Urinary N‐acetyl‐β‐glucosaminidase and estimated Glomerular filtration rate may identify patients to be treated with immuno‐suppression at diagnosis in idiopathic membranous nephropathy

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Great advances have been made in knowledge of pathophysiology and treatment of idiopathic membranous nephropathy (IMN) in the last decade. The discovery of podocyte antigen M‐type phospholipase A2 receptor (PLA2R) and its corresponding IgG autoantibodies confirmed the autoimmune nature of IMN.1 Anti‐PLA2R antibodies are present in 70–80% of IMN patients, and serum levels correlate with degree of proteinuria and predict their outcome, as high values are associated with low probability of spontaneous or treatment‐induced remission.2 Progression rate, defined as 25% increase of serum creatinine (sCr) or sCr ≥1.30 mg/dL, in the third tertile of anti‐PLA2R antibody levels was 69% vs. 25% in the first tertile.5 However, anti‐PLA2R antibody levels do not exactly identify patients who are likely to enter spontaneous remission or progress at diagnosis. Rituximab, the monoclonal antibody directed to podocyte surface antigen CD20 of B cells, is responsible for synthesis of anti‐PLA2R autoantibodies. It has been recognized as effective and safe treatment of IMN with nephrotic syndrome (NS) inducing remission in two‐thirds of patients often unresponsive to other immunosuppressive agents6 and suggested as first‐line therapy.9
Notwithstanding the recent development of numerous novel biomarkers,10 proteinuria still plays a central role in glomerulonephritis (GN) as a marker of disease severity, a factor responsible for further renal damage at glomerular and tubulo‐interstitial level,11 and a predictor of outcome and response to therapy. Moreover, reduction in proteinuria by inhibition of renin‐angiotensin system is associated with lowering progression to renal failure and improvement in kidney survival.13 The tubulo‐interstitial damage associated with abnormal and sustained tubular traffic of proteins and with chronic hypoxia14 is one of the main structural factors responsible for progression to chronic renal failure. Several studies have shown that high and low molecular weight proteins (IgG, IgM, α2‐macroglobulin, α1‐microglobulin, β2‐microglobulin) and the lysosomal enzyme N‐acetyl‐β‐glucosaminidase (NAG) have a higher predictive value than albumin/creatinine ratio in various types of primary GN and diabetic nephropathy.15 The predictive ability of urinary NAG has been seldom evaluated in GN.25 NAG is a lysosomal enzyme of 130 kDa molecular mass normally excreted in urine in low amounts as a consequence of the normal exocytosis process. Its urinary excretion increases after exposure to several tubulo‐toxic substances and in various renal diseases. In glomerular diseases, the analysis of NAG isoenzymes showed that its increased urinary excretion is due to an increased release from the renal tubular cells and not due to increased filtration across the damaged glomerular filtration barrier. Thus, NAG excretion is universally recognized as a marker of functional and/or structural damage of tubular cells. In a study of 136 patients with IMN, focal segmental glomerulosclerosis and minimal change disease,25 NAG/C showed a significant relationship with 24‐h proteinuria and fractional excretion of IgG and α1m. In NS patients with normal renal function, NAG/C below or above selected cut‐off significantly predicted remission and progression to end‐stage renal disease (ESRD).
The treatment of IMN with NS, characterized by about 30–40% of spontaneous remission, requires baseline risk stratification, which enables the identification of patients with high probability of spontaneous remission and long‐lasting normal renal function (NRF) or patients with high risk of progression at diagnosis. Thus, such risk stratification could be of paramount importance for selection of patients for early therapeutic decisions of immunosuppression. Studies to determine biomarkers that can predict prognosis and treatment responsiveness in IMN are still needed.27 The aim of this study was to assess the ability of proteinuric markers for outcome prediction and risk stratification in a longitudinal study of 86 IMN patients with rather long follow‐up period.

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