Publications by authors named "Thomas M Kitzler"

26 Publications

  • Page 1 of 1

Recessive Mutations in as a Candidate of Monogenic Nephrotic Syndrome.

Kidney Int Rep 2021 Feb 10;6(2):472-483. Epub 2020 Nov 10.

Department of Pediatrics, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA.

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 (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 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. shRNA knockdown in podocytes decreased active Rac1, which was rescued by transfection of wild-type 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.
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http://dx.doi.org/10.1016/j.ekir.2020.10.040DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7879128PMC
February 2021

Generation of Monogenic Candidate Genes for Human Nephrotic Syndrome Using 3 Independent Approaches.

Kidney Int Rep 2021 Feb 3;6(2):460-471. Epub 2020 Dec 3.

Department of Pediatrics, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA.

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 . We show that loss-of-function of 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 as a novel potential monogenic cause of NS.
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http://dx.doi.org/10.1016/j.ekir.2020.11.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7879125PMC
February 2021

Mutations in Are a Novel Cause of Galloway-Mowat Syndrome.

J Am Soc Nephrol 2021 Mar 16;32(3):580-596. Epub 2021 Feb 16.

Department of Medicine, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts

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. and studies determined the functional significance of the mutations identified.

Results: Three biallelic variants of the transcriptional regulator 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 embryos disrupted pronephric development. Human wild-type RNA rescued the disruption, but the three variants did not. Finally, CRISPR-mediated knockout of in human podocytes led to dysregulation of several renal developmental genes.

Conclusions: Variants in 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.
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http://dx.doi.org/10.1681/ASN.2020040490DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7920168PMC
March 2021

Recessive variants impair actin remodeling and cause glomerulopathy in humans and mice.

Sci Adv 2021 Jan 1;7(1). Epub 2021 Jan 1.

Department of Medicine, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.

Nephrotic syndrome (NS) is a leading cause of chronic kidney disease. We found recessive variants in two families with early-onset NS by exome sequencing. Overexpression of wild-type (WT) , 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. knockdown reduced podocyte migration rate (PMR), which was rescued by overexpression of WT but not by constructs bearing patient variants. PMR in knockdown podocytes was also rescued by constitutively active or the formin Modeling a patient variant in knock-in human kidney organoids revealed malformed glomeruli with increased apoptosis. mice recapitulated the human phenotype, exhibiting proteinuria, foot process effacement, and glomerulosclerosis. These findings demonstrate that recessive variants impair CDC42/DIAPH-dependent actin remodeling, cause aberrant organoid glomerulogenesis, and lead to a glomerulopathy in humans and mice.
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http://dx.doi.org/10.1126/sciadv.abe1386DOI Listing
January 2021

De novo TRIM8 variants impair its protein localization to nuclear bodies and cause developmental delay, epilepsy, and focal segmental glomerulosclerosis.

Am J Hum Genet 2021 02 27;108(2):357-367. Epub 2021 Jan 27.

Division of Nephrology, Columbia University, New York, NY 10032, USA. Electronic address:

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). In all six cases with available parental DNA, we demonstrated de novo inheritance (p = 2.21 × 10). 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.
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http://dx.doi.org/10.1016/j.ajhg.2021.01.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7895901PMC
February 2021

DAAM2 Variants Cause Nephrotic Syndrome via Actin Dysregulation.

Am J Hum Genet 2020 12 23;107(6):1113-1128. Epub 2020 Nov 23.

Department of Pediatrics, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA. Electronic address:

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 in vitro 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 in vivo 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.
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http://dx.doi.org/10.1016/j.ajhg.2020.11.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7820625PMC
December 2020

Rho GTPase regulatory proteins in podocytes.

Kidney Int 2021 02 26;99(2):336-345. Epub 2020 Oct 26.

Division of Nephrology, McGill University Health Centre, Montreal, Quebec, Canada; Research Institute, McGill University Health Centre, Montreal, Quebec, Canada. Electronic address:

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.
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http://dx.doi.org/10.1016/j.kint.2020.08.035DOI Listing
February 2021

Mutations in transcription factor CP2-like 1 may cause a novel syndrome with distal renal tubulopathy in humans.

Nephrol Dial Transplant 2021 01;36(2):237-246

Division of Nephrology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.

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.
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http://dx.doi.org/10.1093/ndt/gfaa215DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7834595PMC
January 2021

Mutations of the Transcriptional Corepressor ZMYM2 Cause Syndromic Urinary Tract Malformations.

Authors:
Dervla M Connaughton Rufeng Dai Danielle J Owen Jonathan Marquez Nina Mann Adda L Graham-Paquin Makiko Nakayama Etienne Coyaud Estelle M N Laurent Jonathan R St-Germain Lot Snijders Blok Arianna Vino Verena Klämbt Konstantin Deutsch Chen-Han Wilfred Wu Caroline M Kolvenbach Franziska Kause Isabel Ottlewski Ronen Schneider Thomas M Kitzler Amar J Majmundar Florian Buerger Ana C Onuchic-Whitford Mao Youying Amy Kolb Daanya Salmanullah Evan Chen Amelie T van der Ven Jia Rao Hadas Ityel Steve Seltzsam Johanna M Rieke Jing Chen Asaf Vivante Daw-Yang Hwang Stefan Kohl Gabriel C Dworschak Tobias Hermle Mariëlle Alders Tobias Bartolomaeus Stuart B Bauer Michelle A Baum Eva H Brilstra Thomas D Challman Jacob Zyskind Carrie E Costin Katrina M Dipple Floor A Duijkers Marcia Ferguson David R Fitzpatrick Roger Fick Ian A Glass Peter J Hulick Antonie D Kline Ilona Krey Selvin Kumar Weining Lu Elysa J Marco Ingrid M Wentzensen Heather C Mefford Konrad Platzer Inna S Povolotskaya Juliann M Savatt Natalia V Shcherbakova Prabha Senguttuvan Audrey E Squire Deborah R Stein Isabelle Thiffault Victoria Y Voinova Michael J G Somers Michael A Ferguson Avram Z Traum Ghaleb H Daouk Ankana Daga Nancy M Rodig Paulien A Terhal Ellen van Binsbergen Loai A Eid Velibor Tasic Hila Milo Rasouly Tze Y Lim Dina F Ahram Ali G Gharavi Heiko M Reutter Heidi L Rehm Daniel G MacArthur Monkol Lek Kristen M Laricchia Richard P Lifton Hong Xu Shrikant M Mane Simone Sanna-Cherchi Andrew D Sharrocks Brian Raught Simon E Fisher Maxime Bouchard Mustafa K Khokha Shirlee Shril Friedhelm Hildebrandt

Am J Hum Genet 2020 10 4;107(4):727-742. Epub 2020 Sep 4.

Department of Pediatrics, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA. Electronic address:

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 (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 morpholino knockdowns, in which expression of truncated ZMYM2 proteins, based on individual mutations, failed to rescue renal and craniofacial 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 endogenous 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.
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http://dx.doi.org/10.1016/j.ajhg.2020.08.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7536580PMC
October 2020

COL4A1 mutations as a potential novel cause of autosomal dominant CAKUT in humans.

Hum Genet 2019 Oct 22;138(10):1105-1115. Epub 2019 Jun 22.

Department of Medicine, Boston Children's Hospital, Enders 561, Harvard Medical School, 300 Longwood Avenue, Boston, MA, 02115, USA.

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. 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). 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). 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.
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http://dx.doi.org/10.1007/s00439-019-02042-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6745245PMC
October 2019

Monogenic causes of chronic kidney disease in adults.

Kidney Int 2019 04 14;95(4):914-928. Epub 2019 Feb 14.

Department of Medicine, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA. Electronic address:

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 whole exome sequencing (WES) in a multi-centre cohort of 114 families including 138 affected individuals with CKD. Affected adults were recruited from 78 families with a positive family history, 16 families with extra-renal features, and 20 families with neither a family history nor extra-renal features. We detected a pathogenic mutation in a known CKD gene in 42 of 114 families (37%). A monogenic cause was identified in 36% of affected families with a positive family history of CKD, 69% of those with extra-renal features, and only 15% of those without a family history or extra-renal features. There was no difference in the rate of genetic diagnosis in individuals with childhood versus adult onset CKD. Among the 42 families in whom a monogenic cause was identified, WES confirmed the clinical diagnosis in 17 (40%), corrected the clinical diagnosis in 9 (22%), and established a diagnosis for the first time in 16 families referred with CKD of unknown etiology (38%). In this multi-centre study of adults with CKD, a molecular genetic diagnosis was established in over one-third of families. In the evolving era of precision medicine, WES may be an important tool to identify the cause of CKD in adults.
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http://dx.doi.org/10.1016/j.kint.2018.10.031DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6431580PMC
April 2019

Whole-Exome Sequencing Enables a Precision Medicine Approach for Kidney Transplant Recipients.

J Am Soc Nephrol 2019 02 17;30(2):201-215. Epub 2019 Jan 17.

Division of Nephrology,

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.
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http://dx.doi.org/10.1681/ASN.2018060575DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6362619PMC
February 2019

Acute and Chronic Management in an Atypical Case of Ethylmalonic Encephalopathy.

JIMD Rep 2019 23;45:57-63. Epub 2018 Oct 23.

Department of Medical Genetics, McGill University Health Centre, Montreal, QC, Canada.

Ethylmalonic encephalopathy (EE) is caused by mutations in the ETHE1 gene. ETHE1 is vital for the catabolism of hydrogen sulfide (HS). Patients with pathogenic mutations in ETHE1 have markedly increased thiosulfate, which is a reliable index of HS levels. Accumulation of HS 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 HS 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.
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http://dx.doi.org/10.1007/8904_2018_136DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6336558PMC
October 2018

Mutations in multiple components of the nuclear pore complex cause nephrotic syndrome.

J Clin Invest 2018 10 4;128(10):4313-4328. Epub 2018 Sep 4.

Department of Medicine, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA.

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.
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http://dx.doi.org/10.1172/JCI98688DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6159964PMC
October 2018

Whole-Exome Sequencing Identifies Causative Mutations in Families with Congenital Anomalies of the Kidney and Urinary Tract.

J Am Soc Nephrol 2018 09 24;29(9):2348-2361. Epub 2018 Aug 24.

Department of Medicine, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts;

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.
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http://dx.doi.org/10.1681/ASN.2017121265DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6115658PMC
September 2018

Use of genomic and functional analysis to characterize patients with steroid-resistant nephrotic syndrome.

Pediatr Nephrol 2018 10 7;33(10):1741-1750. Epub 2018 Jul 7.

Division of Nephrology, The Montreal Children's Hospital, McGill University Health Center, 1001 Boulevard Décarie, Room EM1.2232, Montreal, Quebec, H4A 3J1, Canada.

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 approach that allows categorization of patients into clinically useful subgroups.

Methods: 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.

Results: 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 < 0.001). All patients with recurrent SRNS (n = 4) in the graft showed absence of podocyte gene mutations but significant FAC loss. Three patients had no mutation nor serum podocyte toxicity.

Conclusions: Our approach allowed categorization of patients into three subgroups: (1) patients with monogenic SRNS; (2) patients with idiopathic SRNS and marked serum podocyte toxicity; and (3) patients without identifiable genetic cause nor evidence of serum podocyte toxicity. Post-transplant SRNS recurrence risk appears to be low in groups 1 and 3, but high in group 2.
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http://dx.doi.org/10.1007/s00467-018-3995-2DOI Listing
October 2018

Glutaric Aciduria Type 3: Three Unrelated Canadian Cases, with Different Routes of Ascertainment.

JIMD Rep 2018 2;39:89-96. Epub 2017 Aug 2.

Department of Medical Genetics, McGill University Health Centre (MUHC), Montreal, QC, Canada.

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.
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http://dx.doi.org/10.1007/8904_2017_49DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5953897PMC
August 2017

Association between genotype and phenotype in uromodulin-associated kidney disease.

Clin J Am Soc Nephrol 2013 Aug 30;8(8):1349-57. Epub 2013 May 30.

Renal Research Institute, 207 East 94th Street, New York, NY 10128, USA.

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: 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.

Results: 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; P<0.01 and 0.04, respectively) compared with the cysteine-rich domains (range, 60-65 years; by shared frailty model).

Conclusions: The UMOD genotype is related to the clinical phenotype of UAKD. This finding may assist in counseling of patients.
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http://dx.doi.org/10.2215/CJN.11151012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3731914PMC
August 2013

Factors affecting loss of residual renal function(s) in dialysis.

Contrib Nephrol 2012 25;178:150-156. Epub 2012 May 25.

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.
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http://dx.doi.org/10.1159/000337836DOI Listing
October 2012

Efficacy of vitamin E and N-acetylcysteine in the prevention of contrast induced kidney injury in patients with chronic kidney disease: a double blind, randomized controlled trial.

Wien Klin Wochenschr 2012 May 24;124(9-10):312-9. Epub 2012 Apr 24.

Department of Human Genetics, The Research Institute of the McGill University Health Centre at The Montreal Children's Hospital, McGill University, H3Z 2Z3, Montreal, QC, Canada.

Background: 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.

Design: Prospective, randomized, single-center, double-masked, double dummy, placebo-controlled, parallel clinical trial.

Methods: 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.

Results: 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.

Conclusion: 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.
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http://dx.doi.org/10.1007/s00508-012-0169-2DOI Listing
May 2012

Complement modulates the function of the ubiquitin-proteasome system and endoplasmic reticulum-associated degradation in glomerular epithelial cells.

Biochim Biophys Acta 2012 May 8;1823(5):1007-16. Epub 2012 Mar 8.

Department of Medicine, McGill University Health Centre, McGill University, Montreal, Quebec, Canada.

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.
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http://dx.doi.org/10.1016/j.bbamcr.2012.03.001DOI Listing
May 2012

Endoplasmic reticulum stress in glomerular epithelial cell injury.

Am J Physiol Renal Physiol 2011 Sep 15;301(3):F496-508. Epub 2010 Dec 15.

Department of Medicine, McGill University Health Centre, McGill University, Montreal, Quebec, Canada.

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.
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http://dx.doi.org/10.1152/ajprenal.00728.2010DOI Listing
September 2011

Proto-dialytic cardiac function relates to intra-dialytic morbid events.

Nephrol Dial Transplant 2011 May 5;26(5):1645-51. Epub 2010 Oct 5.

Department of Internal Medicine, Krankenhaus der Barmherzigen Brüder, Marschallgasse 12, A-8020 Graz, Austria.

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.
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http://dx.doi.org/10.1093/ndt/gfq599DOI Listing
May 2011

Impact of switch of vascular access type on key clinical and laboratory parameters in chronic haemodialysis patients.

Nephrol Dial Transplant 2009 Jul 19;24(7):2194-200. Epub 2009 Feb 19.

Renal Research Institute, New York, NY, USA.

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.
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http://dx.doi.org/10.1093/ndt/gfp052DOI Listing
July 2009

Salt: its role in chronic kidney disease.

J Ren Nutr 2008 Jan;18(1):18-26

Renal Research Institute, New York, New York 10128, USA.

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, extracellular fluid expansion and elevation in blood pressure. For nephrologists, clinical trials that demonstrate no negative outcome of a high salt diet in the general population are thus not particularly assuasive, because patients with chronic kidney disease (CKD) represent an entity that is by no means comparable to the general population. This review takes a look at the challenges associated with salt balance in CKD patients (particularly at K/DOQI stage 5), followed by a summary of current concepts believed to play a part in salt-mediated pathophysiology, and the conclusion, based on the present state of scientific knowledge, that it appears advisable to advocate low dietary salt intake in this patient population.
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http://dx.doi.org/10.1053/j.jrn.2007.10.006DOI Listing
January 2008

Noninvasive measurement of cardiac output in hemodialysis patients by task force monitor: a comparison with the Transonic System.

ASAIO J 2007 Sep-Oct;53(5):561-5

Renal Research Institute, New York, NY 10128, USA.

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.
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http://dx.doi.org/10.1097/MAT.0b013e31812e6a90DOI Listing
October 2007