Immunoglobulin A Nephropathy Urine Protein Profiling in Immunoglobulin A Nephropathy Maria Teresa Rocchetti, PhD,1 Massimo Papale, PhD1 and Loreto Gesualdo, MD2


1. Proteomics Core Facility, BioAgroMed Interdepartmental Research Center, University of Foggia; 2. Section of Nephrology, University of Foggia, and Department of Nephrology, Dialysis and Transplantation, Ospedali Riuniti, Foggia


Abstract


Immunoglobulin A nephropathy (IgAN) is the most common primary glomerulonephritis worldwide. End-stage renal disease develops in approximately 30% of patients. The diagnosis of IgAN requires renal biopsy. Currently, a non-invasive marker to diagnose and monitor IgAN is unavailable. Accordingly, novel biomarkers for the early detection of IgAN are crucially required and increased effort is needed in the development of new therapeutic targets to improve clinical outcome. The ability to predict risk in multifactorial diseases such as IgAN may be enhanced by strategies that employ multiple, simultaneous biomarkers instead of a single biomarker. Proteomics offers an ideal approach to globally characterize the protein content of a biologic sample on the genomic scale. Urinary proteomics has become one of the most attractive subdisciplines in clinical proteomics because it focuses on biomarker discovery and clinical diagnostics in renal diseases. This article summarizes the application of urinary proteomics in the investigation of IgAN.


Keywords Immunoglobulin A nephropathy (IgAN), Berger’s nephropathy, urinary proteome, proteomics, urine, biomarkers


Disclosure: The authors have no conflicts of interest to declare. Acknowledgements: The authors’ research is supported by the Cassa di Risparmio di Puglia Foundation, the Progetto Strategico Regione Puglia (grant number PS_094), the Italian Ministry of Health under Article 12 of the Italian Legislative Decree and the BioAgroMed Interdepartmental Research Center. Received: June 4, 2010 Accepted: September 14, 2010 Citation: US Nephrology, 2010;5(2):56–63 Correspondence: Loreto Gesualdo, MD, Section of Nephrology, Department of Biomedical Sciences, University of Foggia, Viale Pinto, 1, 71100 Foggia, Italy. E: l.gesualdo@unifg.it


Immunoglobulin A nephropathy (IgAN) or Berger’s nephropathy1,2 is the


most common primary glomerulonephritis worldwide. IgAN is characterized by the predominant deposition of IgA in the glomerular mesangium and by a variety of glomerular capillary network injuries. As no clinical presentation is pathognomonic, diagnosis of IgAN always requires renal biopsy,3


which reveals the deposition of


complexes containing polymeric IgA1 in the mesangium. The clinical manifestations of IgAN range from asymptomatic microhematuria and proteinuria to massive edema with nephrotic syndrome, although acute renal failure is uncommon. Approximately 25–30% of cases of IgAN develop end-stage renal disease within 20 years of presentation.4 It has been demonstrated that 1.5% of patients with IgAN require renal replacement therapy each year.3


Many studies have identified features at presentation that mark a poor prognosis. While these prognostic features may be informative for patients, they do not currently have the specificity to identify an individual prognosis with complete confidence.3,4


Although prognostic


formulae using simple clinical and laboratory data have been proposed,5–8


there is not yet sufficient consensus to recommend that they be used in clinical practice for the prediction of individual progression risk. It remains uncertain whether pathologic classification adds predictive power in the individual patient.3,4


56 In fact, Lee’s


glomerular grading system is the most used to compare biopsy specimens and to predict the natural course of disease in IgAN. It is refined as follows: grade I, normal or focal mesangial cell proliferation; grade II, diffuse mesangial cell proliferation or <25% of glomeruli with crescent (Cr)/segmental sclerosis (SS)/global sclerosis (GS); grade III, 25–49% of glomeruli with Cr/SS/GS; grade IV, 50–75% of glomeruli with Cr/SS/GS; grade V, >75% of glomeruli with Cr/SS/GS.9


Recently, a new classification of IgAN was presented by an international working group,10


which recommended that specific pathologic


features be taken into account to predict outcome regardless of clinical characteristics. There is no international consensus for this pathologic or clinical classification. While renal tissue can provide critical information on the disease process, conventional histopathology remains limited and additional strategies are required to better define renal damage at the molecular level.


The pathogenic mechanism of IgAN is still not completely understood. Current treatment options focus mainly on downstream immune and inflammatory events, which may lead to renal scarring, rather than modifying the mesangial deposition of IgA.3


In some cases, it is


necessary to repeat renal biopsy to evaluate treatments; however, biopsy is an invasive technique associated with the risk for serious


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