ABSTRACT
DNASE1L3 is an extracellular nuclease that digests chromatin released from apoptotic cells. DNASE1L3 mutations impair the enzyme function, enhance autoantibody production and type I interferon (IFN-I) responses, and cause different autosomal recessive phenotypes ranging from hypocomplementemic urticarial vasculitis syndrome to full-blown systemic lupus erythematosus (SLE). Kidney involvement in patients with DNASE1L3 mutations is poorly characterised. Herein, we describe the clinical course of three children with monogenic SLE due to DNASE1L3 mutations who developed refractory glomerulonephritis leading to kidney failure. They had different renal histopathological patterns (i.e., membranous, endo- and extra-capillary glomerulonephritis and thrombotic microangiopathy), all belonging to the lupus nephritis (LN) spectrum. One patient had a mixed phenotype, showing an overlap between SLE and ANCA-associated vasculitis. Using immunofluorescence, we detected glomerular expression of the IFN I-induced human myxovirus resistance protein 1 (MXA), which was particularly evident in glomerular endothelial cells. 2/3 patients had increased expression of interferon-stimulated genes in the peripheral blood and all three patients had reduced serum DNAse activity. Our findings suggest that DNASE1L3-related glomerulonephritis can be included in the spectrum of IFN I-mediated kidney disorders, and provide the rationale for IFN I-directed therapies in order to improve the poor outcome of this rare condition.
ABSTRACT
OBJECTIVE: Novel mRNA-based vaccines have been proven to be powerful tools in combating the global pandemic caused by SARS-CoV-2 protecting individuals, especially the immunocompromised, from COVID-19. Still, it remains largely unknown how solid organ transplant and different immunosuppressive medications affect development of vaccine-induced immunity. METHODS: In this work, we monitored humoral and cellular memory responses after mRNA SARS-CoV-2 two-doses and booster doses vaccination in cystic fibrosis lung transplanted patients (CFT) and compared them with both cystic fibrosis patients without lung transplant (CF) and with kidney transplant recipients (KT). In particular, we investigated the effects of immunosuppressive regimens on immune memory to SARS-CoV-2 after mRNA SARS-CoV-2 vaccine in transplanted patients. RESULTS: Our results showed that immunocompromised transplanted patients displayed a weak cellular and humoral memory to SARS-CoV-2 mRNA vaccination. In addition, obtained data clearly demonstrate that immunosuppressive therapy regimen including antimetabolites, further reduces patients' ability to respond to vaccination at both humoral and cell-mediated level. Notably, patient treated with antimetabolites showed a lower humoral and cellular response also after a booster dose vaccination. CONCLUSION: These results, even if obtained on a small patient's cohort, question whether immunocompromised patients need interventions to improve vaccine SARS-CoV-2 mRNA vaccine response such as additional jab or modulation of immunosuppressive therapy.
Subject(s)
Antibodies, Viral , COVID-19 Vaccines , COVID-19 , Immunity, Cellular , Immunity, Humoral , Immunocompromised Host , Immunosuppressive Agents , SARS-CoV-2 , Transplant Recipients , Humans , COVID-19/immunology , COVID-19/prevention & control , SARS-CoV-2/immunology , Male , Female , Immunosuppressive Agents/therapeutic use , COVID-19 Vaccines/immunology , COVID-19 Vaccines/administration & dosage , Antibodies, Viral/immunology , Antibodies, Viral/blood , Adult , Vaccination , Middle Aged , Cystic Fibrosis/immunology , Immunologic Memory , Organ Transplantation/adverse effects , Kidney Transplantation/adverse effects , Lung Transplantation/adverse effects , Immunization, SecondaryABSTRACT
Podocytopathies are glomerular disorders in which podocyte injury drives proteinuria and progressive kidney disease. They encompass a broad spectrum of aetiologies, resulting in pathological pictures of minimal-changes, focal segmental glomerulosclerosis, diffuse mesangial sclerosis or collapsing glomerulopathy. Despite improvement in classifying podocytopathies as a distinct group of disorders, the histological definition fails to capture the relevant biological heterogeneity underlying each case, manifesting as extensive variability in disease progression and response to therapies. Increasing evidence suggests that podocytopathies can result from a single causative factor or a combination of multiple genetic and/or environmental risk factors with different relative contributions, identifying complex physiopathological mechanisms. Consequently, the diagnosis can still be challenging. In recent years, significant advances in genetic, microscopy and biological techniques revolutionized our understanding of the molecular mechanisms underlying podocytopathies, pushing nephrologists to integrate innovative information with more conventional data obtained from kidney biopsy in the diagnostic workflow. In this review, we will summarize current approaches in the diagnosis of podocytopathies, focusing on strategies aimed at elucidating the aetiology underlying the histological picture. We will provide several examples of an integrative view of traditional concepts and new data in patients with suspected podocytopathies, along with a perspective on how a reclassification could help to improve not only diagnostic pathways and therapeutic strategies, but also the management of disease recurrence after kidney transplantation. In the future, the advantages of precision medicine will probably allow diagnostic trajectories to be increasingly focused, maximizing therapeutic results and long-term prognosis.
ABSTRACT
Bartter (BS) and Gitelman (GS) syndrome are autosomal recessive inherited tubulopathies, whose clinical diagnosis can be challenging, due to rarity and phenotypic overlap. Genotype-phenotype correlations have important implications in defining kidney and global outcomes. The aim of our study was to assess the diagnostic rate of whole-exome sequencing (WES) coupled with a bioinformatic analysis of copy number variations in a population of 63 patients with BS and GS from a single institution, and to explore genotype-phenotype correlations. We obtained a diagnostic yield of 86% (54/63 patients), allowing disease reclassification in about 14% of patients. Although some clinical and laboratory features were more commonly reported in patients with BS or GS, a significant overlap does exist, and age at onset, preterm birth, gestational age and nephro-calcinosis are frequently misleading. Finally, chronic kidney disease (CKD) occurs in about 30% of patients with BS or GS, suggesting that the long-term prognosis can be unfavorable. In our cohort the features associated with CKD were lower gestational age at birth and a molecular diagnosis of BS, especially BS type 1. The results of our study demonstrate that WES is useful in dealing with the phenotypic heterogeneity of these disorders, improving differential diagnosis and genotype-phenotype correlation.
Subject(s)
Bartter Syndrome , Gitelman Syndrome , Premature Birth , Renal Insufficiency, Chronic , Bartter Syndrome/diagnosis , Bartter Syndrome/genetics , DNA Copy Number Variations , Female , Gitelman Syndrome/diagnosis , Gitelman Syndrome/genetics , Humans , Infant, NewbornABSTRACT
Plasma DNA fragmentomics is an emerging area in cell-free DNA diagnostics and research. In murine models, it has been shown that the extracellular DNase, DNASE1L3, plays a role in the fragmentation of plasma DNA. In humans, DNASE1L3 deficiency causes familial monogenic systemic lupus erythematosus with childhood onset and anti-dsDNA reactivity. In this study, we found that human patients with DNASE1L3 disease-associated gene variations showed aberrations in size and a reduction of a "CC" end motif of plasma DNA. Furthermore, we demonstrated that DNA from DNASE1L3-digested cell nuclei showed a median length of 153 bp with CC motif frequencies resembling plasma DNA from healthy individuals. Adeno-associated virus-based transduction of Dnase1l3 into Dnase1l3-deficient mice restored the end motif profiles to those seen in the plasma DNA of wild-type mice. Our findings demonstrate that DNASE1L3 is an important player in the fragmentation of plasma DNA, which appears to act in a cell-extrinsic manner to regulate plasma DNA size and motif frequency.
Subject(s)
DNA/genetics , Endodeoxyribonucleases/genetics , Lupus Erythematosus, Systemic/genetics , Mutation , Animals , Case-Control Studies , DNA/blood , DNA Fragmentation , Dependovirus/genetics , Dependovirus/metabolism , Disease Models, Animal , Endodeoxyribonucleases/deficiency , Endodeoxyribonucleases/metabolism , Genetic Therapy , Genetic Vectors/chemistry , Genetic Vectors/metabolism , Humans , Lupus Erythematosus, Systemic/enzymology , Lupus Erythematosus, Systemic/pathology , Mice , Mice, Transgenic , Substrate Specificity , Transduction, GeneticABSTRACT
Noninvasive tools for diagnosis or prediction of acute kidney allograft rejection have been extensively investigated in recent years. Biochemical and molecular analyses of blood and urine provide a liquid biopsy that could offer new possibilities for rejection prevention, monitoring, and therefore, treatment. Nevertheless, these tools are not yet available for routine use in clinical practice. In this systematic review, MEDLINE was searched for articles assessing urinary biomarkers for diagnosis or prediction of kidney allograft acute rejection published in the last five years (from January 1, 2015 to May 31, 2020). This review follows the Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) guidelines. Articles providing targeted or unbiased urine sample analysis for the diagnosis or prediction of both acute cellular and antibody-mediated kidney allograft rejection were included, analyzed, and graded for methodological quality with a particular focus on study design and diagnostic test accuracy measures. Urinary C-X-C motif chemokine ligands were the most promising and frequently studied biomarkers. The combination of precise diagnostic reference in training sets with accurate validation in real-life cohorts provided the most relevant results and exciting groundwork for future studies.
Subject(s)
Graft Rejection/diagnosis , Graft Rejection/urine , Kidney Transplantation , Kidney/metabolism , Allografts , Biomarkers/urine , Humans , Kidney/pathologyABSTRACT
Observation that 1,25-Dihydroxyvitamin-D3 has an immunomodulatory effect on innate and adaptive immunity raises the possible effect on clinical graft outcome. Aim of this study was to evaluate the correlation of biopsy-proven acute rejection, CMV infection, BKV infection, with 1,25-Dihydroxyvitamin-D3 deficiency and the benefit of calcitriol supplementation before and during the transplantation. Risk factors and kidney graft function were also evaluated. All RTRs received induction therapy with basiliximab, cyclosporine, mycophenolic acid, and steroids. During the first year, the incidence of BPAR (4% vs 11%, P=.04), CMV infection (3% vs 9%, P=.04), and BKV infection (6% vs 19%, P=.04) was significantly lower in users compared to controls. By multivariate Cox regression analysis, 1,25-Dihydroxyvitamin-D3 deficiency and no calcitriol exposure were independent risk factors for BPAR (HR=4.30, P<.005 and HR=3.25, P<.05), for CMV infection (HR=2.33, P<.05 and HR=2.31, P=.001), and for BKV infection (HR=2.41, P<.05 and HR=2.45, P=.001). After one year, users had a better renal function: eGFR was 62.5±6.7 mL/min vs 51.4±7.6 mL/min (P<.05). Only one user developed polyomavirus-associated nephropathy vs 15 controls. Two users lost their graft vs 11 controls. 1,25(OH)2-D3 deficiency circulating levels increased the risk of BPAR, CMV infection, BKV infection after kidney transplantation. Administration of calcitriol is a way to obtain adequate 1,25(OH)2-D3 circulating levels.
Subject(s)
Calcitriol/deficiency , Cytomegalovirus Infections/etiology , Graft Rejection/etiology , Kidney Transplantation , Polyomavirus Infections/etiology , Postoperative Complications/etiology , Vitamin D Deficiency/complications , Administration, Oral , Adult , Aged , Biomarkers/blood , Calcitriol/blood , Calcitriol/therapeutic use , Cytomegalovirus Infections/epidemiology , Cytomegalovirus Infections/prevention & control , Female , Follow-Up Studies , Graft Rejection/epidemiology , Graft Rejection/prevention & control , Humans , Incidence , Male , Middle Aged , Polyomavirus Infections/epidemiology , Polyomavirus Infections/prevention & control , Postoperative Complications/epidemiology , Postoperative Complications/prevention & control , Proportional Hazards Models , Retrospective Studies , Risk Factors , Treatment Outcome , Vitamin D Deficiency/blood , Vitamin D Deficiency/diagnosis , Vitamin D Deficiency/drug therapy , Vitamins/therapeutic useABSTRACT
The role of anti-human leukocyte antigens DQ region (HLA-DQ) in transplantation is historically less studied than HLA-DR and HLA class I regions, but several studies are demonstrating that anti HLA-DQ antibodies are among the most frequent anti HLA antibodies that develop after transplantation and can have great influence on the developing of humoral rejection and graft loss. In this article we review the gene structure and nomenclature of the HLA-DQ region, the role of anti HLA-DQ antibodies after and before transplantation and briefly the associations of particular HLA-DQ alleles and other diseases.
Subject(s)
HLA-DQ Antigens/immunology , Isoantibodies/immunology , Kidney Transplantation/adverse effects , Transplantation Immunology , Graft Rejection/immunology , Graft Rejection/physiopathology , Graft Survival/immunology , Histocompatibility Testing , Humans , Kidney Transplantation/methods , Prognosis , Risk Assessment , Tissue Donors , Transplant Recipients , Transplantation Tolerance/immunologyABSTRACT
We report our experience with five patients, with dialysis dependent AKI and multiple myeloma (MM). Two of them were already suffering from a mild degree of renal insufficiency, one was on follow-up for smouldering MM and two had a relapse of symptomatic MM. Median concentration of the involved FLC (iFLC) was 15104 mg/L (range 1196-24384). All patients underwent three times per week HCO-HD for 6 hour sessions using Theralite 2100 (median 10, range 6-13 sessions) with one having further twelve sessions of 4 hours using SUPRA device (Bellco). In addition, they followed a bortezomib and dexamethasone regimen according to a bi-weekly schedule (3-5 cycles) plus Thalidomide. iFLC concentrations were measured by immunonephelometry in blood at the beginning of each dialysis session. All patients but one, showed a very good partial hematological response. The only exception demonstrated a partial response. iFLCs decreased between 72,8% and 99,7% in a median period of three weeks. After 6 months three patients underwent autologous stem-cell transplantation (ASCT), one of whom repeated the procedure 6 months later. In conclusion, three patients became dialysis independent at the end of the HCO-HD period, one patient became dialysis independent three months later and one remained dialysis dependent. Recovery of renal function in 4 out of 5 patients with a very good hematological response is a consequence of an early and fast removal of the iFLC joined to an efficient therapeutic regimen.
Subject(s)
Acute Kidney Injury/etiology , Acute Kidney Injury/therapy , Immunoglobulin Light Chains , Multiple Myeloma/complications , Renal Dialysis , Aged , Female , Humans , Male , Middle Aged , Renal Dialysis/methodsABSTRACT
BACKGROUND: The reliability of kidney biopsy as the sole means for assessing kidneys from extended-criteria donors (ECDs) to be allocated to single or dual transplantation is still a matter of debate. METHODS: We compared retrospectively 3 years graft survival and renal function in 44 recipients of a single kidney graft from a marginal donor with good renal function and a Karpinski histological score of ≤ 3 and 56 recipients of a single transplant with a Karpinski score of 4 or 5. The donors' and recipients' characteristics were compared by means of Wilcoxon's rank-sum test and Fisher's exact test, and survival was analysed using the log-rank test and Cox regression survival analysis. RESULTS: The donors with the worse histological scores were slightly younger (68.0 ± 4.74 versus 71.3 ± 4.6 years, P < 0.01) and had a higher glomerular filtration rate (85.8 ± 28.2 versus 76.3 ± 26.53 mL/min, P = 0.013), but there was no difference in serum creatinine levels (0.83 ± 0.24 versus 0.85 ± 0.30 mg/dL, P = 0.381). Three years after transplantation, there was no difference between the two groups in terms of recipient serum creatinine levels (1.94 ± 0.69 versus 1.74 ± 0.49 mg/dL, P = 0.134), estimated glomerular filtration rate (eGFR, 45.6 ± 21.1 versus 51.7 ± 22.0 mL/min, P = 0.331) or the rates of graft loss (27.3 versus 35.7%, P = 0.47), delayed graft function or acute rejection. CONCLUSIONS: In our experience, provided the donor has a normal renal function, a difference in the pre-transplant histological score of kidneys from marginal cadaveric donors do not have a significant influence on the outcome 3 years after transplantation. Our findings might represent a basis for designing a randomized controlled trial of using a higher histological score threshold for the DKT allocation of grafts from ECDs with a normal renal function.