Association of Treatment Effects on Early Change in Urine Protein and Treatment Effects on GFR Slope in IgA Nephropathy: An Individual Participant Meta-analysis.

RATIONALE & OBJECTIVE: An early change in proteinuria is considered a reasonably likely surrogate end point in immunoglobulin A nephropathy (IgAN) and can be used as a basis for accelerated approval of therapies, with verification in a postmarketing confirmatory trial. Glomerular filtration rate (GFR) slope is a recently validated surrogate end point for chronic kidney disease progression and may be considered as the end point used for verification. We undertook a meta-analysis of clinical trials in IgAN to compare treatment effects on change in proteinuria versus change in estimated GFR (eGFR) slope. STUDY DESIGN: Individual patient-level meta-analysis. SETTING & STUDY POPULATIONS: Individual data of 1,037 patients from 12 randomized trials. SELECTION CRITERIA FOR STUDIES: Randomized trials of IgAN with proteinuria measurements at baseline and 6 (range, 2.5-14) months and at least a further 1 year of follow-up for the clinical outcome. ANALYTICAL APPROACH: For each trial, we estimated the treatment effects on proteinuria and on the eGFR slope, computed as the total slope starting at baseline or the chronic slope starting 3 months after randomization. We used a Bayesian mixed-effects analysis to relate the treatment effects on proteinuria to effects on GFR slope across these studies and developed a prediction model for the treatment effect on the GFR slope based on the effect on proteinuria. RESULTS: Across all studies, treatment effects on proteinuria accurately predicted treatment effects on the total slope at 3 years (median R2 = 0.88; 95% Bayesian credible interval [BCI], 0.06-1) and on the chronic slope (R2 = 0.98; 95% BCI, 0.29-1). For future trials, an observed treatment effect of approximately 30% reduction in proteinuria would confer probabilities of at least 90% for nonzero treatment benefits on the total and chronic slopes of eGFR. We obtained similar results for proteinuria at 9 and 12 months and total slope at 2 years. LIMITATIONS: Study population restricted to 12 trials of small sample size, leading to wide BCIs. There was heterogeneity among trials with respect to study design and interventions. CONCLUSIONS: These results provide new evidence supporting that early reduction in proteinuria can be used as a surrogate end point for studies of chronic kidney disease progression in IgAN.

Computer-Generated Three-Dimensional Airway Models as a Decision-Support Tool for Preoperative Evaluation and Procedure-Planning in Pediatric Anesthesiology.

Technology improvements have rapidly advanced medicine over the last few decades. New approaches are constantly being developed and utilized. Anesthesiology strongly relies on technology for resuscitation, life-support, monitoring, safety, clinical care, and education. This manuscript describes a reverse engineering process to confirm the fit of a medical device in a pediatric patient. The method uses virtual reality and three-dimensional printing technologies to evaluate the feasibility of a complex procedure requiring one-lung isolation and one-lung ventilation. Based on the results of the device fit analysis, the anesthesiology team confidently proceeded with the operation. The approach used and described serves as an example of the advantages available when coupling new technologies to visualize patient anatomy during the procedural planning process.

Renal involvement in primary Sjögren's syndrome: a clinicopathologic study.

BACKGROUND & OBJECTIVES: Renal pathology and clinical outcomes in patients with primary Sjögren's syndrome (pSS) who underwent kidney biopsy (KB) because of renal impairment are reported. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Twenty-four of 7276 patients with pSS underwent KB over 40 years. Patient cases were reviewed by a renal pathologist, nephrologist, and rheumatologist. Presentation, laboratory findings, renal pathology, initial treatment, and therapeutic response were noted. RESULTS: Seventeen patients (17 of 24; 71%) had acute or chronic tubulointerstitial nephritis (TIN) as the primary lesion, with chronic TIN (11 of 17; 65%) the most common presentation. Two had cryoglobulinemic GN. Two had focal segmental glomerulosclerosis. Twenty patients (83%) were initially treated with corticosteroids. In addition, three received rituximab during follow-up. Sixteen were followed after biopsy for more than 12 mo (median 76 mo; range 17 to 192), and 14 of 16 maintained or improved renal function through follow-up. Of the seven patients presenting in stage IV chronic kidney disease, none progressed to stage V with treatment. CONCLUSIONS: This case series supports chronic TIN as the predominant KB finding in patients with renal involvement from pSS and illustrates diverse glomerular lesions. KB should be considered in the clinical evaluation of kidney dysfunction in pSS. Treatment with glucocorticoids or other immunosuppressive agents appears to slow progression of renal disease. Screening for renal involvement in pSS should include urinalysis, serum creatinine, and KB where indicated. KB with characteristic findings (TIN) should be considered as an additional supportive criterion to the classification criteria for pSS because it may affect management and renal outcome.

Enhanced absorption of n-3 fatty acids from emulsified compared with encapsulated fish oil.

Health benefits of n-3 fatty acids are well-established. However, consumption of adequate dietary sources of these fatty acids is inadequate. Oral fish oil supplements are an alternative means of consuming adequate long-chain n-3 fatty acids in individuals who do not consume sufficient dietary sources. However, palatability can present a problem with compliance. Emulsifying fish oil allows for production of a pleasant-tasting supplement and can enhance digestion and absorption of the fatty acids. We investigated the rate and extent of absorption of emulsified fish oil compared with capsular triglyceride fish oil supplements in humans. Participants subjectively rated palatability of these products. A randomized, crossover-designed, open-label trial was performed in which 10 healthy volunteers received emulsified fish oil and capsular triglyceride fish oil orally. Blood samples were collected at 0, 2, 4, 8, 24, and 48 hours to determine the absorption of individual fatty acids into plasma phospholipid fatty acids. At the completion of blood collection, subjects were asked to subjectively rate the tolerance and acceptability of the two supplements. During a 48-hour period, there was enhanced absorption of total n-3 and eicosapentaenoic acid (0.67%+/-0.16%, 0.45%+/-0.06%; P<0.01; 0.34%+/-0.05%, 0.23%+/-0.04%; P=0.05; emulsified fish oil and capsular triglyceride fish oil, respectively) observed for the emulsified fish oil treatment. Our findings indicate that a single dose of emulsified fish oil resulted in enhanced absorption of total n-3 eicosapentaenoic acid and docosahexaenoic acid as evidenced by changes in phospholipid fatty acids composition compared with the capsular triglyceride fish oil during the 48-hour observation period. Both supplements were subjectively rated and found to be well-tolerated by participants.

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.

Is body size a biomarker for optimizing dosing of omega-3 polyunsaturated fatty acids in the treatment of patients with IgA nephropathy?

Re-analysis of the North American IgA Nephropathy Study suggested that efficacy of omega-3 polyunsaturated fatty acids (omega-3 PUFA) was dosage-dependent on the basis of body size and plasma omega-3/omega-6 and eicosapentaenoic acid (EPA)/arachidonic acid (AA) ratios. The objective of this study was to confirm these assertions. Data from a previously reported randomized 2-yr clinical trial in which two dosages of an ethyl ester omega-3 PUFA (Omacor) were given to 73 high-risk patients with IgA nephropathy were reviewed. Omacor also was used in the North American IgA Nephropathy Study. Parameters included body weight; body mass index (BMI); plasma phospholipid AA, EPA, and docosahexanoic acid (DHA) levels and serum creatinine and 24-h urine protein (UP) levels during the 2-yr trial; and time to ESRD after 6.4 yr. Plasma phospholipid levels of EPA, DHA, and EPA/AA ratios were significantly inversely correlated with increasing body weight and BMI in the Omacor 4-g dosage group but not in the Omacor 8-g dosage group. Conversely, increasing levels of lipid parameters were observed with increasing dosages of Omacor (EPA+DHA) in grams per kilogram of body weight at 6 wk of treatment. None of the plasma omega-3 PUFA levels, EPA/AA ratios, or Omacor dosage per kilogram was significantly associated with reciprocal serum creatinine or UP slopes during the 2-yr trial or with ESRD. This post hoc analysis of body weight and BMI, plasma omega-3 PUFA status, and renal outcome did not find that treatment efficacy of omega-3 PUFA was dosage dependent on the basis of body size.

The role of fish oil/omega-3 fatty acids in the treatment of IgA nephropathy.

Beneficial effects of omega-3 polyunsaturated fatty acids (n-3 PUFA) have been reported in recent epidemiologic studies and randomized clinical trials in a variety of cardiovascular and autoimmune diseases. Fish and marine oils are the most abundant and convenient sources of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), the two major n-3 fatty acids that serve as substrates for cyclooxygenase and lipoxygenase pathways leading to less potent inflammatory mediators than those produced through the n-6 PUFA substrate, arachidonic acid. N-3 PUFA can also suppress inflammatory and/or immunologic responses through eicosanoid-independent mechanisms. Although the pathophysiology of IgA nephropathy is incompletely understood, it is likely that n-3 PUFA prevents renal disease progression by interfering with a number of effector pathways triggered by mesangial immune-complex deposition. In addition, potential targets of n-3 PUFA relevant to renal disease progression could be similar to those involved in preventing the development and progression of cardiovascular disease by lowering blood pressure, reducing serum lipid levels, decreasing vascular resistance, or preventing thrombosis. In IgA nephropathy, efficacy of n-3 PUFA contained in fish oil supplements has been tested with varying results. The largest randomized clinical trial performed by our collaborative group provided strong evidence that treatment for 2 years with a daily dose of 1.8 g of EPA and 1.2 g of DHA slowed the progression of renal disease in high-risk patients. These benefits persisted after 6.4 years of follow up. With safety, composition, and dosing convenience in mind, we can recommend two products that are available as pharmaceutical-grade fish-oil concentrates, Omacor (Pronova Biocare, Oslo, Norway) and Coromega (European Reference Botanical Laboratories, Carlsbad, CA).

Proteinuria patterns and their association with subsequent end-stage renal disease in IgA nephropathy.

BACKGROUND: Proteinuria (UP) >1.0 g/24 h at diagnosis is a well-known indicator of progressive renal disease in patients with IgA nephropathy (IgAN). To determine if persistent UP is a more sensitive marker for later progression of IgAN, the hypothesis was tested that the prior level and trend (slope) in UP for 1 year was better at predicting later end-stage renal disease (ESRD) (dialysis or transplant) than a current 24-h UP, serum creatinine (SC), SC slope, hypertension, or total glomerular histopathological score on index renal biopsy in an observational study of 154 high-risk patients enrolled in two clinical trials (IgAN 1, IgAN 2). METHODS: Measurements of 24-h UP and SC were made at time 0, 6 weeks, 6 months and 1 year in all patients, who were then followed for an additional 5.76 years and 1.63 years in the two studies, respectively. The Cox proportional hazards model was used to identify predictors of ESRD following the 1-year visit. RESULTS: Adjusting only for randomized treatment, nearly all UP variables (number of high readings, 1-year level, slopes), SC at 1 year, and SC trends (slopes) over the prior year were significantly associated with subsequent ESRD (all P values <0.05) in both studies. However, among the UP variables, the 1-year readings had the strongest association with ESRD in IgAN 1 (hazard ratio (HR), 95% CI, for a 1g increase: 1.5, 1.2,1.9), and the second strongest association (similar to UP trends) in IgAN 2 (1.4, 1.2,1.6). Males had lower rates of ESRD in both studies (IgAN 1 HR: 0.5, 0.2,1.2, P=0.11; IgAN 2 HR: 0.2, 0.1,0.6, P=0.002). In the multivariate analyses that examined all clinical and histological variables, 1-year levels of 24-h UP and SC, and female gender were independently associated with subsequent ESRD. CONCLUSION: In a high-risk patient with IgAN, the current 24-h UP and SC measurements are as good predictors of subsequent ESRD as UP and SC trends and levels over the prior year. Additionally, it appears that females have poorer outcomes than males.

A randomized trial of high-dose compared with low-dose omega-3 fatty acids in severe IgA nephropathy.

Tested was the hypothesis that high-dose omega (omega)-3 fatty acids will be more effective than low-dose omega-3 fatty acids in preserving renal function in patients with severe IgA nephropathy in a randomized, open-label, parallel-group clinical trial. Patients were assigned to receive either high-dose fatty acids (EPA 3.76 g and DHA 2.94 g) or low-dose fatty acids (EPA 1.88 g and DHA 1.47 g), both given daily in a highly purified ethyl ester concentrate (Omacor). Patients were treated for a minimum of 2 yr in the absence of a treatment failure or until study closure (January 2000). Seventy-three patients were enrolled in the trial with two ranges of elevated serum creatinine (SC): 63 patients (86%) with a range of 1.5 to 2.9 mg/dl and 10 patients (14%) with a range of 3.0 to 4.9 mg/dl. The primary end point, within-patient rates of change in SC (2-yr minimum), showed an annualized median increase in SC of 0.08 mg/dl per yr in the low-dose group and 0.10 mg/dl per yr in the high-dose group (P: = 0.51). Patients in the lower entry SC range had lower SC slopes (P: = 0.02) and less end-stage renal disease (ESRD) (P: < 0.001) compared with those in the higher entry SC range. No patient died, and 18 patients developed ESRD: 10 in the low-dose group and 8 in the high-dose group (P: = 0.56). SC slopes were significantly lower, and survival free of ESRD was significantly higher (both, P: = 0.04) in the 63 Omacor-treated patients compared with the 22 placebo-treated patients from our previously reported clinical trial in which both groups had a similar level of renal impairment. Patient compliance was excellent, and no serious adverse events were noted. Low-dose and high-dose omega-3 fatty acids were similar in slowing the rate of renal function loss in high-risk patients with IgA nephropathy, particularly those with moderately advanced disease.