Acute kidney injury caused by ischemia and subsequent reperfusion is associated with a high rate of mortality and morbidity. Ischemia/reperfusion injury in kidney transplantation causes delayed graft ...function and is associated with more frequent episodes of acute rejection and progression to chronic allograft nephropathy. Alloantigen-independent inflammation is an important process, participating in pathogenesis of injurious response, caused by ischemia and reperfusion. This innate immune response is characterized by the activity of classical cells belonging to the immune system, such as neutrophils, macrophages, dendritic cells, lymphocytes, and also tubular epithelial cells and endothelial cells. These immune cells not only participate in inflammation after ischemia exerting detrimental influence but also play a protective role in the healing response from ischemia/reperfusion injury. Delineating of complex mechanisms of their actions could be fruitful in future prevention and treatment of ischemia/reperfusion injury. Among numerous so far conducted experiments, observed immunomodulatory role of adenosine and adenosine receptor agonists in complex interactions of dendritic cells, natural killer T cells, and T regulatory cells is emphasized as promising in the treatment of kidney ischemia/reperfusion injury. Potential pharmacological approaches which decrease NF-κB activity and antagonize mechanisms downstream of activated Toll-like receptors are discussed.
Hereditary nephropathies are clinically and genetically heterogeneous disorders. For some patients, the clinical phenotype corresponds to a specific hereditary disease but genetic testing reveals ...that the expected genotype is not present (phenocopy). The aim of this study was to evaluate the spectrum and frequency of phenocopies identified by using exome sequencing in a cohort of patients who were clinically suspected to have hereditary kidney disorders.
Cross-sectional cohort study.
174 unrelated patients were recruited for exome sequencing and categorized into 7 disease groups according to their clinical presentation. They included autosomal dominant tubulointerstitial kidney disease, Alport syndrome, congenital anomalies of the kidney and urinary tract, ciliopathy, focal segmental glomerulosclerosis/steroid-resistant nephrotic syndrome, VACTERL association, and “other.”
A genetic diagnosis (either likely pathogenic or pathogenic variant according to the guidelines of the American College of Medical Genetics) was established using exome sequencing in 52 of 174 (30%) cases. A phenocopy was identified for 10 of the 52 exome sequencing–solved cases (19%), representing 6% of the total cohort. The most frequent phenocopies (n=5) were associated with genetic Alport syndrome presenting clinically as focal segmental glomerulosclerosis/steroid-resistant nephrotic syndrome. Strictly targeted gene panels (<25 kilobases) did not identify any of the phenocopy cases.
The spectrum of described phenocopies is small. Selection bias may have altered the diagnostic yield within disease groups in our study population. The study cohort was predominantly of non-Finnish European descent, limiting generalizability. Certain hereditary kidney diseases cannot be diagnosed by using exome sequencing (eg, MUC1-autosomal dominant tubulointerstitial kidney disease).
Phenocopies led to the recategorization of disease and altered clinical management. This study highlights that exome sequencing can detect otherwise occult genetic heterogeneity of kidney diseases.
No efficient treatment exists for nephrotic syndrome (NS), a frequent cause of chronic kidney disease. Here we show mutations in six different genes (MAGI2, TNS2, DLC1, CDK20, ITSN1, ITSN2) as ...causing NS in 17 families with partially treatment-sensitive NS (pTSNS). These proteins interact and we delineate their roles in Rho-like small GTPase (RLSG) activity, and demonstrate deficiency for mutants of pTSNS patients. We find that CDK20 regulates DLC1. Knockdown of MAGI2, DLC1, or CDK20 in cultured podocytes reduces migration rate. Treatment with dexamethasone abolishes RhoA activation by knockdown of DLC1 or CDK20 indicating that steroid treatment in patients with pTSNS and mutations in these genes is mediated by this RLSG module. Furthermore, we discover ITSN1 and ITSN2 as podocytic guanine nucleotide exchange factors for Cdc42. We generate Itsn2-L knockout mice that recapitulate the mild NS phenotype. We, thus, define a functional network of RhoA regulation, thereby revealing potential therapeutic targets.
Congenital anomalies of the kidney and urinary tract (CAKUT) account for 40–50 % of chronic kidney disease that manifests in the first two decades of life. Thus far, 31 monogenic causes of isolated ...CAKUT have been described, explaining ~12 % of cases. To identify additional CAKUT-causing genes, we performed whole-exome sequencing followed by a genetic burden analysis in 26 genetically unsolved families with CAKUT. We identified two heterozygous mutations in
SRGAP1
in 2 unrelated families. SRGAP1 is a small GTPase-activating protein in the SLIT2–ROBO2 signaling pathway, which is essential for development of the metanephric kidney. We then examined the pathway-derived candidate gene
SLIT2
for mutations in cohort of 749 individuals with CAKUT and we identified 3 unrelated individuals with heterozygous mutations. The clinical phenotypes of individuals with mutations in
SLIT2
or
SRGAP1
were cystic dysplastic kidneys, unilateral renal agenesis, and duplicated collecting system. We show that
SRGAP1
is expressed in early mouse nephrogenic mesenchyme and that it is coexpressed with
ROBO2
in SIX2-positive nephron progenitor cells of the cap mesenchyme in developing rat kidney. We demonstrate that the newly identified mutations in
SRGAP1
lead to an augmented inhibition of RAC1 in cultured human embryonic kidney cells and that the
SLIT2
mutations compromise the ability of the SLIT2 ligand to inhibit cell migration. Thus, we report on two novel candidate genes for causing monogenic isolated CAKUT in humans.
Introduction. Coronavirus disease-2019 (COVID-19) usually leads to a mild infectious disease course in children, but serious neurological complications have been described in association with both ...acute infection and the multisystem inflammatory syndrome in children (MIS-C). Cerebrovascular disorders (CVD) in children are rare complication of MIS-C, and various potential mechanisms of CVD in MIS-C have been hypothesized. Case outline. In an eight-year old girl, diagnosis of MIS-C was made according to clinical features of prolonged fever, circulatory shock, heart and renal insufficiency, skin abnormalities, conjunctival hyperemia, and stomach pain associated with laboratory findings (increased CRP, D-dimers, pro BNP, troponins, IL-6), supported by positive contact with SARS-CoV2 one month before the disease onset and increased IgG and IgM anti-SARS-CoV2 antibodies. From the second day of hospitalization, left-side hemiplegia was observed, and using brain CT and MR, CVD was diagnosed. Together with cardiovascular support, corticosteroids and intravenous immunoglobulin were administered. On the fourth day of hospitalization, diagnosis of cerebral salt wasting syndrome (CSWS) was made according to severe dehydration, polyuria, hyponatremia, increased natriuria, and increased urine: serum osmolality ratio. CSWS had very severe course lasting more than one month. The girl was discharged with stable vital signs, normal diuresis and hemiparesis. Conclusion. This is the first case in the literature presenting association of severe CSWS and CVD in a child with MIS-C after COVID-19.
Congenital abnormalities of the kidney and urinary tract (CAKUT) account for approximately half of children with chronic kidney disease and they are the most frequent cause of end-stage renal disease ...in children in the US. However, its genetic etiology remains mostly elusive. VACTERL association is a rare disorder that involves congenital abnormalities in multiple organs including the kidney and urinary tract in up to 60% of the cases. By homozygosity mapping and whole-exome resequencing combined with high-throughput mutation analysis by array-based multiplex PCR and next-generation sequencing, we identified recessive mutations in the gene TNF receptor–associated protein 1 (TRAP1) in two families with isolated CAKUT and three families with VACTERL association. TRAP1 is a heat-shock protein 90–related mitochondrial chaperone possibly involved in antiapoptotic and endoplasmic reticulum stress signaling. Trap1 is expressed in renal epithelia of developing mouse kidney E13.5 and in the kidney of adult rats, most prominently in proximal tubules and in thick medullary ascending limbs of Henle’s loop. Thus, we identified mutations in TRAP1 as highly likely causing CAKUT or VACTERL association with CAKUT.
Factor H-related protein 5 (FHR-5) is a member of the complement Factor H protein family. Due to the homology to Factor H, the main complement regulator of the alternative pathway, it may also be ...implicated in the pathomechanism of kidney diseases where Factor H and alternative pathway dysregulation play a role. Here, we report the first observational study on
variations along with serum FHR-5 levels in immune complex-mediated membranoproliferative glomerulonephritis (IC-MPGN) and C3 glomerulopathy (C3G) patients together with the clinical, genetic, complement, and follow-up data.
A total of 120 patients with a histologically proven diagnosis of IC-MPGN/C3G were enrolled in the study. FHR-5 serum levels were measured in ELISA, the
gene was analyzed by Sanger sequencing, and selected variants were studied as recombinant proteins in ELISA and surface plasmon resonance (SPR).
Eight exonic
variations in 14 patients (12.6%) were observed. Serum FHR-5 levels were lower in patients compared to controls. Low serum FHR-5 concentration at presentation associated with better renal survival during the follow-up period; furthermore, it showed clear association with signs of complement overactivation and clinically meaningful clusters.
Our observations raise the possibility that the FHR-5 protein plays a fine-tuning role in the pathogenesis of IC-MPGN/C3G.
Introduction. Schimke immuno-osseous dysplasia (SIOD) is a rare autosomal recessive multisystem disorder associated with biallelic mutations of the SMAR-CAL1 gene. Vascular central nervous system ...complications in the form of Moyamoya syndrome (MMS) have been reported as a comorbidity in nearly half of the patients clinically presenting with severe migraine-like headaches, transient ischemic attacks (TIA), and ischemic or hemorrhagic infarctions. We present an illustrative case of an infantile form of SIOD with MMS, with a review of the latest diagnostic possibilities, as well as current diagnostic and therapeutic dilemmas in managing SIOD. Case report. We present a female patient with the infantile form of SIOD. The proband was born small for gestational age in the 34th gestation week with characteristic dysmorphic features. Genetic testing found a biallelic, nonsense mutation c.2542G>T in the SMARCAL1 gene. The patient presented early with TIA, seizures, and recurrent ischemic strokes. Magnetic resonance imaging (MRI) confirmed the presence of progressive brain atrophy with bilateral occlusion/stenosis of middle cerebral artery and anterior cerebral artery and a smoke-like collateral vessel appearance consistent with the MMS. At the age of 5 years and 9 months, the patient developed a high fever and cough with unknown cause, with a low erythrocyte and white blood cell count during four weeks, with a poor therapeutic response to antibiotics, transfusion of red blood cells, and granulocyte growth factor. She later died. Conclusion. Patients with SIOD may present progressive cerebral vascular changes and clinical neurologic deterioration early in the course of the disease. In such patients, early diagnosis and preventive revascularization surgery are of paramount importance. In diagnosing MMS, MRI angiography can be an appropriate substitute for standard invasive cerebral angiography.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, ODKLJ, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Disease-causing variants in
COL4A3-
5 are associated with type-IV-collagen-related nephropathy, a genetically and phenotypically multifaceted disorder comprising Alport syndrome (AS) and thin ...basement membrane nephropathy (TBMN) and autosomal, X-linked and a proposed digenic inheritance. Initial symptoms of individuals with AS are microscopic hematuria followed by proteinuria leading to kidney failure (90% on dialysis < age 40 years). In contrast, individuals with TBMN, an outdated histology-derived term, present with microscopic hematuria, only some of them develop kidney failure (>50 years of age). An early diagnosis of type-IV-collagen-related nephropathy is essential for optimized therapy and slowing of the disease. Sixty index cases, in whom exome sequencing had been performed and with disease-causing variant(s) in
COL4A3-5
, were evaluated concerning their clinical tentative diagnosis and their genotype. Of 60 reevaluated individuals with type-IV-collagen-related nephropathy, 72% had AS, 23% TBMN and 5% focal segmental glomerulosclerosis (FSGS) as clinical tentative diagnosis. The FSGS cases had to be re-classified as having type-IV-collagen-related nephropathy. Twelve percent of cases had AS as clinical tentative diagnosis and a monoallelic disease-causing variant in
COL4A3/4
but could not be classified as autosomal dominant AS because of limited or conflicting clinical data. This study illustrates the complex clinical and genetic picture of individuals with a type IV-collagen-related nephropathy indicating the need of a refined nomenclature and the more interdisciplinary teamwork of clinicians and geneticists as the key to optimized patient care.
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