Learning more from the inter-rater reliability of interstitial fibrosis assessment beyond just a statistic.

Interstitial fibrosis assessment by renal pathologists lacks good agreement, and we aimed to investigate its hidden properties and infer possible clinical impact. Fifty kidney biopsies were assessed by 9 renal pathologists and evaluated by intraclass correlation coefficients (ICCs) and kappa statistics. Probabilities of pathologists' assessments that would deviate far from true values were derived from quadratic regression and multilayer perceptron nonlinear regression. Likely causes of variation in interstitial fibrosis assessment were investigated. Possible misclassification rates were inferred on reported large cohorts. We found inter-rater reliabilities ranged from poor to good (ICCs 0.48 to 0.90), and pathologists' assessments had the worst agreements when the extent of interstitial fibrosis was moderate. 33.5% of pathologists' assessments were expected to deviate far from the true values. Variation in interstitial fibrosis assessment was found to be correlated with variation in interstitial inflammation assessment (r2 = 32.1%). Taking IgA nephropathy as an example, the Oxford T scores for interstitial fibrosis were expected to be misclassified in 21.9% of patients. This study demonstrated the complexity of the inter-rater reliability of interstitial fibrosis assessment, and our proposed approaches discovered previously unknown properties in pathologists' practice and inferred a possible clinical impact on patients.

Serological and histopathological assessment of galactose-deficient immunoglobulin A1 deposition in kidney allografts: A multicenter prospective observational study.

BACKGROUND: Recurrent immunoglobulin A (IgA) nephropathy is an important risk factor for kidney allograft loss. However, there is no classification system for IgA deposition in kidney allografts based on serological and histopathological evaluation of galactose-deficient IgA1 (Gd-IgA1). This study aimed to establish a classification system for IgA deposition in kidney allografts based on serological and histological evaluation of Gd-IgA1. METHODS: This multicenter prospective study included 106 adult kidney transplant recipients in whom an allograft biopsy was performed. Serum and urinary Gd-IgA1 levels were investigated in 46 transplant recipients who were IgA-positive and classified into four subgroups according to the presence or absence of mesangial Gd-IgA1 (KM55 antibody) deposits and C3. RESULTS: Minor histological changes without an acute lesion were observed in recipients with IgA deposition. Fourteen (30%) of the 46 IgA-positive recipients were KM55-positive and 18 (39%) were C3-positive. The C3 positivity rate was higher in the KM55-positive group. Serum and urinary Gd-IgA1 levels were significantly higher in KM55-positive/C3-positive recipients than in the other three groups with IgA deposition. Disappearance of IgA deposits was confirmed in 10 of 15 IgA-positive recipients in whom a further allograft biopsy was performed. The serum Gd-IgA1 level at the time of enrollment was significantly higher in recipients in whom IgA deposition continued than in those in whom it disappeared (p = 0.02). CONCLUSIONS: The population with IgA deposition after kidney transplantation is serologically and pathologically heterogeneous. Serological and histological assessment of Gd-IgA1 is useful for identifying cases that should be carefully observed.

Cost Analysis of Screening for IgA Nephropathy Using Novel Biomarkers.

OBJECTIVES: IgA nephropathy (IgAN) is the most common primary chronic glomerulonephritis and a major cause of end-stage kidney disease worldwide. Novel biomarkers, including the aberrantly glycosylated IgA1 and glycan-specific antibodies, could be useful in the diagnosis of IgAN. The aim of this study was to assess the cost analysis of IgAN screening using novel biomarkers in addition to the conventional screening compared with conventional screening alone. METHODS: To estimate the medical expense of each strategy related to renal disease for 40 years, we developed an analytical decision model. The decision tree started at "40 years of age with first-time hematuria." It simulated 2 clinical strategies: IgAN screening using the novel biomarkers (group N) and conventional screening (group C). The analysis results were presented as medical expenses from a societal perspective. Discounting was not conducted. RESULTS: The expected medical expense per person for 40 years was ¥31.2 million (~$291 000) in group N and ¥33.4 million (~$312 000) in group C; hence, expense in group N was lower by ¥2.2 million (~$21 000). In group N, the expected value of IgAN increased by 5.67% points (N 48.44%, C 42.77%) and that of dialysis introduction decreased by 0.85% points (N 19.06%, C 19.91%). In the sensitivity analysis, expenses could be reduced in almost all cases except when renal biopsy using conventional screening was performed at the rate of 73% or higher. CONCLUSION: Screening for IgAN using novel biomarkers would reduce renal disease-related expenses.

Development and assessment of a predictive nomogram for the progression of IgA nephropathy.

The present study is to establish a nomogram for predicting the prognosis of IgA nephropathy (IgAN). Of the 869 IgAN patients, four-fifths were randomly assigned to the development cohort and one-fifth to the validation cohort. The primary outcome was a composite event of either a ≥ 50% reduction in estimated glomerular filtration rate (eGFR), end-stage renal disease or death. The mean follow-up time was 44 months. The Cox regression model identified urinary protein excretion (1-3.5 g/d, HR 11.639, 95% CI 3.601-37.625; ≥ 3.5 g/d, HR 32.435, 95% CI 10.079-104.380), eGFR (G2, HR 5.293, 95% CI 2.011-13.932; G3, HR 15.797, 95% CI 6.584-37.905; G4, HR 34.619, 95% CI 13.887-86.301; G5, HR 217.651, 95% CI 83.807-565.248), hyperuricaemia (HR 7.031, 95% CI 4.126-11.980), mesangial proliferation (HR 36.667, 95% CI 5.098-263.711), segmental glomerulosclerosis (HR 5.122, 95% CI 3.114-8.425), tubular atrophy/interstitial fibrosis (T1, HR 33.351, 95% CI 7.831-142.044; T2, HR 213.888, 95% CI 51.048-896.182), crescents (C1, HR 3.123, 95% CI 1.771-5.510; C2, HR 7.353, 95% CI 3.590-15.062) and glomerulosclerosis (25-49%, HR 3.123, 95% CI 1.771-5.510; ≥ 50%, HR 14.384, 95% CI 8.813-23.479) for developing the nomogram. The C-index was 0.945 (95% CI 0.914-0.976) in both the development and validation cohorts, showing good agreement between the nomogram-predicted probability and actual free-of-progression probability. Thus, our nomogram could accurately predict the progression of IgAN patients.

Contrast-enhanced ultrasonography for assessment of tubular atrophy/interstitial fibrosis in immunoglobulin A nephropathy: a preliminary clinical study.

PURPOSE: To investigate the potential of contrast-enhanced ultrasonography (CEUS) for evaluating the severity of tubular atrophy/interstitial fibrosis (TA/IF) in immunoglobulin A nephropathy (IgAN) patients. MATERIALS AND METHODS: A total of 80 patients with IgAN and 33 healthy adults were investigated. Patients were divided into three groups according to the TA/IF (T) grade of the Oxford classification: T0 (n = 28), T1 (n = 35), and T2 (n = 17). Patients and control subjects underwent conventional ultrasound (US) and CEUS. Time-intensity curves of CEUS were drawn for regions of interest located in the renal cortex and medulla using QLab software. Conventional US and CEUS quantitative parameters were analyzed. One-way analysis of variance (ANOVA), binary logistic regression, and receiver operating characteristic (ROC) curves were used. RESULTS: There were no significant differences in renal size, cortical thickness, and medullary perfusion parameters (P > 0.05), whereas the differences in peak intensity (PI), area under the time-intensity curve (AUC) and wash-in slope (WIS) of cortical perfusion parameters between the control subjects and patients were significant (P < 0.05). PI was significantly lower with the increasing degree of T (P < 0.05). PI was associated independently with the degree of T in IgAN patients (P < 0.05). ROC analysis revealed that using the optimal cutoff values of 15.38 dB for diagnosis of T0-T1 (sensitivity 83.30% and specificity 63.00%) and 14.69 dB for diagnosis of T2 (sensitivity 100.00% and specificity 66.70%), the corresponding areas under the ROC curve were found to be 0.782 and 0.952, respectively. CONCLUSIONS: CEUS can potentially be used as a noninvasive imaging marker to evaluate the severity of TA/IF in IgAN patients.

Prospective assessment of renal histopathological lesions in patients with end-stage liver disease: effects on long-term renal function after liver transplantation.

BACKGROUND & AIMS: The incidence of organic renal lesions in patients with end-stage liver disease is unknown. The goal of this study was to make a prospective evaluation of renal histological lesions in a group of unselected patients awaiting liver transplantation. METHODS: Sixty cirrhotic patients underwent a renal biopsy via the transjugular route. The potential effect of renal lesions on renal function was evaluated five years after transplantation. RESULTS: The yield of biopsies enabling satisfactory analysis was 77%, and no major complications occurred. Proteinuria>0.5 g/day was observed in only 8.7% of these patients, microscopic haematuria in 4.3%, creatinine levels>133 mmol/L (1.5mg/dl) in 10.9%, and Modification of the Diet in Renal Disease (MDRD) clearance<60 ml/min in 13.0%. Twenty-five patients (55.3%) had a morphological diagnosis of renal disease, 15 displayed IgA nephropathy and immunofluorescence testing showed that 12 had specific diabetic linear staining for IgG and albumin, of whom seven had associated histological lesions of diabetic nephropathy. Five years after liver transplantation, renal function had significantly deteriorated more in patients with initial diabetic lesions than in those with normal histology or IgA nephropathy alone. CONCLUSIONS: In patients with end-stage liver disease, IgA nephropathy and diabetic lesions were frequently found despite the absence of renal impairment and/or urinalysis anomalies. Our results strongly suggest that severe renal failure develops preferentially in liver transplant recipients with diabetes or carbohydrate intolerance, and that pre-existing arterial lesions may favour the nephrotoxicity of calcineurin inhibitors. Diabetes prior to transplantation needs to be strictly managed and requires a renal sparing immunosuppressive regimen after transplantation.

Clinical assessment of low-dose steroid therapy for patients with IgA nephropathy: a prospective study in a single center.

BACKGROUND/AIM: No accepted therapy has been established for progressive IgA nephropathy (IgAN). The purpose of the present study was to assess low-dose steroid therapy in the treatment of patients with IgAN. METHODS: A prospective trial of low-dose steroid therapy was performed in patients with IgAN with mild histological activities. Twenty-four patients in the steroid group and 24 patients in the control group were included in this study. The initial dose of prednisolone was 0.4 mg/kgBW/day (20-30 mg/day), gradually tapered to 5-10 mg/day over 24 months. The patients with mild active inflammatory lesions were treated with prednisolone. The patients assigned to the control group were treated with dipyridamole or zilazep hydrochloride in a dose of 150 or 300 mg/day. RESULTS: In all of the patients studied, serum creatinine levels did not significantly change over 24 months. However, daily proteinuria significantly reduced after 24 months of steroid therapy (0.97 +/- 0.75 vs. 0.31 +/- 0.51 g/day, P = 0.0012), even if did not change after 24 months of anti-platelet drugs (0.89 +/- 0.49 vs. 0.68 +/- 0.69 g/day, P = 0.2289), respectively. In addition, the grade of hematuria significantly reduced after 24 months of steroid therapy (35.6 +/- 36.3 RBC/HPF vs. 13.7 +/- 28.4 RBC/HPF, P = 0.0249) and 24 months of anti-platelet drugs (30.1 +/- 37.1 RBC/HPF vs. 12.4 +/- 20.3 RBC/HPF, P = 0.0465), respectively. Systolic and diastolic blood pressures did not significantly change during treatment with steroid or anti-platelet drugs. Vascular changes (0.63 +/- 0.73) in the steroid group were lower than those (1.08 +/- 0.88) in the control group (P = 0.008). CONCLUSION: Our data suggested that low-dose steroid therapy for IgAN patients with mild inflammatory lesions could reduce the amount of urinary protein excretion and prevent deterioration of renal function, provided the histological findings in the renal biopsies showed mild vascular lesions.

Glomerular basement membrane thinning in children: a morphometric assessment.

OBJECTIVE: To develop our own procedures, allowing for a quick evaluation of glomerular basement membrane (GBM) thickness and to present a statistical classification of thin basement membrane disease (TBMD), minimal change disease (MCD), and IgA nephropathy (IgAN) cases. STUDY DESIGN: Measurements were carried out with the aid of the original software for semiautomatic image analysis on biopsies from 31 children with TBMD, 51 with MCD, and 10 with IgAN. RESULTS: The strongest statistically significant dependence between GBM thickness and age was observed in children with MCD below 5 years of age. There was no significant dependence between GBM thickness and age among patients with TBMD. The values of all analyzed parameters characterizing GBM thickness distribution in children with TBMD were significantly lower than those in patients with MCD and IgAN. A slight, statistically significant increase of some parameters was noted in children with IgAN in contrast to patients with MCD. The multivariate logistic regression model with three independent variables--quartile 1, quartile 3, and percentile 30--proved to be the most appropriate in differentiating between patients with TBMD and children with MCD or IgAN. The model allowed for correctly classifying 96.8% of patients with TBMD (30 of 31 children) and 98.4% patients from the MCD and IgAN groups (60 of 61 children). We failed to construct a similarly appropriate model for differentiating between patients with MCD and IgAN. CONCLUSION: The introduction of morphometric and statistical methods to routine nephropathologic diagnostics represents true progress in very precise and quick assessment of GBM thickness.

[Relationship between renal function and morphometric assessment in chronic glomerulonephritis].

In an attempt to reveal a correlation between the degree of glomerular hypertrophy, interstitial damage, and hemodynamic parameters in chronic nephritis, the glomerular area (GA) and proportion of interstitial area (IA%) were determined quantitatively with an image analyzer, and the effective renal plasma flow (ERPF) and filtration fraction (FF) were determined simultaneously. The subjects were 12 patients with focal glomerulosclerosis (FGS) and 12 patients with IgA nephropathy (IgAN), all of whom had a similar glomerular filtration rate (GFR). The GFR was 58.6 +/- 11.4 ml/min/1.48 m2 in the FGS group and 53.9 +/- 13.1 ml/min/1.48 m2 in the IgAN group, and the difference between the two groups was not significant. On the other hand, ERPF was significantly lower and FF was significantly higher in the FGS group than in the IgAN group. GA was significantly higher in the FGS group than in the control group (10 kidney donors), and GA in the IgAN group was equivalent to that in the control group. IA% was almost equal in the FGS and IgAN groups, and significantly higher in both groups than in the control group. Although GA was not correlated with GFR in the two groups, it tended to be positively correlated with FF in the FGS group, and the correlation between GA and FF reached statistical significance when the IgAN group was combined with the FGS group. The above findings suggest that the pattern of progression of the glomeruli and interstitial lesions and of the intrarenal hemodynamics involved in them may differ in the FGS and IgAN groups. However, since ERPF significantly decreased in the FGS group, even though IA% was the same in both groups, the possibility that ERPF was functionally decreased in the FGS group cannot be ruled out.

Clinical assessment of the significance of platelet-derived growth factor in patients with immunoglobulin A nephropathy.

To examine the role of platelet-derived growth factor (PDGF) in the pathogenesis of IgA nephropathy (IgAN), we investigated the expression of PDGF and the PDGF receptor in glomeruli with immunohistochemistry, the plasma levels of PDGF with ELISA, and the expression of PDGF in peripheral blood monocytes (PBMCs) with reverse transcription polymerase chain reaction (RT-PCR). We also assessed the effect of corticosteroid therapy on the plasma levels of the PDGF B-chain. At the time of kidney biopsy, the expression of the PDGF B-chain and the PDGF beta receptor in the glomeruli was upregulated in patients with IgAN. In addition, the plasma concentration of the PDGF B-chain was significantly higher in patients with IgAN than in normal subjects. Moreover, mRNA expression of PDGF beta-chain in PBMCs was up-regulated in patients with IgAN when compared with other patients with glomerulonephritis. We divided the patients into two groups according to the grade of urinary protein excretion (U[p]) after corticosteroid therapy. In patients in group 1 in whom U(p) was decreased by more than 50% or 1 gm/day after corticosteroid therapy, the expression of the PDGF B-chain and the PDGF beta receptor in the glomeruli was up-regulated. Finally, corticosteroid therapy decreased the plasma levels of PDGF B-chain in patients in group 1. Up-regulation of the PDGF B-chain and beta receptor in the glomeruli, elevated plasma levels of PDGF B-chain, and increased expression of PDGF mRNA in PBMCs could be associated with the pathogenesis of IgAN. The plasma concentration of PDGF B-chain may be a useful marker for patients with IgAN who would be responsive to corticosteroid therapy.