Systemic vasculitis involving the kidney: the nephropathologist's point of view.

Kidneys are often targets of systemic vasculitis (SVs), being affected in many different forms and representing a possible sentinel of an underlying multi-organ condition. Renal biopsy still remains the gold standard for the identification, characterization and classification of these diseases, solving complex differential diagnosis thanks to the combined application of light microscopy (LM), immunofluorescence (IF) and electron microscopy (EM). Due to the progressively increasing complexity of renal vasculitis classification systems (e.g. pauci-immune vs immune complex related forms), a clinico-pathological approach is mandatory and adequate technical and interpretative expertise in nephropathology is required to ensure the best standard of care for our patients. In this complex background, the present review aims at summarising the current knowledge and challenges in the world of renal vasculitis, unveiling the potential role of the introduction of digital pathology in this setting, from the creation of hub-spoke networks to the future application of artificial intelligence (AI) tools to aid in the diagnostic and scoring/classification process.

The Matter of Kidney Biopsy in Monoclonal Gammopathy of Renal Significance: A Case Report of a New Pattern of Immunoglobulin-Storing Histiocytosis.

Monoclonal gammopathy of renal significance (MGRS) represents a group of disorders, characterized by paraproteinemia which causes renal damage. These disorders never meet the diagnostic criteria for multiple myeloma (MM) or lymphoproliferative disease. Crystal-storing histiocytosis is one of the rarest patterns of MGRS, characterized by an accumulation of light chains of crystals within histiocyte's cytoplasm, located in bone marrow or other extramedullary sites such as the kidney, cornea, or thyme. A very few cases have been described as immunoglobulin-storing histiocytosis (IgSH) without evidence of crystals. In the recent literature, only 3 cases of IgSH have been described so far, none renal. In all cases, these very peculiar histopathological patterns are associated with lymphoproliferative or plasma cellular disorders. Here, we report a very unusual IgSH pattern in a kidney biopsy, which led to prompt detection and early therapeutic intervention, in a patient with otherwise misdiagnosed MGRS.

The need for kidney biopsy in the management of side effects of target and immunotherapy.

Introduction: The introduction of innovative therapies, resulting from revisiting cancer as a disease of the immune system, has changed the scenario of complications. These new classes of drugs, such as targeted therapies and immune checkpoint inhibitors, assure substantial advantages in cancer therapy, despite some side effects affecting various organs, including the kidney. Histological evaluations of kidney disorders induced by targeted/immunotherapy are limited. Method: In this study we examined the histological features of patients treated with new cancer agents who underwent a kidney biopsy for new onset kidney failure and/or urinary abnormalities. Results: The cohort included 30 adult patients. The most frequently administered therapies were immunotherapy (30%), targeted therapy (26.7%), immunotherapy plus targeted therapy (13.3%), immunotherapy plus chemotherapy (13.3%), targeted therapy plus chemotherapy (16.7%). The most common histological finding was tubular interstitial nephritis (30%) that was associated with acute tubular necrosis in 4 cases, and thrombotic microangiopathy (23.3%). After kidney biopsy, 16 of the 30 patients were treated according to the histological diagnosis. Fourteen patients were treated with steroids. One patient with membranous nephropathy was treated with a single dose of rituximab. A patient with severe thrombotic microangiopathy requiring dialysis received a treatment with eculizumab for 3 months. Overall some renal response was obtained in all patients treated with glucocorticoids, while complete kidney response was achieved in the patient treated with rituximab. Cancer treatment was resumed without change in 21 out of 30 patients. Conclusion: Kidney biopsy is critical for the management of kidney toxicities and should be strongly encouraged for patients showing adverse kidney effects of novel cancer agents.

Focal segmental glomerular sclerosis can be effectively treated using an intensive B-cell depletion therapy.

Background: Focal segmental glomerular sclerosis (FSGS) is a histologic lesion rather than a specific disease entity and represents a cluster of different conditions affecting both children and adults that includes primary, secondary and genetically mediated forms. These forms can be distinguished by electron microscopy and genetic assessment and show different responsiveness to steroids and immunosuppressants. Despite some promising effects of rituximab in nephrotic syndrome in children, the results in adults with FSGS are disappointing. Our group previously explored the effectiveness of rituximab in eight adult patients with unselected forms of FSGS and achieved a consistent reduction in proteinuria in one case. Following this experience, we developed an alternative therapeutic option intended to enhance the potential of rituximab with the support of other synergic drugs. We herein report the results of this therapeutic protocol (six administrations of rituximab plus two of intravenous cyclophosphamide plus glucocorticoids) in seven prospectively enrolled patients with extensive podocyte effacement and recurrent relapses or steroid dependence. Results: Patients had a median baseline serum creatinine level of 2.2 mg/dl (range 1-4.7) that decreased to 1.1 mg/dl (range 0.9-2.2) and 1.1 mg/dl (range 0.75-2.21) after 3 and 6 months, respectively, and remained unchanged at 12 months. Three of five patients with renal failure turned to normal function while the other two patients maintained a stable impairment after 18 and 52 months. The median proteinuria decreased from 6.1 g/24 h to 3.5, 3.5 and 1.9 g/24 h at 3, 6 and 12 months, respectively. Specifically, five of seven patients had a partial response at 12 months and became non-nephrotic. One of them had a complete response at 18 months and was still in complete remission at the last follow-up visit at 36 months. Proteinuria persisted unchanged in two of seven patients with a genetic-related disease. No serious late adverse events were observed. Conclusions: Our results show that intensive B-cell depletion therapy is able to reverse the nephrotic syndrome of steroid-dependent or frequently relapsing adult patients with putatively idiopathic FSGS (i.e. with extensive podocyte effacement).

Histology for nephrology, from pre-implantation to post-transplant kidney biopsy. Lesson learned from ReBIrth (Renal BIopsy for Kidney Transplantation Therapy).

A meeting entitled Renal BIopsy for Kidney Transplantation Therapy (ReBIrth) took place on May 31st, 2022 in Bologna, Italy. The meeting drew together nephrologists, surgeons, and pathologists and recognized as experts in the field of kidney transplantation in Italy. In this paper, we present our experience working with kidney transplants in the current era of immunosuppression therapy. The primary aim is to report the histopathological characteristics of failed kidney allografts after a consensus of experts reviewed the cases on a wholeslide imaging digital platform. Regardless of the cases discussed, digital pathology was reliable in identifying all the morphological and immunohistochemical features required to improve the correct use of immunosuppressive therapy to prevent graft failure and optimize patient management.

Chasing the Zebra: a case of membranous-like Glomerulopathy with SSA/RO52 deposits and no overt connective tissue disease.

BACKGROUND: The nature of the deposits in immune-mediated glomerulonephritis with a membranous pattern and masked IgG-Kappa deposits (MGMID) remains still to be elucidated. CASE PRESENTATION: We present a case of 33-year-old woman developing a continuous asymptomatic proteinuria (0.8-1 g/24 h) with no overt connective tissue diseases. She tested positive at high titers for SSA antibodies (Ro52 838 UI/mL, Ro60 2716 UI/mL) and at the kidney biopsy histological findings were compatible with an immune-mediated glomerulonephritis with a membranous pattern and masked IgG-Kappa deposits. Also, we demonstrated a positive immunohistochemistry staining for anti-Ro52-SSA antibodies, with a granular positivity in mesangium and along rare glomerular capillaries. To date, only one case of a patient with overt diagnosis of Sjögren's syndrome with MGMID has been described but a pathogenic role for SSA and SSB antibodies has never been proven. CONCLUSIONS: In this case, we described for the first time by immunohistochemistry a Ro52+ granular positivity in the mesangium and glomerular capillaries, potentially paving the way for a better understanding of MGMID.

Clinical-Pathological Characteristics of Renal Injuries Identify Different Clusters in Patients With Antiphospholipid Antibodies.

Introduction: Significant heterogeneity still exists in the nomenclature of renal involvement in antiphospholipid syndrome (APS). Methods: We applied a hierarchical cluster analysis to determine subgroups of patients according to clinical, laboratory, and renal histology characteristics in a cohort of subjects with confirmed antiphospholipid antibodies (aPL) positivity and biopsy proven aPL-related renal injuries. Kidney outcomes were then assessed at 12 months. Results: A total of 123 aPL-positive patients were included in the study (101 [82%] female, 109 [88.6%] with systemic lupus erythematosus [SLE], 14 (11.4%) with primary APS [PAPS]). Three clusters were identified. Twenty-three patients (18.7%) were included in the first cluster (cluster 1), characterized by a higher prevalence of glomerular capillary and arteriolar thrombi and fragmented red blood cells in the subendothelial space. Cluster 2 included 33 patients (26.8%) and showed a higher prevalence of fibromyointimal proliferative lesions as seen in hyperplastic vasculopathy. Cluster 3 was the largest (67 patients, mainly with SLE) and was characterized by higher prevalence of subendothelial edema, of both glomerular capillaries and arterioles. Conclusion: Three different clusters of patients with aPL and renal injuries emerged from our study as follows: the first, with the worst renal prognosis, was associated with features of thrombotic microangiopathy (TMA), thrombosis, triple aPL positivity and higher adjusted Global APS Score (aGAPSS) values; the second, characterized by hyperplastic vasculopathy with an intermediate prognosis, was seen more frequently in patients with cerebrovascular manifestations; and the third, more benign in terms of outcomes and with no overt association with thrombotic features, was characterized by endothelial swelling in concomitant lupus nephritis (LN).

Renal involvement as a unique manifestation of hemophagocytic syndrome.

Renal-limited hemophagocytic syndrome (HPS) is a rare clinical setting characterized by abnormal activation of the immune system. Fever associated with pancytopenia, hepatosplenomegaly with liver dysfunction, and hypofibrinogenemia are usually observed in HPS. From a histological level, the presence of non-malignant macrophages infiltrating bone marrow and organs represents the hallmark of this condition. Non-malignant macrophages are associated with phagocytizing activities involving other blood cells. While primary HPS is usually associated with inherited dysregulation of the immune system, secondary HPS usually occurs in the context of infection or is linked to a neoplastic process. Clinical presentation varies and can potentially lead to life-threatening settings. While renal involvement has frequently been reported, however, detailed descriptions of the kidney manifestations of HPS are lacking. More critically, the diagnosis of HPS is rarely supported by renal biopsy specimens. We report four rare cases of biopsy-proven renal-limited HPS in patients presenting with acute kidney injury (AKI). The available evidence on this topic is critically discussed in light of the possible emergence of an autonomous entity characterized by an isolated kidney involvement.

Treating Patients With ANCA-Associated Vasculitis and Very Severe Renal Injury With an Intensified B Cell Depletion Therapy: Comparison With a Control Cohort Receiving a Conventional Therapy.

Rituximab (RTX), an anti-CD20 monoclonal antibody, has shown to be an effective induction treatment for small-vessel vasculitides associated with antineutrophil cytoplasm antibodies (AAV) in both newly diagnosed and relapsing patients. However, the role of RTX in the management of the most severe cases of AAV remains to be fully elucidated. The aim of this study was to assess both safety and efficacy of an intensified B-cell depletion therapy (IBCDT) protocol, including RTX, cyclophosphamide (CYC), and methylprednisolone pulses without additional maintenance immunosuppressive therapy in a cohort of 15 AAV patients with the most severe features of AVV renal involvement (as <15 ml/min GFR and histological findings of paucimmune necrotizing glomerulonephritis with more than 50% crescents of non-sclerotic glomeruli at the renal biopsy). Results of the IBCDT regimen have been compared to those obtained in a control cohort of 10 patients with AAV treated with a conventional therapy regimen based on oral CYC and steroids followed by a prolonged maintenance therapy with azathioprine (AZA). Plasma exchange was equally employed in the study and the control group. Complete clinical remission (BVAS 0) was observed at 6 months in 14 of 15 patients treated with IBCDT (93%). All cases who achieved a complete clinical remission experienced a depletion of peripheral blood B cells at the end of therapy. Of the 10 dialysis dependent patients at onset, 6 subjects (60%) experienced a functional recovery allowing the suspension of dialysis treatment. When compared to the control group, no statistically significant difference was observed in patients treated with IBCDT in terms of overall survival, 6-month therapeutic response rate, and 6-, and 12-month functional renal recovery. The cumulative total dose of CYC in the case group was on average 1 g/patient while in the control group on average 8.5 g/patient (p = 0.00008). Despite the retrospective design and relative limited sample size, IBCDT appeared to be safe and had the same efficacy profile when compared to the conventional therapy with CYC plus AZA in the management of the most severe patients with AAV. Additionally, this avoided the need of prolonged maintenance therapy for long, and limited the exposure to CYC with consequent reduced toxicity and drug-related side effect rates.

Renal Involvement in Transthyretin Amyloidosis: The Double Presentation of Transthyretin Amyloidosis Deposition Disease.

Transthyretin (TTR) amyloidosis (ATTR) is either an inherited condition or a non hereditary disease due to misfolding of wild-type (WT) TTR. Amyloid deposits can be mainly detected in nerves in the inherited form and in myocardium in the acquired variant. Renal involvement has been described only in the Val30Met mutation of the familial form and is thought to be extremely rare in the WT TTR. However, ATTR is multi-organ disease, and even in the WT forms, apparently limited to the heart, carpal tunnel syndrome and lumbar or cervical spine amyloid deposition have been described. A series of 4 cases of biopsy-proven renal TTR amyloid deposition is reported in the present paper. We describe 2 WT ATTR patients, 1 patient with c.424G>A (p.(Val142Ile)) mutation of the TTR gene, and 1 patient with Val30Met mutation of the TTR gene. In all patients, the biopsy showed the presence of amyloid deposits with different distribution (#1 pericapsular, #2-3 vessels, #4 vessels, interstitium of medulla and cortex, and tubular basement membrane). The use of immunohistochemistry has enabled the identification of TTR, and identify the precursor protein. The possibility of kidney involvement in TTR amyloidosis should be taken into account in patients with renal impairment and unexplained cardiomyopathy and/or neuropathy. This is even of greater interest to the elderly for the possible confounding co-existence of plasma cell dyscrasia that could lead the clinician, in the presence of renal amyloid deposits, to misdiagnose AL amyloidosis and undertake inappropriate treatments.

Adult-onset CblC deficiency: a challenging diagnosis involving different adult clinical specialists.

BACKGROUND: Methylmalonic aciduria and homocystinuria, CblC type (OMIM #277400) is the most common disorder of cobalamin intracellular metabolism, an autosomal recessive disease, whose biochemical hallmarks are hyperhomocysteinemia, methylmalonic aciduria and low plasma methionine. Despite being a well-recognized disease for pediatricians, there is scarce awareness of its adult presentation. A thorough analysis and discussion of cobalamin C defect presentation in adult patients has never been extensively performed. This article reviews the published data and adds a new case of the latest onset of symptoms ever described for the disease. RESULTS: We present the emblematic case of a 45-year-old male, describing the diagnostic odyssey he ventured through to get to the appropriate treatment and molecular diagnosis. Furthermore, available clinical, biochemical and molecular data from 22 reports on cases and case series were collected, resulting in 45 adult-onset CblC cases, including our own. We describe the onset of the disease in adulthood, encompassing neurological, psychiatric, renal, ophthalmic and thromboembolic symptoms. In all cases treatment with intramuscular hydroxycobalamin was effective in reversing symptoms. From a molecular point of view adult patients are usually compound heterozygous carriers of a truncating and a non-truncating variant in the MMACHC gene. CONCLUSION: Adult onset CblC disease is a rare disorder whose diagnosis can be delayed due to poor awareness regarding its presenting insidious symptoms and biochemical hallmarks. To avoid misdiagnosis, we suggest that adult onset CblC deficiency is acknowledged as a separate entity from pediatric late onset cases, and that the disease is considered in the differential diagnosis in adult patients with atypical hemolytic uremic syndromes and/or slow unexplained decline in renal function and/or idiopathic neuropathies, spinal cord degenerations, ataxias and/or recurrent thrombosis and/or visual field defects, maculopathy and optic disc atrophy. Plasma homocysteine measurement should be the first line for differential diagnosis when the disease is suspected. To further aid diagnosis, it is important that genes belonging to the intracellular cobalamin pathway are included within gene panels routinely tested for atypical hemolytic uremic syndrome and chronic kidney disorders.

Spectrum of Kidney Injury Following COVID-19 Disease: Renal Biopsy Findings in a Single Italian Pathology Service.

The onset of coronavirus disease (COVID-19) as a pandemic infection, has led to increasing insights on its pathophysiology and clinical features being revealed, such as a noticeable kidney involvement. In this study, we describe the histopathological, immunofluorescence, and ultrastructural features of biopsy-proven kidney injury observed in a series of SARS-CoV-2 positive cases in our institution from April 2020 to November 2021. We retrieved and retrospectively reviewed nine cases (two pediatric and seven adults) that experienced nephrotic syndrome (six cases), acute kidney injury (two cases), and a clinically silent microhematuria and leukocyturia. Kidney biopsies were investigated by means of light microscopy, direct immunofluorescence, and electron microscopy. The primary diagnoses were minimal change disease (four cases), acute tubular necrosis (two cases), collapsing glomerulopathy (two cases), and C3 glomerulopathy (one case). None of the cases showed viral or viral-like particles on ultrastructural analysis. Novel and specific histologic features on kidney biopsy related to SARS-CoV-2 infection have been gradually disclosed and reported, harboring relevant clinical and therapeutic implications. Recognizing and properly diagnosing renal involvement in patients experiencing COVID-19 could be challenging (due to the lack of direct proof of viral infection, e.g., viral particles) and requires a proper integration of clinical and pathological data.

PGNMID and anti-CD38 monoclonal antibody: a therapeutic challenge.

Monoclonal gammopathy of renal significance (MGRS) designates disorders induced by a monoclonal protein secreted by plasma cells or B-cell clones in patients who do not meet the diagnostic criteria for multiple myeloma or other B-cell malignancies. Proliferative glomerulonephritis with monoclonal immunoglobulin deposits (PGNMID) is a form MGRS. Until now, no guidelines to decide the best therapeutic approach to manage PGNMID exist, and most patients progress to End Stage Renal Disease (ESRD) without therapy. Recently, daratumumab has showed an acceptable improvement in proteinuria and renal function in patients with PGNMID. We report the clinical outcome and the histological renal evolution and treatment complication of our patient, who was initially treated with a combination regimen including bortezomib, dexamethasone, and cyclophosphamide and then with anti-CD38 monoclonal antibody-based regimen.

Caveolin-1 expression predicts favourable outcome and correlates with PDGFRA mutations in gastrointestinal stromal tumours (GISTs).

AIMS: Novel prognostic markers are warranted for gastrointestinal stromal tumours. Caveolin-1 is a multifunctional protein that proved to be associated with outcome in multiple tumour types. Aim of this study was to investigate Caveolin-1 expression and prognostic efficacy in a series of gastrointestinal stromal tumours. METHODS: Caveolin-1 expression was assessed by immunohistochemistry in a retrospective series of 66 gastrointestinal stromal tumours representative of the different molecular subtypes. Correlations with clinical, histopathological and molecular features were investigated. Statistical analyses were performed as appropriate. RESULTS: Thirty-five cases out of 66 (53.0%) expressed Caveolin-1. Presence of Caveolin-1 expression correlated with favourable histopathologic and clinical traits, including a lower mitotic count (p=0.003) and lower relapse rate (p=0.005). Caveolin-1 expression also resulted associated with the presence of PDGFRA mutations (p=0.010). Outcome analyses showed a favourable prognostic significance of Caveolin-1 expression in terms of relapse-free survival (HR=0.14; 95% CI=0.03 to 0.63) and overall survival (HR=0.29; 95% CI=0.11 to 0.74), even after adjusting for the mutational subgroup (relapse-free survival: HR=0.14, 95% CI=0.04 to 0.44; overall survival: HR=0.29, 95% CI=0.11 to 0.51) and imatinib treatment (relapse-free survival: HR=0.14, 95% CI=0.02 to 0.81; overall survival: HR=0.29, 95% CI=0.17 to 0.48). CONCLUSION: Caveolin-1 represents a novel prognostic marker in gastrointestinal stromal tumours. Further studies are warranted to validate these results and to explore the mechanisms linking Caveolin-1 expression with the PDGFRA oncogenic pathway.

Contactin 1, a Potential New Antigen Target in Membranous Nephropathy: A Case Report.

Several novel antigens have recently been characterized in membranous nephropathy (MN), but those involved in the rare cases of MN associated with inflammatory neuropathies remain elusive. Although several antibodies have been identified in the serum, there is no evidence so far for their deposition in glomeruli. We report the case of a 73-year-old woman who was referred because of subacute onset of proximal asymmetric lower limb weakness together with ataxic gait. She was diagnosed with inflammatory neuropathy. Testing showed an estimated glomerular filtration rate of 73mL/min/1.73m2, hypoalbuminemia (2.89g/dL), and proteinuria (3.6g/d). Autoantibodies (antinuclear antibody, anti-extractable nuclear antigen antibody, anti-double stranded DNA antibody, lupus anticoagulant, anticardiolipin antibody, antineutrophil cytoplasmic antibody) were undetectable. Serum immunoglobulin and complement levels were normal. A kidney biopsy with electron microscopy examination showed a classical picture of MN. Testing for antibodies to phospholipase A2 receptor (PLA2R) gave negative results in the serum, and PLA2R and THSD7A antigens were not detected in kidney tissue. Anti-contactin 1 (CNTN1) antibody was detected by enzyme-linked immunosorbent assay at a 1:100 dilution of serum and shown to be mostly of IgG4 subclass by Western blot. CNTN1 antigen was colocalized with IgG4 within immune deposits by confocal microscopy. This observation suggests a pathophysiological link between inflammatory neuropathies and MN. CNTN1 should be considered as a potential candidate antigen involved in MN and tested in PLA2R-negative forms associated with inflammatory neuropathies.

[Atheroembolic renal disease: risk factors, diagnostics, histology, and therapeutic approaches].

The increase in patients' average age, the enhancement of anticoagulation therapy and the growth of vascular interventions represent the perfect conditions for the onset of atheroembolic renal disease. AERD is observed in patients with diffuse atherosclerosis, generally after a triggering event such as surgery on the aorta, invasive procedures (angiography, catheterization of the left ventricle, coronary angioplasty) and anticoagulant or fibrinolytic therapy. The clinical signs are heterogeneous, a consequence of the occlusion of downstream small arterial vessels by cholesterol emboli coming from atheromatous plaques of the aorta, or one of its main branches. The proximity of the kidneys to the abdominal aorta, and the high flow of blood they receive, make them a major target organ. For this reason, AERD represents a pathological condition that always needs to be taken into account in the nephropathic patient, although its systemic nature makes the diagnosis difficult. This manuscript presents a review of the existing literature on this pathology, to provide an updated summary of the state of the art: risk factors, diagnostics, histology and therapeutic approaches.

Immunohistochemical typing of amyloid in fixed paraffin-embedded samples by an automatic procedure: Comparison with immunofluorescence data on fresh-frozen tissue.

Amyloidosis comprises a spectrum of disorders characterized by the extracellular deposition of amorphous material, originating from an abnormal serum protein. The typing of amyloid into its many variants represents a pivotal step for a correct patient management. Several methods are currently used, including mass spectrometry, immunofluorescence, immunohistochemistry, and immunogold labeling. The aim of the present study was to investigate the accuracy and reliability of immunohistochemistry by means of a recently developed amyloid antibody panel applicable on fixed paraffin-embedded tissues in an automated platform. Patients with clinically and pathologically proven amyloidosis were divided into two cohorts: a pilot one, which included selected amyloidosis cases from 2009 to 2018, and a retrospective one (comprising all consecutive amyloidosis cases analyzed between November 2018 and May 2020). The above-referred panel of antibodies for amyloid classification was tested in all cases using an automated immunohistochemistry platform. When fresh-frozen material was available, immunofluorescence was also performed. Among 130 patients, a total of 143 samples from different organs was investigated. They corresponded to 51 patients from the pilot cohort and 79 ones from the retrospective cohort. In 82 cases (63%), fresh-frozen tissue was tested by immunofluorescence, serving to define amyloid subtype only in 30 of them (36.6%). On the contrary, the automated immunohistochemistry procedure using the above-referred new antibodies allowed to establish the amyloid type in all 130 cases (100%). These included: ALλ (n = 60, 46.2%), ATTR (n = 29, 22.3%), AA (n = 19, 14.6%), ALκ (n = 18, 13.8%), ALys (n = 2, 1.5%), and Aß2M amyloidosis (n = 2, 1.5%). The present immunohistochemistry antibody panel represents a sensitive, reliable, fast, and low-cost method for amyloid typing. Since immunohistochemistry is available in most pathology laboratories, it may become the new gold standard for amyloidosis classification, either used alone or combined with mass spectrometry in selected cases.

[Multiple myeloma, plasma cell dyscrasias and kidneys: a few symptoms, extensive damage].

Multiple myeloma represents one of the main universal oncological diseases. Due to its clinical characteristics, it is often diagnosed only too late, when it has already determined systemic effects; this results in greater therapeutic difficulty and worse prognostic results. Through the clinical case discussed in this article, we want to focus on the often aspecific manifestations of this pathology and on the need for a correct clinical and diagnostic framework. The main renal manifestations secondary to the deposition of immunoglobulins in both the glomerular and tubular areas will also be examined.

Protective Role of the M-Sec-Tunneling Nanotube System in Podocytes.

BACKGROUND: Podocyte dysfunction and loss are major determinants in the development of proteinuria. FSGS is one of the most common causes of proteinuria, but the mechanisms leading to podocyte injury or conferring protection against FSGS remain poorly understood. The cytosolic protein M-Sec has been involved in the formation of tunneling nanotubes (TNTs), membrane channels that transiently connect cells and allow intercellular organelle transfer. Whether podocytes express M-Sec is unknown and the potential relevance of the M-Sec-TNT system in FSGS has not been explored. METHODS: We studied the role of the M-Sec-TNT system in cultured podocytes exposed to Adriamycin and in BALB/c M-Sec knockout mice. We also assessed M-Sec expression in both kidney biopsies from patients with FSGS and in experimental FSGS (Adriamycin-induced nephropathy). RESULTS: Podocytes can form TNTs in a M-Sec-dependent manner. Consistent with the notion that the M-Sec-TNT system is cytoprotective, podocytes overexpressed M-Sec in both human and experimental FSGS. Moreover, M-Sec deletion resulted in podocyte injury, with mitochondrial abnormalities and development of progressive FSGS. In vitro, M-Sec deletion abolished TNT-mediated mitochondria transfer between podocytes and altered mitochondrial bioenergetics. Re-expression of M-Sec reestablishes TNT formation and mitochondria exchange, rescued mitochondrial function, and partially reverted podocyte injury. CONCLUSIONS: These findings indicate that the M-Sec-TNT system plays an important protective role in the glomeruli by rescuing podocytes via mitochondrial horizontal transfer. M-Sec may represent a promising therapeutic target in FSGS, and evidence that podocytes can be rescued via TNT-mediated horizontal transfer may open new avenues of research.