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BACKGROUND: Spina bifida (SB) is the second most common nonlethal congenital malformation. The existence of monogenic SB mouse models and human monogenic syndromes with SB features indicate that human SB may be caused by monogenic genes. We hypothesized that whole exome sequencing (WES) allows identification of potential candidate genes by i) generating a list of 136 candidate genes for SB, and ii) by unbiased exome-wide analysis. METHODS: We generated a list of 136 potential candidate genes from three categories: and evaluated WES data of 50 unrelated SB cases for likely deleterious variants in 136 potential candidate genes, and for potential SB candidate genes exome-wide. RESULTS: We identified 6 likely deleterious variants in 6 of the 136 potential SB candidate genes in 6 of the 50 SB cases, whereof 4 genes were derived from mouse models, 1 gene was derived from human non-syndromic SB, and 1 gene was derived from candidate genes known to cause human syndromic SB. In addition, by unbiased exome-wide analysis, we identified 12 genes as potential candidates for SB. CONCLUSIONS: Identification of these 18 potential candidate genes in larger SB cohorts will help decide which ones can be considered as novel monogenic causes of human SB.

Background Galloway-Mowat syndrome (GAMOS) is characterized by neurodevelopmental defects and a progressive nephropathy, which typically manifests as steroid-resistant nephrotic syndrome. The prognosis of GAMOS is poor, and the majority of children progress to renal failure. The discovery of monogenic causes of GAMOS has uncovered molecular pathways involved in the pathogenesis of disease. Methods Homozygosity mapping, whole-exome sequencing, and linkage analysis were used to identify mutations in four families with a GAMOS-like phenotype, and high-throughput PCR technology was applied to 91 individuals with GAMOS and 816 individuals with isolated nephrotic syndrome. In vitro and in vivo studies determined the functional significance of the mutations identified. Results Three biallelic variants of the transcriptional regulator PRDM15 were detected in six families with proteinuric kidney disease. Four families with a variant in the protein's zinc-finger (ZNF) domain have additional GAMOS-like features, including brain anomalies, cardiac defects, and skeletal defects. All variants destabilize the PRDM15 protein, and the ZNF variant additionally interferes with transcriptional activation. Morpholino oligonucleotide-mediated knockdown of Prdm15 in Xenopus embryos disrupted pronephric development. Human wild-type PRDM15 RNA rescued the disruption, but the three PRDM15 variants did not. Finally, CRISPR-mediated knockout of PRDM15 in human podocytes led to dysregulation of several renal developmental genes. Conclusions Variants in PRDM15 can cause either isolated nephrotic syndrome or a GAMOS-type syndrome on an allelic basis. PRDM15 regulates multiple developmental kidney genes, and is likely to play an essential role in renal development in humans.

The Rho family of small GTPases (Rho GTPases) are the master regulators of the actin cytoskeleton and consist of 22 members. Previous studies implicated dysregulation of Rho GTPases in podocytes in the pathogenesis of proteinuric glomerular diseases. Rho GTPases are primarily regulated by the three families of proteins; guanine nucleotide exchange factors (GEFs; 82 members), GTPase-activating proteins (GAPs; 69 members), and GDP dissociation inhibitors (GDIs; 3 members). Since the regulatory proteins far outnumber their substrate Rho GTPases and act in concert in a cell/context-dependent manner, the upstream regulatory mechanism directing Rho GTPases in podocytes is largely unknown. In this review, we summarize recent advances in the understanding of the role of Rho GTPase regulatory proteins in podocytes, including the known mutations of these proteins that cause proteinuria in humans. We also provide critical appraisal of the in vivo and in vitro studies and identify the knowledge gap in the field that will require further studies.

Introduction Steroid-resistant nephrotic syndrome (SRNS) is the second most common cause of chronic kidney disease during childhood. Identification of 63 monogenic human genes has delineated 12 distinct pathogenic pathways. Methods Here, we generated 2 independent sets of nephrotic syndrome (NS) candidate genes to augment the discovery of additional monogenic causes based on whole-exome sequencing (WES) data from 1382 families with NS. Results We first identified 63 known monogenic causes of NS in mice from public databases and scientific publications, and 12 of these genes overlapped with the 63 known human monogenic SRNS genes. Second, we used a set of 64 genes that are regulated by the transcription factor Wilms tumor 1 (WT1), which causes SRNS if mutated. Thirteen of these WT1-regulated genes overlapped with human or murine NS genes. Finally, we overlapped these lists of murine and WT1 candidate genes with our list of 120 candidate genes generated from WES in 1382 NS families, to identify novel candidate genes for monogenic human SRNS. Using this approach, we identified 7 overlapping genes, of which 3 genes were shared by all datasets, including SYNPO. We show that loss-of-function of SYNPO leads to decreased CDC42 activity and reduced podocyte migration rate, both of which are rescued by overexpression of wild-type complementary DNA (cDNA), but not by cDNA representing the patient mutation. Conclusion Thus, we identified 3 novel candidate genes for human SRNS using 3 independent, nonoverlapping hypotheses, and generated functional evidence for SYNPO as a novel potential monogenic cause of NS., Graphical abstract

Focal 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.

Introduction Most of the approximately 60 genes that if mutated cause steroid-resistant nephrotic syndrome (SRNS) are highly expressed in the glomerular podocyte, rendering SRNS a “podocytopathy.” Methods We performed whole-exome sequencing (WES) in 1200 nephrotic syndrome (NS) patients. Results We discovered homozygous truncating and homozygous missense mutation in SYNPO2 (synaptopodin-2) (p.Lys1124∗ and p.Ala1134Thr) in 2 patients with childhood-onset NS. We found SYNPO2 expression in both podocytes and mesangial cells; however, notably, immunofluorescence staining of adult human and rat kidney cryosections indicated that SYNPO2 is localized mainly in mesangial cells. Subcellular localization studies reveal that in these cells SYNPO2 partially co-localizes with α-actinin and filamin A−containing F-actin filaments. Upon transfection in mesangial cells or podocytes, EGFP-SYNPO2 co-localized with α-actinin-4, which gene is mutated in autosomal dominant SRNS in humans. SYNPO2 overexpression increases mesangial cell migration rate (MMR), whereas shRNA knockdown reduces MMR. Decreased MMR was rescued by transfection of wild-type mouse Synpo2 cDNA but only partially by cDNA representing mutations from the NS patients. The increased mesangial cell migration rate (MMR) by SYNPO2 overexpression was inhibited by ARP complex inhibitor CK666. SYNPO2 shRNA knockdown in podocytes decreased active Rac1, which was rescued by transfection of wild-type SYNPO2 cDNA but not by cDNA representing any of the 2 mutant variants. Conclusion We show that SYNPO2 variants may lead to Rac1-ARP3 dysregulation, and may play a role in the pathogenesis of nephrotic syndrome.

Background An underlying monogenic cause of early-onset chronic kidney disease (CKD) can be detected in ∼20% of individuals. For many etiologies of CKD manifesting before 25 years of age, >200 monogenic causative genes have been identified to date, leading to the elucidation of mechanisms of renal pathogenesis. Methods In 51 families with echogenic kidneys and CKD, we performed whole-exome sequencing to identify novel monogenic causes of CKD. Results We discovered a homozygous truncating mutation in the transcription factor gene transcription factor CP2-like 1 (TFCP2L1) in an Arabic patient of consanguineous descent. The patient developed CKD by the age of 2 months and had episodes of severe hypochloremic, hyponatremic and hypokalemic alkalosis, seizures, developmental delay and hypotonia together with cataracts. We found that TFCP2L1 was localized throughout kidney development particularly in the distal nephron. Interestingly, TFCP2L1 induced the growth and development of renal tubules from rat mesenchymal cells. Conversely, the deletion of TFCP2L1 in mice was previously shown to lead to reduced expression of renal cell markers including ion transporters and cell identity proteins expressed in different segments of the distal nephron. TFCP2L1 localized to the nucleus in HEK293T cells only upon coexpression with its paralog upstream-binding protein 1 (UBP1). A TFCP2L1 mutant complementary DNA (cDNA) clone that represented the patient’s mutation failed to form homo- and heterodimers with UBP1, an essential step for its transcriptional activity. Conclusion Here, we identified a loss-of-function TFCP2L1 mutation as a potential novel cause of CKD in childhood accompanied by a salt-losing tubulopathy.

ITSN1 plays an important role in brain development. Recent studies in large cohorts of subjects with neurodevelopmental disorders have identified de novo variants in ITSN1 gene thereby suggesting that this gene is involved in the development of such disorders. The aim of this study is to provide further proof of such a link. We performed trio exome sequencing in a patient presenting autism, intellectual disability, and severe behavioral difficulties. Additional affected patients with a neurodevelopmental disorder harboring a heterozygous variant in ITSN1 (NM_003024.2) were collected through a worldwide collaboration. All patients underwent detailed phenotypic and genetic assessment and data was collected and shared by healthcare givers. We identified ten novel patients from eight families with heterozygous truncating or missense variants in ITSN1 gene. In addition, four previously published patients from large meta-analysis studies were included. In total, 7/14 patients presented a de novo variant in ITSN1. All patients showed neurodevelopmental disorders from autism spectrum disorders (90%), intellectual disability (86%), and epilepsy (30%). We demonstrated that truncating variants are in the first half of ITSN1 whereas missense variants are clustered in C-terminal region. We suggest ITSN1 gene is involved in development of an autism spectrum disorder with variable additional neurodevelopmental deficiency, thus confirming the hypothesis that ITSN1 is important for brain development.

Purpose of Review: To understand the impact of kidney disease in Canada and the priority areas of kidney research that can benefit from patient-oriented, precision medicine research using novel technologies. Sources of Information: Information was collected through discussions between health care professionals, researchers, and patient partners. Literature was compiled using search engines (PubMed, PubMed central, Medline, and Google) and data from the Canadian Organ Replacement Register. Methods: We reviewed the impact, prevalence, economic burden, causes of kidney disease, and priority research areas in Canada. After reviewing the priority areas for kidney research, potential avenues for future research that can integrate precision medicine initiatives for patient-oriented research were outlined. Key Findings: Chronic kidney disease (CKD) remains among the top causes of morbidity and mortality in the world and exerts a large financial strain on the health care system. Despite the increasing number of people with CKD, funding for basic kidney research continues to trail behind other diseases. Current funding strategies favor existing clinical treatment and patient educational strategies. The identification of genetic factors for various forms of kidney disease in the adult and pediatric populations provides mechanistic insight into disease pathogenesis. Allocation of resources and funding toward existing high-yield personalized research initiatives have the potential to significantly affect patient-oriented research outcomes but will be difficult due to a constant decline of funding for kidney research. Limitations: This is an overview primarily focused on Canadian-specific literature rather than a comprehensive systematic review of the literature. The scope of our findings and conclusions may not be applicable to health care systems in other countries.

International audience; Congenital anomalies of the kidney and urinary tract (CAKUT) constitute one of the most frequent birth defects and represent the most common cause of chronic kidney disease in the first three decades of life. Despite the discovery of dozens of monogenic causes of CA-KUT, most pathogenic pathways remain elusive. We performed whole-exome sequencing (WES) in 551 individuals with CAKUT and identified a heterozygous de novo stop-gain variant in ZMYM2 in two different families with CAKUT. Through collaboration, we identified in total 14 different heterozygous loss-of-function mutations in ZMYM2 in 15 unrelated families. Most mutations occurred de novo, indicating possible interference with reproductive function. Human disease features are replicated in X. tropicalis larvae with morpho-lino knockdowns, in which expression of truncated ZMYM2 proteins, based on individual mutations, failed to rescue renal and cranio-facial defects. Moreover, heterozygous Zmym2-deficient mice recapitulated features of CAKUT with high penetrance. The ZMYM2 protein is a component of a transcriptional corepressor complex recently linked to the silencing of developmentally regulated endoge-nous retrovirus elements. Using protein-protein interaction assays, we show that ZMYM2 interacts with additional epigenetic silencing complexes, as well as confirming that it binds to FOXP1, a transcription factor that has also been linked to CAKUT. In summary, our findings establish that loss-of-function mutations of ZMYM2, and potentially that of other proteins in its interactome, as causes of human CAKUT, offering new routes for studying the pathogenesis of the disorder.

INTRODUCTION: Congenital anomalies of the kidney and urinary tract (CAKUT) are the most common cause of chronic kidney disease (~45%) that manifests before 30 years of age. The genetic locus containing COL4A1 (13q33–34) has been implicated in vesicoureteral reflux (VUR), but mutations in COL4A1 have not been reported in CAKUT. We hypothesized that COL4A1 mutations cause CAKUT in humans. METHODS: We performed whole exome sequencing (WES) in 550 families with CAKUT. As negative control cohorts we used WES sequencing data from patients with nephronophthisis (NPHP) with no genetic cause identified (n=257) and with nephrotic syndrome (NS) due to monogenic causes (n=100). RESULTS: We identified a not previously reported heterozygous missense variant in COL4A1 in three siblings with isolated VUR. When examining 549 families with CAKUT, we identified nine additional different heterozygous missense mutations in COL4A1 in 11 individuals from 11 unrelated families with CAKUT, while no COL4A1 mutations were identified in a control cohort with NPHP and only one in the cohort with NS. Most individuals (12/14) had isolated CAKUT with no extrarenal features. The predominant phenotype was VUR (9/14). There were no clinical features of the COL4A1-related disorders (e.g., HANAC syndrome, porencephaly, tortuosity of retinal arteries). Whereas COL4A1-related disorders are typically caused by glycine substitutions in the collagenous domain (84.4% of variants), only one variant in our cohort is a glycine substitution within the collagenous domain (1/10). CONCLUSION: We identified heterozygous COL4A1 mutations as a potential novel autosomal dominant cause of CAKUT that is allelic to the established COL4A1-related disorders and predominantly caused by non-glycine substitutions.

INTRODUCTION: The acronym VATER/VACTERL refers to the rare non-random association of the following component features (CFs): vertebral defects (V), anorectal malformations (ARM) (A), cardiac anomalies (C), tracheoesophageal fistula with or without esophageal atresia (TE), renal malformations (R), and limb anomalies (L). For the clinical diagnosis the presence of at least three CFs is required, individuals presenting with only two CFs have been categorized as VATER/VACTERL-like. The majority of VATER/VACTERL individuals displays a renal phenotype. Hitherto, variants in FGF8, FOXF1, HOXD13, LPP, TRAP1, PTEN and ZIC3 have been associated with the VATER/VACTERL association; however, large-scale re-sequencing could only confirm TRAP1 and ZIC3 as VATER/VACTERL disease genes, both associated with a renal phenotype. METHODS: In this study, we performed exome sequencing in 21 individuals and their families with a renal VATER/VACTERL or VATER/VACTERL-like phenotype to identify potentially novel genetic causes. RESULTS: Exome analysis identified biallelic and X-chromosomal hemizygous potentially pathogenic variants in six individuals (29%) in B9D1, FREM1, ZNF157, SP8, ACOT9, and TTLL11, respectively. The online tool GeneMatcher revealed another individual with a variant in ZNF157. CONCLUSION: Our study suggests six biallelic and X-chromosomal hemizygous VATER/VACTERL disease gene implicating all six genes in the expression of human renal malformations.

Nephrotic syndrome (NS) is a leading cause of chronic kidney disease. We found recessive NOS1AP variants in two families with early-onset NS by exome sequencing. Overexpression of wild-type (WT) NOS1AP, but not cDNA constructs bearing patient variants, increased active CDC42 and promoted filopodia and podosome formation. Pharmacologic inhibition of CDC42 or its effectors, formin proteins, reduced NOS1AP-induced filopodia formation. NOS1AP knockdown reduced podocyte migration rate (PMR), which was rescued by overexpression of WT Nos1ap but not by constructs bearing patient variants. PMR in NOS1AP knockdown podocytes was also rescued by constitutively active CDC42Q61L or the formin DIAPH3 Modeling a NOS1AP patient variant in knock-in human kidney organoids revealed malformed glomeruli with increased apoptosis. Nos1apEx3-/Ex3- mice recapitulated the human phenotype, exhibiting proteinuria, foot process effacement, and glomerulosclerosis. These findings demonstrate that recessive NOS1AP variants impair CDC42/DIAPH-dependent actin remodeling, cause aberrant organoid glomerulogenesis, and lead to a glomerulopathy in humans and mice.

The discovery of >60 monogenic causes of nephrotic syndrome (NS) has revealed a central role for the actin regulators RhoA/Rac1/Cdc42 and their effectors, including the formin INF2. By whole-exome sequencing (WES), we here discovered bi-allelic variants in the formin DAAM2 in four unrelated families with steroid-resistant NS. We show that DAAM2 localizes to the cytoplasm in podocytes and in kidney sections. Further, the variants impair DAAM2-dependent actin remodeling processes: wild-type DAAM2 cDNA, but not cDNA representing missense variants found in individuals with NS, rescued reduced podocyte migration rate (PMR) and restored reduced filopodia formation in shRNA-induced DAAM2-knockdown podocytes. Filopodia restoration was also induced by the formin-activating molecule IMM-01. DAAM2 also co-localizes and co-immunoprecipitates with INF2, which is intriguing since variants in both formins cause NS. Using invitro bulk and TIRF microscopy assays, we find that DAAM2 variants alter actin assembly activities of the formin. In a Xenopus daam2-CRISPR knockout model, we demonstrate actin dysregulation invivo and glomerular maldevelopment that is rescued by WT-DAAM2 mRNA. We conclude that DAAM2 variants are a likely cause of monogenic human SRNS due to actin dysregulation in podocytes. Further, we provide evidence that DAAM2-associated SRNS may be amenable to treatment using actin regulating compounds.

Nephrotic syndrome (NS) is a leading cause of chronic kidney disease. We found recessive

BACKGROUND: Galloway-Mowat syndrome (GAMOS) is characterized by neurodevelopmental defects and a progressive nephropathy, which typically manifests as steroid-resistant nephrotic syndrome. The prognosis of GAMOS is poor, and the majority of children progress to renal failure. The discovery of monogenic causes of GAMOS has uncovered molecular pathways involved in the pathogenesis of disease. METHODS: Homozygosity mapping, whole-exome sequencing, and linkage analysis were used to identify mutations in four families with a GAMOS-like phenotype, and high-throughput PCR technology was applied to 91 individuals with GAMOS and 816 individuals with isolated nephrotic syndrome. In vitro and in vivo studies determined the functional significance of the mutations identified. RESULTS: Three biallelic variants of the transcriptional regulator PRDM15 were detected in six families with proteinuric kidney disease. Four families with a variant in the protein’s zinc-finger (ZNF) domain have additional GAMOS-like features, including brain anomalies, cardiac defects, and skeletal defects. All variants destabilize the PRDM15 protein, and the ZNF variant additionally interferes with transcriptional activation. Morpholino oligonucleotide-mediated knockdown of Prdm15 in Xenopus embryos disrupted pronephric development. Human wild-type PRDM15 RNA rescued the disruption, but the three PRDM15 variants did not. Finally, CRISPR-mediated knockout of PRDM15 in human podocytes led to dysregulation of several renal developmental genes. CONCLUSIONS: Variants in PRDM15 can cause either isolated nephrotic syndrome or a GAMOS-type syndrome on an allelic basis. PRDM15 regulates multiple developmental kidney genes, and is likely to play an essential role in renal development in humans.

Item does not contain fulltext Steroid-resistant nephrotic syndrome (SRNS) almost invariably progresses to end-stage renal disease. Although more than 50 monogenic causes of SRNS have been described, a large proportion of SRNS remains unexplained. Recently, it was discovered that mutations of NUP93 and NUP205, encoding 2 proteins of the inner ring subunit of the nuclear pore complex (NPC), cause SRNS. Here, we describe mutations in genes encoding 4 components of the outer rings of the NPC, namely NUP107, NUP85, NUP133, and NUP160, in 13 families with SRNS. Using coimmunoprecipitation experiments, we showed that certain pathogenic alleles weakened the interaction between neighboring NPC subunits. We demonstrated that morpholino knockdown of nup107, nup85, or nup133 in Xenopus disrupted glomerulogenesis. Re-expression of WT mRNA, but not of mRNA reflecting mutations from SRNS patients, mitigated this phenotype. We furthermore found that CRISPR/Cas9 knockout of NUP107, NUP85, or NUP133 in podocytes activated Cdc42, an important effector of SRNS pathogenesis. CRISPR/Cas9 knockout of nup107 or nup85 in zebrafish caused developmental anomalies and early lethality. In contrast, an in-frame mutation of nup107 did not affect survival, thus mimicking the allelic effects seen in humans. In conclusion, we discovered here that mutations in 4 genes encoding components of the outer ring subunits of the NPC cause SRNS and thereby provide further evidence that specific hypomorphic mutations in these essential genes cause a distinct, organ-specific phenotype.

Children with genetic causes of steroid-resistant nephrotic syndrome (SRNS) usually do well after renal transplantation, while some with idiopathic SRNS show recurrence due to a putative podocyte-toxic factor. Distinguishing different forms of SRNS based on clinical criteria has been difficult. The aim of our study was to test a novel approach that allows categorization of patients into clinically useful subgroups. Seventeen patients with clinically confirmed SRNS were analyzed by next-generation sequencing (NGS) of 37 known SRNS genes and a functional assay of cultured human podocytes, which indirectly tests for toxicity of patients’ sera by evidenced loss of podocyte focal adhesion complex (FAC) number. We identified a pathogenic mutation in seven patients (41%). Sera from patients with monogenic SRNS caused mild loss of FAC number down to 73% compared to untreated controls, while sera from seven of the remaining ten patients with idiopathic SRNS caused significant FAC number loss to 43% (non-overlapping difference 30%, 95% CI 26–36%, P

Item does not contain fulltext BACKGROUND: Congenital anomalies of the kidney and urinary tract (CAKUT) are the most prevalent cause of kidney disease in the first three decades of life. Previous gene panel studies showed monogenic causation in up to 12% of patients with CAKUT. METHODS: We applied whole-exome sequencing to analyze the genotypes of individuals from 232 families with CAKUT, evaluating for mutations in single genes known to cause human CAKUT and genes known to cause CAKUT in mice. In consanguineous or multiplex families, we additionally performed a search for novel monogenic causes of CAKUT. RESULTS: In 29 families (13%), we detected a causative mutation in a known gene for isolated or syndromic CAKUT that sufficiently explained the patient's CAKUT phenotype. In three families (1%), we detected a mutation in a gene reported to cause a phenocopy of CAKUT. In 15 of 155 families with isolated CAKUT, we detected deleterious mutations in syndromic CAKUT genes. Our additional search for novel monogenic causes of CAKUT in consanguineous and multiplex families revealed a potential single, novel monogenic CAKUT gene in 19 of 232 families (8%). CONCLUSIONS: We identified monogenic mutations in a known human CAKUT gene or CAKUT phenocopy gene as the cause of disease in 14% of the CAKUT families in this study. Whole-exome sequencing provides an etiologic diagnosis in a high fraction of patients with CAKUT and will provide a new basis for the mechanistic understanding of CAKUT. 01 september 2018

Infections are a major contributor to morbidity and mortality in end-stage renal disease (ESRD) patients. A better understanding of the interplay between infectious processes and ESRD may eventually lead to the development of targeted treatment strategies aimed at lowering overall disease morbidity and mortality. Monogenic causes are a major contributor to the development of adult chronic kidney disease (CKD). Recent studies identified a genetic cause in 10% to 20% of adults with CKD. With the introduction of whole-exome sequencing (WES) into clinical mainstay, this proportion is expected to increase in the future. Once patients develop CKD/ESRD due to a genetic cause, secondary changes, such as a compromised immune status, affect overall disease progression and clinical outcomes. Stratification according to genotype may enable us to study its effects on secondary disease outcomes, such as infectious risk. Moreover, this knowledge will enable us to better understand the molecular interplay between primary disease and secondary disease outcomes.We conducted a literature review using search engines such as PubMed, PubMed central, and Medline, as well as cumulative knowledge from our respective areas of expertise.This is a transdisciplinary perspective on infectious complications in ESRD due to monogenic causes, such as autosomal dominant polycystic kidney disease (ADPKD), combining expertise in genomics and immunology.In ADPKD, infection is a frequent complication manifesting primarily as lower urinary tract infection and less frequently as renal infection. Infectious episodes may be a direct consequence of a specific underlying structural abnormality, for example the characteristic cysts, among others. However, evidence suggests that infectious disease risk is also increased in ESRD due to secondary not-well-understood disease mechanisms. These disease mechanisms may vary depending on the underlying nature of the primary disease. While the infectious disease risk is well documented in ADPKD, there are currently insufficient data on the risk in other monogenic causes of ESRD. WES in combination with novel technologies, such as RNA sequencing and single-cell RNA sequencing, can provide insight into the molecular mechanisms of disease progression in different monogenic causes of CKD/ESRD and may lead to the development of novel risk-stratification profiles in the future.This is not a systematic review of the literature and the proposed perspective is tainted by the authors' point of view on the topic.WES in combination with novel technologies such as RNA sequencing may enable us to fully unravel underlying disease mechanisms and secondary disease outcomes in monogenic causes of CKD and better characterize individual risk profiles. This understanding will hopefully facilitate the development of novel targeted therapies.Les infections contribuent largement à la morbidité et à la mortalité observées chez les patients atteints d’insuffisance rénale terminale (IRT). Une meilleure compréhension des interactions entre le processus infectieux et l’IRT pourrait éventuellement mener au développement de traitements ciblés visant la réduction de la morbidité et de la mortalité liées à la maladie. Les causes monogéniques sont en bonne partie responsables du développement de l’insuffisance rénale chronique (IRC) chez l’adulte. Des études récentes pointent vers une cause génétique dans 10 à 20 % des cas d’IRC, une proportion qui devrait s’accroître avec l’introduction du séquençage de l’exome entier (WES) comme soutien clinique principal. Lorsque les patients évoluent vers l’IRC/IRT de cause génétique, des changements secondaires, notamment un état immunologique fragilisé, affectent la progression globale de la maladie et les résultats cliniques. La stratification selon le génotype pourrait permettre d’étudier ses effets sur l’issue de pathologies secondaires comme le risque infectieux. En outre, cette information nous permettrait de mieux comprendre l’interaction moléculaire entre les résultats des pathologies primaires et secondaires.Nous avons procédé à une revue de la littérature à l’aide des moteurs de recherche PubMed, PubMed central et Medline, de même qu’avec nos connaissances cumulatives dans nos domaines d’expertise respectifs.Il s’agit d’une perspective interdisciplinaire sur les complications infectieuses en contexte d’IRT dues à des causes monogéniques, notamment une la polykystose rénale autosomique dominante (ADPKD), qui combine l’expertise en génomique et en immunologie.Les infections constituent une complication fréquente en contexte d’ADPKD et se manifestent principalement sous la forme d’une infection urinaire basse et moins souvent comme une infection rénale. Les épisodes infectieux pourraient être une conséquence directe d’une anomalie structurelle sous-jacente, notamment des kystes caractéristiques, entre autres. Toutefois, des données indiquent que le risque de maladie infectieuse en contexte d’IRT augmente aussi en raison de mécanismes secondaires mal connus; ceux-ci peuvent varier selon la nature sous-jacente de la pathologie primaire. Bien que le risque de maladie infectieuse soit bien documenté en contexte d’ADPKD, on dispose actuellement de données insuffisantes sur ce risque pour les autres causes monogéniques de l’IRT. Le WES, combiné aux nouvelles technologies telles que le séquençage d’ARN et le séquençage d’ARN unicellulaire, peut éclairer sur les mécanismes moléculaires régissant la progression de la maladie pour les différentes causes monogéniques de l’IRC/IRT et pourrait jouer un rôle dans l’élaboration de nouveaux profils de stratification des risques dans le futur.L’étude ne constitue pas une revue systématique de la littérature. De plus, la perspective proposée est teintée du point de vue des auteurs sur le sujet.Le WES, combiné aux nouvelles technologies telles que le séquençage d’ARN, pourrait nous permettre d’abord de mieux comprendre les mécanismes sous-jacents de la maladie et l’issue des pathologies secondaires des causes monogéniques de l’IRT, puis de mieux caractériser les profils de risque individuels. Ces informations, nous l’espérons, contribueront à faciliter le développement de nouveaux traitements ciblés.

A 39-year-old woman was referred to the cancer genetics outpatient clinic for a clinical diagnosis of Carney complex (CNC) in her deceased brother. The patient had some characteristic clinical features such as periorbital lentigines and coarse facial features, suggestive of CNC; however, she did not meet major diagnostic criteria for CNC. Previous extensive investigations revealed a mild insulin-like growth factor 1 elevation, a stable left adrenal gland adenoma and a slightly enlarged pituitary gland. Single gene sequencing confirmed a novel pathogenic mutation in the PRKAR1A gene. This case, to our knowledge, is the first report of this mutation identified in a family of French-Canadian origin. This report broadens our understanding of the genotypic and phenotypic spectrum of this rare disease, while it highlights the value of a multidisciplinary approach in rare diseases, for genetic testing facilitated a timely diagnosis and enabled the initiation of early surveillance of CNC-related manifestations in our patient.

Background Whole-exome sequencing (WES) finds a CKD-related mutation in approximately 20% of patients presenting with CKD before 25 years of age. Although provision of a molecular diagnosis could have important implications for clinical management, evidence is lacking on the diagnostic yield and clinical utility of WES for pediatric renal transplant recipients. Methods To determine the diagnostic yield of WES in pediatric kidney transplant recipients, we recruited 104 patients who had received a transplant at Boston Children’s Hospital from 2007 through 2017, performed WES, and analyzed results for likely deleterious variants in approximately 400 genes known to cause CKD. Results By WES, we identified a genetic cause of CKD in 34 out of 104 (32.7%) transplant recipients. The likelihood of detecting a molecular genetic diagnosis was highest for patients with urinary stone disease (three out of three individuals), followed by renal cystic ciliopathies (seven out of nine individuals), steroid-resistant nephrotic syndrome (nine out of 21 individuals), congenital anomalies of the kidney and urinary tract (ten out of 55 individuals), and chronic glomerulonephritis (one out of seven individuals). WES also yielded a molecular diagnosis for four out of nine individuals with ESRD of unknown etiology. The WES-related molecular genetic diagnosis had implications for clinical care for five patients. Conclusions Nearly one third of pediatric renal transplant recipients had a genetic cause of their kidney disease identified by WES. Knowledge of this genetic information can help guide management of both transplant patients and potential living related donors.

Ethylmalonic encephalopathy (EE) is caused by mutations in the ETHE1 gene. ETHE1 is vital for the catabolism of hydrogen sulfide (H2S). Patients with pathogenic mutations in ETHE1 have markedly increased thiosulfate, which is a reliable index of H2S levels. Accumulation of H2S is thought to cause the characteristic metabolic derangement found in EE. Recently introduced treatment strategies in EE, such as combined use of metronidazole (MNZ) and N-acetylcysteine (NAC), are aimed at lowering chronic H2S load. Experience with treatment strategies directed against acute episodes of metabolic decompensation (e.g., hemodialysis) is limited. Here we present an unusually mild, molecularly confirmed, case of EE in a 19-year-old male on chronic treatment with MNZ and NAC. During an acute episode of metabolic decompensation, we employed continuous renal replacement therapy (CRRT) to regain metabolic control. On continuous treatment with NAC and MNZ during the months preceding the acute event, plasma thiosulfate levels ranged from 1.6 to 4 μg/mL (reference range up to 2 μg/mL) and had a mean value of 2.5 μg/mL. During the acute decompensation, thiosulfate levels were 6.7 μg/mL, with hyperlactatemia and perturbed organic acid, acylglycine, and acylcarnitine profiles. CRRT decreased thiosulfate within 24 h to 1.4 μg/mL. Following discontinuation of CRRT, mean thiosulfate levels were 3.2 μg/mL (range, 2.4–3.7 μg/mL) accompanied by clinical improvement with metabolic stabilization of blood gas, acylcarnitine, organic acid, and acylglycine profiles. In conclusion, CRRT may help to regain metabolic control in patients with EE who have an acute metabolic decompensation on chronic treatment with NAC and MNZ.

Glutaric aciduria type 3 (GA3) is associated with decreased conversion of free glutaric acid to glutaryl-coA, reflecting deficiency of succinate-hydroxymethylglutarate coA-transferase, caused by variants in the SUGCT (C7orf10) gene. GA3 remains less well known, characterised and understood than glutaric aciduria types 1 and 2. It is generally considered a likely "non-disease," but this is based on limited supporting information, with only nine individuals with GA3 described in the literature. Clinicians encountering a patient with GA3 therefore still face a dilemma of whether or not this should be dismissed as irrelevant.We have identified three unrelated Canadian patients with GA3. Two came to clinical attention because of symptoms, while the third was identified by a population urine-based newborn screening programme and has so far remained asymptomatic. We describe the clinical histories, biochemical characterisation and genotypes of these individuals. Examination of allele frequencies underlines the fact that GA3 is underdiagnosed. While one probable factor is that some GA3 patients remain asymptomatic, we highlight other plausible reasons whereby this diagnosis might be overlooked.Gastrointestinal disturbances were previously reported in some GA3 patients. In one of our patients, severe episodes of cyclic vomiting were the major problem. A trial of antibiotic treatment, to minimise bacterial GA production, was followed by significant clinical improvement.At present, there is insufficient evidence to define any specific clinical phenotype as attributable to GA3. However, we consider that it would be premature to assume that this condition is completely benign in all individuals at all times.

Focal segmental glomerulosclerosis (FSGS) is frequently found in biopsies of patients with steroid resistant nephrotic syndrome (SRNS). The pathogenesis of SRNS/FSGS is often unknown and the disease will recur in up to 50% of patients post-transplant, indicating the presence of circulating podocyte-toxic factor(s). Several studies have reported clinical improvement after anti-TNFα therapy. However, prediction of the clinical outcome in SRNS/FSGS is difficult, and novel predictive biomarkers are needed. An image-based assay, which measures disassembly of focal adhesion complexes in cultured podocytes, was used to ascertain the presence of podocyte toxic activity in SRNS/FSGS sera. Expression of TNFα pathway genes was analysed in the Nephroseq FSGS cohort and in cultured podocytes treated with SRNS/FSGS sera. Podocyte toxic activity was detected in 48/96 SRNS/FSGS patients. It did not correlate with serum TNFα levels, age, sex, ethnicity or glomerular filtration rate. In ~25% of the toxic samples, the toxicity was strongly inhibited by blockade of TNFα signaling. Transcriptional profiling of human FSGS biopsies and podocytes treated with FSGS sera revealed significant increases in expression of TNFα pathway genes. We identified patients with serum podocyte toxic activity who may be at risk for FSGS recurrence, and those patients in whom serum podocyte toxicity may be reversed by TNFα blockade. Activation of TNFα pathway genes occurs in podocytes of FSGS patients suggesting a causative effect of this pathway in response to circulating factor(s). In vitro analyses of patient sera may stratify patients according to prognostic outcomes and potential responses to specific clinical interventions.

Uromodulin-associated kidney disease (UAKD) is an autosomal dominant disease caused by uromodulin (UMOD) gene mutations. This study explored genotype-phenotype correlations by examining the relationship between the type of UMOD mutation and the age at onset of ESRD.Extensive bibliographic research was used to ascertain patient-level data of all patients with UAKD published up to October 2011. Data included sex; ages at onset of hyperuricemia, gout, and ESRD; and UMOD genotype. Kaplan-Meier analysis and Cox proportional hazards models fitted with shared gamma frailty terms to adjust for within-family correlations were used to model time to event.Thirty-one peer-reviewed publications reporting on 202 patients from 74 families with 59 different UMOD mutations were included. Median ages at onset of hyperuricemia, gout, and ESRD were 24, 40, and 56 years, respectively. Men developed gout and ESRD significantly earlier than did women (age at ESRD was 50 years for men and 60 for women; P=0.04, shared frailty model). Median ages at ESRD development were lowest with Cys77Tyr (37.5 years) and highest with Gln316Pro (65.5 years) UMOD mutations. Onset of ESRD was significantly earlier with UMOD mutations located within the epidermal growth factor domains 2 and 3 (range, 45-52 years; P0.01 and 0.04, respectively) compared with the cysteine-rich domains (range, 60-65 years; by shared frailty model).The UMOD genotype is related to the clinical phenotype of UAKD. This finding may assist in counseling of patients.

In experimental membranous nephropathy, complement C5b-9 induces sublethal glomerular epithelial cell (GEC) injury and proteinuria. C5b-9 also activates mechanisms that restrict injury or facilitate recovery. The ubiquitin-proteasome system (UPS) selectively degrades damaged or abnormal proteins, while misfolded proteins in the endoplasmic reticulum (ER) undergo ER-associated degradation (ERAD). In this study, we investigated the effect of complement on the UPS and ERAD. We monitored UPS function by transfection of rat GECs with a UPS reporter, GFP(u) (CL1 degron fused with green fluorescent protein). By analogy, CD3δ-yellow fluorescent protein (YFP) was employed as a reporter of ERAD. We demonstrated decreased GFP(u) levels in GECs after incubation with antibody and complement, compared with control. Using C8-deficient serum with or without purified C8, cycloheximide (an inhibitor of protein synthesis), and the proteasome inhibitor, MG132, we confirmed that the decrease of GFP(u) was mediated by C5b-9, and subsequent proteasomal degradation of the reporter. Inhibition of the c-Jun N-terminal kinase attenuated the effect of complement on GFP(u) degradation. Complement, however, increased the level of CD3δ-YFP in GECs, implying an impairment of ERAD, likely due to an overabundance of misfolded proteins in the ER. The overall ubiquitination of proteins was enhanced in complement-treated GECs and in glomeruli of rats with experimental membranous nephropathy, although ubiquitin mRNA was unchanged in GECs. Proteasome inhibition with MG132 increased the cytotoxic effect of complement in GECs. Complement-stimulated UPS function, by accelerating removal of damaged proteins, may be a novel mechanism to limit complement-induced injury.

Aim: The aim of this study was to demonstrate the ability of widely used bioimpedance techniques to assess dry weight (DW) and to predict a state of normal hydration in haemodialysis patients whose post-dialysis weight had been gradually reduced from baseline in successive treatments over time. Methods: Calf bioimpedance spectroscopy (cBIS) was employed to determine DW (DWcBIS) as defined by flattening of an intradialytic continuously measured resistance curve and by normalized resistivity (nRho) being in the gender-specific normal range. The wECV/TBW ratio was determined by ‘classical’ wrist-to-ankle whole body bioimpedance spectroscopy (wBIS); in addition, a novel whole body model (WBM) based on wBIS was used to predict normal hydration weight (NHWWBM). Results: Twenty-one haemodialysis patients were studied; 11 ± 6 measurements were performed per patient. Nine patients reached DWcBIS (DWcBIS group), while 12 patients remained fluid-overloaded (non-DWcBIS group). Change in wECV as measured by wBIS accounted for 46 ± 23% in DWcBIS group, which was higher than in non-DWcBIS group (33 ± 48%, P

BACKGROUND: Observational studies demonstrate poor clinical outcomes in chronic haemodialysis patients with venous catheters as vascular access. This longitudinal study examines the impact of vascular access change on key clinical and laboratory parameters. METHODS: We studied 2616 haemodialysis patients who had no or one vascular access change between January 2002 and June 2003. Two hundred and seventy-one patients switched from a catheter to an arteriovenous (AV) access (AV fistula or graft) and 69 patients from an AV access to a catheter. Accesses remained unchanged in 430 patients with catheters, and in 1846 patients with an AV access, who served as controls. Levels of serum albumin, white blood cell count (WBC), enPCR, eKdrt/V, blood haemoglobin and erythropoietin dosage were obtained monthly. Data were averaged over 6 months preceding (pre) and 6 months following the access change (post). Differences between post- and pre-access change were compared to changes in respective parameters between the last and first 6 months of the study period in controls. RESULTS: The change from a catheter to an AV access was associated with a rise of serum albumin (+0.12 g/dL; P < 0.001), enPCR (+0.05 g/kg body weight/day; P = 0.001) and haemoglobin (+0.41 g/dL; P < 0.001) and a decrease in WBC (-370/microL; P = 0.048). Conversely, switching from an AV access to a catheter was followed by a significant fall in albumin (-0.11 g/dL; P = 0.035), enPCR (-0.07 g/ kg body weight/day; P = 0.001) and eKdrt/V (-0.09; P < 0.001) and a rise in erythropoietin dosage (+89 IU/kg body weight/week; P = 0.002), as compared to controls. CONCLUSION: Change from a catheter to an AV access seems to alleviate malnutrition, inflammation and anaemia. Efforts to replace catheters with fistulae or grafts should be intensified.

Cardiovascular disease is the leading cause of morbidity and mortality in maintenance hemodialysis (MHD) patients. The Transonic (TRS; Transonic Systems, Ithaca, NY) device is frequently used for determination of cardiac output (CO) by an indicator dilution technique. The Task Force Monitor (TFM; CN Systems, Graz, Austria) has gained attention as noninvasive tool for continuous beat-to-beat assessment of cardiovascular variables, including CO by impedance cardiography. Despite its use in cardiology and intensive care settings, the TFM has yet not been validated in dialysis patients. This study compares CO measurements in 12 MHD patients by TFM and TRS. Bland-Altman and regression analysis were used. CO was measured simultaneously by TRS and TFM. Average CO was 5.4 L/min by TRS and 5.0 L/min by TFM, respectively. Bland-Altman analysis revealed no significant systematic differences between the two methods (mean difference: 0.4 L/min; SD: 0.6; p > 0.05). Linear regression analysis showed significant correlation between both techniques (r = 0.802, p = 0.002). The SD of mean individual CO values was 1.1 L/min with TRS and 0.8 L/min with TFM, respectively.CO measured by TFM and TRS does not differ significantly, thus making the TFM an attractive noninvasive tool for the continuous beat-to-beat assessment of CO in MHD patients.

Focal segmental glomerular sclerosis (FSGS) is an irreversible renal pathology characterized by podocyte detachment from the glomerular basement membrane, hyalinosis, and sclerosis. Clinically, it manifests with proteinuria and progressive loss of glomerular filtration. Primary idiopathic FSGS can occur in isolation and frequently progresses to end-stage renal disease, requiring dialysis or kidney transplantation. In 30–50% of these patients, proteinuria and FSGS recur in the renal allograft, suggesting the presence of a podocyte-toxic factor(s) in the recipient's serum. Currently, there is no reliable way to quantify the serum activity or predict the subset of FSGS patients at risk for recurrence after transplantation. We describe a novel in vitro method that measures the podocyte-toxic activity of sera from FSGS patients using cultured human podocytes; we compare this with the effect of compounds such as adriamycin. Using immunofluorescence microscopy followed by computerized image-processing analysis, we show that incubation of human podocytes with adriamycin leads to a dose-dependent disassembly of focal adhesion complexes (FACs). We then demonstrate that sera from patients with posttransplant recurrent or idiopathic FSGS cause a similar FAC disturbance. In contrast, sera from nonrecurrent FSGS patients do not affect FACs. In some FSGS patients, toxic effects of serum can be prevented by blockade of the tumor necrosis factor-α pathway. We propose that this method may be useful as a diagnostic tool to identify FSGS patients with serum podocyte-toxic activity that presumably places them at increased risk for recurrence in the renal allograft.

The pursuit of evidence for the effectiveness of medical interventions was an early characteristic of western medicine. The development of scientific methods to identify the most effective treatment modalities culminated in the concepts and paradigms of evidence-based medicine (EBM) in the second half of the 20th century. The premise of Archie Cochrane, a founder of EBM, that “all treatment must be proved to be effective” is still valid today. Meanwhile, the increasing awareness that many patients do not receive the best standard of care as determined by scientific evidence raised questions on how to better assist physicians in their clinical decision making. This brought the attention to clinical practice guidelines (CPGs), which include graded recommendations developed by experts based on the quality of the available scientific evidence. CPGs are considered one of the most potential tools in helping to improve patient outcomes by providing doctors and patients with information on best-practice standards. While previous approaches for guideline development were often based on tradition or authority, the recommendations found in modern best-practice guidelines are based on standardized methods for grading quality of evidence and strength of recommendation.

Many physiological processes relate to two aspects of kidney function: (1) excretory and secretory (excretion of electrolytes and water, elimination of metabolic end products and uremic toxins, regulation of the acid-base status), and (2) endocrine functions (regulating bone and mineral metabolism and red blood cell production). Decreases in renal functions are known to be associated with shortened survival. The exact mechanisms for this are still to be elucidated but evidence in the literature suggests mechanisms such as adverse effects of accumulation of uremic toxins, fluid overload, inflammation and possibly loss of antioxidant functions. Knowledge of factors affecting decrease of residual renal function is currently based on observational data only. Possible strategies to preserve residual renal function have been suggested but require confirmation in adequately powered prospective trials to test their effectiveness.

Many physiological processes relate to two aspects of kidney function: (1) excretory and secretory (excretion of electrolytes and water, elimination of metabolic end products and uremic toxins, regulation of the acid-base status), and (2) endocrine functions (regulating bone and mineral metabolism and red blood cell production). Decreases in renal functions are known to be associated with shortened survival. The exact mechanisms for this are still to be elucidated but evidence in the literature suggests mechanisms such as adverse effects of accumulation of uremic toxins, fluid overload, inflammation and possibly loss of antioxidant functions. Knowledge of factors affecting decrease of residual renal function is currently based on observational data only. Possible strategies to preserve residual renal function have been suggested but require confirmation in adequately powered prospective trials to test their effectiveness.

Contrast induced acute kidney injury is one of the most frequent causes of hospital acquired acute kidney injury. The present study aims to investigate the efficacy of vitamin E or N-acetylcysteine as an adjunct to current standard therapy in the prevention of this clinical predicament. We tested the hypothesis that vitamin E or N-acetylcysteine added to standard therapy with 0.45 % saline is superior in preserving renal function in patients with chronic kidney disease stage 1-4 undergoing elective computer-assisted tomography with nonionic radiocontrast agents when compared to 0.45 % saline alone.Prospective, randomized, single-center, double-masked, double dummy, placebo-controlled, parallel clinical trial.The patients were randomized to either vitamin E (total dose 2160 mg i.v.) or N-acetylcysteine (total dose 4800 mg p.o.) in addition to 0.45 % saline (1 mL/kg/h over 24 h) or saline alone. Serum creatinine change between baseline and 24 h after radiocontrast was the primary outcome. Contrast induced acute kidney injury was defined as a rise in serum creatinine 25 % over the baseline value within 48 h.Thirty patients (mean age 74.6 years; 17 females; 9 diabetics; all Caucasians; mean serum creatinine 1.35 mg/dL; mean creatinine clearance 56 mL/min) were enrolled. No patient developed contrast induced acute kidney injury. There was no significant difference in serum creatinine change between the three study arms.Following radiocontrast administration, neither vitamin E nor N-acetylcystein in addition to saline demonstrated an additional beneficial effect on kidney function when compared to saline alone.

Focal segmental glomerulosclerosis (FSGS) may be associated with glomerular epithelial cell (GEC; podocyte) apoptosis due to acquired injury or mutations in specific podocyte proteins. This study addresses mediation of GEC injury, focusing on endoplasmic reticulum (ER) stress. We studied signaling in cultured GECs in the presence or absence of the extracellular matrix (ECM). Adhesion to collagen supports cell survival, but adhesion to plastic (loss of contact with ECM) leads to apoptosis. Compared with collagen-adherent cells, GECs on plastic showed increased protein misfolding in the ER, and an adaptive-protective ER stress response, including increased expression of ER chaperones, increased phosphorylation of eukaryotic translation initiation factor-2α (eIF2α), and a reduction in protein synthesis. Activation of these ER stress pathways counteracted apoptosis. However, tunicamycin (a potent stimulator of ER stress) changed the ER stress response from protective to cytotoxic, as tunicamycin induced the proapoptotic ER stress gene, C/EBP homologous protein-10, and exacerbated apoptosis in GECs adherent to plastic, but not collagen. In GECs adherent to plastic, adaptive ER stress was associated with an increase in polyubiquitinated proteins and “choking” of the proteasome. Furthermore, pharmacological inhibition of the proteasome induced ER stress in GECs. Finally, we show that ER stress (induction of ER chaperones and eIF2α phosphorylation) was evident in experimental FSGS in vivo. Thus interactions of GECs with ECM may regulate protein folding and induction of the ER stress response. FSGS is associated with induction of ER stress. Enhancing protective aspects of the ER stress response may reduce apoptosis and possibly glomerulosclerosis.

Background. Intra-dialytic morbid events (IDME) such as intra-dialytic hypotension (IDH) and muscle cramps frequently complicate haemodialysis (HD). Cardiac dysfunction is highly prevalent in HD patients. We investigated the relationship between proto-dialytic (i.e. early intra-dialytic) cardiac function and IDME in HD patients. Methods. Heart rate, beat-to-beat blood pressure (BP) and cardiac output were continuously measured during the first 30 min of dialysis treatment using the Task Force™ Monitor. Total peripheral resistance index (TPRI) was calculated from cardiac index (CI) and BP. Univariate, multivariate and logistic regression analyses were employed to relate IDME to haemodynamic predictors; Kaplan-Meier method was employed for time-to-event analysis. Results. Fourteen HD patients (age 67 ± 15 years; 7 females) were studied. Dialysis treatment was complicated by IDH and muscle cramps in 4 and 8 out of 30 sessions, respectively. CI was higher in patients without IDME (2.6 ± 0.5 L/ min/m 2 ) as compared to those with muscle cramps (2.0 ± 0.3 L/min/m 2 ) or IDH (1.8 ± 0.2 L/min/m 2 ; all P < 0.05). CI and TPRI at baseline independently predicted IDME in a multivariate regression analysis (odds ratio: 0.043 per unit of CI, 95% confidence interval: 0.003-0.611; odds ratio: 1.124 per unit of TPRI, 95% confidence interval: 1.25-1.01). Patients were stratified by tertiles of CI. IDME occurred in the two lower tertiles, whereas patients in the upper tertile were event free (log-rank test, P < 0.002). Conclusions. Low CI and high TPRI in the first 30 min of HD are associated with an increased risk of IDME.

An essential but frequently neglected aspect of dialysis treatment is the dialysis fluid produced by blending treated tap water with concentrated solutions containing electrolytes and buffer. Chemical and microbiological contaminants as well as the electrolyte and buffer composition of the dialysis fluid play major roles in the induction or modulation of morbidity associated with regular dialysis therapy.

Background Intensified insulin therapy requires outstanding compliance but no measure of therapy adherence has been agreed upon. The aim of the current study was to test the hypothesis that treatment adherence, as described by a novel multiple regression model, relates to glycosylated haemoglobin and hypoglycaemia frequency in type 1 diabetes. Furthermore, we sought to analyse the complex diurnal patterns of therapy adherence. Materials and methods Thirty type 1 diabetes patients (20 females and 10 males), treated with intensified insulin therapy, were studied in a retrospective manner. Patients were trained to follow treatment algorithms for adjusting regular insulin dosage which took into account the actual blood glucose, food intake and the time of the day. By means of multiple linear regression analysis, with regular insulin dosage as the dependent variable, blood glucose and food intake as the independent variables, the insulin treatment algorithms actually used by the individual patient were retrieved. The correlation between prescribed and implemented insulin therapy served as a measure of adherence. Metabolic control was assessed by glycosylated haemoglobin and hypoglycaemia frequency. Results Median glycosylated haemoglobin was 7·7% (range: 6·3–10·8); median monthly hypoglycaemia frequency was 3·8 (range: 0–9·8). Patients with good metabolic control (glycosylated haemoglobin

In hemodialysis patients a low body mass index (BMI) is correlated with an unfavorable clinical outcome, a phenomenon known as ‘reverse epidemiology’. Mechanisms underlying this observation are unclear. We propose the following: uremic toxin generation occurs predominantly in visceral organs and the mass of key uremiogenic viscera (gut, liver) relative to body weight is higher in small people. Consequently, the rate of uremic toxin generation per unit of BMI is higher in patients with a low BMI. Body water, mainly determined by muscle mass, serves as a dilution compartment for uremic toxins. Therefore, the concentration of uremic toxins is higher in small subjects. Uremic toxins are taken up by adipose and muscle tissues, subsequently metabolized and stored. Thus, the larger the ratio of fat and muscle mass to visceral mass, the lower the concentration of uremic toxins and the better the survival. To test this hypothesis, studies on uremic toxin kinetics in relation to body composition are needed.

Peritoneal dialysis (PD) has been used as a home dialysis therapy for renal replacement for more than 30 years. In a recent assessment of treatment quality, the mortality of patients on PD was refer