Association of Coding Variants in Hydroxysteroid 17-beta Dehydrogenase 14 (HSD17B14) with Reduced Progression to End Stage Kidney Disease in Type 1 Diabetes

2021 ◽  
pp. ASN.2020101457
Author(s):  
Josyf Mychaleckyj ◽  
Erkka Valo ◽  
Takaharu Ichimura ◽  
Tarunveer Ahluwalia ◽  
Christian Dina ◽  
...  
Keyword(s):  
Gene Expression ◽  
Type 1 Diabetes ◽  
Kidney Disease ◽  
Rare Variants ◽  
Disease Stage ◽  
End Stage Kidney Disease ◽  
Gene And Protein Expression ◽  
End Stage ◽  
Coding Variants

Background: Rare variants in gene coding regions likely have a greater impact on disease-related phenotypes than common variants through disruption of their encoded protein. We searched for rare variants associated with onset of end stage kidney disease (ESKD) in individuals with type 1 diabetes at advanced kidney disease stage. Methods: Gene-based exome array analysis of 15,449 genes in 5 large incidence cohorts of individuals with type 1 diabetes and proteinuria were analyzed for survival time-to-ESKD, testing the top gene in a 6th cohort (N=2,372/1,115 events all cohorts) and replicating in two retrospective case-control studies (N=1,072 cases, 752 controls). Deep resequencing of the top associated gene in 5 cohorts confirmed the findings. We performed immunohistochemistry and gene expression experiments in human control and diseased cells, and in mouse ischemia reperfusion and aristolochic acid nephropathy models. Results: Protein coding variants in the hydroxysteroid 17-beta dehydrogenase 14 gene (HSD17B14), predicted to affect protein structure, had a net protective effect against development of ESKD at exome-wide significance (N=4,196; p-value=3.3x10-7). The HSD17B14 gene and encoded enzyme were robustly expressed in healthy human kidney, maximally in proximal tubular cells. Paradoxically, gene and protein expression were attenuated in human diabetic proximal tubules and in mouse kidney injury models. Expressed HSD17B14 gene and protein levels remained low without recovery after 21 days in a murine ischemic reperfusion injury model. Decreased gene expression was found in other chronic kidney disease-associated renal pathologies. Conclusions: HSD17B14 gene is mechanistically involved in diabetic kidney disease. The encoded sex steroid enzyme is a druggable target, potentially opening a new avenue for therapeutic development.

scholarly journals A Validated Prediction Model for End-Stage Kidney Disease in Type 1 Diabetes. Diabetes Care 2021;44:901–907

Diabetes Care ◽  
2021 ◽  
pp. dci210010
Author(s):  
Dorte Vistisen ◽  
Gregers S. Andersen ◽  
Adam Hulman ◽  
Stuart J. McGurnaghan ◽  
Helen M. Colhoun ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Kidney Disease ◽  
Prediction Model ◽  
Diabetes Care ◽  
End Stage Kidney Disease ◽  
End Stage

1615-P: Predicting End-Stage Kidney Disease in Type 1 Diabetes

Diabetes ◽  
2020 ◽  
Vol 69 (Supplement 1) ◽  
pp. 1615-P
Author(s):  
DORTE VISTISEN ◽  
GREGERS S. ANDERSEN ◽  
ADAM HULMAN ◽  
STUART MCGURNAGHAN ◽  
HELEN M. COLHOUN ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Kidney Disease ◽  
End Stage Kidney Disease ◽  
End Stage

scholarly journals A Validated Prediction Model for End-Stage Kidney Disease in Type 1 Diabetes. Diabetes Care 2021;44:901–907

Diabetes Care ◽  
2021 ◽  
pp. dc210364
Author(s):  
Helena Bleken Østergaard ◽  
Joep van der Leeuw ◽  
Frank L.J. Visseren ◽  
Jan Westerink
Keyword(s):  
Type 1 Diabetes ◽  
Kidney Disease ◽  
Prediction Model ◽  
Diabetes Care ◽  
End Stage Kidney Disease ◽  
End Stage

scholarly journals A Validated Prediction Model for End-Stage Kidney Disease in Type 1 Diabetes

2021 ◽  
Author(s):  
Dorte Vistisen ◽  
Gregers S. Andersen ◽  
Adam Hulman ◽  
Stuart J. McGurnaghan ◽  
Helen M. Colhoun ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Kidney Disease ◽  
Prediction Model ◽  
Clinical Decision Making ◽  
External Validation ◽  
End Stage Kidney Disease ◽  
Risk Of Death ◽  
Increased Risk ◽  
End Stage

<b>OBJECTIVE </b> <p>End-stage kidney disease (ESKD) is a life-threatening complication of diabetes which can be prevented or delayed by intervention. Hence, early detection of persons at increased risk is essential.</p> <p> </p> <p><b>RESEARCH DESIGN AND METHODS </b></p> <p>From a population-based cohort of 5,460 clinically diagnosed Danish adults with type 1 diabetes followed 2001-2016, we developed a prediction model for ESKD accounting for the competing risk of death. Poisson regression analysis was used to estimate the model based on information routinely collected from clinical examinations. The effect of including an extended set of predictors (lipids, alcohol intake etc.) was further evaluated, and potential interactions identified in a survival tree analysis were tested. The final model was externally validated in 9,175 adults from Denmark and Scotland.</p> <p> </p> <p><b>RESULTS</b> </p> <p>During a median follow-up of 10.4 years (interquartile limits: 5.1;14.7), 303 (5.5%) of the participants (mean (SD) age 42.3 (16.5) years) developed ESKD and 764 (14.0%) died without having developed ESKD. The final ESKD prediction model included age, male sex, diabetes duration, estimated glomerular filtration rate, micro- and macroalbuminuria, systolic blood pressure, HbA<sub>1c</sub>, smoking and previous cardiovascular disease. Discrimination was excellent for 5-year risk of ESKD event with a C-statistic of 0.888 (95%CI: 0.849;0.927) in the derivation cohort and confirmed at 0.865 (0.811;0.919) and 0.961 (0.940;0.981) in the external validation cohorts from Denmark and Scotland. </p> <p> </p> <p><b>CONCLUSIONS</b> </p> <p>We have derived and validated a novel, high-performing ESKD prediction model for risk stratification in the adult type 1 diabetes population. This model may improve clinical decision making and potentially guide early intervention.</p>

scholarly journals A Validated Prediction Model for End-Stage Kidney Disease in Type 1 Diabetes

2021 ◽  
Author(s):  
Dorte Vistisen ◽  
Gregers S. Andersen ◽  
Adam Hulman ◽  
Stuart J. McGurnaghan ◽  
Helen M. Colhoun ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Kidney Disease ◽  
Prediction Model ◽  
Clinical Decision Making ◽  
External Validation ◽  
End Stage Kidney Disease ◽  
Risk Of Death ◽  
Increased Risk ◽  
End Stage

<b>OBJECTIVE </b> <p>End-stage kidney disease (ESKD) is a life-threatening complication of diabetes which can be prevented or delayed by intervention. Hence, early detection of persons at increased risk is essential.</p> <p> </p> <p><b>RESEARCH DESIGN AND METHODS </b></p> <p>From a population-based cohort of 5,460 clinically diagnosed Danish adults with type 1 diabetes followed 2001-2016, we developed a prediction model for ESKD accounting for the competing risk of death. Poisson regression analysis was used to estimate the model based on information routinely collected from clinical examinations. The effect of including an extended set of predictors (lipids, alcohol intake etc.) was further evaluated, and potential interactions identified in a survival tree analysis were tested. The final model was externally validated in 9,175 adults from Denmark and Scotland.</p> <p> </p> <p><b>RESULTS</b> </p> <p>During a median follow-up of 10.4 years (interquartile limits: 5.1;14.7), 303 (5.5%) of the participants (mean (SD) age 42.3 (16.5) years) developed ESKD and 764 (14.0%) died without having developed ESKD. The final ESKD prediction model included age, male sex, diabetes duration, estimated glomerular filtration rate, micro- and macroalbuminuria, systolic blood pressure, HbA<sub>1c</sub>, smoking and previous cardiovascular disease. Discrimination was excellent for 5-year risk of ESKD event with a C-statistic of 0.888 (95%CI: 0.849;0.927) in the derivation cohort and confirmed at 0.865 (0.811;0.919) and 0.961 (0.940;0.981) in the external validation cohorts from Denmark and Scotland. </p> <p> </p> <p><b>CONCLUSIONS</b> </p> <p>We have derived and validated a novel, high-performing ESKD prediction model for risk stratification in the adult type 1 diabetes population. This model may improve clinical decision making and potentially guide early intervention.</p>

scholarly journals A Validated Prediction Model for End-Stage Kidney Disease in Type 1 Diabetes

Diabetes Care ◽  
2021 ◽  
pp. dc202586
Author(s):  
Dorte Vistisen ◽  
Gregers S. Andersen ◽  
Adam Hulman ◽  
Stuart J. McGurnaghan ◽  
Helen M. Colhoun ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Kidney Disease ◽  
Prediction Model ◽  
End Stage Kidney Disease ◽  
End Stage

scholarly journals Calciphylaxis or vascular oxalosis?

2020 ◽  
Author(s):  
Skye El-Saygeh ◽  
Douglas Roese ◽  
Sharon M Moe
Keyword(s):  
Kidney Disease ◽  
Primary Hyperoxaluria ◽  
Abrupt Onset ◽  
Limb Amputation ◽  
Peripheral Vascular ◽  
End Stage Kidney Disease ◽  
Primary Hyperoxaluria Type 1 ◽  
End Stage ◽  
Hyperoxaluria Type

Abstract We report the case of a 31-year-old female with primary hyperoxaluria type 1 with end-stage kidney disease who developed severe peripheral vascular disease leading to limb amputation initially thought to be secondary to calciphylaxis. However, polarized review of the pathologic specimen revealed calcium oxalate deposition in the lumen of blood vessels. This unusual presentation of systemic oxalosis demonstrates the adverse consequences of elevations of serum oxalate in patients with hyperoxaluria and that levels can acutely worsen with abrupt onset of kidney failure.

scholarly journals Primary Hyperoxaluria Type 1 (PH1) Presenting With End-Stage Kidney Disease and Cutaneous Manifestations in Adulthood: A Case Report

2021 ◽  
Vol 8 ◽  
pp. 205435812110589
Author(s):  
Penelope Poyah ◽  
Joel Bergman ◽  
Laurette Geldenhuys ◽  
Glenda Wright ◽  
Noreen M. Walsh ◽  
...  
Keyword(s):  
Case Report ◽  
Kidney Disease ◽  
Primary Hyperoxaluria ◽  
End Stage Kidney Disease ◽  
Primary Hyperoxaluria Type 1 ◽  
History Of ◽  
End Stage ◽  
Recurrent Nephrolithiasis ◽  
Hyperoxaluria Type

Rationale: Primary hyperoxaluria (PH) is a rare autosomal recessive disorder more commonly diagnosed in children or adolescents. Owing to its rarity and heterogeneous phenotype, it is often underrecognized, resulting in delayed diagnosis, including diagnosis after end-stage kidney disease (ESKD) has occurred or recurrence after kidney-only transplantation. Case Presentation: A 40-year-old Caucasian Canadian woman with a history of recurrent nephrolithiasis since age 19 presented with ESKD and cutaneous symptoms. She had no known prior kidney disease and no family history of kidney disease or nephrolithiasis. Diagnosis: A diagnosis of primary hyperoxaluria type 1 (PH1) due to homozygous splice donor mutation (AGXT c.680+1G>A) was made with kidney and cutaneous pathology demonstrating calcium oxalate deposition and ultrasound suggestive of nephrocalcinosis. Interventions: She was initiated on frequent, high-efficiency, high-flux conventional hemodialysis and oral pyridoxine. Lumasiran was added 11 months later, after she developed bilateral swan-neck deformities. Outcomes: After 14 months of high-intensity dialysis and 3 months of lumasiran, there have been no signs of renal recovery, and extra-renal involvement has increased with progressive swan-neck deformities, reduced cardiac systolic function, and pulmonary hypertension. The patient has been waitlisted for kidney-liver transplantation. Teaching Points: This case report describes an adult presentation of PH1. The case highlights the importance of timely workup of metabolic causes of recurrent nephrolithiasis or nephrocalcinosis in adults which can be a presenting sign of PH and genetic testing for PH to facilitate early diagnosis and treatment especially in the era of novel therapeutics that may alter disease course and outcomes. The case also demonstrates the value of testing for PH in adults presenting with unexplained ESKD and a history of recurrent nephrolithiasis or nephrocalcinosis due to implications for organ transplantation strategy and presymptomatic family screening.

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