Abstract
Background
Risk of kidney function decline in immunoglobulin A (IgA) nephropathy (IgAN) is significant and may not be predicted by available clinical and histological tools. To serve this ...unmet need, we aimed at developing a urinary biomarker-based algorithm that predicts rapid disease progression in IgAN, thus enabling a personalized risk stratification.
Methods
In this multicentre study, urine samples were collected in 209 patients with biopsy-proven IgAN. Progression was defined by tertiles of the annual change of estimated glomerular filtration rate (eGFR) during follow-up. Urine samples were analysed using capillary electrophoresis coupled mass spectrometry. The area under the receiver operating characteristic curve (AUC) was used to evaluate the risk prediction models.
Results
Of the 209 patients, 64% were male. Mean age was 42 years, mean eGFR was 63 mL/min/1.73 m2 and median proteinuria was 1.2 g/day. We identified 237 urine peptides showing significant difference in abundance according to the tertile of eGFR change. These included fragments of apolipoprotein C-III, alpha-1 antitrypsin, different collagens, fibrinogen alpha and beta, titin, haemoglobin subunits, sodium/potassium-transporting ATPase subunit gamma, uromodulin, mucin-2, fractalkine, polymeric Ig receptor and insulin. An algorithm based on these protein fragments (IgAN237) showed a significant added value for the prediction of IgAN progression AUC 0.89; 95% confidence interval (CI) 0.83–0.95, as compared with the clinical parameters (age, gender, proteinuria, eGFR and mean arterial pressure) alone (0.72; 95% CI 0.64–0.81).
Conclusions
A urinary peptide classifier predicts progressive loss of kidney function in patients with IgAN significantly better than clinical parameters alone.
Graphical Abstract
Graphical Abstract
IgA nephropathy (IgAN) is a progressive form of kidney disease defined by glomerular deposition of IgA. Here we performed a genome-wide association study of 10,146 kidney-biopsy-diagnosed IgAN cases ...and 28,751 controls across 17 international cohorts. We defined 30 genome-wide significant risk loci explaining 11% of disease risk. A total of 16 loci were new, including TNFSF4/TNFSF18, REL, CD28, PF4V1, LY86, LYN, ANXA3, TNFSF8/TNFSF15, REEP3, ZMIZ1, OVOL1/RELA, ETS1, IGH, IRF8, TNFRSF13B and FCAR. The risk loci were enriched in gene orthologs causing abnormal IgA levels when genetically manipulated in mice. We also observed a positive genetic correlation between IgAN and serum IgA levels. High polygenic score for IgAN was associated with earlier onset of kidney failure. In a comprehensive functional annotation analysis of candidate causal genes, we observed convergence of biological candidates on a common set of inflammatory signaling pathways and cytokine ligand-receptor pairs, prioritizing potential new drug targets.
The onset of IgA nephropathy (IgAN), characterized by glomerular deposition of IgA-containing immune complexes, is often associated with synpharyngitic hematuria. Innate immune responses mediated by ...Toll-like receptors (TLR) may play a role in IgAN onset and/or progression. Here, we assessed the expression of TLR 4, 7, 8, and 9 in renal-biopsy specimens from patients with IgAN, with different degree of proteinuria and eGFR, compared with normal-kidney and disease-control tissues (ANCA-associated vasculitis). Renal-biopsy specimens from 34 patients with IgAN and 7 patients with ANCA-associated vasculitis were used. In addition, we used 15 healthy portions of renal-tissue specimens from kidneys after nephrectomy for cancer as control specimens. Expression of TLR 4, 7, 8, and 9 was assessed using immunohistochemical staining of paraffin-embedded renal-biopsy tissue specimens with specific antibodies and evaluated semiquantitatively by light microscopy. Linear discriminant analysis (LDA) was used to test whether intrarenal staining of TLR 4, 7, 8, and 9 distinguished patients with IgAN from controls or correlated with eGFR and/or proteinuria. eGFR was calculated using the creatinine-based formula. Moreover, the biopsies from patients with IgAN were scored according to the Oxford Classification. LDA showed that staining for TLR 4, 7, 8, and 9 was more intense in specimens from IgAN patients compared to normal kidney tissues. The intensity of intrarenal staining of TLRs discriminated four groups of IgAN patients with different eGFR and proteinuria and MEST scoring.
Abstract
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.
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 m
2
and an eGFR of <90 ml/min/1.73 m
2
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 m
2
) 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.
Abstract
Background and Aims
Although IgA nephropathy (IgAN) is the most common primary glomerulonephritis in many parts of the world, risk of progressive kidney function decline is significant. ...Furthermore, the effect of immunosuppressive treatment in IgAN currently remains uncertain. There is no validated tool to predict disease progression or response to treatment. To serve this unmet need, we aimed at developing a urinary biomarker-based algorithm that predicts fast disease progression in patients with IgAN, thus enabling a personalized risk stratification and potentially improving patient management.
Method
In this multicenter study in 7 centers in Europe and in Canada urine samples were collected as part of clinical routine at time of biopsy in n= 300 patients (63% male, age 42±14 years) with biopsy proven IgAN. The follow-up data were collected for at least one year. Progressive disease was defined as an annual loss of kidney function (estimated glomerular filtration rate, eGFR) of more than -5ml/min/1.73m2 per year or when end-stage kidney disease (ESKD) was reached. The institutional review boards of each of the participating centers approved this study.
Urine samples were analyzed using capillary electrophoresis coupled mass spectrometry (CE-MS). Whole proteome/peptidome profile was obtained for each sample.
This study received funding from the European Union´s ERA PerMed program.
Results
Urine proteome/peptidome profiles were obtained from n=294 patients. On average, 2383 peptides were detected per sample. The data were subsequently divided into a discovery (n=154) and validation cohort (n=140). The comparison of the progressors (n=35) and non-progressors (n=119) in the discovery cohort resulted in the definition of more than 100 significant peptides. These included mainly fragments from collagen, mostly type 1 (decreased in progressors) and from different blood derived proteins like alpha-1-antitrypsin, alpha-2-HS-glycoprotein and apolipoproteins (increased in progressors). The distribution of the 100 most significant peptides in the progressor and non-progressor group is shown in the figure. The peptides were combined into a classifier using support vector machine. After optimizing the classifier employing a take-one-out procedure combined with n-1 cross-validation, the urine-peptide based algorithm enabled separation of progressors versus no progressors with an accuracy of 90% in take-one-out cross-validation. This classifier was subsequently applied to the validation cohort and resulted in highly significant separation of progressive from non-progressive IgAN patients. Furthermore, this classifier will be further applied blinded in an independent well characterized multicenter cohort of 267 IgAN patients.
Conclusion
We identified a urinary proteome profile which was associated with progressive loss of GFR in patients with IgAN. Further validation of this profile in an independent cohort is ongoing. The data indicate that CE-MS-based urinary proteomics enables identifying IgAN patients at high risk of disease progression. These patients may benefit from aggressive immunosuppressive treatment. Upon validation of the classifier in an independent cohort, its value in predicting response to immunosuppression will be assessed, aiming at establishing an innovative strategy that could improve patient management and personalize treatment of IgAN patients.
Figure: Distribution of the 100 most significant peptides in the progressor and no progressor group of IgAN patients. The molecular mass (on a logarithmic scale) is plotted against normalized migration time. Signal intensity is encoded by peak height. In the lower panel the most intensive peptides were omitted and the other peptides showed in fivefold magnification
Background
We describe data on 10,472 renal biopsies gathered by the Czech Registry of Renal Biopsies over a period of 18 years.
Methods
We assessed the main demographic, clinical and histological ...data of individuals who underwent renal biopsies of native kidneys in 31 centers in the Czech Republic (population 10.3 million) during the period 1994–2011.
Results
We evaluated 10,472 renal biopsies: males 57.8 %, children (≤15 years) 13.6 %, elderly (>60 years) 19.1 %. The most frequent biopsy-proven diseases were primary (55.7 %) and secondary (29.1 %) glomerulonephritides (GN). Tubulointerstitial nephritis (TIN) was observed in 3.4 % and vascular diseases in 4.1 %. The samples were non-diagnostic in 4.2 %. Among primary GN the most frequent diagnoses were IgA nephropathy (IgAN) (37.4 %), membranous GN (MGN) (13 %) and focal segmental glomerulosclerosis (FSGS) (12.6 %). Among secondary GN, systemic lupus erythematosus (SLE) represented 23.2 %, hereditary diseases 19.8 % and necrotizing vasculitis (NV) 19.4 %. Among adults, mild renal insufficiency serum creatinine (SCr) 111–200 μmol/l was present in 24.7 %, advanced renal insufficiency (SCr 201–400 μmol/l) in 15.3, and 12.3 % of patients had SCr > 400 μmol/l. The most common diseases in patients with nephrotic proteinuria were minimal change disease (MCD) (39.7 %) among children, IgAN (26.2 %) in adults aged 16–60 years and amyloidosis (42.7 %) among the elderly. The mean annual incidence (per million population) was: primary GN 30.9, secondary GN 18.1, IgAN 11.6, MGN 4.0, SLE 4.0, FSGS 3.9, MCD 3.4, NV 3.2, diabetic nephropathy 2.3, thin basement membrane glomerulopathy 2.0, mesangioproliferative GN 1.9, and TIN 1.9. Ultrasound needle guidance was used in 66.8 %. The frequency of serious complications (symptomatic hematoma, gross hematuria, blood transfusion) was approximately 3.2 %.
Conclusions
This report provides representative population-based data on native biopsy-proven renal diseases in the Czech Republic. Over the 18 years of nationwide biopsy survey, we noted an increase of the mean age of renal biopsy cases, an increasing proportion of elderly, and a cardinal change in biopsy technique towards ultrasonography needle guidance.
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