Publications by authors named "Peter Lavin"

24 Publications

  • Page 1 of 1

Renal transplant outcomes in patients with autosomal dominant tubulointerstitial kidney disease.

Clin Transplant 2020 02 5;34(2):e13783. Epub 2020 Feb 5.

Nephrology Department, Beaumont Hospital, Dublin, Ireland.

Introduction: Autosomal dominant tubulointerstitial kidney disease (ADTKD) is a rare genetic cause of chronic kidney disease (CKD) and end-stage renal disease (ESRD). We aimed to compare renal transplant outcomes in people with ESRD due to ADTKD to those with other causes of renal failure.

Methods: Patients with clinical characteristics consistent with ADTKD by the criteria outlined in the 2015 KDIGO consensus were included. We compared ADTKD transplant outcomes with those of 4633 non-ADTKD renal transplant recipients.

Results: We included 31 patients who met diagnostic criteria for ADTKD in this analysis, 23 of whom had an identified mutation (28 were categorized as definite-ADTKD and 3 as suspected ADTKD). Five patients received a second transplant during follow-up. In total, 36 grafts were included. We did not identify significant differences between groups in terms of graft or patient survival after transplantation. Twenty-five transplant biopsies were performed during follow-up, and none of these showed signs of recurrent ADTKD post-transplant.

Conclusion: In patients with ESRD due to ADTKD, we demonstrate that transplant outcomes are comparable with the general transplant population. There is no evidence that ADTKD can recur after transplantation.
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http://dx.doi.org/10.1111/ctr.13783DOI Listing
February 2020

Utility of Genomic Testing after Renal Biopsy.

Am J Nephrol 2020 10;51(1):43-53. Epub 2019 Dec 10.

Department of Nephrology and Transplantation, Beaumont Hospital, Dublin, Ireland.

Background: Renal biopsy is the mainstay of renal pathological diagnosis. Despite sophisticated diagnostic techniques, it is not always possible to make a precise pathological diagnosis. Our aim was to identify a genetic cause of disease in patients who had undergone renal biopsy and determine if genetic testing altered diagnosis or treatment.

Methods: Patients with suspected familial kidney disease underwent a variety of next-generation sequencing (NGS) strategies. The subset of these patients who had also undergone native kidney biopsy was identified. Histological specimens were reviewed by a consultant pathologist, and genetic and pathological diagnoses were compared.

Results: Seventy-five patients in 47 families underwent genetic sequencing and renal biopsy. Patients were grouped into 5 diagnostic categories based on pathological diagnosis: tubulointerstitial kidney disease (TIKD; n = 18); glomerulonephritis (GN; n = 15); focal segmental glomerulosclerosis and Alport Syndrome (n = 11); thrombotic microangiopathy (TMA; n = 17); and nonspecific pathological changes (n = 14). Thirty-nine patients (52%) in 21 families (45%) received a genetic diagnosis; 13 cases (72%) with TIKD, 4 (27%) with GN, 6 (55%) with focal segmental glomerulosclerosis/Alport syndrome, and 10 (59%) with TMA and 6 cases (43%) with nonspecific features. Genetic testing resulted in changes in understanding of disease mechanism in 21 individuals (54%) in 12 families (57%). Treatment would have been altered in at least 26% of cases (10/39).

Conclusions: An accurate genetic diagnosis can result in changes in clinical diagnosis, understanding of pathological mechanism, and treatment. NGS should be considered as a complementary diagnostic technique to kidney biopsy in the evaluation of patients with kidney disease.
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http://dx.doi.org/10.1159/000504869DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6957728PMC
February 2021

Monogenic causes of chronic kidney disease in adults.

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

National Paediatric Haemodialysis Centre and Renal Transplant Unit, Temple Street Children's University Hospital, Dublin, Ireland.

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

Spectrum of rhabdomyolysis in an acute hospital.

Ir J Med Sci 2019 Nov 24;188(4):1423-1426. Epub 2019 Jan 24.

Department of Nephrology, Tallaght University Hospital, Dublin 24, Ireland.

Rhabdomyolysis is a state of muscle necrosis with the hallmark being elevated creatine kinase that may cause acute kidney injury with serious consequences. It happens in many clinical settings. We sought to investigate all cases of rhabdomyolysis admitted to an acute hospital in Ireland over one calendar year. All cases of rhabdomyolysis admitted to a tertiary hospital over a 12-month period were reviewed. It was defined as serum creatine kinase greater than five times upper limit normal. The incidence, presenting characteristics and clinical outcomes, was collected from electronic records, electronic consult system and discharge summaries. Rhabdomyolysis was observed in 306 (1.7%) of all 18,297 admissions. It was seen most commonly in the setting of acute coronary syndrome (19.6%), post-operative state (18.0%), long-term confinement in the same position (16.3%), infection (9.2%) and seizures (6.5%). Overall mortality in this group was 16%. Acute kidney injury occurred in 43% of patients. Those with severe acute kidney injury (stage 3) had a mortality of 50%. Length of stay was significantly prolonged in the presence of acute kidney injury (p < 0.001). Surprisingly, in 44% of those with acute kidney injury, nephrology advice was not requested. Rhabdomyolysis is a common and a serious clinical condition across many specialties in an acute hospital that would likely benefit from nephrology involvement should acute kidney injury supervene.
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http://dx.doi.org/10.1007/s11845-019-01968-yDOI Listing
November 2019

Noninvasive Immunohistochemical Diagnosis and Novel Mutations Causing Autosomal Dominant Tubulointerstitial Kidney Disease.

J Am Soc Nephrol 2018 09 2;29(9):2418-2431. Epub 2018 Jul 2.

Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, Massachusetts.

Background: Autosomal dominant tubulointerstitial kidney disease caused by mucin-1 gene () mutations (ADTKD-) is characterized by progressive kidney failure. Genetic evaluation for ADTKD- specifically tests for a cytosine duplication that creates a unique frameshift protein (MUC1fs). Our goal was to develop immunohistochemical methods to detect the MUC1fs created by the cytosine duplication and, possibly, by other similar frameshift mutations and to identify novel mutations in individuals with positive immunohistochemical staining for the MUC1fs protein.

Methods: We performed MUC1fs immunostaining on urinary cell smears and various tissues from ADTKD-positive and -negative controls as well as in individuals from 37 ADTKD families that were negative for mutations in known ADTKD genes. We used novel analytic methods to identify frameshift mutations.

Results: After technique refinement, the sensitivity and specificity for MUC1fs immunostaining of urinary cell smears were 94.2% and 88.6%, respectively. Further genetic testing on 17 families with positive MUC1fs immunostaining revealed six families with five novel frameshift mutations that all predict production of the identical MUC1fs protein.

Conclusions: We developed a noninvasive immunohistochemical method to detect MUC1fs that, after further validation, may be useful in the future for diagnostic testing. Production of the MUC1fs protein may be central to the pathogenesis of ADTKD-.
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http://dx.doi.org/10.1681/ASN.2018020180DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6115665PMC
September 2018

Kidney transplant outcomes in familial C3 glomerulopathy.

Clin Kidney J 2016 Jun 14;9(3):403-7. Epub 2016 Apr 14.

Department of Nephrology, Beaumont Hospital, Dublin, Ireland; Royal College of Surgeons in Ireland, Dublin, Ireland.

C3 glomerulopathy, a newly designated entity, is characterized by glomerular disease associated with dysregulation of the alternative complement pathway and is a rare cause of end-stage kidney disease. Overall disease characteristics that include clinical presentation, laboratory assessment, histopathology and genetic background have only been unravelled in recent years and have led to the development of anti-complement therapies targeting different levels of the alternative pathway. We describe the long-term outcomes following kidney transplantation in an Irish family with familial C3 glomerulopathy due to a hybrid CFHR3-1 gene.
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http://dx.doi.org/10.1093/ckj/sfw020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4886915PMC
June 2016

Unusual cause of loin pain.

Kidney Int 2015 Sep;88(3):644

Department of Radiology, Tallaght Hospital, Dublin, Ireland.

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http://dx.doi.org/10.1038/ki.2014.418DOI Listing
September 2015

The Irish Kidney Gene Project--Prevalence of Family History in Patients with Kidney Disease in Ireland.

Nephron 2015 18;130(4):293-301. Epub 2015 Jul 18.

Department of Nephrology and Transplantation, Beaumont Hospital, Dublin, Ireland.

Background: The prevalence of kidney disease (KD) due to inherited genetic conditions in Ireland is unknown. The aim of this study was to characterise an adult kidney disease population in Ireland and to identify familial clusters of kidney disease within the population.

Methods: This was a multicenter cross-sectional study of patients with kidney disease in the Republic of Ireland, from January 2014 to September 2014, recruiting from dialysis units and out-patient renal departments. A survey was performed by collecting data on etiology of kidney disease and whether a family history of kidney disease exists. Medical records were cross-referenced to confirm the etiology of kidney disease.

Results: A total of 1,840 patients were recruited with a mean age of 55.9 years (range 17-94.5) and a male predominance (n = 1,095; 59.5%). A positive family history was reported by 629 participants (34.2%). Excluding polycystic kidney disease (n = 134, 7.3%), a positive family history was reported by 495 participants (26.9%). Kidney disease due to an unknown etiology was the commonest etiology in the non-polycystic kidney disease group with a positive family history (10.6%, n = 67). Kidney diseases that are not classically associated with familial inheritance including tubulo-interstitial kidney disease, congenital abnormalities of the kidney and urinary tract and glomerulonephritis demonstrated familial clustering.

Conclusion: In an Irish non-polycystic kidney disease population, 26.9% reports a positive family history. The commonest etiology of kidney disease in the positive family history cohort, excluding autosomal dominant polycystic kidney disease, was kidney disease due to unknown etiology. Examining families with kidney disease provides an opportunity to better understand disease pathogenesis and potentially identify genetic predispositions to kidney disease.
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http://dx.doi.org/10.1159/000436983DOI Listing
May 2016

A novel missense mutation of Wilms' Tumor 1 causes autosomal dominant FSGS.

J Am Soc Nephrol 2015 Apr 21;26(4):831-43. Epub 2014 Aug 21.

Division of Nephrology, Departments of Medicine, Duke Molecular Physiology Institute,

FSGS is a clinical disorder characterized by focal scarring of the glomerular capillary tuft, podocyte injury, and nephrotic syndrome. Although idiopathic forms of FSGS predominate, recent insights into the molecular and genetic causes of FSGS have enhanced our understanding of disease pathogenesis. Here, we report a novel missense mutation of the transcriptional regulator Wilms' Tumor 1 (WT1) as the cause of nonsyndromic, autosomal dominant FSGS in two Northern European kindreds from the United States. We performed sequential genome-wide linkage analysis and whole-exome sequencing to evaluate participants from family DUK6524. Subsequently, whole-exome sequencing and direct sequencing were performed on proband DNA from family DUK6975. We identified multiple suggestive loci on chromosomes 6, 11, and 13 in family DUK6524 and identified a segregating missense mutation (R458Q) in WT1 isoform D as the cause of FSGS in this family. The identical mutation was found in family DUK6975. The R458Q mutation was not found in 1600 control chromosomes and was predicted as damaging by in silico simulation. We depleted wt1a in zebrafish embryos and observed glomerular injury and filtration defects, both of which were rescued with wild-type but not mutant human WT1D mRNA. Finally, we explored the subcellular mechanism of the mutation in vitro. WT1(R458Q) overexpression significantly downregulated nephrin and synaptopodin expression, promoted apoptosis in HEK293 cells and impaired focal contact formation in podocytes. Taken together, these data suggest that the WT1(R458Q) mutation alters the regulation of podocyte homeostasis and causes nonsyndromic FSGS.
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http://dx.doi.org/10.1681/ASN.2013101053DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4378093PMC
April 2015

Phosphodiesterase 5 inhibition ameliorates angiontensin II-induced podocyte dysmotility via the protein kinase G-mediated downregulation of TRPC6 activity.

Am J Physiol Renal Physiol 2014 Jun 16;306(12):F1442-50. Epub 2014 Apr 16.

Division of Nephrology, Duke University Medical Center, Durham, North Carolina; Center for Human Genetics, Duke University Medical Center, Durham, North Carolina;

The emerging role of the transient receptor potential cation channel isotype 6 (TRPC6) as a central contributor to various pathological processes affecting podocytes has generated interest in the development of therapeutics to modulate its function. Recent insights into the regulation of TRPC6 have revealed PKG as a potent negative modulator of TRPC6 conductance and associated signaling via its phosphorylation at two highly conserved amino acid residues: Thr(69)/Thr(70) (Thr(69) in mice and Thr(70) in humans) and Ser(321)/Ser(322) (Ser(321) in mice and Ser(322) in humans). Here, we tested the role of PKG in modulating TRPC6-dependent responses in primary and conditionally immortalized mouse podocytes. TRPC6 was phosphorylated at Thr(69) in nonstimulated podocytes, but this declined upon ANG II stimulation or overexpression of constitutively active calcineurin phosphatase. ANG II induced podocyte motility in an in vitro wound assay, and this was reduced 30-60% in cells overexpressing a phosphomimetic mutant TRPC6 (TRPC6T70E/S322E) or activated PKG (P < 0.05). Pretreatment of podocytes with the PKG agonists S-nitroso-N-acetyl-dl-penicillamine (nitric oxide donor), 8-bromo-cGMP, Bay 41-2772 (soluble guanylate cyclase activator), or phosphodiesterase 5 (PDE5) inhibitor 4-{[3',4'-(methylenedioxy)benzyl]amino}[7]-6-methoxyquinazoline attenuated ANG II-induced Thr(69) dephosphorylation and also inhibited TRPC6-dependent podocyte motility by 30-60%. These data reveal that PKG activation strategies, including PDE5 inhibition, ameliorate ANG II-induced podocyte dysmotility by targeting TRPC6 in podocytes, highlighting the potential therapeutic utility of these approaches to treat hyperactive TRPC6-dependent glomerular disease.
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http://dx.doi.org/10.1152/ajprenal.00212.2013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4059973PMC
June 2014

Prevention of sudden cardiac death in hemodialysis patients.

Cardiovasc Hematol Disord Drug Targets 2014 ;14(3):195-204

Trinity Health Kidney Centre, Tallaght Hospital, Trinity College, Dublin, Ireland.

One quarter of all hemodialysis patients will succumb to sudden cardiac death (SCD), a rate far exceeding that observed in the general population. A high prevalence of atherosclerotic coronary artery disease amongst patients with end-stage kidney disease (ESKD) partly explains this exaggerated risk. However, uremia and dialysis related factors are also of critical importance. Interventions aimed at preventing SCD have been inadequately studied in patients with ESKD. Data extrapolated from non-renal populations cannot necessarily be applied to hemodialysis patients, who possess relatively unique risk factors for SCD including "uremic cardiomyopathy", electrolyte shifts, fluctuations in intravascular volume and derangements of mineral and bone metabolism. Pending data derived from proposed randomized controlled clinical trials, critical appraisal of existing evidence and the selective application of guidelines developed for the general population to dialysis patients are required if therapeutic nihilism, or excessive intervention, are to be avoided. We discuss the evidence supporting a role for medical therapies, dialysis prescription refinements, revascularization procedures and electrical therapies as potential interventions to prevent SCD amongst hemodialysis patients. Based on current best available evidence, we present suggested strategies for the prevention of arrhythmia-mediated death in this highly vulnerable patient population.
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http://dx.doi.org/10.2174/1871529x14666140401112956DOI Listing
June 2015

Mutations in the gene that encodes the F-actin binding protein anillin cause FSGS.

J Am Soc Nephrol 2014 Sep 27;25(9):1991-2002. Epub 2014 Mar 27.

Center for Human Genetics, Duke University Medical Center, Durham, North Carolina; Medicine, and.

FSGS is characterized by segmental scarring of the glomerulus and is a leading cause of kidney failure. Identification of genes causing FSGS has improved our understanding of disease mechanisms and points to defects in the glomerular epithelial cell, the podocyte, as a major factor in disease pathogenesis. Using a combination of genome-wide linkage studies and whole-exome sequencing in a kindred with familial FSGS, we identified a missense mutation R431C in anillin (ANLN), an F-actin binding cell cycle gene, as a cause of FSGS. We screened 250 additional families with FSGS and found another variant, G618C, that segregates with disease in a second family with FSGS. We demonstrate upregulation of anillin in podocytes in kidney biopsy specimens from individuals with FSGS and kidney samples from a murine model of HIV-1-associated nephropathy. Overexpression of R431C mutant ANLN in immortalized human podocytes results in enhanced podocyte motility. The mutant anillin displays reduced binding to the slit diaphragm-associated scaffold protein CD2AP. Knockdown of the ANLN gene in zebrafish morphants caused a loss of glomerular filtration barrier integrity, podocyte foot process effacement, and an edematous phenotype. Collectively, these findings suggest that anillin is important in maintaining the integrity of the podocyte actin cytoskeleton.
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http://dx.doi.org/10.1681/ASN.2013090976DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4147982PMC
September 2014

C3 glomerulopathy: consensus report.

Kidney Int 2013 Dec 30;84(6):1079-89. Epub 2013 Oct 30.

Centre for Complement and Inflammation Research, Imperial College London, London, UK.

C3 glomerulopathy is a recently introduced pathological entity whose original definition was glomerular pathology characterized by C3 accumulation with absent or scanty immunoglobulin deposition. In August 2012, an invited group of experts (comprising the authors of this document) in renal pathology, nephrology, complement biology, and complement therapeutics met to discuss C3 glomerulopathy in the first C3 Glomerulopathy Meeting. The objectives were to reach a consensus on: the definition of C3 glomerulopathy, appropriate complement investigations that should be performed in these patients, and how complement therapeutics should be explored in the condition. This meeting report represents the current consensus view of the group.
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http://dx.doi.org/10.1038/ki.2013.377DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3842953PMC
December 2013

TNXB mutations can cause vesicoureteral reflux.

J Am Soc Nephrol 2013 Jul 25;24(8):1313-22. Epub 2013 Apr 25.

Divisions of Nephrology, Duke University Medical Center, Durham, NC 27710, USA.

Primary vesicoureteral reflux (VUR) is the most common congenital anomaly of the kidney and the urinary tract, and it is a major risk factor for pyelonephritic scarring and CKD in children. Although twin studies support the heritability of VUR, specific genetic causes remain elusive. We performed a sequential genome-wide linkage study and whole-exome sequencing in a family with hereditary VUR. We obtained a significant multipoint parametric logarithm of odds score of 3.3 on chromosome 6p, and whole-exome sequencing identified a deleterious heterozygous mutation (T3257I) in the gene encoding tenascin XB (TNXB in 6p21.3). This mutation segregated with disease in the affected family as well as with a pathogenic G1331R change in another family. Fibroblast cell lines carrying the T3257I mutation exhibited a reduction in both cell motility and phosphorylated focal adhesion kinase expression, suggesting a defect in the focal adhesions that link the cell cytoplasm to the extracellular matrix. Immunohistochemical studies revealed that the human uroepithelial lining of the ureterovesical junction expresses TNXB, suggesting that TNXB may be important for generating tensile forces that close the ureterovesical junction during voiding. Taken together, these results suggest that mutations in TNXB can cause hereditary VUR.
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http://dx.doi.org/10.1681/ASN.2012121148DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3736717PMC
July 2013

A hybrid CFHR3-1 gene causes familial C3 glomerulopathy.

J Am Soc Nephrol 2012 Jul 24;23(7):1155-60. Epub 2012 May 24.

Centre for Complement and Inflammation Research, Imperial College, London, United Kingdom.

Controlled activation of the complement system, a key component of innate immunity, enables destruction of pathogens with minimal damage to host tissue. Complement factor H (CFH), which inhibits complement activation, and five CFH-related proteins (CFHR1-5) compose a family of structurally related molecules. Combined deletion of CFHR3 and CFHR1 is common and confers a protective effect in IgA nephropathy. Here, we report an autosomal dominant complement-mediated GN associated with abnormal increases in copy number across the CFHR3 and CFHR1 loci. In addition to normal copies of these genes, affected individuals carry a unique hybrid CFHR3-1 gene. In addition to identifying an association between these genetic observations and complement-mediated kidney disease, these results provide insight into the protective role of the combined deletion of CFHR3 and CFHR1 in IgA nephropathy.
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http://dx.doi.org/10.1681/ASN.2012020166DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3380655PMC
July 2012

Arhgap24 inactivates Rac1 in mouse podocytes, and a mutant form is associated with familial focal segmental glomerulosclerosis.

J Clin Invest 2011 Oct 12;121(10):4127-37. Epub 2011 Sep 12.

Department of Pathology, Barnes-Jewish Hospital, St. Louis, Missouri 63110, USA.

The specialized epithelial cell of the kidney, the podocyte, has a complex actin-based cytoskeleton. Dynamic regulation of this cytoskeleton is required for efficient barrier function of the kidney. Podocytes are a useful cell type to study the control of the actin cytoskeleton in vivo, because disruption of components of the cytoskeleton results in podocyte damage, cell loss, and a prototypic injury response called focal segmental glomerulosclerosis (FSGS). Searching for actin regulatory proteins that are expressed in podocytes, we identified a RhoA-activated Rac1 GTPase-activating protein (Rac1-GAP), Arhgap24, that was upregulated in podocytes as they differentiated, both in vitro and in vivo. Increased levels of active Rac1 and Cdc42 were measured in Arhgap24 knockdown experiments, which influenced podocyte cell shape and membrane dynamics. Consistent with a role for Arhgap24 in normal podocyte functioning in vivo, sequencing of the ARHGAP24 gene in patients with FSGS identified a mutation that impaired its Rac1-GAP activity and was associated with disease in a family with FSGS. Thus, Arhgap24 contributes to the careful balancing of RhoA and Rac1 signaling in podocytes, the disruption of which may lead to kidney disease.
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http://dx.doi.org/10.1172/JCI46458DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3195463PMC
October 2011

Inverted formin 2 mutations with variable expression in patients with sporadic and hereditary focal and segmental glomerulosclerosis.

Kidney Int 2012 Jan 24;81(1):94-9. Epub 2011 Aug 24.

Department of Pediatrics, Duke University Medical Center, Durham, North Carolina 27710, USA.

Focal and segmental glomerulosclerosis (FSGS) is a major cause of end-stage kidney disease. Recent advances in molecular genetics show that defects in the podocyte play a major role in its pathogenesis and mutations in inverted formin 2 (INF2) cause autosomal dominant FSGS. In order to delineate the role of INF2 mutations in familial and sporadic FSGS, we sought to identify variants in a large cohort of patients with FSGS. A secondary objective was to define an approach for genetic screening in families with autosomal dominant disease. A total of 248 individuals were identified with FSGS, of whom 31 had idiopathic disease. The remaining patients clustered into 64 families encompassing 15 from autosomal recessive and 49 from autosomal dominant kindreds. There were missense mutations in 8 of the 49 families with autosomal dominant disease. Three of the detected variants were novel and all mutations were confined to exon 4 of INF2, a regulatory region responsible for 90% of all changes reported in FSGS due to INF2 mutations. Thus, in our series, INF2 mutations were responsible for 16% of all cases of autosomal dominant FSGS, with these mutations clustered in exon 4. Hence, screening for these mutations may represent a rapid, non-invasive and cost-effective method for the diagnosis of autosomal dominant FSGS.
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http://dx.doi.org/10.1038/ki.2011.297DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3694501PMC
January 2012

TORCing up the importance of calcium signaling.

J Am Soc Nephrol 2011 Aug 14;22(8):1391-3. Epub 2011 Jul 14.

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http://dx.doi.org/10.1681/ASN.2011060595DOI Listing
August 2011

Hepatorenal correction in murine glycogen storage disease type I with a double-stranded adeno-associated virus vector.

Mol Ther 2011 Nov 5;19(11):1961-70. Epub 2011 Jul 5.

Department of Pediatrics, Division of Medical Genetics, Duke University Medical Center, Durham, North Carolina 27710, USA.

Glycogen storage disease type Ia (GSD-Ia) is caused by the deficiency of glucose-6-phosphatase (G6Pase). Long-term complications of GSD-Ia include life-threatening hypoglycemia and proteinuria progressing to renal failure. A double-stranded (ds) adeno-associated virus serotype 2 (AAV2) vector encoding human G6Pase was pseudotyped with four serotypes, AAV2, AAV7, AAV8, and AAV9, and we evaluated efficacy in 12-day-old G6pase (-/-) mice. Hypoglycemia during fasting (plasma glucose <100 mg/dl) was prevented for >6 months by the dsAAV2/7, dsAAV2/8, and dsAAV2/9 vectors. Prolonged fasting for 8 hours revealed normalization of blood glucose following dsAAV2/9 vector administration at the higher dose. The glycogen content of kidney was reduced by >65% with both the dsAAV2/7 and dsAAV2/9 vectors, and renal glycogen content was stably reduced between 7 and 12 months of age for the dsAAV2/9 vector-treated mice. Every vector-treated group had significantly reduced glycogen content in the liver, in comparison with untreated G6pase (-/-) mice. G6Pase was expressed in many renal epithelial cells of with the dsAAV2/9 vector for up to 12 months. Albuminuria and renal fibrosis were reduced by the dsAAV2/9 vector. Hepatorenal correction in G6pase (-/-) mice demonstrates the potential of AAV vectors for the correction of inherited diseases of metabolism.
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http://dx.doi.org/10.1038/mt.2011.126DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3222521PMC
November 2011

TRPC6 enhances angiotensin II-induced albuminuria.

J Am Soc Nephrol 2011 Mar 21;22(3):526-35. Epub 2011 Jan 21.

Center for Human Genetics, Duke University Medical Center, Durham, NC 27710, USA.

Mutations in the canonical transient receptor potential cation channel 6 (TRPC6) are responsible for familial forms of adult onset focal segmental glomerulosclerosis (FSGS). The mechanisms by which TRPC6 mutations cause kidney disease are not well understood. We used TRPC6-deficient mice to examine the function of TRPC6 in the kidney. We found that adult TRPC6-deficient mice had BP and albumin excretion rates similar to wild-type animals. Glomerular histomorphology revealed no abnormalities on both light and electron microscopy. To determine whether the absence of TRPC6 would alter susceptibility to hypertension and renal injury, we infused mice with angiotensin II continuously for 28 days. Although both groups developed similar levels of hypertension, TRPC6-deficient mice had significantly less albuminuria, especially during the early phase of the infusion; this suggested that TRPC6 adversely influences the glomerular filter. We used whole-cell patch-clamp recording to measure cell-membrane currents in primary cultures of podocytes from both wild-type and TRPC6-deficient mice. In podocytes from wild-type mice, angiotensin II and a direct activator of TRPC6 both augmented cell-membrane currents; TRPC6 deficiency abrogated these increases in current magnitude. Our findings suggest that TRPC6 promotes albuminuria, perhaps by promoting angiotensin II-dependent increases in Ca(2+), suggesting that TRPC6 blockade may be therapeutically beneficial in proteinuric kidney disease.
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http://dx.doi.org/10.1681/ASN.2010050522DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3060446PMC
March 2011

Pathogenesis and therapy of focal segmental glomerulosclerosis: an update.

Pediatr Nephrol 2011 Jul 26;26(7):1001-15. Epub 2010 Nov 26.

Department of Pediatrics, Duke University Medical Center, Durham, NC 27710, USA.

Focal and segmental glomerulosclerosis (FSGS) is an important cause of steroid-resistant nephrotic syndrome in adults and children. It is responsible for 5-20% of all cases of end-stage kidney disease (ESKD) in the United States. The pathogenesis of FSGS has not been fully elucidated; however, data from molecular studies of familial cases in the last two decades suggest that FSGS is a defect of the podocyte. The therapeutic agents available for treatment of FSGS are not very effective and only a small percentage of affected individuals will achieve complete remission. Recent data from molecular biology and molecular genetics has provided insight into the mechanisms of action of old agents and also identification of other novel therapeutic targets. This review focuses on recent advances in the molecular pathogenesis of FSGS and currently available therapeutic agents as well as potential novel therapies.
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http://dx.doi.org/10.1007/s00467-010-1692-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3624015PMC
July 2011

A new locus for familial FSGS on chromosome 2p.

J Am Soc Nephrol 2010 Aug 8;21(8):1390-7. Epub 2010 Jul 8.

Department of Pediatrics, Duke University Medical Center, Durham, NC 27710, USA.

FSGS is a clinicopathologic entity characterized by nephrotic syndrome and progression to ESRD. Although the pathogenesis is unknown, the podocyte seems to play a central role in this disorder. Here, we present six kindreds with hereditary FSGS that did not associate with mutations in known causal genes, and we report a new locus for the disease on chromosome 2p15 in one kindred. We performed genome-wide linkage analysis and refined the linkage area with microsatellite markers and haplotype analysis to define the minimal candidate region. Genome-wide linkage analysis yielded a maximum two-point logarithm of odds (LOD) score of 3.6 for the six families on chromosome 2p. One family contributed the largest proportion of the additive score (LOD 2.02) at this locus. Multipoint parametric LOD score calculation in this family yielded a significant LOD score of 3.1 at markers D2S393 and D2S337, and fine mapping of this region with microsatellite markers defined a minimal candidate region of 0.9 Mb with observed recombinations at markers D2S2332 and RS1919481. We excluded the remaining five families from linkage to this region by haplotype analysis. These data support a new gene locus for familial FSGS on chromosome 2p15. Identification of the mutated gene at this locus may provide further insight into the disease mechanisms of FSGS.
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http://dx.doi.org/10.1681/ASN.2009101046DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2938593PMC
August 2010

Exclusion of homozygous PLCE1 (NPHS3) mutations in 69 families with idiopathic and hereditary FSGS.

Pediatr Nephrol 2009 Feb 31;24(2):281-5. Epub 2008 Oct 31.

Department of Pediatrics, Duke University Medical Center, Durham, NC, 27710, USA.

Focal and segmental glomerulosclerosis (FSGS) is the most common glomerular cause of end-stage kidney disease (ESKD). Although the etiology of FSGS has not been fully elucidated, recent results from the positional cloning of genes mutated in nephrotic syndromes are now beginning to provide insight into the pathogenesis of these diseases. Mutations in PLCE1/NPHS3 have recently been reported as a cause of nephrotic syndrome characterized by diffuse mesangial sclerosis (DMS) histology. One single family with a missense mutation had late onset of the disease that was characterized by FSGS. To further define the role of PLCE1 mutations in the etiology of FSGS, we performed mutational analysis in 69 families with FSGS. A total of 69 families with 231 affected individuals were examined. The median age of disease onset was 26 years (range 1-66 years). Onset of ESKD was at a median age of 35.5 years. Seven variants leading to non-synonymous changes were found, of which only two are new variants (exon 4 c.1682 G>A R561Q, exon 31 c.6518A>G K2173R). No known disease-causing mutations were identified in the families screened. PLCE1/NPHS3 mutations are not a cause of FSGS in this cohort. The absence of mutations in PLCE1/NPHS3 in this study indicates that there are additional genetic causes of FSGS and that hereditary FSGS is a heterogeneous disease. Kindreds appropriate for genome-wide screening are currently being subjected to analysis with the aim of identifying other genetic causes of FSGS.
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http://dx.doi.org/10.1007/s00467-008-1025-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3070354PMC
February 2009

Therapeutic targets in focal and segmental glomerulosclerosis.

Curr Opin Nephrol Hypertens 2008 Jul;17(4):386-92

Department of Medicine, Duke University Medical Center, Durham, North Carolina 27710, USA.

Purpose Of Review: Focal and segmental glomerulosclerosis occurs due to a defect in the glomerular filtration barrier. This review highlights contributions from the past year that have enhanced our understanding of the pathophysiology of focal and segmental glomerulosclerosis with emphasis on discoveries which may lead to the identification of therapeutic targets.

Recent Findings: Slit diaphragm proteins have become increasingly important in signal transduction and in mediating downstream events. Actin polymerization occurs after the podocin-nephrin-Neph-1 complex is phosphorylated by Src kinase and Fyn. Recent studies of angiotensin receptor antagonists, corticosteroids and erythropoietin unravel new mechanisms that ameliorate proteinuria by targeting the cell cycle within the podocyte. The discovery that an N-acetylmannosamine kinase (MNK) mutant mouse has glomerulopathy is suggestive that human sialylation pathways may represent therapeutic targets. Proteinuria before podocyte effacement demonstrated in laminin-beta2 null mice highlights the importance of the glomerular basement membrane. Interferon-beta reduced proteinuria in three models of kidney injury, showing greatest effect on glomerular endothelial cells in vitro.

Summary: Basic research has illuminated mechanisms by which classic therapies have antiproteinuric effects directly on the podocyte. As knowledge expands with improved molecular techniques, understanding signaling pathways in health and proteinuric states should lead to potential therapeutic targets in focal and segmental glomerulosclerosis.
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http://dx.doi.org/10.1097/MNH.0b013e32830464f4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2674376PMC
July 2008
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