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Anti-glomerular basement membrane (GBM) antibody disease is a rare pathological condition that mainly involves renal and/or pulmonary parenchyma. It is characterized by the presence of circulating anti-GBM antibodies accompanied by a linear deposition of immunoglobulins (Ig) detected through immunofluorescence (IF) technique and typical signs and symptoms of organ dysfunction, such as rapidly progressive glomerulonephritis (RPGN) and pulmonary hemorrhage (PH). However, recently atypical forms of anti-GBM disease have been described and the presence of overlapping diseases contributed to make its diagnosis challenging. In this review will be discussed the entire spectrum of renal anti-GBM related conditions, focusing the attention on the differences in terms of pathogenesis, diagnosis and therapy of these disparate entities.

Purpose Matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI-MSI) technology has advanced rapidly during recent years with the development of instruments equipped with low-diameter lasers that are suitable for high spatial resolution imaging. This may provide significant advantages in certain fields of molecular pathology where more specific protein fingerprints of individual cell types are required, such as renal pathology. Experimental design Here MALDI-MSI analysis of a cohort of membranous nephropathy (MN) patients is performed among which patients either responded favorably (R; n = 6), or unfavorably (NR; n = 4), to immunosuppressive treatment (Ponticelli Regimen), employing a 10 µm laser spot diameter. Results Specific tryptic peptide profiles of the different cellular regions within the glomerulus can be generated, similarly for the epithelial cells belonging to the proximal and distal tubules. Conversely, specific glomerular and sub-glomerular profiles cannot be obtained while using the pixel size performed in previous studies (50 µm). Furthermore, two proteins are highlighted, sonic hedgehog and α-smooth muscle actin, whose signal intensity and spatial localization within the sub-glomerular and tubulointerstitial compartments differ between treatment responders and non-responders. Conclusions and clinical relevance The present study exemplifies the advantage of using high spatial resolution MALDI-MSI for the study of MN and highlights that such findings have the potential to provide complementary support in the routine prognostic assessment of MN patients.

Purpose Membranous nephropathy (MN) is the most frequent cause of nephrotic syndrome in adults and the disease course is characterized by the "rule of third", with one-third of patients experiencing complete remission and the remaining experiencing relapses or progression of the disease. Additionally, the therapeutic approach is not standardized, leading to further heterogeneity in terms of response and outcome. Experimental design In this pilot study, MALDI-MSI analysis is performed on renal biopsies (n = 13) obtained from two homogeneous groups of patients, which differentially responded to the immunosuppressive treatments (Ponticelli regimen). Results A signal at m/z 1303 displays the greatest discriminatory power when comparing the two groups and is observed to be of higher intensity in the glomeruli of the non-responding patients. The corresponding tryptic peptide is identified as macrophage migration inhibitory factor (MIF). Conclusions and clinical relevance Despite much effort being made in recent years to understand the pathogenesis of MN, a biomarker able to predict the outcome of these patients following therapeutic treatment is still lacking. Here, a protein (MIF), verified by immunohistochemistry, that can differentiate between these MN patients and could be a valuable starting point for a further study focused on verifying its predictive role in therapy response is highlighted.

Kidneys accomplish many important physiological tasks, ranging from the continuous blood filtration and consequent formation of urine, detoxification from endogenous and exogenous substances, production of active and inactive hormones (e.g., Vitamin D, Erythropoietin, and renin), and maintenance of the electrolytes balance. However, its function can be readily impaired by many pathogen noxae, leading to the so-called chronic kidney disease (CKD). This condition can be clinically assessed by the estimation of the glomerular filtration rate (eGFR), an indirect index of the renal function, that do not give any further information of which kind of injury affects the kidney. For this reason, the gold standard to determine the CKD cause is represented by the renal biopsy and the histomorphological criteria are essential for the interpretation of the tissue sample. In this chapter, the clinical and histopathological aspects of CKD will be discussed, with a final section on the future challenges represented by the molecular analysis and digital pathology in renal disease.

Membranous Nephropathy (MN) is an immunocomplex mediated renal disease that represents the leading cause of nephrotic syndrome in adults and is one of the most frequent glomerulopathies worldwide. This glomerular disease can manifest as primary (idiopathic) or secondary and this distinction is crucial when choosing the most appropriate management of patients. In secondary cases, the best strategy consists in treating the underlying disease whereas in primary forms, the possible identification of confirmatory markers of the idiopathic etiology underlining the process is requested by clinicians. Among those currently reported, the positivity to circulating antigens (PLA2R, IgG4 and THSD7A) was demonstrated in approximately 75% of iMN patients, while approximately 1 in 4 patients with iMN still lack a putative diagnostic marker. Ultimately, the discovery of useful biomarkers to help further stratify these two different forms of glomerulopathy seems mandatory. Here, MALDI-MSI was applied to formalin-fixed paraffin-embedded (FFPE) renal biopsies from histologically diagnosed primary and secondary MN patients (n=20) in order to evaluate the capability of this technology to detect alterations in their tissue proteome. MALDI-MSI was able to generate molecular signatures of primary and secondary MN, with one particular signal (m/z 1459), identified as Serine/threonine-protein kinase MRCK gamma, being over-expressed in the glomeruli of primary MN patients with respect to secondary MN. Furthermore, this proteomic approach detected a number of signals that could differentiate the different forms of iMN that were positive to PLA2R or IgG4 as well as a further set of signals (m/z 1094, 1116, 1381 and 1459) that distinguish these patients from those who were negative to both. These signals could potentially represent future targets to be investigated as proteomic markers for the further stratification of iMN patients. This article is part of a Special Issue entitled: MALDI Imaging, edited by Dr. Corinna Henkel and Prof. Peter Hoffmann

Il saggio si sofferma su un dettaglio narrativo di Una questione privata che in apparenza non sembra dipendere se non dalla scontrosità del protagonista: il rifiuto di Milton, verso il finale del romanzo, di aiutare un ragazzino a fare un tema scolastico dal titolo “I nostri amici, gli alberi”. L’analisi testuale dimostra invece come i riferimenti alla natura vegetale siano, in ogni momento dell’opera, attentamente studiati e ponderati. Così i ciliegi del giardino di Fulvia, nella prima parte, s’identificano con gli alberi dell’amore, mentre il peregrinare del partigiano sulle colline è contrassegnato dalla presenza delle acacie, gli alberi della morte. In questa tramatura arborea il rifiuto di Milton, contro il quale perfino gli elementi naturali sembrano accanirsi durante i quattro giorni della sua disperata e infruttuosa ricerca, ha tutto il sapore di un infausto presagio

Background and aims: Clinical studies exploring the relationship between serum uric acid (SUA) and arterial stiffness yielded conflicting results. Only in a few of these studies, arterial distensibility was examined by measuring aortic pulse wave velocity (PWV), which is considered the gold standard for evaluating arterial stiffness. In none of the previous investigations was the influence of SUA on aortic distensibility assessed, taking into account the effect of albuminuria. The purpose of our study was to comprehensively analyse the relationships between SUA and aortic PWV in a group of essential hypertensive patients. Methods and results: We enrolled 222 untreated and uncomplicated hypertensive subjects (mean age: 44 ± 10 years; 60% males), without gout. In all patients, SUA and urinary albumin excretion rate (AER) were determined. Moreover, carotid-femoral (c-f) PWV was measured. C-f PWV was significantly higher in hypertensive patients belonging to the uppermost tertile of SUA distribution, compared to subjects of the lowest tertiles (10.9 ± 2.2 vs. 10 ± 1.8 vs. 9.9 ± 1.7 m s-1; p = 0.001). In univariate analysis, SUA correlated with c-f PWV (r = 0.24; p < 0.001). This association disappeared when AER was added in a multiple regression model, including SUA, age, mean arterial pressure, gender, metabolic syndrome components and glomerular filtration rate. Conclusion: The results of our study showed that, in essential hypertensive subjects, there is a positive relationship between mild hyperuricaemia and aortic stiffness. This association weakened after adjustment for covariates and lost statistical significance after further correction for albuminuria.

Introduction: In experimental studies conducted in rats, raising serum uric acid (SUA) levels resulted in stimulation of renin expression. Studies in humans exploring the association of SUA with plasma renin activity (PRA) yielded conflicting results. Moreover, little is known about the relationship between plasma aldosterone concentration (PAC) and SUA. Aim: To analyse the relationships between SUA, PRA and PAC in a group of subjects with primary hypertension. Methods: We enrolled 372 patients (mean age 45 ± 12 years; women 33 %), with untreated primary hypertension, with normal renal function and without cardiovascular complications. Results: Spearman’s rank-correlation analyses showed that SUA was significantly associated with PRA and with PAC in the overall study population (rho = 0.127, p = 0.01 and rho = 0.206, p

Studi sperimentali e clinici hanno indotto ad ipotizzare una interazione fisiopatologica tra aldosterone (PAC) e paratormone (PTH) nello sviluppo dell’ipertensione arteriosa e delle alterazioni cardiovascolari . Scopo di questo studio è stato di valutare il rapporto tra PAC e PTH nell’ipertensione essenziale (EH) e le eventuali interazioni con FGF23, proteina modulatrice della secrezione di PTH. In 105 H ed in 50 controlli sani sono stati analizzati i livelli plasmatici di PAC, PTH, FGF23 Vitamina D. L’analisi di correlazione multipla condotta considerando PAC come variabile dipendente ha mostrato una correlazione di PAC con FGF23 (β = 0.337; p = 0.0021) e con PTH (β = 0.241; p = 0.039) indipendente da pressione arteriosa 24h, Vitamina D, funzione renale. I nostri dati suggeriscono che sia PTH che FGF23 siano coinvolti nella fisiopatologia dell’ipertensione arteriosa, anche in assenza di malattia renale cronica