IgA vasculitis with nephritis: update of pathogenesis with clinical implications.

IgA vasculitis with nephritis (IgAVN) shares many pathogenetic features with IgA nephropathy (IgAN). The purpose of this review is to describe our current understanding of the pathogenesis of pediatric IgAVN, particularly as it relates to the four-hit hypothesis for IgAN. These individual steps, i.e., hits, in the pathogenesis of IgAN are (1) elevated production of IgA1 glycoforms with some O-glycans deficient in galactose (galactose-deficient IgA1; Gd-IgA1), (2) generation of circulating IgG autoantibodies specific for Gd-IgA1, (3) formation of pathogenic circulating Gd-IgA1-containing immune complexes, and (4) kidney deposition of the Gd-IgA1-IgG immune complexes from the circulation and induction of glomerular injury. Evidence supporting the four-hit hypothesis in the pathogenesis of pediatric IgAVN is detailed. The genetics, pediatric outcomes, and kidney histopathologic features and the impact of these findings on future treatment and potential biomarkers are discussed. In summary, the evidence points to the critical roles of Gd-IgA1-IgG immune complexes and complement activation in the pathogenesis of IgAVN. Future studies are needed to characterize the features of the immune and autoimmune responses that enable progression of IgA vasculitis to IgAVN.

Predictors of Hypophosphatemia and Outcomes during Continuous Renal Replacement Therapy.

INTRODUCTION: Hypophosphatemia occurs in up to 80% of patients undergoing continuous renal replacement therapy (CRRT) and has been associated with poor outcomes. Whether preemptive phosphate supplementation is warranted in select patients has not been adequately explored. This single-center, retrospective cohort study evaluates predictors of hypophosphatemia and characterizes treatment approaches in adult patients undergoing at least 12 h of CRRT. METHODS: Patients were divided into 2 groups based on the presence or absence of hypophosphatemia as defined by serum phosphorus <2.5 mg/dL. Select laboratory values at baseline and during CRRT, medications and nutritional sources affecting phosphorus, and CRRT parameters were compared. Patient outcomes including resolution of acute kidney injury (AKI), freedom from renal replacement therapy at hospital discharge, duration of intensive care unit (ICU) and hospital stay, duration of mechanical ventilation, and ICU mortality were evaluated. RESULTS: Seventy-two patients were included. The group was 43% female and 51% African American. CRRT was ordered for AKI in 83% and for end-stage renal disease in 15%. Hypophosphatemia occurred in 45 patients (63%). Mean time to development of hypophosphatemia was 34 ± 22 h. Patients who developed hypophosphatemia received a longer duration of CRRT (p = 0.001), were more likely to have a diet ordered (p = 0.005), less likely to have received calcium infusions (p = 0.045), and had lower phosphorus (p = 0.017) and potassium levels (p = 0.038) and higher calcium levels at baseline (p = 0.048). Development of hypophosphatemia was associated with an increased duration of ICU stay (p = 0.014) but not with the other patient outcomes evaluated. Twenty-seven of the 45 patients (60%) who developed hypophosphatemia received phosphorus supplementation with near equal use of intravenous, oral, and combination routes. Only 17 patients (38%) achieved resolution of hypophosphatemia while on CRRT. CONCLUSION: Hypophosphatemia is common, difficult to correct, and contributes to longer ICU stays in patients requiring CRRT. A preemptive approach to address hypophosphatemia including aggressive supplementation strategies to correct phosphorus is warranted in patients requiring CRRT.

Life Expectancy for Patients From the Southeastern United States With IgA Nephropathy.

INTRODUCTION: Although end-stage renal disease (ESRD) and surrogate markers for renal dysfunction are frequently used as outcome markers for IgA nephropathy, the clinical course after reaching ESRD is not well documented. This study examined outcomes of progression to ESRD and age at death in a cohort of adults with IgA nephropathy with a long duration of follow-up. METHODS: Patient and kidney survival of 251 adult patients with IgA nephropathy from the southeastern United States diagnosed between January 1, 1976 and December 31, 2005 were analyzed. RESULTS: Median age at diagnosis was 36.9 years. Most patients were men (69%) and Caucasian (95%). Only 46% had an estimated glomerular filtration rate >60 ml/min per 1.73 m2 at diagnosis. Mean follow-up time from time of diagnostic biopsy to death or end of study was 19.3 years. Of 251 patients, 132 (53%) progressed to ESRD and 97 (39%) died. Life expectancy was reduced by 10.1 years, with a median observed age of death at 65.7 years and a median expected age at death of 75.8 years. Eighty-three percent of the deaths occurred after progression to ESRD. CONCLUSION: Life expectancy is substantially reduced for patients diagnosed with IgA nephropathy in the southeastern United States.

Serial Galactose-Deficient IgA1 Levels in Children with IgA Nephropathy and Healthy Controls.

Galactose-deficient IgA1 (Gd-IgA1) is a key pathogenic factor for IgA nephropathy (IgAN) and a potential biomarker for the disease. This study examined serial serum Gd-IgA1 levels over 1 year in 13 children with IgAN and 40 healthy children, to determine whether or not serum Gd-IgA1 levels changed over time. Subjects were younger than 18 years of age. Follow-up measurements were scheduled 6 and/or 12 months later. Analysis of variance and regression models for repeated measures were used to estimate group and time effects. Serum Gd-IgA1 level was higher in initial samples for IgAN patients compared to those of healthy children (P < 0.0001). Serum Gd-IgA1 levels did not change over time for healthy controls but increased for IgAN patients (P = 0.001). Serum Gd-IgA1 level was elevated for 9 children with IgAN at study entry and remained elevated. Two of the 4 IgAN patients with initially normal Gd-IgA1 levels had a subsequent elevated level. The persistent elevation of the serum Gd-IgA1 level in children with IgAN enhances its utility as a potential diagnostic test for IgAN.

Glomerular filtration rate equations do not accurately predict vancomycin trough concentrations in pediatric patients.

BACKGROUND: The Bedside Chronic Kidney Disease in Children (CKiD) equation was developed using data from children with chronic kidney disease. Some institutions are using this equation in all pediatric patients, regardless of renal function, to adjust medications. No data have shown that the Bedside CKiD equation is equivalent or better than the Schwartz equation in estimating glomerular filtration rate (GFR) in pediatric patients with normal renal function. OBJECTIVE: To compare GFR estimates using the Bedside CKiD and Schwartz equations and determine if either offers sufficient vancomycin dosing guidance in hospitalized pediatric patients. METHODS: This retrospective review at a single-center, academic, pediatric hospital included patients 2 to 12 years old with a steady-state vancomycin trough collected between January 1, 2010 and December 31, 2011. Patients with acute kidney injury or lacking essential data (e.g., height and serum creatinine), were excluded. An estimated GFR (eGFR) was calculated using the Schwartz and Bedside CKiD equations. Pearson correlations and linear regressions compared the eGFR values and vancomycin troughs. RESULTS: A total of 50 vancomycin troughs were analyzed. There was a weak relationship between the eGFR and troughs for the Schwartz equation (r (2) = 0.028) and Bedside CKiD equation (r (2) = 0.028). A weak relationship between serum creatinine and troughs was observed (r (2) = 0.132). Limitations include small sample size and retrospective design. CONCLUSIONS: Neither equation correlates well with vancomycin troughs, suggesting that therapeutic monitoring remains important. Better GFR estimation methods are needed in pediatrics to aid appropriate dosing of renally eliminated medications.

Association of IgG co-deposition with serum levels of galactose-deficient IgA1 in pediatric IgA nephropathy.

OBJECTIVE: To determine whether the absence of mesangial IgG deposits is associated with the absence of elevated blood levels of galactose-deficient IgA1 (Gd-IgA1) in pediatric patients with IgA nephropathy (IgAN). DESIGN AND METHODS: Serum Gd-IgA1 levels were determined by ELISA using an N-acetylgalactosamine-specific lectin from Helix aspersa. Levels of Gd-IgA1 above the 90th percentile for healthy pediatric controls were considered to be elevated. Renal biopsy samples were examined by immunofluorescence for presence and intensity of staining for IgA, IgG, IgM, C3 and C1q and by light microscopy for histological changes. Findings were graded by a single pathologist (L. Gaber) at UTHSC until 2007 and by NephropathTM (Little Rock, AR, USA) thereafter. Staining for the mesangial deposits was considered negative when intensity was trace or less, and positive at greater intensity. Fisher's exact test was used to determine significance of 2 × 2 tables. RESULTS: Serum samples were obtained from 30 patients with IgAN diagnosed before age 18 years. Male:female ratio was 2.3:1. Twenty were Caucasian and 10 were African-American. Blood was obtained within 3 months of biopsy (incident cases) for 12, while 18 provided blood > 3 months after biopsy (prevalent cases). Serum Gd-IgA1 level was elevated in 23 (77%) of cases and 20 (67%) had a biopsy positive for IgG. Of those 20 patients, 18 (90%) had an elevated serum Gd-IgA1 level, whereas 5 (50%) of patients with biopsies without IgG had a normal serum Gd-IgA1 level (p = 0.026). SUMMARY: In this small study we found a weak association between the absence of IgG in the biopsy and normal serum Gd-IgA1 level.

Serum galactose-deficient IgA1 level is not associated with proteinuria in children with IgA nephropathy.

Introduction. Percentage of galactose-deficient IgA1 (Gd-IgA1) relative to total IgA in serum was recently reported to correlate with proteinuria at time of sampling and during follow-up for pediatric and adult patients with IgA nephropathy. We sought to determine whether this association exists in another cohort of pediatric patients with IgA nephropathy. Methods. Subjects were younger than 18 years at entry. Blood samples were collected on one or more occasions for determination of serum total IgA and Gd-IgA1. Gd-IgA1 was expressed as serum level and percent of total IgA. Urinary protein/creatinine ratio was calculated for random specimens. Spearman's correlation coefficients assessed the relationship between study variables. Results. The cohort had 29 Caucasians and 11 African-Americans with a male : female ratio of 1.9 : 1. Mean age at diagnosis was 11.7 ± 3.7 years. No statistically significant correlation was identified between serum total IgA, Gd-IgA1, or percent Gd-IgA1 versus urinary protein/creatinine ratio determined contemporaneously with biopsy or between average serum Gd-IgA1 or average percent Gd-IgA1 and time-average urinary protein/creatinine ratio. Conclusion. The magnitude of proteinuria in this cohort of pediatric patients with IgA nephropathy was influenced by factors other than Gd-IgA1 level, consistent with the proposed multi-hit pathogenetic pathways for this renal disease.

Has the incidence of childhood steroid sensitive nephrotic syndrome changed?

Nephrotic syndrome is among the most common types of pediatric kidney disease. However, there are few published data on its incidence and racial patterns. This study examines the incidence and racial patterns of childhood steroid sensitive nephrotic syndrome (SSNS). For the period 1/1/1996 to 12/31/2006, a retrospective chart review was performed of children less than 10 years of age who presented to Le Bonheur Children's Hospital in Memphis, TN with newly diagnosed SSNS. At the time of diagnosis, 38 children were found to reside in Shelby County, TN, with 31 children residing within the Memphis city limits. The annual incidence of SSNS in Shelby County was 2.4 cases/100,000 children. The incidence was higher in males (4.0/100,000) (p = 0.0002), children less than 5 years of age (3.6/100,000) (p = 0.007), and African Americans (3.7/100,000) compared to Caucasians (0.9/100,000) (p = 0.00006). These findings confirm that SSNS is a rare pediatric disease. They also suggest that the incidence of SSNS in Shelby County is comparable to that in prior reports. Our study is one of the first to show that SSNS may be more common in African Americans.

Galactose-deficient IgA1 in African Americans with IgA nephropathy: serum levels and heritability.

BACKGROUND AND OBJECTIVES: Serum levels of galactose-deficient IgA1 (Gd-IgA1) are elevated and heritable in Caucasian and Asian patients with IgA nephropathy (IgAN), but have not been characterized in African Americans (AA). Our objective was to determine whether serum Gd-IgA1 levels are increased in AA patients with IgAN and whether this is a heritable trait in this group. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Blood and urine samples were obtained from 18 adult and 11 pediatric AA patients with biopsy-proven IgAN and from 34 of their first-degree relatives. Healthy controls included 150 Caucasian adults, 65 AA adults, 45 Caucasian children, and 49 AA children. Serum total IgA and Gd-IgA1 levels were measured in patients and controls. Significant differences between patient and control groups for serum total IgA, Gd-IgA1, and ratio of Gd-IgA1/total IgA were determined by the Mann-Whitney U test. Heritability was calculated using SOLAR. RESULTS: After stratifying by age, 7 of 11 pediatric and 9 of 18 adult AA patients with IgAN had serum Gd-IgA1 levels above the 95th percentile for age-appropriate AA controls. For first-degree relatives, the serum Gd-IgA1 level was >95th percentile for 1 of 8 when the patient's level was <95th percentile and 12 of 26 when the patient's level was >95th percentile (P = 0.116, Fisher exact test). Heritability was 0.74 (P = 0.007). CONCLUSIONS: Serum levels of Gd-IgA1 are often elevated in AA patients with IgAN and their first-degree relatives. Thus, aberrant IgA1 glycosylation is a heritable risk factor for IgAN in African Americans.

Gastroenteritis caused by Edwardsiella tarda in a pediatric renal transplant recipient.

Edwardsiella tarda, a member of the family Enterobacteriaceae, is a Gram-negative bacillus that is most often pathogenic in aquatic environments. Human infections with Edwardsiella are rare, with most occurring in immunocompromised or immunosuppressed hosts. Reported infections include meningitis, cholecystitis, endocarditis, osteomyelitis, soft tissue infections, bacteremia and septicemia, dysentery, and gastroenteritis. This report describes a case of E. tarda gastroenteritis in a renal transplant patient receiving immunosuppressive therapy. The epidemiology, diagnosis, clinical presentation, and treatment options pertaining to E. tarda infections are examined.

Diagnosis of de novo localized thrombotic microangiopathy by surveillance biopsy.

Thrombotic microangiopathy has been reported in association with calcineurin inhibitors and less frequently with sirolimus in renal transplant patients. The diagnosis of thrombotic microangiopathy is typically made by diagnostic biopsy in the setting of allograft dysfunction. The finding of thrombotic microangiopathy on surveillance biopsy without a significant elevation of baseline serum creatinine is unusual. The optimal treatment of this disorder remains controversial. Treatment strategies have included dose adjustment, drug substitution, plasmapheresis, and intravenous immunoglobulin G. We report a case of de novo thrombotic microangiopathy diagnosed by surveillance biopsy in a patient without hematologic abnormalities or elevated serum creatinine. This patient had resolution of the renal lesion following conversion from tacrolimus to sirolimus-based immunosuppression.