Albuminuria predicts kidney events in IgA nephropathy.

BACKGROUND & HYPOTHESIS: KDIGO recommends proteinuria <1 g/d as a treatment target in patients with immunoglobulin A nephropathy (IgAN) because of high-risk of progression to kidney failure. However, long-term kidney outcomes in patients with low-grade proteinuria remain insufficiently studied. METHODS: We enrolled patients with biopsy-proven primary IgAN from the Swedish Renal Registry and analyzed associations between urine albumin-to-creatinine ratio (uACR, in categories < 0.3, ≥0.3-0.5, ≥0.5-1.0, ≥1.0-1.5, ≥1.5-2.0 and ≥ 2.0 g/g) and the occurrence of major adverse kidney events (MAKE, a composite of kidney replacement therapy [KRT] and > 30% decline in eGFR). We also explored the risk of kidney events associated with change in uACR within a year. RESULTS: We included 1269 IgAN patients (74% men, median 53 years, mean eGFR 33 mL/min/1.73m², median uACR 0.7 g/g). Over median follow-up of 5.5 [2.8;9.2] years, 667 MAKE and 517 KRT events occurred, and 528 patients experienced > 30% eGFR decline. Compared with uACR < 0.3 g/g, any higher uACR category was strongly and incrementally associated with the risk of MAKE (adjusted HR ranging from 1.56 [95%CI 1.14-2.14] if uACR 0.3-0.5 g/g to 4.53 [3.36-6.11] if uACR ≥ 2.0 g/g), KRT (HR ranging from 1.39 to 4.65), and eGFR decline > 30% (HR ranging from 1.76 to 3.47). In 785 patients who had repeated uACR measurements within a year, and compared with stable uACR, the risk of kidney events was lower if uACR decreased by 2-fold (HR ranging from 0.47 to 0.49), and higher if uACR increased by 2-fold (HR from 1.18 to 2.56), irrespective of baseline uACR. CONCLUSIONS: There is substantial risk of adverse kidney outcomes among patients with IgAN and uACR between 0.3 and 1.0 g/g, a population currently considered at low-risk of CKD progression. Reduction in uACR is associated with better kidney outcomes, irrespective of baseline uACR.

The switch from proteasome to immunoproteasome is increased in circulating cells of patients with fast progressive immunoglobulin A nephropathy and associated with defective CD46 expression.

The proteasome to immunoproteasome (iPS) switch consists of ß1, ß2 and ß5 subunit replacement by low molecular weight protein 2 (LMP2), LMP7 and multicatalytic endopeptidase-like complex-1 (MECL1) subunits, resulting in a more efficient peptide preparation for major histocompatibility complex 1 (MHC-I) presentation. It is activated by toll-like receptor (TLR) agonists and interferons and may also be influenced by genetic variation. In a previous study we found an iPS upregulation in peripheral cells of patients with immunoglobulin A nephropathy (IgAN). We aimed to investigate in 157 IgAN patients enrolled through the multinational Validation Study of the Oxford Classification of IgAN (VALIGA) study the relationships between iPS switch and estimated glomerular filtration rate (eGFR) modifications from renal biopsy to sampling. Patients had a previous long follow-up (6.4 years in median) that allowed an accurate calculation of their slope of renal function decline. We also evaluated the effects of the PSMB8/PSMB9 locus (rs9357155) associated with IgAN in genome-wide association studies and the expression of messenger RNAs (mRNAs) encoding for TLRs and CD46, a C3 convertase inhibitor, acting also on T-regulatory cell promotion, found to have reduced expression in progressive IgAN. We detected an upregulation of LMP7/ß5 and LMP2/ß1 switches. We observed no genetic effect of rs9357155. TLR4 and TLR2 mRNAs were found to be significantly associated with iPS switches, particularly TLR4 and LMP7/ß5 (P < 0.0001). The LMP7/ß5 switch was significantly associated with the rate of eGFR loss (P = 0.026), but not with eGFR at biopsy. Fast progressors (defined as the loss of eGFR >75th centile, i.e. -1.91 mL/min/1.73 m2/year) were characterized by significantly elevated LMP7/ß5 mRNA (P = 0.04) and low CD46 mRNA expression (P < 0.01). A multivariate logistic regression model, categorizing patients by different levels of kidney disease progression, showed a high prediction value for the combination of high LMP7/ß5 and low CD46 expression.

Immunoglobulin A nephropathy and ischemic heart disease: a nationwide population-based cohort study.

BACKGROUND: Chronic kidney disease has been linked to cardiovascular disease and specifically ischemic heart disease (IHD), but large-scale population data in patients with immunoglobulin A nephropathy (IgAN) are missing. OBJECTIVE: To examine absolute and relative risks for IHD in patients with IgAN. METHODS: Population-based register-based cohort study in Sweden. We identified 3945 patients with biopsy-verified IgAN, and 19,272 age- and sex-matched reference individuals from the general population. To reduce residual confounding from genetic factors and early environmental factors we carried out secondary analyses, where we compared 3039 IgAN patients with 6729 siblings, whereas a spousal analysis consisted of 2377 married couples where one of the spouses had IgAN. Data on IHD and end-stage renal disease (ESRD) were retrieved from the nationwide Patient Register. Cox regression estimated hazard ratios (HRs) adjusted for matching variables, education, country of birth, cancer, diabetes mellitus, and other systemic inflammatory diseases. RESULTS: During a follow-up of 55,527 person-years (py; mean follow-up 14.1 years), 371 patients (9.4%) with IgAN developed IHD (6.7/1000 py), compared with 1070 (5.6%) in 287,677 py in reference individuals (3.7/1000 py). The corresponding adjusted HR was 1.86 (95%CI = 1.63-2.13), equivalent to one extra case of IHD per 34 IgAN patients followed-up for 10 years. HRs were similar in men and women with IgAN, but higher in the first year after diagnosis and in patients born outside the Nordic countries. Patients with IgAN were at increased risk of IHD also compared to siblings (HR = 2.07; 95%CI = 1.62-2-64) and spouses (HR = 1.91; 95%CI = 1.40-2.61). CONCLUSIONS: In this nationwide population-based study, patients with IgAN were at an 86% increased risk of future IHD.

Is there long-term value of pathology scoring in immunoglobulin A nephropathy? A validation study of the Oxford Classification for IgA Nephropathy (VALIGA) update.

BACKGROUND: It is unknown whether renal pathology lesions in immunoglobulin A nephropathy (IgAN) correlate with renal outcomes over decades of follow-up. METHODS: In 1130 patients of the original Validation Study of the Oxford Classification for IgA Nephropathy (VALIGA) cohort, we studied the relationship between the MEST score (mesangial hypercellularity, M; endocapillary hypercellularity, E; segmental glomerulosclerosis, S; tubular atrophy/interstitial fibrosis, T), crescents (C) and other histological lesions with both a combined renal endpoint [50% estimated glomerular filtration rate (eGFR) loss or kidney failure] and the rate of eGFR decline over a follow-up period extending to 35 years [median 7 years (interquartile range 4.1-10.8)]. RESULTS: In this extended analysis, M1, S1 and T1-T2 lesions as well as the whole MEST score were independently related with the combined endpoint (P < 0.01), and there was no effect modification by age for these associations, suggesting that they may be valid in children and in adults as well. Only T lesions were associated with the rate of eGFR loss in the whole cohort, whereas C showed this association only in patients not treated with immunosuppression. In separate prognostic analyses, the whole set of pathology lesions provided a gain in discrimination power over the clinical variables alone, which was similar at 5 years (+2.0%) and for the whole follow-up (+1.8%). A similar benefit was observed for risk reclassification analyses (+2.7% and +2.4%). CONCLUSION: Long-term follow-up analyses of the VALIGA cohort showed that the independent relationship between kidney biopsy findings and the risk of progression towards kidney failure in IgAN remains unchanged across all age groups and decades after the renal biopsy.

Mortality in IgA Nephropathy: A Nationwide Population-Based Cohort Study.

BACKGROUND: The clinical course of IgA nephropathy (IgAN) varies from asymptomatic nonprogressive to aggressive disease, with up to one in four patients manifesting ESRD within 20 years of diagnosis. Although some studies have suggested that mortality appears to be increased in IgAN, such studies lacked matched controls and did not report absolute risk. METHODS: We conducted a population-based cohort study in Sweden, involving patients with biopsy-verified IgAN diagnosed in 1974-2011; main outcome measures were death and ESRD. Using data from three national registers, we linked 3622 patients with IgAN with 18,041 matched controls; we also conducted a sibling analysis using 2773 patients with IgAN with 6210 siblings and a spousal analysis that included 2234 pairs. RESULTS: During a median follow-up of 13.6 years, 577 (1.1%) patients with IgAN died (10.67 per 1000 person-years) compared with 2066 deaths (0.7%) in the reference population during a median follow-up of 14.1 years (7.45 per 1000 person-years). This corresponded to a 1.53-fold increased risk and an absolute excess mortality of 3.23 per 1000 person-years (equaling one extra death per 310 person-years) and a 6-year reduction in median life expectancy. Similar increases in risk were seen in comparisons with siblings and spouses. IgAN was associated with one extra case of ESRD per 54 person-years. Mortality preceding ESRD was not significantly increased compared with controls, spouses, or siblings. Overall mortality did not differ significantly between patients with IgAN-associated ESRD and patients with ESRD from other causes. CONCLUSIONS: Patients with IgAN have an increased mortality compared with matched controls, with one extra death per 310 person-years and a 6-year reduction in life expectancy.

Defective gene expression of the membrane complement inhibitor CD46 in patients with progressive immunoglobulin A nephropathy.

BACKGROUND: Complement is thought to play a role in immunoglobulin A nephropathy (IgAN), though the activating mechanisms are unknown. This study focused on the gene expression of CD46 and CD55, two key molecules for regulating C3 convertase activity of lectin and alternative complement pathways at a cellular level. METHODS: The transcriptional expression in peripheral white blood cells (WBCs) of CD46 and CD55 was investigated in 157 patients enrolled by the Validation of the Oxford Classification of IgAN group, looking for correlations with clinical and pathology features and estimated glomerular filtration rate (eGFR) modifications from renal biopsy to sampling. Patients had a previous median follow-up of 6.4 (interquartile range 2.8-10.7) years and were divided into progressors and non-progressors according to the median value of their velocity of loss of renal function per year (-0.41 mL/min/1.73 m2/year). RESULTS: CD46 and CD55 messenger RNA (mRNA) expression in WBCs was not correlated with eGFR values or proteinuria at sampling. CD46 mRNA was significantly correlated with eGFR decline rate as a continuous outcome variable (P = 0.014). A significant difference was found in CD46 gene expression between progressors and non-progressors (P = 0.013). CD46 and CD55 mRNA levels were significantly correlated (P < 0.01), although no difference between progressors and non-progressors was found for CD55 mRNA values. The prediction of progression was increased when CD46 and CD55 mRNA expressions were added to clinical data at renal biopsy (eGFR, proteinuria and mean arterial blood pressure) and Oxford MEST-C (mesangial hypercellularity, endocapillary hypercellularity, segmental glomerulosclerosis, tubular atrophy/interstitial fibrosis, presence of any crescents) score. CONCLUSIONS: Patients with progressive IgAN showed lower expression of mRNA encoding for the complement inhibitory protein CD46, which may implicate a defective regulation of C3 convertase with uncontrolled complement activation.

Risk factors for progression in children and young adults with IgA nephropathy: an analysis of 261 cases from the VALIGA European cohort.

BACKGROUND: There is a need for early identification of children with immunoglobulin A nephropathy (IgAN) at risk of progression of kidney disease. METHODS: Data on 261 young patients [age <23 years; mean follow-up of 4.9 (range 2.5-8.1) years] enrolled in VALIGA, a study designed to validate the Oxford Classification of IgAN, were assessed. Renal biopsies were scored for the presence of mesangial hypercellularity (M1), endocapillary hypercellularity (E1), segmental glomerulosclerosis (S1), tubular atrophy/interstitial fibrosis (T1-2) (MEST score) and crescents (C1). Progression was assessed as end stage renal disease and/or a 50 % loss of estimated glomerular filtration rate (eGFR) (combined endpoint) as well as the rate of renal function decline (slope of eGFR). Cox regression and tree classification binary models were used and compared. RESULTS: In this cohort of 261 subjects aged <23 years, Cox analysis validated the MEST M, S and T scores for predicting survival to the combined endpoint but failed to prove that these scores had predictive value in the sub-group of 174 children aged <18 years. The regression tree classification indicated that patients with M1 were at risk of developing higher time-averaged proteinuria (p < 0.0001) and the combined endpoint (p < 0.001). An initial proteinuria of ≥0.4 g/day/1.73 m2 and an eGFR of <90 ml/min/1.73 m2 were determined to be risk factors in subjects with M0. Children aged <16 years with M0 and well-preserved eGFR (>90 ml/min/1.73 m2) at presentation had a significantly high probability of proteinuria remission during follow-up and a higher remission rate following treatment with corticosteroid and/or immunosuppressive therapy. CONCLUSION: This new statistical approach has identified clinical and histological risk factors associated with outcome in children and young adults with IgAN.

Risk of renal disease in patients with both type 1 diabetes and coeliac disease.

AIMS/HYPOTHESIS: Our aim was to study the risk of renal disease in patients with type 1 diabetes (T1D) and coexisting coeliac disease (CD). METHODS: Individuals with T1D were defined as having a diagnosis of diabetes recorded at ≤30 years of age in the Swedish Patient Register between 1964 and 2009. Individuals with CD were identified through biopsy reports with villous atrophy (Marsh stage 3) from 28 pathology departments in Sweden between 1969 and 2008. We identified 954 patients with both T1D and CD. For each patient with T1D + CD, we selected five age- and sex-matched reference individuals with T1D only (n = 4,579). Cox regression was used to estimate the following risks: (1) chronic renal disease and (2) end-stage renal disease in patients with CD + T1D compared with T1D patients only. RESULTS: Forty-one (4.3%) patients with CD + T1D and 143 (3.1%) patients with T1D only developed chronic renal disease. This corresponded to an HR of 1.43 for chronic renal disease (95% CI 0.94, 2.17) in patients with CD + T1D compared with T1D only. In addition, for end-stage renal disease there was a positive (albeit statistically non-significant) HR of 2.54 (95% CI 0.45, 14.2). For chronic renal disease, the excess risk was more pronounced after >10 years of CD (HR 2.03, 95% CI 1.08, 3.79). Risk estimates were similar when we restricted our cohort to the following T1D patients: (1) those who had an inpatient diagnosis of T1D; (2) those who had never received oral glucose-lowering medication; and (3) those who had not received their first diabetes diagnosis during pregnancy. CONCLUSIONS/INTERPRETATION: Overall this study found no excess risk of chronic renal disease in patients with T1D and CD. However, in a subanalysis we noted a positive association between longstanding CD and chronic renal disease in T1D.

Circulating anti-glomerular basement membrane antibodies with predominance of subclass IgG4 and false-negative immunoassay test results in anti-glomerular basement membrane disease.

Autoantibodies against a constituent of the glomerular basement membrane (GBM), the α3-chain of type IV collagen, can cause both rapidly progressive glomerulonephritis and alveolar hemorrhage, referred to as anti-GBM disease or Goodpasture disease. Anti-GBM antibodies generally are of immunoglobulin G subclass 1 (IgG1) and can in most cases readily be detected in the circulation using enzyme-linked immunosorbent assays (ELISAs). We report 4 cases in which anti-GBM ELISA yielded negative or borderline results despite life-threatening disease. All 4 patients had positive results by IgG4 anti-GBM ELISA and all had undetectable antineutrophil cytoplasmic antibody. All cases were confirmed with kidney biopsy. Two of the patients showed higher signal in anti-GBM ELISA when using a nondenaturing coating buffer. All 4 were young women with severe alveolar hemorrhage and favorable renal outcome, suggesting that patients with predominance of IgG4 autoantibodies may constitute a distinct subgroup of anti-GBM disease. We conclude that patients with idiopathic alveolar hemorrhage can have anti-GBM disease detected by only IgG subclass-specific tests or kidney biopsy.

Soluble interleukin-2 receptor alfa predicts renal outcome in IgA nephropathy.

BACKGROUND: Both systemic and mucosal IgA production are controlled by T lymphocytes and infiltrating T lymphocytes are involved in the progression of interstitial fibrosis in chronic kidney disease (CKD). Since the concentration of soluble interleukin-2 receptor alfa (sIL-2Ra) reflects the degree of T cell activation over time, we studied the impact of interleukin-2 receptor alfa levels on disease progression in patients with biopsy-proven IgA nephropathy (IgAN), a disease in which 20-30% of the patients progress to end-stage renal failure. METHODS: sIL-2Ra plasma levels were measured in 194 patients (median age 39 years, 70% men) and 84 matched controls. One hundred and seventy-nine of the patients, with an estimated glomerular filtration rate (GFR) of ≥15 mL/min/1.73m(2) at baseline (CKD Stages 1-4), were followed for up to 15 years (median 52 months; range 12-188). sIL-2Ra was evaluated as a risk marker for severe renal progression, here defined by the development of CKD Stage 5 (GFR <15 mL/min/1.73m(2)), a 50% decline in GFR during the follow-up period or a 30% GFR decline within 5 years of follow-up. In 51 patients, upon whom a renal biopsy had been performed within 2 years of IL2-Ra measurement, the biopsies were scored according to the Oxford classification. The correlations between the histopathological findings and the sIL-2Ra levels were examined. RESULTS: sIL2-Ra levels were significantly higher in patients than in controls (P < 0.001). sIL-2Ra levels in the upper third tertile predicted a severe renal outcome, even after adjustment for the main clinical risk factors: time average albuminuria and GFR at baseline (Relative risk 5.35, P < 0.001). sIL-2Ra levels also correlated significantly to the yearly GFR slope (ß = -0.24, P = 0.01). According to the Oxford classification, the presence of >25% tubular atrophy/interstitial fibrosis (T1-2) was associated with higher sIL-2Ra levels, after adjustment for serum creatinine levels, if analysed within 4 months [n = 24, odds ratio (OR) 1.0, P = 0.044] or within 2 years from the kidney biopsy (n = 51, OR 1.0, P = 0.017). CONCLUSIONS: The plasma levels of sIL-2Ra were predictive of long-term renal disease progression in a large cohort of patients with biopsy-proven IgAN. Further studies are warranted to evaluate if sIL-2Ra levels can feasibly contribute in the monitoring of effects of treatment, aimed to prevent the progression of interstitial fibrosis and progressive glomerulosclerosis in IgAN.

Long-Term Outcomes of Patients with IgA Nephropathy Categorized by the International IgAN Risk Prediction Tool and by the Degree of Hematuria at Diagnosis.

INTRODUCTION: Within 30 years, 20-50% of IgA nephropathy (IgAN) patients progress to end-stage kidney disease (ESKD). Identifying these patients can be difficult since renal function may deteriorate after being stable for years. The International IgAN Risk Prediction tool (IgAN-RPT) combines histologic lesions and clinical risk factors to predict renal outcome up to 5 or 7 years of follow-up. The clinical value beyond 7 years is unknown and microhematuria data has not been assessed. METHODS: We studied the long-term renal outcome of 95 Swedish IgAN patients from the derivation cohort for the IgAN-RPT. The median follow-up was 11.2 years. Microhematuria at baseline was defined as high-degree by microscopy measurement of >10 red blood cell/high-power field of view or urine dipstick grading of 2-3. Primary outcome was defined as a 50% decrease in estimated glomerular filtration rate or ESKD. RESULTS: The mean predicted 5-year risk for increasing quartiles was 0.95%, 2.57%, 5.88%, and 23.31% and the observed 5-year-outcome was 0%, 0%, 0%, and 33.33%. During continued follow-up, 0%, 4.2%, 21.7%, and 75.0% of patients reached the primary outcome. ROC curve analysis identified the 5-year risk thresholds of under 4% and over 11% for very low and very high-risk patients, respectively. High-degree microhematuria was not significantly associated with renal outcome (p = 0.14). CONCLUSIONS: The IgAN-RPT identifies long-term high- and low-risk patients, which can guide decisions on the frequency of clinical control visits and the selection of patients for clinical trials. Patients with intermediate risk remain a clinical challenge with an urgent need for novel biomarkers and treatments. Microhematuria could be a valuable marker of inflammatory activity, but measurement needs to be standardized for implementation in risk prediction tools.

Pregnancy outcomes in women with immunoglobulin A nephropathy: a nationwide population-based cohort study.

BACKGROUND: Immunoglobulin A nephropathy (IgAN) incidence peaks in childbearing age. Data on pregnancy outcomes in women with IgAN are limited. METHODS: We performed a register-based cohort study in a nationwide cohort of women with biopsy-verified IgAN in Sweden, comparing 327 pregnancies in 208 women with biopsy-verified IgAN and 1060 pregnancies in a matched reference population of 622 women without IgAN, with secondary comparisons with sisters to IgAN women. Adverse pregnancy outcomes, identified by way of the Swedish Medical Birth Register, were compared through multivariable logistic regression and presented as adjusted odds ratios (aORs). Main outcome was preterm birth (< 37 weeks). Secondary outcomes were preeclampsia, small for gestational age (SGA), low 5-min Apgar score (< 7), fetal or infant loss, cesarean section, and gestational diabetes. RESULTS: We found that IgAN was associated with an increased risk of preterm birth (13.1% vs 5.6%; aOR = 2.69; 95% confidence interval [CI] = 1.52-4.77), preeclampsia (13.8% vs 4.2%; aOR = 4.29; 95%CI = 2.42-7.62), SGA birth (16.0% vs 11.1%; aOR = 1.84; 95%CI = 1.17-2.88), and cesarean section (23.9% vs 16.2%; aOR = 1.74, 95%CI = 1.14-2.65). Absolute risks were low for intrauterine (0.6%) or neonatal (0%) death and for low 5-min Apgar score (1.5%), and did not differ from the reference population. Sibling comparisons suggested increased risks of preterm birth, preeclampsia, and SGA in IgAN, but not of cesarean section. CONCLUSION: We conclude that although most women with IgAN will have a favorable pregnancy outcome, they are at higher risk of preterm birth, preeclampsia and SGA. Intensified supervision during pregnancy is warranted.

B cell and monocyte phenotyping: A quick asset to investigate the immune status in patients with IgA nephropathy.

BACKGROUND: IgA nephropathy (IgAN) advances from multiple pathogenic "hits" resulting in poorly O-galactosylated IgA1 glycoforms (Gd-IgA1), production of antibodies and glomerular deposition of immune complexes. A sequence of immune responses arising from plasma cells, T cells and antigen presenting cells (APCs), causes glomerular injury. This study was designed to phenotype subsets of B cells, monocytes and T cells in the peripheral circulation and their association with inflammatory cytokines and kidney function in patients with IgAN, healthy controls (HC) and disease controls with autosomal dominant polycystic kidney disease (ADPKD). METHODS: Patients with IgAN (n = 13), median estimated glomerular filtration rate (eGFR) of 57 ml/min/1.73m2 (IQR 42-84), patients with ADPKD (n = 13) matched for kidney function, gender and age and gender and age-matched HC (n = 13) were recruited. CD3+ and CD3- peripheral blood mononuclear cells were isolated and profiled based on their specific surface markers for different subsets of monocytes, B and T cells and analyzed by flow cytometry. Cytokines were analyzed by ELISA. RESULTS: We observed a significant decrease in the proportion of pre-switched B cells and plasmablasts, but an increase in long-lived plasma cells in the peripheral circulation of IgAN patients compared to HC. The proportion of non-classical monocytes was significantly higher in IgAN patients compared to both HC and ADPKD. We also report an association between sCD40L levels and the proportion of pre-switched B cells, as well as sCD40L and MCP-1 levels and albuminuria in IgAN patients. CONCLUSIONS: We applied an easy-access method to analyze subsets of immune cells as well as relevant inflammatory mediators in IgAN patients. Our data demonstrate an altered B cell profile that indicates a pathophysiological role of the B cell lineage and an increased proportion of non-classical monocytes that suggests their role in the disease process.

Association of soluble CD89 levels with disease progression but not susceptibility in IgA nephropathy.

The Fc-α receptor (FcαR/CD89) is involved in IgA complex formation and may affect the development of IgA nephropathy (IgAN). In this study, we tested the genetic variations of the CD89 gene in relation to disease susceptibility in IgAN and the expression of soluble CD89 (sCD89) in sera of patients with IgAN and in controls. There was a significant difference between the levels of sCD89-IgA complexes, measured by sandwich enzyme-linked immunosorbent assay (ELISA), in 177 patients with IgAN with and without disease progression at the time of first diagnosis. No such difference was found in 42 patients with other renal diseases. The patients with IgAN without disease progression had stable but high levels of sCD89 over 5-15 years of follow-up in contrast to stable but low levels of sCD89 in the disease progression group. Moreover, levels of sCD89 complexes were correlated with one of the five CD89 genetic variants in 212 patients with IgAN and 477 healthy Caucasians; the single-nucleotide polymorphism (SNP) rs11084377 was significantly associated with a lower expression of sCD89. However, no association between CD89 gene polymorphisms and susceptibility to IgAN was detected. Thus, we found an association between the levels of sCD89-IgA complexes in serum and the severity of IgAN, and a possible genetic component in regulating the production or expression of sCD89.

Genetic variation in the transforming growth factor-beta1 gene is associated with susceptibility to IgA nephropathy.

BACKGROUND: There is growing evidence of genetic risk for susceptibility to IgA nephropathy. Among several candidate genes related to immunological regulation in renal tissue, TGFB1 is known to be a contributor to proliferation and the development of fibrosis. METHODS: We analysed several SNPs in a region of this gene using 212 DNA samples from biopsy-proven IgA nephropathy patients, 146 men and 66 women and 477 healthy age-matched controls (321 men and 156 women) from the same population in Sweden. RESULTS: Frequencies of four out of five selected SNPs (rs6957, rs2241715, rs1800471, rs1982073 and rs1800469) were found to significantly differ between male patients and male controls in a co-dominant model (corrected P

B cell-depleting therapy with rituximab or ofatumumab in immunoglobulin A nephropathy or vasculitis with nephritis.

BACKGROUND: Approximately 30% of adult patients with immunoglobulin A (IgA) nephropathy (IgAN) or IgA vasculitis with nephritis (IgAVN) develop end-stage renal disease during long-term follow-up. In particular, patients with nephritic-nephrotic syndrome have an increased risk of rapid progression. Conventional immunosuppressive therapy with corticosteroids (CSs) may be insufficient for disease control and is associated with a number of side effects. Rituximab (RTX) has been shown to be well tolerated and effective in a range of glomerular diseases, but there is little information on its therapeutic potential in IgAN. The humanized anti-CD20 monoclonal antibody ofatumumab (OFAB) may be an alternative drug for patients intolerant or unresponsive to RTX, but so far there is no report on its use in IgAVN or IgAN. METHODS: We describe clinical outcomes after 17-22 months in four adult patients with biopsy-confirmed IgAVN or IgAN treated with RTX or OFAB as well as CS soon after diagnosis. All presented with nephritic-nephrotic syndrome and one had crescentic IgAN. Rebiopsy was performed in two cases. RESULTS: RTX and OFAB were well tolerated. Albuminuria was <250 mg/day in three patients at last evaluation and two regained normal renal function. In all cases, renal function improved after therapy. In one patient with severe IgA vasculitis, rebiopsy showed disappearance of subendothelial but not mesangial immune complexes. In the case with crescentic IgAN, rebiopsy after 9 months showed no active necrotic lesions. CONCLUSIONS: B cell-depleting therapy may be an alternative treatment for patients with IgAN or IgAVN and nephritic-nephrotic syndrome. A possible CS-sparing effect should be further evaluated in randomized controlled clinical trials.

Clinical validation of immunoglobulin A nephropathy diagnosis in Swedish biopsy registers.

AIMS: The aims of this study were to validate the diagnosis of IgA nephropathy (IgAN) in Swedish biopsy registers against patient charts and to describe the clinical characteristics of patients with a biopsy indicating IgAN. METHODS: This is a population-based cohort study. Out of 4,069 individuals with a renal biopsy consistent with IgAN (biopsies performed in 1974-2011), this study reviewed patient charts of a random subset of 127 individuals. Clinical and biopsy characteristics at the time of biopsy were evaluated, and positive predictive values (PPV) were calculated with 95% confidence intervals (CI). RESULTS: Out of 127 individuals with a renal biopsy consistent with IgAN, 121 had a likely or confirmed clinical diagnosis of IgAN, primary or secondary to Henoch-Schönlein purpura, yielding a PPV of 95% (95% CI =92%-99%). The median age at biopsy was 39 years (range: 4-79 years); seven patients (6%) were <16 years. The male to female ratio was 2.8:1. The most common causes for consultation were macroscopic hematuria (n=37; 29%), screening (n=33; 26%), and purpura (n=14, 11%). In patients with available data, the median creatinine level was 104 µmol/L (range 26-986 µmol/L, n=110) and glomerular filtration rate 75 mL/min/1.73m2 (range 5-173 mL/min/1.73m2, n=114). Hypertension was noted in 59 (46%) individuals. IgA deposits were reported in 97% of the biopsy records (n=123), mesangial hypercellularity in 76% (n=96), C3 deposits in 89% (n=113), and C1q deposits in 12% (n=15). CONCLUSION: A histologic diagnosis of IgAN has a high PPV for a diagnosis of IgAN confirmed by review of patient charts.

Diarrhea-associated hemolytic uremic syndrome with severe neurological manifestations treated with IgG depletion through immunoadsorption.

BACKGROUND: Diarrhea-associated hemolytic uremic syndrome (HUS) is characterized by acute kidney injury with microangiopathic hemolytic anemia and thrombocytopenia with a diarrhea prodrome, typically caused by Shiga-like toxin-producing Escherichia coli. Supportive management is generally recommended. CASE REPORT: A 58-year-old female with diarrhea-associated HUS developed delayed-onset severe neurological manifestations including coma, status epilepticus, and subcortical magnetic resonance imaging signal alterations. Rescue treatment with immunoglobulin (Ig)G depletion through immunoadsorption was followed by significant improvement in neurological and renal function. The patient recovered with only minimal sequelae. CONCLUSION: Delayed-onset neurological abnormalities may occur in diarrhea-associated HUS. Novel specific treatment options include IgG depletion through immunoadsorption. Severe clinical and imaging findings do not preclude a good outcome.