31 research outputs found
Molecular and clinical Endo-phenotyping of patients affected by Chronic Kidney Diseases and Podocytopathies
No full textBetween 15–20% of patients with end stage renal disease (ESRD) do not know the cause of the primary kidney disease and can develop complications after kidney transplantation. We performed a genetic screening in 300 patients with kidney transplantation, or undiagnosed primary renal disease, in order to identify the primary disease cause and discriminate between overlapping phenotypes. We used a custom-made panel for next-generation sequencing (Agilent technology, Santa Clara, CA, USA), including genes associated with Fabry disease, podocytopaties, complementmediated nephropathies and Alport syndrome-related diseases. We detected candidate diagnostic variants in genes associated with nephrotic syndrome, collagen genes and Focal Segmental Glomerulosclerosis (FSGS) in 29 out of 300 patients, solving about 10% of the probands. Interestingly we also found one female patient carrying a novel missense variant, c.1259C>A (p.Thr420Lys), in the GLA gene not previously associated with Fabry disease, which is in silico defined as a likely pathogenic and destabilizing, and associated with a mild alteration in GLA enzymatic activity. Thanks to a collaborative international collaboration we also identified anti-NPHS1 antibody in a cohort of patients affected by podocytopathies, clarifying important new insight. The identification of the specific genetic background may provide an opportunity to evaluate the risk of recurrence of the primary disease, especially among patient candidates living with a donor kidney transplant.Tra il 15 e il 20% dei pazienti con malattia renale allo stadio terminale (ESRD) non conosce la causa che ha condotto alla malattia renale cronica e può sviluppare complicanze dopo il trapianto di rene. Abbiamo eseguito uno screening genetico in 300 pazienti sottoposti a trapianto di rene o affetti da malattia renale cronica/ ESRd da causa sconosciuta, al fine di identificare la causa primaria della malattia e discriminare tra potenziali fenotipi sovrapposti. Abbiamo utilizzato un pannello personalizzato per il sequenziamento di DNA attraverso Next Generation Sequencing (tecnologia Agilent, Santa Clara, CA, USA), che includeva il gene GLA associato alla malattia di Fabry, geni che causano sindrome nefrosica e podocitopatie, geni del complemento e geni associati a collagenopatie e sindrome di Alport. Abbiamo individuato varianti patogeniche nei geni associati alla sindrome nefrosica, sindrome di Alport ed alla glomerulosclerosi focale segmentale (FSGS) in 29 pazienti su 300, risolvendo circa il 10% dei probandi. È interessante notare che abbiamo anche trovato una paziente portatrice di una nuova variante missense, c.1259C>A (p.Thr420Lys), nel gene GLA non precedentemente associato alla malattia di Fabry, che è in silico definita come probabilmente patogena e destabilizzante e associata a una lieve alterazione dell’attività enzimatica del GLA. Grazie ad una collaborazione internazionale abbiamo identificato in una coorte di pazienti affetti da podocitopatie, la presenza di anticorpi anti NPHS1, chiarendo alcuni aspetti non noti della fisiopatologia della sindrome nefrosica. L'identificazione del background genetico specifico può fornire l'opportunità di valutare il rischio di recidiva della malattia primaria, soprattutto tra i pazienti candidati che vivono con un trapianto di rene da donatore
Podocytes: the role of lysosomes in the development of nephrotic syndrome
No full textThis commentary highlights the article by Guangbi Li et al that links ceramide accumulation in podocytes to cellular damage and nephrotic syndrome
Hidden genetics behind glomerular scars: an opportunity to understand the heterogeneity of focal segmental glomerulosclerosis?
No full textFocal segmental glomerulosclerosis (FSGS) is a complex disease which describes different kinds of kidney defects, not exclusively linked with podocyte defects. Since nephrin mutation was first described in association with early-onset nephrotic syndrome (NS), many advancements have been made in understanding genetic patterns associated with FSGS. New genetic causes of FSGS have been discovered, displaying unexpected genotypes, and recognizing possible site of damage. Many recent large-scale sequencing analyses on patients affected by idiopathic chronic kidney disease (CKD), kidney failure (KF) of unknown origin, or classified as FSGS, have revealed collagen alpha IV genes, as one of the most frequent sites of pathogenic mutations. Also, recent interest in complex and systemic lysosomal storage diseases, such as Fabry disease, has highlighted GLA mutations as possible causes of FSGS. Tubulointerstitial disease, recently classified by KDIGO based on genetic subtypes, when associated with UMOD variants, may phenotypically gain FSGS features, as well as ciliopathy genes or others, otherwise leading to completely different phenotypes, but found carrying pathogenic variants with associated FSGS phenotype. Thus, glomerulosclerosis may conceal different heterogeneous conditions. When a kidney biopsy is performed, the principal objective is to provide an accurate diagnosis. The broad spectrum of phenotypic expression and genetic complexity is demonstrating that a combined path of management needs to be applied. Genetic investigation should not be reserved only to selected cases, but rather part of medical management, integrating with clinical and renal pathology records. FSGS heterogeneity should be interpreted as an interesting opportunity to discover new pathways of CKD, requiring prompt genotype-phenotype correlation. In this review, we aim to highlight how FSGS represents a peculiar kidney condition, demanding multidisciplinary management, and in which genetic analysis may solve some otherwise unrevealed idiopathic cases. Unfortunately there is not a uniform correlation between specific mutations and FSGS morphological classes, as the same variants may be identified in familial cases or sporadic FSGS/NS or manifest a variable spectrum of the same disease. These non-specific features make diagnosis challenging. The complexity of FSGS genotypes requires new directions. Old morphological classification does not provide much information about the responsible cause of disease and misdiagnoses may expose patients to immunosuppressive therapy side effects, mistaken genetic counseling, and misguided kidney transplant programs
MUSIC THERAPY REDUCES ANXIETY AND PAIN AND IMPROVES SATISFACTION IN PATIENTS UNDERGOING PERCUTANEOUS RENAL BIOPSY
No full textBACKGROUND AND AIMS
Percutaneous kidney biopsy (PRB) is an invasive procedure performed under local anaesthesia that often creates anxiety, stress and pain in the patient before, during and after the procedure. Music therapy (MT), defined as the clinical- and evidence-based use of music, is administered by a trained professional to achieve individualized goals within a therapeutic relationship between patient, music and music therapist. MT can be used as a complementary non-drug intervention to prevent and treat emotional distress and pain. The main objectives of the study were
1. evaluate the effectiveness of MT in managing anxiety, pain and satisfaction in patients undergoing PRB.
2. investigate the effect of MTI on heart rate variability (HRV).
METHOD
This study was a two-arm, single-centre, parallel-group and pre–post PRB randomized controlled trial. Patients programmed for PRB were enrolled (n = 80) and assigned to the MT intervention group (MG, n = 40) or standard treatment [control group (CG), n = 40]. MG received, from a FAMI-certified music therapist, a personalized playlist administered during the PRB, adapted to the individual patient. Patient anxiety was assessed before and after PRB using the State Y-1 Trait Anxiety Inventory (STAI-Y1). A visual analog scale (VAS) was used for self-assessment of pain (VAS-P) and satisfaction (VAS-S). Physiological stress parameters (PRE–POST) were assessed using HRV (SDNN, RMSSD, LH/HF, SD1, SD2) from E4 wristbands—Empatica Inc.1. The bracelet was placed 5 min before the patient entered the operating room for the procedure and removed after the completion of the PRB. The data of each session were divided into two segments: (1) pre, before the administration of the local anesthetic and (2) post, after the conclusion of the biopsy.
RESULTS
A statistically significant difference in anxiety levels was observed between the MG and CG groups (35.35 ± 6.208 versus 42.83 ± 9.027; P < 0.001, Fig. 1). The MG group showed significantly lower VAS-P values (4.95 ± 1.377 versus 6.28 ± 1.281; P < 0.001, Fig. 2) and higher VAS-S values (7.75 ± 0.981 versus 6.03 ± 0.800; P < 0.001) after PRB compared with the CG group (Fig. 3). The SDNN (P < 0.034), RMSDD (P < 0.04) and SD2 (P < 0.027) measurements of HRV were significantly higher in MG than in CG, while LF/HF decreased (P < 0.033).
CONCLUSION
This study supports the efficacy of MT in reducing anxiety and pain and improving satisfaction in patients undergoing PRB. MT modulates the autonomic nervous system, reducing sympathetic activity, increasing parasympathetic activity and inducing physiological relaxation
What Is Hidden in Patients with Unknown Nephropathy? Genetic Screening Could Be the Missing Link in Kidney Transplantation Diagnosis and Management.
No full textBetween 15-20% of patients with end stage renal disease (ESRD) do not know the cause of the primary kidney disease and can develop complications after kidney transplantation. We performed a genetic screening in 300 patients with kidney transplantation, or undiagnosed primary renal disease, in order to identify the primary disease cause and discriminate between overlapping phenotypes. We used a custom-made panel for next-generation sequencing (Agilent technology, Santa Clara, CA, USA), including genes associated with Fabry disease, podocytopaties, complement-mediated nephropathies and Alport syndrome-related diseases. We detected candidate diagnostic variants in genes associated with nephrotic syndrome and Focal Segmental Glomerulosclerosis (FSGS) in 29 out of 300 patients, solving about 10% of the probands. We also identified the same genetic cause of the disease (PAX2: c.1266dupC) in three family members with different clinical diagnoses. Interestingly we also found one female patient carrying a novel missense variant, c.1259C>A (p.Thr420Lys), in the GLA gene not previously associated with Fabry disease, which is in silico defined as a likely pathogenic and destabilizing, and associated with a mild alteration in GLA enzymatic activity. The identification of the specific genetic background may provide an opportunity to evaluate the risk of recurrence of the primary disease, especially among patient candidates living with a donor kidney transplant
The frequency of rare and monogenic diseases in pediatric organ transplant recipients in Italy
No full textBackground Rare diseases are chronic and life-threatening disorders affecting < 1 person every 2,000. For most of them, clinical symptoms and signs can be observed at birth or childhood. Approximately 80% of all rare diseases have a genetic background and most of them are monogenic conditions. In addition, while the majority of these diseases is still incurable, early diagnosis and specific treatment can improve patients' quality of life. Transplantation is among the therapeutic options and represents the definitive treatment for end-stage organ failure, both in children and adults. The aim of this paper was to analyze, in a large cohort of Italian patients, the main rare genetic diseases that led to organ transplantation, specifically pointing the attention on the pediatric cohort. Results To the purpose of our analysis, we considered heart, lung, liver and kidney transplants included in the Transplant Registry (TR) of the Italian National Transplantation Center in the 2002-2019 timeframe. Overall, 49,404 recipients were enrolled in the cohort, 5.1% of whom in the pediatric age. For 40,909 (82.8%) transplant recipients, a disease diagnosis was available, of which 38,615 in the adult cohort, while 8,495 patients (17.2%) were undiagnosed. There were 128 disease categories, and of these, 117 were listed in the main rare disease databases. In the pediatric cohort, 2,294 (5.6%) patients had a disease diagnosis: of the 2,126 (92.7%) patients affected by a rare disease, 1,402 (61.1%) presented with a monogenic condition. As expected, the frequencies of pathologies leading to organ failure were different between the pediatric and the adult cohort. Moreover, the pediatric group was characterized, compared to the adult one, by an overall better survival of the graft at ten years after transplant, with the only exception of lung transplants. When comparing survival considering rare vs non-rare diseases or rare and monogenic vs rare non-monogenic conditions, no differences were highlighted for kidney and lung transplants, while rare diseases had a better survival in liver as opposed to heart transplants. Conclusions This work represents the first national survey analyzing the main genetic causes and frequencies of rare and/or monogenic diseases leading to organ failure and requiring transplantation both in adults and children
Convalescent plasma therapy in aHUS patient with SARS-CoV-2 infection
No full textEndotheliosis, thrombotic microangiopathy and complement system over activation have been described as pathologic features of tissue damage in the setting of coronavirus disease. Interestingly, complement-mediated cell injury is also a typical feature of atypical Hemolytic Uremic Syndrome. Indeed, a growing body of literature has described a higher risk of microangiopathy recurrence, in aHUS patients who test positive for SARS-CoV-2. The correct clinical and therapeutic management patients with a history of HUS and SARS-CoV-2 infection is not well established.We report a case of SARS-CoV-2 infection in an aHUS patient who did not develop a recurrence of the disease and that was successfully treated with convalescent immune plasma therapy
The frequency of rare and monogenic diseases in pediatric organ transplant recipients in Italy
No full textAbstract Background Rare diseases are chronic and life-threatening disorders affecting < 1 person every 2,000. For most of them, clinical symptoms and signs can be observed at birth or childhood. Approximately 80% of all rare diseases have a genetic background and most of them are monogenic conditions. In addition, while the majority of these diseases is still incurable, early diagnosis and specific treatment can improve patients’ quality of life. Transplantation is among the therapeutic options and represents the definitive treatment for end-stage organ failure, both in children and adults. The aim of this paper was to analyze, in a large cohort of Italian patients, the main rare genetic diseases that led to organ transplantation, specifically pointing the attention on the pediatric cohort. Results To the purpose of our analysis, we considered heart, lung, liver and kidney transplants included in the Transplant Registry (TR) of the Italian National Transplantation Center in the 2002–2019 timeframe. Overall, 49,404 recipients were enrolled in the cohort, 5.1% of whom in the pediatric age. For 40,909 (82.8%) transplant recipients, a disease diagnosis was available, of which 38,615 in the adult cohort, while 8,495 patients (17.2%) were undiagnosed. There were 128 disease categories, and of these, 117 were listed in the main rare disease databases. In the pediatric cohort, 2,294 (5.6%) patients had a disease diagnosis: of the 2,126 (92.7%) patients affected by a rare disease, 1,402 (61.1%) presented with a monogenic condition. As expected, the frequencies of pathologies leading to organ failure were different between the pediatric and the adult cohort. Moreover, the pediatric group was characterized, compared to the adult one, by an overall better survival of the graft at ten years after transplant, with the only exception of lung transplants. When comparing survival considering rare vs non-rare diseases or rare and monogenic vs rare non-monogenic conditions, no differences were highlighted for kidney and lung transplants, while rare diseases had a better survival in liver as opposed to heart transplants. Conclusions This work represents the first national survey analyzing the main genetic causes and frequencies of rare and/or monogenic diseases leading to organ failure and requiring transplantation both in adults and children
The burden of Candidate pathogenic variants for kidney and genitourinary disorders emerging from exome sequencing
No full textBackground: Exome sequencing is increasingly being used for clinical diagnostics, with an impetus to expand reporting of incidental findings across a wide range of disorders. Analysis of population cohorts can help reduce risk for genetic variant misclassification and resultant unnecessary referrals to subspecialists. Objective: To examine the burden of candidate pathogenic variants for kidney and genitourinary disorders emerging from exome sequencing. Design: Secondary analysis of genetic data. Setting: A tertiary care academic medical center. Patients: A convenience sample of exome sequence data from 7974 self-declared healthy adults. Measurements: Assessment of the prevalence of candidate pathogenic variants in 625 genes associated with Mendelian kidney and genitourinary disorders. Results: Of all participants, 23.3% carried a candidate pathogenic variant, most of which were attributable to previously reported variants that had implausibly high allele frequencies. In particular, 25 genes (discovered before the creation of the Exome Aggregation Consortium, a genetic database comprising data from a large control population) accounted for 67.7% of persons with candidate pathogenic variants. After stringent filtering based on allele frequency, 1.4% of persons still had a candidate pathogenic variant, an excessive rate given the prevalence of monogenic kidney and genitourinary disorders. Manual annotation of a subset of variants showed that the majority would be classified as nonbenign under current guidelines for clinical sequence interpretation and could prompt subspecialty referrals if returned. Limitation: Limited access to health record data prevented comprehensive assessment of the phenotypic concordance with genetic diagnoses. Conclusion: Widespread reporting of incidental genetic findings related to kidney and genitourinary disorders will require stringent curation of clinical variant databases and detailed case-level review to avoid genetic misdiagnosis and unnecessary referrals. These findings motivate similar analyses for genes relevant to other medical subspecialties
De novo TRIM8 variants impair its protein localization to nuclear bodies and cause developmental delay, epilepsy, and focal segmental glomerulosclerosis
No full textFocal segmental glomerulosclerosis (FSGS) is the main pathology underlying steroid-resistant nephrotic syndrome (SRNS) and a leading cause of chronic kidney disease. Monogenic forms of pediatric SRNS are predominantly caused by recessive mutations, while the contribution of de novo variants (DNVs) to this trait is poorly understood. Using exome sequencing (ES) in a proband with FSGS/SRNS, developmental delay, and epilepsy, we discovered a nonsense DNV in TRIM8, which encodes the E3 ubiquitin ligase tripartite motif containing 8. To establish whether TRIM8 variants represent a cause of FSGS, we aggregated exome/genome-sequencing data for 2,501 pediatric FSGS/SRNS-affected individuals and 48,556 control subjects, detecting eight heterozygous TRIM8 truncating variants in affected subjects but none in control subjects (p = 3.28 × 10-11). In all six cases with available parental DNA, we demonstrated de novo inheritance (p = 2.21 × 10-15). Reverse phenotyping revealed neurodevelopmental disease in all eight families. We next analyzed ES from 9,067 individuals with epilepsy, yielding three additional families with truncating TRIM8 variants. Clinical review revealed FSGS in all. All TRIM8 variants cause protein truncation clustering within the last exon between residues 390 and 487 of the 551 amino acid protein, indicating a correlation between this syndrome and loss of the TRIM8 C-terminal region. Wild-type TRIM8 overexpressed in immortalized human podocytes and neuronal cells localized to nuclear bodies, while constructs harboring patient-specific variants mislocalized diffusely to the nucleoplasm. Co-localization studies demonstrated that Gemini and Cajal bodies frequently abut a TRIM8 nuclear body. Truncating TRIM8 DNVs cause a neuro-renal syndrome via aberrant TRIM8 localization, implicating nuclear bodies in FSGS and developmental brain disease.</p
