Clinical Heterogeneity in Familial IgA Nephropathy

Fennelly, Neil K.; Kennedy, Claire; Jenkinson, Allan; Connaughton, Dervla M.; Stapleton, Caragh; Dorman, Anthony; Doyle, Brendan; Conlon, Peter J.

doi:10.1159/000486018

Cited by 7 publications

(4 citation statements)

References 43 publications

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“…The incidence of family clustering is almost comparable to that in previous studies: 6.7% in China [ 8 ] and 17.2–34% in Italy [ 5 ] (Additional file 2 ). Other studies with Caucasians showed a lower frequency of familial aggregation in total sporadic cases: 1.8% in Ireland [ 6 ] and 1.4% in the US [ 15 ]. The difference in frequency of familial clustering may be due to the geographic and/or racial difference in genetic background.…”

Section: Discussionmentioning

confidence: 99%

Positive renal familial history in IgA nephropathy is associated with worse renal outcomes: a single-center longitudinal study

et al. 2021

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Background IgA nephropathy (IgAN) is the most common primary glomerulonephritis worldwide. Although most IgAN cases are sporadic, few show a familial aggregation. However, the prevalence and prognosis of IgAN individuals with positive familial history (FH) of renal disorders remains uncertain. To address these issues, we conducted a longitudinal observational study on a single-institution cohort of patients with biopsy-proven IgAN. Methods A total of 467 IgAN patients who underwent renal biopsy during 1994 to 2019 were ascertained to have positive- or negative-FH by history taking and were followed for an average of 8.9 years. We compared the clinical and pathological features of the two subgroups. The primary outcome, a composite of a hard endpoint (end-stage renal disease [ESRD]) and surrogate endpoint (a 50% or more reduction in the estimated glomerular filtration rate [eGFR] from baseline), was evaluated. To estimate the risk for progression to ESRD, a Cox proportional hazards analysis was performed for a subset of patients who underwent follow-up for > 2 years and had an eGFR > 30 mL/min/1.73 m2 at baseline (n = 389; observation, 8.7 years). Results Positive-FH subtype accounted for 11.6% (n = 54) of all IgAN patients. At baseline, there were no significant differences between the positive- and negative-FH subgroups regarding age, sex, comorbid disease, MEST-C score, observation period, and therapeutic interventions. However, the eGFR value at baselines was significantly lower in the positive-FH subgroup than in the negative-FH subgroup (P < 0.01). On multivariate analysis, positive-FH emerged an independent determinant of poorer renal outcomes (odds ratio, 2.31; 95% confidence interval, 1.10–4.85; P = 0.03), after adjusting for confounding factors. eGFR at follow-up was significantly lower in the positive-FH subgroup than in the negative-FH subgroup after adjustment for age and observation period. Conclusions Positive-FH was found in 11.6% of all IgAN patients, consistent with the incidence seen in previous literature. A significantly lower eGFR at baseline and last follow-up and unfavorable renal outcomes in the positive-FH subgroup suggest that certain genetic risk factors predisposing to renal failure may exist in a fraction of our IgAN cohort. (331 words).

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Section: Discussionmentioning

confidence: 99%

Positive renal familial history in IgA nephropathy is associated with worse renal outcomes: a single-center longitudinal study

et al. 2021

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“…Families presenting with IgAN were identified through a clinical analysis carried out by Fennelly et al (15). Patients were selected on the basis that they had a clinical picture compatible with IgAN predominantly.…”

Section: Selection Of Familiesmentioning

confidence: 99%

“…DNA from these patients was obtained at Beaumont Hospital from these collected blood or saliva samples and processed through the Rare Kidney Disease Biobank at St. James Hospital, Dublin, Ireland. We then chose families who had at least one family member with biopsy proven IgAN and one other family member with either biopsy-proven IgAN or ESRD as previously described (15) and selected families that had at least two affected members with DNA available. This left us with ten families for the exome sequencing analysis.…”

Section: Selection Of Familiesmentioning

confidence: 99%

An Exome Sequencing Study of 10 Families with IgA Nephropathy

Stapleton¹,

Kennedy²,

Fennelly³

et al. 2019

Nephron

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Background: Immunoglobulin A nephropathy (IgAN) is a heterogeneous disorder with a strong genetic component. The advent of whole exome sequencing (WES) has accelerated the discovery of genetic risk factors underlying familial disorders. Objectives: We set out to test whether damaging variants in known kidney disease genes explain a proportion of IgAN cases recruited in Ireland. Methods: We performed WES in 10 Irish families with multiple affected members having kidney disease where at least one member had biopsy confirmed IgAN. Candidate variants were identified based on being shared between affected family members, minor allele frequency, function and predicted pathogenicity. Pathogenicity of variants was determined according to American College of Medical Genetics and Genomics guidelines. Results: We detected candidate variants in 3 of 10 families. We identified a likely pathogenic variant in COL4A5 in one family and a variant of unknown significance (VUS) in COL4A3 in another. Variants in COL4A5 and COL4A3 are known to cause Alport syndrome. In the third family, we identified a VUS in LMX1B, a gene associated with Nail-patella syndrome. Conclusions: We identified a number of cases of familial IgAN where the families harbored variants in known kidney disease-related genes indicating that potentially a number of cases of familial IgAN are mistaken for other familial kidney disorders. However, the majority of families studied did not carry a candidate variant in a known kidney disease causing gene indicating that there may be >1 underlying genetic mechanism present in these families.

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“…IgAN may occur in a sporadic or familial form[ 13 ]. Intriguingly, clinical manifestations of IgAN can overlap considerably with AS, which results from mutations in the COL4A3 , COL4A4 , and COL4A5 genes[ 14 , 15 ].…”

Section: Discussionmentioning

confidence: 99%

Novel COL4A3 synonymous mutation causes Alport syndrome coexistent with immunoglobulin A nephropathy in a woman: A case report

Chen,

Jiang,

2023

World J Clin Cases

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Insulin, a small protein with 51 amino acids synthesized by pancreatic β-cells, is crucial to sustain glucose homeostasis at biochemical and molecular levels. Numerous metabolic dysfunctions are related to insulin-mediated altered glucose homeostasis. One of the significant pathophysiological conditions linked to the insulin associated disorder is diabetes mellitus (DM) (type 1, type 2, and gestational). Insulin resistance (IR) is one of the major underlying causes of metabolic disorders despite its association with several physiological conditions. Metabolic syndrome (MS) is another pathophysiological condition that is associated with IR, hypertension, and obesity. Further, several other pathophysiological disorders/diseases are associated with the insulin malfunctioning, which include polycystic ovary syndrome, neuronal disorders, and cancer. Insulinomas are an uncommon type of pancreatic β-cell-derived neuroendocrine tumor that makes up 2% of all pancreatic neoplasms. Literature revealed that different biochemical events, molecular signaling pathways, microRNAs, and microbiota act as connecting links between insulin disorder and associated pathophysiology such as DM, insuloma, neurological disorder, MS, and cancer. In this review, we focus on the insulin-related disorders and the underlying mechanisms associated with the pathophysiology.

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Clinical Heterogeneity in Familial IgA Nephropathy

Cited by 7 publications

References 43 publications

Positive renal familial history in IgA nephropathy is associated with worse renal outcomes: a single-center longitudinal study

Positive renal familial history in IgA nephropathy is associated with worse renal outcomes: a single-center longitudinal study

An Exome Sequencing Study of 10 Families with IgA Nephropathy

Novel COL4A3 synonymous mutation causes Alport syndrome coexistent with immunoglobulin A nephropathy in a woman: A case report

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