Natural History and Clinicopathological Associations of TRPC6-Associated Podocytopathy.

BACKGROUND: Understanding the genetic basis of human diseases has become integral to drug development and precision medicine. Recent advancements have enabled the identification of molecular pathways driving diseases, leading to targeted treatment strategies. The increasing investment in rare diseases by the biotech industry underscores the importance of genetic evidence in drug discovery and approval processes. Here we studied a monogenic Mendelian kidney disease, TRPC6-associated podocytopathy (TRPC6-AP), to present its natural history, genetic spectrum, and clinicopathological associations in a large cohort of patients with causal variants in TRPC6, in order to help define the specific features of disease and further facilitate drug development and clinical trials design. METHODS: the study involved 64 individuals from 39 families with TRPC6 causal missense variants. Clinical data, including age of onset, laboratory results, response to treatment, kidney biopsy findings, and genetic information, were collected from multiple centers nationally and internationally. Exome or targeted sequencing was performed and variant classification was based on strict criteria. Structural and functional analyses of TRPC6 variants were conducted to understand their impact on protein function. In depth re-analysis of light and electron microscopy specimens for 9 available kidney biopsies was conducted to identify pathological features and correlates of TRPC6-AP. RESULTS: Large-scale sequencing data did not support causality for TRPC6 protein-truncating variants. We identified 21 unique TRPC6 missense variants, clustering in three distinct regions of the protein, and with different effects on TRPC6 3D protein structure. Kidney biopsy analysis revealed FSGS patterns of injury in most cases, along with distinctive podocyte features including diffuse foot process effacement and swollen cell bodies. The majority of patients presented in adolescence or early adulthood but with ample variation (average 22, SD ± 14 years), with frequent progression to kidney failure but with variability in time between presentation and ESKD. CONCLUSIONS: This study provides insights into the genetic spectrum, clinicopathological associations, and natural history of TRPC6-AP.

Drug utilization in patients starting haemodialysis with a focus on cardiovascular and antidiabetic medications: an epidemiological study in the Lazio region (Italy), 2016-2020.

BACKGROUND: Entering dialysis is a critical moment in patients' healthcare journey, and little is known about drug therapy around it. A study funded by the Italian Medicines Agency offered the opportunity to leverage data from the Lazio Regional Dialysis and Transplant Registry (RRDTL) and perform an observational study on drug use patterns before and after initiating chronic dialysis. METHODS: Individuals initiating dialysis in 2016-2020 were identified from RRDTL, excluding patients with prior renal transplantation, stopping dialysis early, or dying within 12 months. Use of study drugs, predefined by clinicians, in the two years around the index date was retrieved from the drug claims register and described by semester. For each drug group, proportions of users (min 2 claims in 6 months) by semester, and intensity of treatment in terms of Defined Daily Doses (DDDs) for cardiovascular and antidiabetic agents were compared across semesters, stratifying by sex and age. RESULTS: In our cohort of 3,882 patients we observed a general increase in drug use after initiating dialysis, with the mean number rising from 5.5 to 6.2. Cardiovascular agents accounted for the highest proportions, along with proton pump inhibitors and antithrombotics over all semesters. Dialysis-specific therapies showed the most evident increase, in particular anti-anaemics (iron 4-fold, erythropoietins almost 2-fold), anti-parathyroids (6-fold), and chelating agents (4-fold). Use of cardiovascular and antidiabetic drugs was characterised by significant variations in terms of patterns and intensity, with some differences between sexes and age groups. CONCLUSIONS: Entering dialysis is associated with increased use of specific drugs and goes along with adaptations of chronic therapies.

The risks associated with percutaneous native kidney biopsies: a prospective study.

BACKGROUND: The known risks and benefits of native kidney biopsies are mainly based on the findings of retrospective studies. The aim of this multicentre prospective study was to evaluate the safety of percutaneous renal biopsies and quantify biopsy-related complication rates in Italy. METHODS: The study examined the results of native kidney biopsies performed in 54 Italian nephrology centres between 2012 and 2020. The primary outcome was the rate of major complications 1 day after the procedure, or for longer if it was necessary to evaluate the evolution of a complication. Centre and patient risk predictors were analysed using multivariate logistic regression. RESULTS: Analysis of 5304 biopsies of patients with a median age of 53.2 years revealed 400 major complication events in 273 patients (5.1%): the most frequent was a ≥2 g/dL decrease in haemoglobin levels (2.2%), followed by macrohaematuria (1.2%), blood transfusion (1.1%), gross haematoma (0.9%), artero-venous fistula (0.7%), invasive intervention (0.5%), pain (0.5%), symptomatic hypotension (0.3%), a rapid increase in serum creatinine levels (0.1%) and death (0.02%). The risk factors for major complications were higher plasma creatinine levels [odds ratio (OR) 1.12 for each mg/dL increase, 95% confidence interval (95% CI) 1.08-1.17], liver disease (OR 2.27, 95% CI 1.21-4.25) and a higher number of needle passes (OR for each pass 1.22, 95% CI 1.07-1.39), whereas higher proteinuria levels (OR for each g/day increase 0.95, 95% CI 0.92-0.99) were protective. CONCLUSIONS: This is the first multicentre prospective study showing that percutaneous native kidney biopsies are associated with a 5% risk of a major post-biopsy complication. Predictors of increased risk include higher plasma creatinine levels, liver disease and a higher number of needle passes.

Rituximab or Cyclophosphamide in the Treatment of Membranous Nephropathy: The RI-CYCLO Randomized Trial.

BACKGROUND: A cyclic corticosteroid-cyclophosphamide regimen is the first-line therapy for membranous nephropathy. Compared with this regimen, rituximab therapy might have a more favorable safety profile, but a head-to-head comparison is lacking. METHODS: We randomly assigned 74 adults with membranous nephropathy and proteinuria >3.5 g/d to rituximab (1 g) on days 1 and 15, or a 6-month cyclic regimen with corticosteroids alternated with cyclophosphamide every other month. The primary outcome was complete remission of proteinuria at 12 months. Other outcomes included determination of complete or partial remission at 24 months and occurrence of adverse events. RESULTS: At 12 months, six of 37 patients (16%) randomized to rituximab and 12 of 37 patients (32%) randomized to the cyclic regimen experienced complete remission (odds ratio [OR], 0.4; 95% CI, 0.13 to 1.23); 23 of 37 (62%) receiving rituximab and 27 of 37 (73%) receiving the cyclic regimen had complete or partial remission (OR, 0.61; 95% CI, 0.23 to 1.63). At 24 months, the probabilities of complete and of complete or partial remission with rituximab were 0.42 (95% CI, 0.26 to 0.62) and 0.83 (95% CI, 0.65 to 0.95), respectively, and 0.43 (95% CI, 0.28 to 0.61) and 0.82 (95% CI, 0.68 to 0.93), respectively, with the cyclic regimen. Serious adverse events occurred in 19% of patients receiving rituximab and in 14% receiving the cyclic regimen. CONCLUSIONS: This pilot trial found no signal of more benefit or less harm associated with rituximab versus a cyclic corticosteroid-cyclophosphamide regimen in the treatment of membranous nephropathy. A head-to-head, pragmatic comparison of the cyclic regimen versus rituximab may require a global noninferiority trial. CLINICAL TRIAL REGISTRY NAME AND REGISTRATION NUMBER: Rituximab versus Steroids and Cyclophosphamide in the Treatment of Idiopathic Membranous Nephropathy (RI-CYCLO), NCT03018535.

Multicenter evaluation of use of dried blood spot compared to conventional plasma in measurements of globotriaosylsphingosine (LysoGb3) concentration in 104 Fabry patients.

OBJECTIVES: Fabry disease (FD) is an X-linked lysosomal storage disorder, resulting from a deficiency of the enzyme α-galactosidase A, responsible for breaking down glycolipids such as globotriaosylceramide and its deacylated derivative, globotriaosylsphingosine (LysoGb3). Here, we compare the levels of LysoGb3 in dried blood spots (DBS) and plasma in patients with classic and late-onset phenotypes. METHODS: LysoGb3 measurements were performed in 104 FD patients, 39 males and 65 females. Venous blood was collected. A portion was spotted onto filter paper and another portion separated to obtain plasma. The LysoGb3 concentrations in DBS and plasma were determined by highly sensitive electrospray ionization liquid chromatography tandem mass spectrometry. Agreement between different matrices was assessed using linear regression and Bland Altman analysis. RESULTS: The method on DBS was validated by evaluating its precision, accuracy, matrix effect, recovery, and stability. The analytical performances were verified by comparison of a total of 104 paired DBS and plasma samples from as many FD patients (representing 46 GLA variants). There was a strong correlation between plasma and the corresponding DBS LysoGb3 concentrations, with few exceptions. Discrepancies were observed in anemic patients with typically low hematocrit levels compared to the normal range. CONCLUSIONS: The method proved to be efficient for the rapid analysis of LysoGb3. DBS provides a convenient, sensitive, and reproducible method for measuring LysoGb3 levels for diagnosis, initial phenotypic assignment, and therapeutic monitoring in patients with FD.

Pathology and pathogenic pathways in fabry nephropathy.

BACKGROUND: The pathophysiology of renal damage in Fabry nephropathy involves a complex biological mechanism. The intracellular deposition globotriaosylceramide (Gb3) is just the first step of the mechanism. The glycolipid deposition occurs in all renal cells (endothelial, epithelial and mesangial cells). It stimulates many biological processes, including cytokine release, epithelial-mesenchymal transdifferentiation, oxidative stress and the remodelling of vascular walls, resulting in subtle initial inflammation and eventually tissue fibrosis. It has been hypothesized that the processes activated by Gb3 deposition can subsequently progress independently of cellular deposition and that even Gb3 clearance by specific therapy cannot retard or stop these pathways. AIM: This review aims to gather the reported evidence of these cellular alterations and the resulting histological changes. Our approach is similar to a routine study of kidney biopsy. RESULTS: In the first part of the review, "histology" section, we describe the structures involved (glomeruli, vessels, tubules and interstitium) from a histological point of view. While in the second part, "pathogenesis" section, we present some interpretations about the implicated pathways based on the up-to-date available evidence.

Pathogenesis of Fabry nephropathy: The pathways leading to fibrosis.

BACKGROUND: Kidney is one of the main target organs in Fabry disease, a lysosomal X-linked genetic disorder. Renal involvement is characterized by proteinuria and progressive chronic kidney disease leading to end-stage renal disease. Pathogenic mechanisms in the progression of renal damage in Fabry disease are not thoroughly known yet. The lysosomal Gb3 deposition is the first step of complex pathological pathways resulting in renal sclerosis/fibrosis. Our hypothesis is that Fabry disease associated cellular alterations in tubular cells induce the production of TGF-ß1, which mediate transdifferentiation of renal cells into myofibroblasts resulting in fibrosis of renal tissue. OBJECTIVES: The aim of this work is to study the mechanisms leading to fibrosis in kidney from human Fabry patients. METHODS: Fifteen renal biopsies from naïve Fabry patients were included. Histological and immunohistochemical analysis was carried out. RESULTS: Positive staining for TGF-ß1 was found in tubular epithelial cells in biopsies from Fabry patients. Apoptosis was determined by active caspase 3 staining in tubular and mesangial glomerular cells. Due to TGF-ß1 is the main profibrotic cytokine and induces accumulation of myofibroblasts, we performed a study for its marker α-smooth muscle actin (α-SMA). This study revealed expression of α-SMA on pericytes surrounding peritubular capillaries, smooth muscle cells of blood vessels, mesangial cells and periglomerular zone. TGF-ß1 is produced mainly by tubular cells in Fabry kidney biopsies probably inducing cellular trans-differentiation of renal cells into myofibroblasts. A positive staining for a marker of myofibroblasts was present, affirming the presence of those profibrotic cells. CONCLUSIONS: These results show for the first time that TGF-ß1 is expressed in human renal tissue from Fabry patients, and that this profibrotic cytokine is mainly produced by proximal tubular cells. In addition both, peritubular interstitium and glomeruli, presented cells positive for myofibroblasts markers.

Is there long-term value of pathology scoring in immunoglobulin A nephropathy? A validation study of the Oxford Classification for IgA Nephropathy (VALIGA) update.

BACKGROUND: It is unknown whether renal pathology lesions in immunoglobulin A nephropathy (IgAN) correlate with renal outcomes over decades of follow-up. METHODS: In 1130 patients of the original Validation Study of the Oxford Classification for IgA Nephropathy (VALIGA) cohort, we studied the relationship between the MEST score (mesangial hypercellularity, M; endocapillary hypercellularity, E; segmental glomerulosclerosis, S; tubular atrophy/interstitial fibrosis, T), crescents (C) and other histological lesions with both a combined renal endpoint [50% estimated glomerular filtration rate (eGFR) loss or kidney failure] and the rate of eGFR decline over a follow-up period extending to 35 years [median 7 years (interquartile range 4.1-10.8)]. RESULTS: In this extended analysis, M1, S1 and T1-T2 lesions as well as the whole MEST score were independently related with the combined endpoint (P < 0.01), and there was no effect modification by age for these associations, suggesting that they may be valid in children and in adults as well. Only T lesions were associated with the rate of eGFR loss in the whole cohort, whereas C showed this association only in patients not treated with immunosuppression. In separate prognostic analyses, the whole set of pathology lesions provided a gain in discrimination power over the clinical variables alone, which was similar at 5 years (+2.0%) and for the whole follow-up (+1.8%). A similar benefit was observed for risk reclassification analyses (+2.7% and +2.4%). CONCLUSION: Long-term follow-up analyses of the VALIGA cohort showed that the independent relationship between kidney biopsy findings and the risk of progression towards kidney failure in IgAN remains unchanged across all age groups and decades after the renal biopsy.

Parapelvic cysts, a distinguishing feature of renal Fabry disease.

Background: Fabry's disease (FD) is a rare, multi-organ lysosomal disease, caused by the deficiency of the enzyme α-galactosidase A, and is difficult to diagnose. Although parapelvic cysts (PC) were previously associated with FD, their prevalence and significance are unclear. Methods: The present study aimed to: (i) evaluate, by renal ultrasound, the real prevalence of PC and of their determinants in a multicentre, nationwide cohort of FD patients (n = 173, Study 1) and (ii) ascertain whether a greater accuracy of PC detection improved their identification, in FD patients from a single centre (n = 67, Study 2). In both studies, for each FD patient, an age- and renal function-matched subject was selected for comparison (1:1). Results: In Study 1, PC were detected in 28.9% of FD subjects and in only 1.1% of control subjects (P < 0.001). The presence of other renal abnormalities did not differ between the groups, nor differences exist in the main demographic and laboratory parameters between the groups. In Study 2, the greater accuracy of ultrasound increased PC prevalence from 29.8% to 43.3% in the same subjects (P < 0.05). In both studies, no correlation was detected between PC and the main demographic, clinical and biochemical parameters, including use of enzyme replacement therapy (P < 0.1, minimum value). Finally, no difference existed between FD patients with and without PC. Conclusions: The present study suggests that the presence of PC in renal patients should alert physicians to consider the diagnosis of FD, primarily in subjects with an unclear family history of renal disease and in the presence of other stigmata of the disease.

Mutations in the GLA Gene and LysoGb3: Is It Really Anderson-Fabry Disease?

Anderson-Fabry disease (FD) is a rare, progressive, multisystem storage disorder caused by the partial or total deficit of the lysosomal enzyme α-galactosidase A (α-Gal A). It is an X-linked, lysosomal enzymopathy due to mutations in the galactosidase alpha gene (GLA), encoding the α-Gal A. To date, more than 900 mutations in this gene have been described. In our laboratories, the study of genetic and enzymatic alterations related to FD was performed in about 17,000 subjects with a symptomatology referable to this disorder. The accumulation of globotriaosylsphingosine (LysoGb3) was determined in blood of positives. Exonic mutations in the GLA gene were detected in 471 patients (207 Probands and 264 relatives): 71.6% of mutations were associated with the classic phenotype, 19.8% were associated with the late-onset phenotype, and 8.6% of genetic variants were of unknown significance (GVUS). The accumulation of LysoGb3 was found in all male patients with a mutation responsible for classic or late-onset FD. LysoGb3 levels were consistent with the type of mutations and the symptomatology of patients. α-Gal A activity in these patients is absent or dramatically reduced. In recent years, confusion about the pathogenicity of some mutations led to an association between non-causative mutations and FD. Our study shows that the identification of FD patients is possible by associating clinical history, GLA gene analysis, α-Gal A assay, and blood accumulation of LysoGB3. In our experience, LysoGB3 can be considered a reliable marker, which is very useful to confirm the diagnosis of Fabry disease.

Contribution of inflammatory pathways to Fabry disease pathogenesis.

Lysosomal storage diseases are usually considered to be pathologies in which the passive deposition of unwanted materials leads to functional changes in lysosomes. Lysosomal deposition of unmetabolized glycolipid substrates stimulates the activation of pathogenic cascades, including immunological processes, and particularly the activation of inflammation. In lysosomal storage diseases, the inflammatory response is continuously being activated because the stimulus cannot be eliminated. Consequently, inflammation becomes a chronic process. Lysosomes play a role in many steps of the immune response. Leukocyte perturbation and over-expression of immune molecules have been reported in Fabry disease. Innate immunity is activated by signals originating from dendritic cells via interactions between toll-like receptors and globotriaosylceramide (Gb3) and/or globotriaosylsphingosine (lyso-Gb3). Evidence indicates that these glycolipids can activate toll-like receptors, thus triggering inflammation and fibrosis cascades. In the kidney, Gb3 deposition is associated with the increased release of transforming growth factor beta and with epithelial-to-mesenchymal cell transition, leading to the over-expression of pro-fibrotic molecules and to renal fibrosis. Interstitial fibrosis is also a typical feature of heart involvement in Fabry disease. Endomyocardial biopsies show infiltration of lymphocytes and macrophages, suggesting a role for inflammation in causing tissue damage. Inflammation is present in all tissues and may be associated with other potentially pathologic processes such as apoptosis, impaired autophagy, and increases in pro-oxidative molecules, which could all contribute synergistically to tissue damage. In Fabry disease, the activation of chronic inflammation over time leads to organ damage. Therefore, enzyme replacement therapy must be started early, before this process becomes irreversible.

Corpus callosum involvement: a useful clue for differentiating Fabry Disease from Multiple Sclerosis.

PURPOSE: Multiple sclerosis (MS) has been proposed as a possible differential diagnosis for Fabry disease (FD). The aim of this work was to evaluate the involvement of corpus callosum (CC) on MR images and its possible role as a radiological sign to differentiate between FD and MS. METHODS: In this multicentric study, we retrospectively evaluated the presence of white matter lesions (WMLs) on the FLAIR images of 104 patients with FD and 117 patients with MS. The incidence of CC-WML was assessed in the two groups and also in a subgroup of 37 FD patients showing neurological symptoms. RESULTS: WMLs were detected in 50 of 104 FD patients (48.1%) and in all MS patients. However, a lesion in the CC was detected in only 3 FD patients (2.9%) and in 106 MS patients (90.6%). In the FD subgroup with neurological symptoms, WMLs were present in 26 of 37 patients (70.3%), with two subjects (5.4%) showing a definite callosal lesion. CONCLUSION: FD patients have a very low incidence of CC involvement on conventional MR images compared to MS, independently from the clinical presentation and the overall degree of WM involvement. Evaluating the presence of CC lesions on brain MR scans can be used as a radiological sign for a differential diagnosis between MS and FD, rapidly addressing the physician toward a correct diagnosis and subsequent treatment options.

Fabry's disease: an example of cardiorenal syndrome type 5.

Cardiorenal syndrome type 5 (CRS-5) includes conditions where there is a simultaneous involvement of the heart and kidney from a systemic disorder. This is a bilateral organ cross talk. Fabry's disease (FD) is a devastating progressive inborn error of metabolism with lysosomal glycosphingolipid deposition in variety of cell types, capillary endothelial cells, renal, cardiac and nerve cells. Basic effect is absent or deficient activity of lysosomal exoglycohydrolase a-galactosidase A. Renal involvement consists of proteinuria, isosthenuria, altered tubular function, presenting in second or third decade leading to azotemia and end-stage renal disease in third to fifth decade mainly due to irreversible changes to glomerular, tubular and vascular structures, especially highlighted by podocytes foot process effacement. Cardiac involvement consists of left ventricular hypertrophy, right ventricular hypertrophy, arrhythmias (sinus node and conduction system impairment), diastolic dysfunction, myocardial ischemia, infarction, transmural replacement fibrosis, congestive heart failure and cardiac death. Management of FD is based on enzymatic replacement therapy and control of renal (with anti-proteinuric agents such as angiotensin-converting enzyme inhibitors-and/or angiotensin II receptor blockers), brain (coated aspirin, clopidogrel and statin to prevent strokes) and heart complications (calcium channel blockers for ischemic cardiomyopathy, warfarin and amiodarone or cardioverter device for arrhythmias).

Extracapillary proliferation is an independent predictive factor in Immunoglobulin A nephropathy.

BACKGROUND: Oxford classification of Immunoglobulin A Nephropathy (IgAN) identifies four pathological features as predictors of renal outcome (MEST-score): mesangial proliferation (M); endocapillary proliferation (E); segmental glomerulosclerosis (S); tubular atrophy/interstitial fibrosis (T). In particular extracapillary proliferation (Ex) was not considered as an independent histological variable predicting renal outcome. Recently the VALIGA study provided a validation of the Oxford classification in a large European cohort of IgAN patients and re-stated that Ex is not associated with a worse renal prognosis. We propose a retrospective study to evaluate the predictive value of the MEST-score in a multi-centre, single region group of patients from central Italy and in addition, to investigate Ex as a marker predicting renal outcome. METHODS: One hundred and seven patients were enrolled in this study. Clinical data of each patient were available at diagnosis and follow-up. The median age at diagnosis was 36.7 years; 72% of the patients were males. Histological parameters were those included in the MEST-score of the Oxford classification; in addition, Ex was also assessed. RESULTS: Multiple linear regression models for survey were used. Statistical analysis showed a correlation between the progression of renal decline, in terms of estimated glomerular filtration rate (slope eGFR), and M, S, T. Differently from Oxford and VALIGA studies, no correlation was found with E, while Ex correlated with a decline of eGFR. CONCLUSIONS: Our results suggest that Ex represents an additional independent variable associated with a faster decline of renal function in IgAN.

Validation of the Oxford classification of IgA nephropathy in cohorts with different presentations and treatments.

The Oxford Classification of IgA Nephropathy (IgAN) identified mesangial hypercellularity (M), endocapillary proliferation (E), segmental glomerulosclerosis (S), and tubular atrophy/interstitial fibrosis (T) as independent predictors of outcome. Whether it applies to individuals excluded from the original study and how therapy influences the predictive value of pathology remain uncertain. The VALIGA study examined 1147 patients from 13 European countries that encompassed the whole spectrum of IgAN. Over a median follow-up of 4.7 years, 86% received renin-angiotensin system blockade and 42% glucocorticoid/immunosuppressive drugs. M, S, and T lesions independently predicted the loss of estimated glomerular filtration rate (eGFR) and a lower renal survival. Their value was also assessed in patients not represented in the Oxford cohort. In individuals with eGFR less than 30 ml/min per 1.73 m(2), the M and T lesions independently predicted a poor survival. In those with proteinuria under 0.5 g/day, both M and E lesions were associated with a rise in proteinuria to 1 or 2 g/day or more. The addition of M, S, and T lesions to clinical variables significantly enhanced the ability to predict progression only in those who did not receive immunosuppression (net reclassification index 11.5%). The VALIGA study provides a validation of the Oxford classification in a large European cohort of IgAN patients across the whole spectrum of the disease. The independent predictive value of pathology MEST score is reduced by glucocorticoid/immunosuppressive therapy.

Fabry nephropathy: a review - how can we optimize the management of Fabry nephropathy?

Fabry disease is a rare, X-linked, lysosomal storage disease caused by mutations in the gene encoding the enzyme alpha-galactosidase A. Complete or partial deficiency in this enzyme leads to intracellular accumulation of globotriaosylceramide (Gb3) and related glycosphingolipids in many cell types throughout the body, including the kidney. Progressive accumulation of Gb3 in podocytes, epithelial cells and the tubular cells of the distal tubule and loop of Henle contribute to the renal symptoms of Fabry disease, which manifest as proteinuria and reduced glomerular filtration rate leading to chronic kidney disease and progression to end-stage renal disease. Early diagnosis and timely initiation of treatment of Fabry renal disease is an important facet of disease management. Initiating treatment with enzyme replacement therapy (ERT; agalsidase alfa, Replagal®, Shire; agalsidase beta, Fabrazyme®, Genzyme) as part of a comprehensive strategy to prevent complications of the disease, may be beneficial in stabilizing renal function or slowing its decline. Early initiation of ERT may also be more effective than initiating therapy in patients with more advanced disease. Several strategies are required to complement the use of ERT and treat the myriad of associated symptoms and organ involvements. In particular, patients with renal Fabry disease are at risk of cardiovascular events, such as high blood pressure, cardiac arrhythmias and stroke. This review discusses the management of renal involvement in Fabry disease, including diagnosis, treatments, and follow-up, and explores recent advances in the use of biomarkers to assist with diagnosis, monitoring disease progression and response to treatment.

The role of tubular cells in the pathogenesis of Fabry nephropathy.

The pathophysiology of Fabry nephropathy (FN) is induced by galactosidase A deficiency with a chronic exposure of glycolipids to every lineage of renal cells. Tissue damage is attributed to the activation of molecular pathways, resulting in tissue fibrosis and chronic kidney disease. Podocytes have been the primary focus in clinical pathophysiological research because of the striking accumulation of large glycolipid deposits observable in histology. Yet, the tubular interstitium makes up a large portion of the whole organ, and therefore, its role must be further considered in pathogenic processes. In this review, we would like to propose Fabry tubulopathy and its ensuing functional effects as the first pathological signs and contributing factors to the development of FN. We will summarize and discuss the current literature regarding the role of tubular cells in Fabry kidney pathophysiology. Starting from clinical and histological evidence, we will highlight the data from animal models and cell cultures outlining the pathophysiological pathways associated with tubular interstitial injury causing renal fibrosis in Fabry nephropathy.

Updated Evaluation of Agalsidase Alfa Enzyme Replacement Therapy for Patients with Fabry Disease: Insights from Real-World Data.

The clinical use of agalsidase alfa as enzyme replacement therapy (ERT) for Fabry disease (FD) has spread since 2001, and a large body of evidence of its effectiveness has been collected. This review presents the clinical and laboratory results achieved with agalsidase alfa, which has been published in the literature. Agalsidase alfa infusion slows down or stops the progression of renal damage, expressed by reduction or stabilization of the annual decline of the glomerular filtration rate; yearly decrease of glomerular filtration rate (slope) sometimes is reduced until its stabilization. ERT prevents or reduces the occurrence of hypertrophic cardiomyopathy or slows the increase over time if it is already present. Moreover, regarding neurological manifestations, ERT improves neuropathic pain and quality of life, and recent data indicated that it may also prevent the burden of cerebrovascular disease. In addition to ERT's clinical benefits, crucial topics like the most appropriate time to start therapy and the role of anti-drug antibodies (ADA) are analyzed. Treatment with agalsidase alfa in patients with FD substantially improves their outcomes and enhances their quality of life in patients with FD.

Pathogenic pathways of renal damage in Fabry nephropathy: interplay between immune cell infiltration, apoptosis and fibrosis.

BACKGROUND: Fabry nephropathy is a consequence of the deposition of globotriaosylceramide, caused by deficient GLA enzyme activity in all types of kidney cells. These deposits are perceived as damage signals leading to activation of inflammation resulting in renal fibrosis. There are few studies related to immunophenotype characterization of the renal infiltrate in kidneys in patients with Fabry disease and its relationship to mechanisms of fibrosis. This work aims to quantify TGF-ß1 and active caspase 3 expression and to analyze the profile of cells in inflammatory infiltration in kidney biopsies from Fabry naïve-patients, and to investigate correlations with clinical parameters. METHODS: Renal biopsies from 15 treatment-naïve Fabry patients were included in this study. Immunostaining was performed to analyze active caspase 3, TGF-ß1, TNF-α, CD3, CD20, CD68 and CD163. Clinical data were retrospectively gathered at time of kidney biopsy. RESULTS: Our results suggest the production of TNFα and TGFß1 by tubular cells, in Fabry patients. Active caspase 3 staining revealed that tubular cells are in apoptosis, and apoptotic levels correlated with clinical signs of chronic kidney disease, proteinuria, and inversely with glomerular filtration rate. The cell infiltrates consisted of macrophages, T and B cells. CD163 macrophages were found in biopsy specimens and their number correlates with TGFß1 and active caspase 3 tubular expression. CONCLUSIONS: These results suggest that CD163+ cells could be relevant mediators of fibrosis in Fabry nephropathy, playing a role in the induction of TGFß1 and apoptotic cell death by tubular cells. These cells may represent a new player in the pathogenic mechanisms of Fabry nephropathy.