IgA nephropathy is the most common glomerular disease worldwide, yet there is no international consensus for its pathological or clinical classification. Here a new classification for IgA nephropathy is presented by an international consensus working group. The goal of this new system was to identify specific pathological features that more accurately predict risk of progression of renal disease in IgA nephropathy, thus enabling both clinicians and pathologists to improve individual patient prognostication. In a retrospective analysis, sequential clinical data were obtained on 265 adults and children with IgA nephropathy who were followed for a median of 5 years. Renal biopsies from all patients were scored by pathologists blinded to the clinical data for pathological variables identified as reproducible by an iterative process. Four of these variables: (1) the mesangial hypercellularity score, (2) segmental glomerulosclerosis, (3) endocapillary hypercellularity, and (4) tubular atrophy/interstitial fibrosis were subsequently shown to have independent value in predicting renal outcome. These specific pathological features withstood rigorous statistical analysis even after taking into account all clinical indicators available at the time of biopsy as well as during follow-up. The features have prognostic significance and we recommended they be taken into account for predicting outcome independent of the clinical features both at the time of presentation and during follow-up. The value of crescents was not addressed due to their low prevalence in the enrolled cohort.

Pathological classifications in current use for the assessment of glomerular disease have been typically opinion-based and built on the expert assumptions of renal pathologists about lesions historically thought to be relevant to prognosis. Here we develop a unique approach for the pathological classification of a glomerular disease, IgA nephropathy, in which renal pathologists first undertook extensive iterative work to define pathologic variables with acceptable inter-observer reproducibility. Where groups of such features closely correlated, variables were further selected on the basis of least susceptibility to sampling error and ease of scoring in routine practice. This process identified six pathologic variables that could then be used to interrogate prognostic significance independent of the clinical data in IgA nephropathy (described in the accompanying article). These variables were (1) mesangial cellularity score; percentage of glomeruli showing (2) segmental sclerosis, (3) endocapillary hypercellularity, or (4) cellular/fibrocellular crescents; (5) percentage of interstitial fibrosis/tubular atrophy; and finally (6) arteriosclerosis score. Results for interobserver reproducibility of individual pathological features are likely applicable to other glomerulonephritides, but it is not known if the correlations between variables depend on the specific type of glomerular pathobiology. Variables identified in this study withstood rigorous pathology review and statistical testing and we recommend that they become a necessary part of pathology reports for IgA nephropathy. Our methodology, translating a strong evidence-based dataset into a working format, is a model for developing classifications of other types of renal disease.

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At 2 years, SRL conversion among patients with baseline GFR more than 40 mL/min was associated with excellent patient and graft survival, no difference in BCAR, increased urinary protein excretion, and a lower incidence of malignancy compared with CNI continuation. Superior renal function was observed among patients who remained on SRL through 12 to 24 months, particularly in the subgroup of patients with baseline GFR more than 40 mL/min and UPr/Cr less than or equal to 0.11.

Diabetes is the leading cause of ESRD because diabetic nephropathy develops in 30 to 40% of patients. Diabetic nephropathy does not develop in the absence of hyperglycemia, even in the presence of a genetic predisposition. Multigenetic predisposition contributes in the development of diabetic nephropathy, thus supporting that many factors are involved in the pathogenesis of the disease. Hyperglycemia induces renal damage directly or through hemodynamic modifications. It induces activation of protein kinase C, increased production of advanced glycosylation end products, and diacylglycerol synthesis. In addition, it is responsible for hemodynamic alterations such as glomerular hyperfiltration, shear stress, and microalbuminuria. These alterations contribute to an abnormal stimulation of resident renal cells that produce more TGF-␤1. This growth factor upregulates GLUT-1, which induces an increased intracellular glucose transport and D-glucose uptake. TGF-␤1 causes augmented extracellular matrix protein deposition (collagen types I, IV, V, and VI; fibronectin, and laminin) at the glomerular level, thus inducing mesangial expansion and glomerular basement membrane thickening. However, low enzymatic degradation of extracellular matrix contributes to an excessive accumulation. Because hyperglycemia is the principal factor responsible for structural alterations at the renal level, glycemic control remains the main target of the therapy, whereas pancreas transplantation is the best approach for reducing the renal lesions.