Diagnosis, treatment, and follow-up of patients with cerebral amyloid angiopathy-related inflammation.

PURPOSE: Cerebral amyloid angiopathy-related inflammation (CAA-ri) is a rare potentially reversible encephalopathy associated with an autoimmune process against proteins deposited in the walls of cortical and leptomeningeal brain vessels. Definite diagnosis requires histopathological features of vascular inflammation and amyloid deposition from brain biopsy. Clinical-neuroradiological criteria have been recently introduced and validated to reduce the need for biopsy. The purpose of this paper is to report a historical retrospective review of clinical-neuroradiological follow-up of two patients with probable CAA-ri and five patients with a reasonably probable suspect of CAA-ri (4 females, 3 males, patient's age at admission: 66-79 years) seen at our institution between 2007 and 2021, focusing on clinical and neuroradiological awareness to this entity and variable response to immunotherapy. MATERIALS AND METHODS: Clinical features at presentation included subacute to acute confusion (6/7), seizures (4/7), cognitive impairment (5/7), and focal neurological signs (3/7). Neuroradiology included braincomputed tomography followed by magnetic resonance imaging. Infectious diseases and autoimmune workups were then performed. RESULTS: CSF analysis was performed in two patients. Cerebral angiography was performed in two patients, to rule out vascular malformations. Hemorrhagic posterior reversible encephalopathy syndrome has been suspected in two patients. Four patients underwent immunotherapy with corticosteroids followed by reduction of brain dysfunctions. Three patients did not undergo immunotherapy but underwent clinical and/or neuroradiological remission. CONCLUSIONS: Patients with CAA-ri present a rare steroid-responsive acute to subacute brain dysfunction. Thus, it has to be known and recognized both clinically and neuroradiologically. Spontaneous clinical and/or neuroradiological improvement is possible in patients with mild symptoms.

Expert consensus guidelines for the genetic diagnosis of Alport syndrome.

Recent expert guidelines recommend genetic testing for the diagnosis of Alport syndrome. Here, we describe current best practice and likely future developments. In individuals with suspected Alport syndrome, all three COL4A5, COL4A3 and COL4A4 genes should be examined for pathogenic variants, probably by high throughput-targeted next generation sequencing (NGS) technologies, with a customised panel for simultaneous testing of the three Alport genes. These techniques identify up to 95% of pathogenic COL4A variants. Where causative pathogenic variants cannot be demonstrated, the DNA should be examined for deletions or insertions by re-examining the NGS sequencing data or with multiplex ligation-dependent probe amplification (MLPA). These techniques identify a further 5% of variants, and the remaining few changes include deep intronic splicing variants or cases of somatic mosaicism. Where no pathogenic variants are found, the basis for the clinical diagnosis should be reviewed. Genes in which mutations produce similar clinical features to Alport syndrome (resulting in focal and segmental glomerulosclerosis, complement pathway disorders, MYH9-related disorders, etc.) should be examined. NGS approaches have identified novel combinations of pathogenic variants in Alport syndrome. Two variants, with one in COL4A3 and another in COL4A4, produce a more severe phenotype than an uncomplicated heterozygous change. NGS may also identify further coincidental pathogenic variants in genes for podocyte-expressed proteins that also modify the phenotype. Our understanding of the genetics of Alport syndrome is evolving rapidly, and both genetic and non-genetic factors are likely to contribute to the observed phenotypic variability.

Urine-derived podocytes-lineage cells: A promising tool for precision medicine in Alport Syndrome.

Alport Syndrome (ATS) is a rare genetic disorder caused by collagen IV genes mutations, leading to glomerular basement membrane damage up to end-stage renal disease. Podocytes, the main component of the glomerular structure, are the only cells able to produce all the three collagens IV alpha chains associated with ATS and thus, they are key players in ATS pathogenesis. However, podocytes-targeted therapeutic strategies have been hampered by the difficulty of non-invasively isolating them and transcripts-based diagnostic approaches are complicated by the inaccessibility of other COL4 chains-expressing cells. We firstly isolated podocyte-lineage cells from ATS patients' urine samples, in a non-invasive way. RT-PCR analysis revealed COL4A3, COL4A4, and COL4A5 expression. Transcripts analysis on RNA extracted from patient's urine derived podocyte-lineage cells allowed defining the pathogenic role of intronic variants, namely one mutation in COL4A3 (c.3882+5G>A), three mutations in COL4A4 (c.1623+2T>A, c.3699_3706+1del, c.2545+143T>A), and one mutation in COL4A5 (c.3454+2T>C). Therefore, our cellular model represents a novel tool, essential to unequivocally prove the effect of spliceogenic intronic variants on transcripts expressed exclusively at a glomerular level. This process is a key step for providing the patient with a definite molecular diagnosis and with a proper recurrence risk. The established system also opens up the possibility of testing personalized therapeutic approaches on disease-relevant cells.

Alport syndrome: a unified classification of genetic disorders of collagen IV α345: a position paper of the Alport Syndrome Classification Working Group.

Mutations in the genes COL4A3, COL4A4, and COL4A5 affect the synthesis, assembly, deposition, or function of the collagen IV α345 molecule, the major collagenous constituent of the mature mammalian glomerular basement membrane. These mutations are associated with a spectrum of nephropathy, from microscopic hematuria to progressive renal disease leading to ESRD, and with extrarenal manifestations such as sensorineural deafness and ocular anomalies. The existing nomenclature for these conditions is confusing and can delay institution of appropriate nephroprotective therapy. Herein we propose a new classification of genetic disorders of the collagen IV α345 molecule with the goal of improving renal outcomes through regular monitoring and early treatment.

Immunohistochemical Evaluation of Renal Biopsy with Anti-PD1 and p53 to Solve the Dilemma between Platinum- and Pembrolizumab-Induced AKI: Case Report and Review.

Introduction: The combination therapy of platinum and pembrolizumab looks like a promising treatment in advanced non-small-cell lung cancer. However, both platinum-based chemotherapy and pembrolizumab can lead to AKI. AKI can occur due to acute tubular necrosis or interstitial nephritis. It is essential to identify the drug responsible for renal damage. For this purpose, we used new immunohistochemistry markers (p53 and anti-PD1 analysis). Case Description: A 77-year-old female patient with advanced non-small-cell lung cancer received the PD-1 inhibitor pembrolizumab and platinum-based chemotherapy carboplatin. The patient, after 60 days, experienced AKI. A kidney biopsy was performed, and two new immunohistochemical techniques for p53 (experimental markers of ATN from platinum) and anti-PDL1 (experimental markers of PD-1 inhibitors nephritis) were employed. Renal biopsies revealed severe tubular damage. No infiltration was detected, and the immunohistochemical assessment of PDL-1 was negative. The expression of p53 was positive. The renal biopsy suggested platinum-induced acute tubular necrosis. After discontinuing steroids and reducing carboplatin, the patient continued with pembrolizumab, and their renal function returned to normal within two months. Discussion: Combining checkpoint inhibitors and platinum-based therapies may result in AKI. The standard method of examining kidney tissue may not provide sufficient information about the effects of these drugs on the kidneys. To address this issue, we recommend incorporating an assessment of the analysis of the expression of PDL1 and p53. This personalized approach will help identify the best treatment option for the patient while ensuring the best possible cancer treatment plan.

HCMV infection in renal transplant recipients: a retrospective cohort study.

Human Cytomegalovirus (HCMV) represents the most common viral complication affecting solid organ transplant recipients (SOTRs) and its management is still debated. This study analyzes the association between HCMV infection and renal transplant recipients' outcomes. From January 2008 through December 2009, 97 consecutive renal transplant recipients were retrospectively studied. HCMV disease prevention was pursued by pre-emptive therapy, reserving long-term prophylaxis for high-risk patients. A total of 32/97 patients (32.9%) developed HCMV positivity in blood for a cumulative estimated proportion at 3 months post-transplantation of 0.21. HCMV disease developed in 7 patients (7.2%), while 25 patients had asymptomatic infection (25.7%). No patient died from HCMV. HCMV disease, older graft age and post-transplant renal dysfunction were independent predictors of rejection while HCMV infection without disease was associated with a higher number of other complications. The use of basiliximab was independently associated with a reduced hazard of HCMV infection/ disease. In renal transplant recipients HCMV infection still represents a major issue influencing the outcome, not only because of the potential to develop the disease and its link to graft rejection, but also in terms of higher number of complications. The choice of different immunosuppressive strategies might be associated with HCMV replication.

Purtscher-like retinopathy in a patient with systemic tacrolimus vasculopathy.

INTRODUCTION: Purtscher-like retinopathy is a rare occlusive retinal microangiopathy, whose pathogenesis has not been totally defined yet. Most frequent cause of Purtscher-like retinopathy is acute pancreatitis, but it may be triggered by other systemic or toxic conditions. We report herein a case of Purtscher-like retinopathy in the context of systemic tacrolimus vasculopathy. CASE REPORT: A 56-years old male with history of kidney transplant was referred to local emergency room because of a global worsening of health conditions, with fatigue, muscular pain and diuresis contraction. During hospitalization the patient came to our attention for sudden and severe visual acuity impairment in both eyes. Extensive ophthalmological assessment, optical coherence tomography (OCT) and fluorescein angiography (FA) were performed disclosing a marked drop in best corrected visual acuity (BCVA) (20/200 in the right eye and 10/400 in the left eye) caused by a bilateral severe occlusive retinal microangiopathy complicated by diffuse retinal ischaemia and neovascular glaucoma. Muscular biopsy showed a necrotizing myopathy with autoimmune features, as indicated by conspicuous upregulation of MHC-I complex and microangiopathic changes, consistent with tacrolimus toxicity. Tacrolimus administration was interrupted, and intravenous glucocorticoids were administered. The large areas of retinal ischemia and neovascular glaucoma were treated with pan-retinal photocoagulation and intravitreal injections of bevacizumab with complete regression of iris neovascolarization. BCVA measured 20/200 in both eyes at last follow-up visit, 20 months after symptoms onset. CONCLUSIONS: Purtscher-like retinopathy should be suspected in patients under treatment with calcineurin inhibitors especially in case of sudden and severe bilateral visual impairment.

Rationale for the evaluation of renal functional reserve in allogeneic stem cell transplantation candidates: a pilot study.

Background: The main purpose of our study was to evaluate the ability of renal functional reserve (RFR) to stratify the risk of acute kidney injury (AKI) occurrence within 100 days of hematopoietic stem cell transplantation (HSCT) and to predict any functional recovery or the onset of chronic kidney disease. A secondary aim was to identify the clinical/laboratory risk factors for the occurrence of AKI. Methods: The study design is prospective observational. We enrolled 48 patients with normal basal glomerular filtration rate (bGFR) who underwent allogenic HSCT. A multiparameter assessment and the Renal Functional Reserve Test (RFR-T) using an oral protein load stress test were performed 15 days before the HSCT. Results: Different RFRs corresponded to the same bGFR values. Of 48 patients, 29 (60%) developed AKI. Comparing the AKI group with the group that did not develop AKI, no statistically significant difference emerged in any characteristic related to demographic, clinical or multiparameter assessment variables except for the estimated GFR (eGFR). eGFR ≤100 mL/min/1.73 m2 was significantly related to the risk of developing AKI (Fisher's exact test, P = .001). Moreover, RFR-T was lower in AKI+ patients vs AKI- patients, but did not allow statistical significance (28% vs 40%). In AKI patients, RFR >20% was associated with complete functional recovery (one-sided Fisher's exact test, P = .041). The risk of failure to recover increases significantly when RFR ≤20% (odds ratio = 5.50, 95% confidence interval = 1.06-28.4). Conclusion: RFR identifies subclinical functional deterioration conditions essential for post-AKI recovery. In our cohort of patients with no kidney disease (NKD), the degree of pre-HSCT eGFR is associated with AKI risk, and a reduction in pre-HSCT RFR above a threshold of 20% is related to complete renal functional recovery post-AKI. Identifying eGFR first and RFR second could help select patients who might benefit from changes in transplant management or early nephrological assessment.

Using Renal Elastography to Predict the Therapeutic Response of Nephrological Patients.

BACKGROUND: The standard method for assessing chronic renal damage is renal biopsy, which has limitations due to its invasiveness. Ultrasound elastography is a non-invasive technique that quantifies tissue elasticity and can be used to determine Young's modulus (YM). Although this breakthrough technology has been successfully employed to evaluate liver stiffness and the extent of fibrosis, its application in kidney-related conditions still needs improvement. METHODS: Our study aimed to verify the correlation between renal elastography and the chronic histological score determined via renal biopsy, evaluate the correlation between elastography and response to treatment in the short-term follow-up (6 months), and compare elastography data between renal disease patients (AKD-P) and healthy controls (HP). RESULTS: The analyzed population consisted of 82 patients (41 HP and 41 AKD-P). The AKD-P were divided into responders (R) or non-responders (NR) based on the criteria established by the guidelines. No association was found between renal stiffness and chronic histological score. Elastography data revealed median YM values of 6.15 kPa for AKD-P and 12.2 kPa for HP, with a statistically significant difference. The median YM values of the R and NR groups were 7.4 KPa and 5.6 KPa, respectively (p = 0.037). CONCLUSIONS: Patient responsiveness was associated with YM, with lower values observed in the NR group. We also found that the healthy controls exhibited significantly higher YM values than the renal disease population.

[The genetic basis of post-bone marrow transplant thrombotic microangiopathy: is this the last piece of the puzzle?]

Transplant-associated thrombotic microangiopathy (TA-TMA) is a complication of hematopoietic stem cell transplantation (HSCT) associated with kidney injury and significant mortality. Recent studies indicate that dysregulation of the alternate complement pathway may be at the basis of the development of TA-TMA. Currently, there are no pre-transplant screening tools to identify patients at risk. To explore the mechanism of TA-TMA, we performed a genetic study that allowed us to identify the deletion of the CFHR3-CFHR1 region in homozygosity. We report the clinical case of a 47-year-old woman who underwent haploidentical HSCT complicated by TA-TMA confirmed by renal biopsy. The patient discontinued treatment with calcineurin inhibitors (potential inducers of TA-TMA) with a brief introduction of prednisone until complete resolution of renal damage and microangiopathy. Identifying genetic variants that affect the mechanism of the alternate complement pathway could help in the stratification of the risk of TA-TMA and in implementing a personalized therapeutic approach.

Health-Related Quality of Life in pre-dialysis patients with chronic kidney disease: the role of Big-Five personality traits and illness denial.

BACKGROUND: Health-Related Quality of Life (HRQoL) in patients with chronic kidney disease (CKD) is significantly affected, regardless of the stage of the disease, as regards the physical, psychological and social functioning dimension. Big-Five personality traits can affect patients' HRQoL and willingness to take treatment options. Illness denial consists of denial of negative emotions, resistance to change and conscious avoidance. Poorer HRQoL can predict a higher risk of hospitalization and mortality, and broadly a worse adjustment to the dialytic therapy. Thus, a clearer knowledge of the psychological variables associated with a worse HRQoL in the predialysis stage might improve the intervention planning. No study investigated illness denial and personality traits simultaneously. We investigated the role of illness denial and Big-Five personality traits in the domains of HRQoL in predialysis patients with CKD. METHODS: One hundred adults (mean age: 75.87 years) with CKD participated. The Kidney Disease Quality of Life Short form, the Italian version of Ten Item Personality Inventory Revised, the Illness Denial Questionnaire, and the State-Trait Anxiety Inventory Form-Y were administered. RESULTS: Illness denial was associated with increased HRQoL related to symptoms/problems, effect and burden of CKD and cognitive functions domains, and it was a predictor of higher HRQoL in the last three domains mentioned above. Extraversion was related to better work status and sexual function; agreeableness was linked to elevated cognitive function, quality of social interaction and sexual function; conscientiousness was related to better sexual function; neuroticism was linked to improved cognitive and sexual functions; in the end, openness to experience was related to fewer symptoms and problems. CONCLUSIONS: This is the first study which simultaneously assessed Big-Five personality traits and illness denial in different domains of HRQoL of CKD patients. Personalised psychological interventions aimed at improving HRQoL in this population might focus on specific illness denial processes and personality traits.

A vitamin E-coated polysulfone membrane reduces serum levels of inflammatory markers and resistance to erythropoietin-stimulating agents in hemodialysis patients: results of a randomized cross-over multicenter trial.

BACKGROUND: Oxidative stress is prevalent in dialysis patients and has been implicated in the pathogenesis of cardiovascular disease and anemia. Vitamin E is a fat-soluble antioxidant that plays a central role in reducing lipid peroxidation and inhibiting the generation of reactive oxygen species. The aim of this cross-over randomized study was to compare the effects of a vitamin E-coated polysulfone (Vit E PS) membrane and a non-vitamin E-coated polysulfone (PS) membrane on inflammatory markers and resistance to erythropoietin-stimulating agents (ESAs). METHODS: After a 1-month run-in period of standard bicarbonate dialysis with a synthetic membrane, 62 patients of both genders, and older than 18 years, dialysis vintage 48 ± 27 months, BMI 22 ± 3 (from 13 different dialysis units) were randomized (A-B or B-A) in a cross-over design to Vit E PS (treatment A) and to PS (treatment B) both for 6 months. C-reactive protein (CRP) and interleukin-6 (IL-6) concentrations were determined by a sandwich enzyme immunoassay at baseline and every 2 months; red blood cell count, ESA dose and ESA resistance index (ERI) were assessed monthly. RESULTS: Hemoglobin (Hb) levels significantly increased in the Vit E PS group from 11.1 ± 0.6 g/dl at baseline to 11.5 ± 0.7 at 6 months (p < 0.001) and remained unchanged in the PS group. Although ESA dosage remained stable during the observation periods in both groups, ERI was significantly reduced in the Vit E PS group from 10.3 ± 2.2 IU-dl/kg/g Hb week at baseline to 9.2 ± 1.7 at 6 months (p < 0.001). No significant variation of ERI was observed in the PS group. A significant reduction in plasma CRP and IL-6 levels was observed in the Vit E PS group: CRP from 6.7 ± 4.8 to 4.8 ± 2.2 mg/l (p < 0.001) and IL-6 from 12.1 ± 1.4 to 7.5 ± 0.4 pg/ml (p < 0.05). In the PS group, CRP varied from 6.2 ± 4.0 to 6.4 ± 3.7, and IL-6 from 10.6 ± 2.1 to 9.6 ± 3.5 (p = n.s.). CONCLUSIONS: Treatment with Vit E PS membranes seems to lead to a reduction in ESA dosage in HD patients; in addition, a low chronic inflammatory response may contribute to a sparing effect on exogenous ESA requirements.

SARS-CoV-2 in pleural fluid in a kidney transplant patient.

Coronavirus disease 2019 (COVID-19), caused by infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has quickly spread all over the globe from China. Pleural involvement is not common; around 5-10% of patients can develop pleural effusion and little is known about the involvement of pleural structures in this new infection.A 61-year-old male kidney transplant patient with a history of multiple biopsy-confirmed acute rejections and chronic allograft rejection was admitted to our COVID-19 Unit with dry cough, exertional dyspnea, oliguria, and abdominal distension. Lung ultrasound imaging, chest X-ray, and CT scan showed left pleural effusion and atelectasis of the neighboring lung parenchyma. RT-PCR was positive for SARS-CoV-2 in the pleural fluid and cytology showed mesothelial cells with large and multiple nuclei, consistent with a cytopathic effect of the virus.This is one of few reports describing detection of SARS-CoV-2 in the pleural fluid and to the best of our knowledge, is the first to document the simultaneous presence of a direct cytopathic effect of the virus on mesothelial cells in a kidney transplant patient with COVID-19 pneumonia. The pleura proved to be a site of viral replication where signs of a direct pathological effect of the virus on cells can be observed, as we report here. RT-PCR for SARS-CoV-2 should be part of routine examination of pleural effusion even in patients with mild respiratory symptoms or with comorbidities that seem to explain the cause of effusion.

Diagnostic accuracy of anti-phospholipase A2 receptor (PLA2R) antibodies in idiopathic membranous nephropathy: an Italian experience.

BACKGROUND: Autoantibodies against-phospholipase A2 receptor (PLA2R) are specific markers of idiopathic membranous nephropathy (iMN). Enzyme-linked immunosorbent assay (ELISA) is becoming the preferred method in many laboratories for the determination of anti-PLA2R antibodies, because it provides quantitative results, and is not prone to subjective interpretation, as is the case with indirect immunofluorescence assay. METHODS: The purpose of our study was to determine the diagnostic performance of serum PLA2R antibodies detected by commercially available ELISA in a large Italian multicenter cohort of patients with biopsy-proven iMN and in patients with other renal diseases, with special focus on evaluating the optimal cut-off value to discriminate positive and negative results. A total of 495 consecutive patients were recruited. Renal biopsies were performed in all patients, and blood samples were taken before the initiation of immunosuppressive treatment. RESULTS: According to the clinical diagnosis and to kidney biopsy, 126 patients were diagnosed with iMN and 369 had other non-membranous nephropathies. Anti-PLA2R autoantibodies were detected using a commercial anti-PLA2R ELISA. At a cut-off value of 20 relative units (RU)/ml indicated by the manufacturer for positive classification, sensitivity was 61.1% and specificity 99.7%. At a cut-off value of 14 RU/ml indicated by the manufacturer for borderline results, sensitivity was 63.5% and specificity remained the same (99.7%). At a cut-off of 2.7 RU/ml, selected as the optimal cut-off on the basis of ROC curve analysis, sensitivity was 83.3% and specificity 95.1%. The best overall efficiency of the test was observed at 2.7 RU/ml; however, the highest positive likelihood ratio and diagnostic odds ratio were achieved at 14 RU/ml. A cut-off threshold higher than 14 RU/ml or lower than 2.7 RU/ml entailed worse test performance. CONCLUSION: Depending on the clinical use (early diagnosis or as a support to confirm clinical diagnosis), nephrologists may take advantage of this evidence by choosing the most convenient cut-off. However, renal biopsy remains mandatory for the definitive diagnosis of iMN and for the assessment of disease severity.

The role of color Doppler in acute kidney injury.

In recent years, echographic studies of the kidney have improved radically due to new technologies which have recently become available. Among these, perhaps the most useful one is the ultrasonographic (US) procedure for the simultaneous laboratory and clinical workup of patients affected with acute nephropathic syndromes. However, traditional B-mode ultrasonography lack of sensibility and specificity in identifying and evaluating Acute Kidney Injury (AKI) is well known. Although the most objective measure in the study of different nephropathies remains by far the biopsy, several studies have indicated the usefulness of combining the B-mode ultrasound (US) with echo-color Doppler as a tool in determining intrarenal parenchymal arteries in the for differential diagnosis and predicion of clinical outcomes. In fact, the resistivity index (RI), determined by the formula: IR = (peak systolic velocity)--(end-diastolic or telediastolic velocity)/(peak systolic velocity) can be, after proper technical correction, easily measured at the level of the arcuate arteries or at the interlobar arteries. The final value is the average of 3-5 peaks, consecutively determined for each kidney at the upper pole, in the mesorenal area and also at the lower pole. The variation in normal IR values is < or = 0.70 with the difference diminishing progressively from segmental to interlobar vessels. Acute Kidney Injury (AKI) is perhaps one of the most important areas for the application of the Resistivity Index (RI). The differential diagnosis between prerenal AKI (which is functional and reversible if the cause of hypoperfusion is corrected) and renal AKI (which is organic and mainly caused by tubular necrosis (ATN) or acute interstitial nephritis) is facilitated by measurements of the RI, in addition to the normal clinical laboratory and clinical data. In fact, most pre-renal AKI patients show normal parenchymal vascular flow, with RI < 0.70, whereas those with AKI due to NTA have a reduced parenchymal perfusion, accompanied by elevated RI values, prior to any evidence of abnormal values of creatinine or of oligoanuria. Follow-up of patients with both renal and prerenal AKI by serial monitoring of RI during medical treatment of AKI shows a progressive reduction and ultimately the normalization of RI values of renal parenchymal vessels and often precedes the return to normal kidney function. In post-renal obstructive AKI patients, absolute values of RI > 0.70 on the obstructed kidney and a RI difference (deltaRI) between the two kidneys of > 0.06-0.08 are considered diagnostic of an obstruction. Elevated values of RI are also considered useful in the diagnosis of hemolytic-uremic syndrome (HUS) and are a significant predictor of prognosis: the normalization of IR precedes the return of normal renal functionality. Similarly, measurement of RI in patients with liver disease and normal renal function may help in early detection of latent hepato-renal syndrome. Although the IR is not, strictly speaking, a measure of renal function it may nevertheless be correlated with it especially if elevated arterial resistivity is accompanied by a reduction in renal function itself. Thus, IR may be considered a useful predictive index in specific clinical settings.

[Peritoneal dialysis: a time-limited therapy because of encapsulating peritoneal sclerosis? No, but better approaches are available]. / Dialisi peritoneale: metodica a termine a causa della peritonite sclerosante? No, ma ci sono approcci migliori.

In recent years the fear of encapsulating peritoneal sclerosis (EPS) prompted some nephrologists to consider peritoneal dialysis a time-limited therapy. Such an expiry date is devoid of a rational basis because peritoneal dialysis is a mere risk factor for EPS, not an etiological cause. This disease is in fact triggered by a second stimulus different from peritoneal dialysis and often even consisting of its withdrawal. Epidemiological studies have confirmed that interrupting peritoneal dialysis at a fixed time not only is useless in preventing EPS but might be counterproductive. Moreover, the quality of life of the patient should also be taken into account. Evidence obtained in recent years strongly suggests the effectiveness of other approaches in the prevention of EPS: 1) routine use of biocompatible peritoneal dialysis solutions; 2) inhibition of the renin-angiotensin-aldosterone axis as an elective therapy for hypertension in peritoneal dialysis; 3) prophylaxis with low-dose tamoxifen (10 mg per day) in high-risk patients (peritoneal dialysis >5 years, development of ultrafiltration failure and/or transport alterations); 4) a specific immunosuppressive protocol for former peritoneal dialysis patients undergoing transplantation: a sirolimus- or everolimus-based regimen with mycophenolate, avoidance or at least minimization of cyclosporine and tacrolimus, and use of steroids in the first 6-12 months. All of us should seriously consider the efficacy of these approaches in controlled clinical trials.

Detection of Cryptic Mosaicism in X-linked Alport Syndrome Prompts to Re-evaluate Living-donor Kidney Transplantation.

BACKGROUND: Alport syndrome is a hereditary nephropathy caused by mutations in collagen IV genes and characterized by ultrastructural lesions of the glomerular basement membrane. Some patients have a negative family history with apparently de novo mutations. Although somatic mosaicism has been postulated, as cryptic mosaicism cannot be detected from mutational screening on peripheral blood samples, cases in kidney-confined mosaic form have been missed. METHODS: We report the case of a 24-year-old male patient with X-linked Alport syndrome diagnosis due to a COL4A5 pathogenic mutation (c.3334_3337dup [p.Gly1113Alafs25]). The same mutation had not been previously detected on a peripheral blood sample of maternal DNA. However, the mother, who was undertaking a clinical re-evaluation to take in consideration the possibility of a living-kidney transplantation, had experienced persistent microhematuria since the age of 10 years. RESULTS: A next-generation sequencing approach performed on maternal DNA from both peripheral blood sample and urine-derived podocyte-lineage cells unmasked the COL4A5 mutation only in the podocyte-lineage cells. CONCLUSIONS: This finding unveils an early postzygotic event which can explain both the renal involvement and germline mosaicism. It changes the inheritance risk for each pregnancy raising it to 50% and underlines the need for different clinical management in the mother. This seems to indicate that a case-by-case more cautious approach is needed with mother-to-son kidney transplants.