Thomas Kitzler

McGill University Health Centre · Medicine Clinic

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-...

Background and objectives: 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. Design, setting, participants & measurements: Extensi...

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...

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 ad...

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. Lit...

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 lis...

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...

The acronym VATER/VACTERL refers to the rare nonrandom 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...

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 pathway...

p>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 s...

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 o...

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 loc...

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 addition...

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 1,200 NS patients. Results We discovered homozygous truncating and homozygous missense mutation in...

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 echogeni...

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 fact...

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 CAKUT, most pathogenic pathways remain elusive. We performed whole-exome sequencing (W...

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 mutati...

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 cli...

Purpose of review 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...

Approximately 500 monogenic causes of chronic kidney disease (CKD) have been identified, mainly in pediatric populations. The frequency of monogenic causes among adults with CKD has been less extensively studied. To determine the likelihood of detecting monogenic causes of CKD in adults presenting to nephrology services in Ireland, we conducted who...

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 transpl...

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...

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 com...

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 familie...

Background: 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...

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 consi...

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 Coch...

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...

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 reticulu...

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. Calf bioimpedance spectroscopy (cBIS) was employed to deter...

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. Heart rate, beat-to-beat blood...

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. We studied 2616 haemodialysis patients who had no or one vascular access change between January 2002 and...

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 modulat...

Few controversies in medicine have such a long history as that of whether salt is identifiably dangerous or not dangerous. The most common reported association between excess dietary salt intake and clinical outcome has been in the field of hypertension, but dietary sodium intake mediates effects that go far beyond, and are independent of, extracel...

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 n...

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...

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) rela...

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 referenced as being higher than of those on hemodialysis. Several reports suggest that a high proportion of PD patients are overhydrated. Clinical assessment...