responsiveness to ω-3 fatty acid supplementation in IgAN patients.

Rasburicase for hyperuricemia in hemolytic uremic syndrome.

BACKGROUND: Acute kidney injury (AKI) with elevated serum uric acid (UA) levels has been reported in patients with hemolytic uremic syndrome (HUS). AKI is thought to result from tubular obstruction by UA crystals. Inducing a diuresis may ameliorate the oligoanuria in such patients. We describe a child with HUS in whom reducing UA with fluids and rasburicase appeared to accelerate the recovery of renal function. CASE-DIAGNOSIS/TREATMENT: A 9-month-old Caucasian male infant presented with 6 days of diarrhea, 3 days of vomiting, and 24 h of oliguria. On admission, hemoglobin was 8.3 g/dL, platelet count 36,000/L, blood urea nitrogen 73 mg/dL, and serum creatinine (SCr) 2.7 mg/dL. Diarrhea-associated HUS was diagnosed. The day after admission, SCr was 2.9 mg/dL and UA 12.3 mg/dL. On hospital day 2, he received a dose of intravenous rasburicase 0.18 mg/kg, and less than 12 h later, the UA had fallen to 0.3 mg/dL. The SCr level also started to fall, and urine output progressively increased without the use of diuretics. Renal function continued to improve, and the UA level remained normal despite ongoing hemolysis requiring a second red blood cell transfusion on hospital day 5. The patient was discharged on hospital day 7 in good physical condition. Two months later, he was in good health, with a SCr level of 0.2 mg/dL and UA of 4.2 mg/dL. CONCLUSIONS: We postulate that aggressive management of the high serum UA level with rasburicase and fluid hydration accelerated the recovery of our patient. Further studies are needed to determine the role of rasburicase in the treatment of hyperuricemia in patients with HUS.

Clinical trial of focal segmental glomerulosclerosis in children and young adults.

This NIH-funded multicenter randomized study of focal segmental glomerulosclerosis (FSGS) treatment compared the efficacy of a 12-month course of cyclosporine to a combination of oral pulse dexamethasone and mycophenolate mofetil in children and adults with steroid-resistant primary FSGS. Of the 192 patients enrolled, 138 were randomized to cyclosporine (72) or to mycophenolate/dexamethasone (66). The primary analysis compared the levels of an ordinal variable measuring remission during the first year. The odds ratio (0.59) for achieving at least a partial remission with mycophenolate/dexamethasone compared to cyclosporine was not significant. Partial or complete remission was achieved in 22 mycophenolate/dexamethasone- and 33 cyclosporine-treated patients at 12 months. The main secondary outcome, preservation of remission for 26 weeks following cessation of treatment, was not significantly different between these two therapies. During the entire 78 weeks of study, 8 patients treated with cyclosporine and 7 with mycophenolate/dexamethasone died or developed kidney failure. Thus, our study did not find a difference in rates of proteinuria remission following 12 months of cyclosporine compared to mycophenolate/dexamethasone in patients with steroid-resistant FSGS. However, the small sample size might have prevented detection of a moderate treatment effect.

Clinical trials treating focal segmental glomerulosclerosis should measure patient quality of life.

Optimal therapy of patients with steroid-resistant primary focal segmental glomerulosclerosis (FSGS) remains controversial. This report describes the initial study design, baseline characteristics, and quality of life of patients enrolled in the FSGS Clinical Trial, a large multicenter randomized study of this glomerulopathy comparing a 12-month regimen of cyclosporine to the combination of mycophenolate mofetil and oral dexamethasone. Patients with age ranging 2-40 years, with an estimated glomerular filtration rate > 40 ml/min per 1.73 m², a first morning urine protein-to-creatinine ratio over one, and resistant to corticosteroids were eligible. The primary outcome was complete or partial remission of proteinuria over 52 weeks after randomization. In all, 192 patients were screened, of whom 138 were randomized for treatment. Ethnic distributions were 53 black, 78 white, and 7 other. By self- or parent-proxy reporting, 26 of the 138 patients were identified as Hispanic. The baseline glomerular filtration rate was 112.4 (76.5, 180.0) ml/min per 1.73 m², and urine protein was 4.0 (2.1, 5.3) g/g. Overall, the quality of life of the patients with FSGS was lower than healthy controls and similar to that of patients with end-stage renal disease. Thus, the impact of FSGS on quality of life is significant and this measurement should be included in all trials.

The Oxford IgA nephropathy clinicopathological classification is valid for children as well as adults.

To study the predictive value of biopsy lesions in IgA nephropathy in a range of patient ages we retrospectively analyzed the cohort that was used to derive a new classification system for IgA nephropathy. A total of 206 adults and 59 children with proteinuria over 0.5 g/24 h/1.73 m(2) and an eGFR of stage-3 or better were followed for a median of 69 months. At the time of biopsy, compared with adults children had a more frequent history of macroscopic hematuria, lower adjusted blood pressure, and higher eGFR but similar proteinuria. Although their outcome was similar to that of adults, children had received more immunosuppressants and achieved a lower follow-up proteinuria. Renal biopsies were scored for variables identified by an iterative process as reproducible and independent of other lesions. Compared with adults, children had significantly more mesangial and endocapillary hypercellularity, and less segmental glomerulosclerosis and tubulointerstitial damage, the four variables previously identified to predict outcome independent of clinical assessment. Despite these differences, our study found that the cross-sectional correlation between pathology and proteinuria was similar in adults and children. The predictive value of each specific lesion on the rate of decline of renal function or renal survival in IgA nephropathy was not different between children and adults.

Idiopathic immunoglobulin A nephropathy in children and adolescents.

Immunoglobulin A nephropathy is now recognized as the glomerular disease most often associated with progressive renal failure in patients around the world. In many cases it is not known when the disease starts to inflict glomerular injury, but recent studies that have shown genetically determined abnormalities in glycosylation of the IgA molecule suggest that this may begin in early life. This review focuses on recent advances in our understanding of IgA nephropathy, with special emphasis on clinical aspects of the disease when it presents in children and adolescents. In addition, the sections dealing with therapeutic options for patients with IgA nephropathy concentrate on studies that have been carried out on children. Whenever possible, data from randomized controlled clinical trials have formed the basis for recommendations. Unfortunately, this is not always possible, because of the lack of such trials in patients with IgA nephropathy.

The Oxford classification of IgA nephropathy: pathology definitions, correlations, and reproducibility.

Pathological classifications in current use for the assessment of glomerular disease have been typically opinion-based and built on the expert assumptions of renal pathologists about lesions historically thought to be relevant to prognosis. Here we develop a unique approach for the pathological classification of a glomerular disease, IgA nephropathy, in which renal pathologists first undertook extensive iterative work to define pathologic variables with acceptable inter-observer reproducibility. Where groups of such features closely correlated, variables were further selected on the basis of least susceptibility to sampling error and ease of scoring in routine practice. This process identified six pathologic variables that could then be used to interrogate prognostic significance independent of the clinical data in IgA nephropathy (described in the accompanying article). These variables were (1) mesangial cellularity score; percentage of glomeruli showing (2) segmental sclerosis, (3) endocapillary hypercellularity, or (4) cellular/fibrocellular crescents; (5) percentage of interstitial fibrosis/tubular atrophy; and finally (6) arteriosclerosis score. Results for interobserver reproducibility of individual pathological features are likely applicable to other glomerulonephritides, but it is not known if the correlations between variables depend on the specific type of glomerular pathobiology. Variables identified in this study withstood rigorous pathology review and statistical testing and we recommend that they become a necessary part of pathology reports for IgA nephropathy. Our methodology, translating a strong evidence-based dataset into a working format, is a model for developing classifications of other types of renal disease.

The Oxford classification of IgA nephropathy: rationale, clinicopathological correlations, and classification.

IgA nephropathy is the most common glomerular disease worldwide, yet there is no international consensus for its pathological or clinical classification. Here a new classification for IgA nephropathy is presented by an international consensus working group. The goal of this new system was to identify specific pathological features that more accurately predict risk of progression of renal disease in IgA nephropathy, thus enabling both clinicians and pathologists to improve individual patient prognostication. In a retrospective analysis, sequential clinical data were obtained on 265 adults and children with IgA nephropathy who were followed for a median of 5 years. Renal biopsies from all patients were scored by pathologists blinded to the clinical data for pathological variables identified as reproducible by an iterative process. Four of these variables: (1) the mesangial hypercellularity score, (2) segmental glomerulosclerosis, (3) endocapillary hypercellularity, and (4) tubular atrophy/interstitial fibrosis were subsequently shown to have independent value in predicting renal outcome. These specific pathological features withstood rigorous statistical analysis even after taking into account all clinical indicators available at the time of biopsy as well as during follow-up. The features have prognostic significance and we recommended they be taken into account for predicting outcome independent of the clinical features both at the time of presentation and during follow-up. The value of crescents was not addressed due to their low prevalence in the enrolled cohort.

Screening for CKD in children: a global controversy.

This review addresses the relevance of urinary screening for chronic kidney disease (CKD) in children. Ambiguity about screening children exists because of the uncertainty as to whether early detection of renal disorders in childhood will lead to effective interventions and reduction in the number of individuals who subsequently progress to ESRD. A related concern is whether the adoption of urinary screening programs is cost effective. The most common method that is used for screening children for CKD involves the measurement of spot samples of urine for hematuria and or proteinuria. Although mass screening is now well established in Japan, Taiwan, and Korea, there appears to be movement away from mass screening to detect CKD in children and adolescents in North America and Europe. In December 2007, the American Academy of Pediatrics published their latest recommendations, in which no urinalyses were recommended at any age during childhood. The second issue addressed in this review is the reporting of estimated glomerular filtration rates (GFR) in children by clinical laboratories.

Serum levels of galactose-deficient IgA in children with IgA nephropathy and Henoch-Schönlein purpura.

IgA nephropathy and Henoch-Schönlein purpura nephritis (HSPN) are related diseases characterized by deposits of IgA1-containing immune complexes in the renal mesangium. Adult patients with IgA nephropathy have aberrantly glycosylated IgA1 (galactose-deficient O-linked glycans) in the circulation and renal deposits. However, IgA1 glycosylation has not been studied in pediatric patients with IgA nephropathy. Using our quantitative lectin enzyme-linked immunosorbent assay (ELISA) test, we measured serum levels of galactose-deficient IgA1 of children with IgA nephropathy and HSPN and controls. Children with IgA nephropathy and HSPN had serum levels higher than those of healthy children or renal-disease controls with C1q nephropathy. Furthermore, lectin ELISA identified patients with HSPN whose clinical course mimicked that of IgA nephropathy. In summary, pediatric patients with IgA nephropathy and HSPN have an aberrancy in the glycosylation in IgA1 O-linked glycans that is similar to that in adults with IgA nephropathy.

IgA nephropathy: what's new?

Although IgA nephropathy has only been recognized as a definitive entity for fewer than 40 years, its place in the world as a prominent cause for progressive kidney disease is well established. The extent to which we understand the role of genetically derived abnormal forms of the IgA molecule in the disease is evolving, and this will, hopefully, translate into more specific modes of treatment for patients in the future. In the meantime, we have few specific therapeutic options, most of which have not been well studied in large numbers of patients. The extent to which we can define which patients are likely to progress--and hence should be considered candidates for treatment--will be discussed in this Commentary. In addition, the notion that some patients may have reached "the point of no return" will also be addressed. Unfortunately, most of the comments will be based on results obtained in studies conducted in adults--a situation that is very familiar to pediatric nephrologists.

A multicenter study of the pharmacokinetics of lisinopril in pediatric patients with hypertension.

The pharmacokinetic (PK) parameters of lisinopril were obtained in 46 children aged 6 months to 15 years. A lisinopril suspension (0.15 mg/kg per day) was administered to patients <6 years of age; the remaining children received lisinopril tablets, the daily dose being adjusted according to body weight, i.e., 2.5 mg if <25 kg, 5 mg if 25-45 kg, and 10 mg if >45 kg. Blood was drawn predose and on eight occasions postdose in children aged 4-15 years, and on five occasions in those aged <4 years. PK data are reported for the 46 children in terms of age groups: Group I (n=9), aged 6-23 months; Group II (n=8), aged 2-5 years; Group III (n=12), aged 6-11 years; Group IV (n=17), aged 12-15 years. The dose of lisinopril ranged from 3.07 mg/m(2) per day in Group I to 4.78 mg/m(2) per day in Group IV. C(max) of lisinopril, which occurred 5-6 h postdose, varied from 22 ng/ml in Groups I and II to 44 ng/ml in Groups III and IV; AUC(0-24 h) ranged from 301-311 ng.h/ml in Groups I and II to 550-570 ng.h/ml in Groups III and IV. No serious adverse events related to lisinopril were reported.

Clinical trial to evaluate omega-3 fatty acids and alternate day prednisone in patients with IgA nephropathy: report from the Southwest Pediatric Nephrology Study Group.

This randomized, placebo-controlled, double-blind trial evaluated the role of prednisone and omega 3 fatty acids (O3FA) in patients with IgA nephropathy. Entry criteria were (1) biopsy-proven IgA nephropathy, (2) estimated GFR > or = 50 ml/min per 1.73 m2, and (3) moderate to severe proteinuria. Thirty-three patients were randomly assigned to receive prednisone 60 mg/m2 every other day for 3 mo, then 40 mg/m2 every other day for 9 mo, then 30 mg/m2 every other day for 12 mo (prednisone group); 32 were randomly assigned to receive O3FA 4 g/d for 2 yr (1.88 g eicosapentaenoic acid, 1.48 g docosahexaenoic acid; O3FA group); and 31 were randomly assigned to receive placebo (placebo group). Most (73%) patients completed 2 yr of treatment. Randomly assigned patients who were hypertensive were given enalapril 2.5 to 40 mg/d. The primary end point was time to failure, defined as estimated GFR <60% of baseline. An overall significance level of 0.10 was used. The three groups were comparable at baseline except that the O3FA group had higher urine protein to creatinine (UP/C) ratios than the placebo group (P = 0.003). Neither treatment group showed benefit over the placebo group with respect to time to failure, with 14 patient failures overall (two in the prednisone group, eight in the O3FA group, and four in the placebo group). The primary factor associated with time to failure was higher baseline UP/C ratios (P = 0.009). Superiority of prednisone or O3FA over placebo in slowing progression of renal disease was not demonstrated in this study. However, the relatively short follow-up period, inequality of baseline UP/C ratios, and small numbers of patients precludes definitive conclusions.