Dataset Information

Long-term outcomes and response to treatment in diacylglycerol kinase epsilon nephropathy.

ABSTRACT: Recessive mutations in diacylglycerol kinase epsilon (DGKE) display genetic pleiotropy, with pathological features reported as either thrombotic microangiopathy or membranoproliferative glomerulonephritis (MPGN), and clinical features of atypical hemolytic uremic syndrome (aHUS), nephrotic syndrome or both. Pathophysiological mechanisms and optimal management strategies have not yet been defined. In prospective and retrospective studies of aHUS referred to the United Kingdom National aHUS service and prospective studies of MPGN referred to the National Registry of Rare Kidney Diseases for MPGN we defined the incidence of DGKE aHUS as 0.009/million/year and so-called DGKE MPGN as 0.006/million/year, giving a combined incidence of 0.015/million/year. Here, we describe a cohort of sixteen individuals with DGKE nephropathy. One presented with isolated nephrotic syndrome. Analysis of pathological features reveals that DGKE mutations give an MPGN-like appearance to different extents, with but more often without changes in arterioles or arteries. In 15 patients presenting with aHUS, ten had concurrent substantial proteinuria. Identified triggering events were rare but coexistent developmental disorders were seen in six. Nine with aHUS experienced at least one relapse, although in only one did a relapse of aHUS occur after age five years. Persistent proteinuria was seen in the majority of cases. Only two individuals have reached end stage renal disease, 20 years after the initial presentation, and in one, renal transplantation was successfully undertaken without relapse. Six individuals received eculizumab. Relapses on treatment occurred in one individual. In four individuals eculizumab was withdrawn, with one spontaneously resolving aHUS relapse occurring. Thus we suggest that DGKE-mediated aHUS is eculizumab non-responsive and that in individuals who currently receive eculizumab therapy it can be safely withdrawn. This has important patient safety and economic implications.

SUBMITTER: Brocklebank V

PROVIDER: S-EPMC7242908 | biostudies-literature | 2020 Jun

REPOSITORIES: biostudies-literature

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Long-term outcomes and response to treatment in diacylglycerol kinase epsilon nephropathy.

Brocklebank Vicky V Kumar Gurinder G Howie Alexander J AJ Chandar Jayanthi J Milford David V DV Craze Janet J Evans Jonathan J Finlay Eric E Freundlich Michael M Gale Daniel P DP Inward Carol C Mraz Martin M Jones Caroline C Wong William W Marks Stephen D SD Connolly John J Corner Bronte M BM Smith-Jackson Kate K Walsh Patrick R PR Marchbank Kevin J KJ Harris Claire L CL Wilson Valerie V Wong Edwin K S EKS Malina Michal M Johnson Sally S Sheerin Neil S NS Kavanagh David D

Kidney international 20200228 6

Recessive mutations in diacylglycerol kinase epsilon (DGKE) display genetic pleiotropy, with pathological features reported as either thrombotic microangiopathy or membranoproliferative glomerulonephritis (MPGN), and clinical features of atypical hemolytic uremic syndrome (aHUS), nephrotic syndrome or both. Pathophysiological mechanisms and optimal management strategies have not yet been defined. In prospective and retrospective studies of aHUS referred to the United Kingdom National aHUS servic ...[more]

PMID: 32386968

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Project description:In mammals there are at least 10 isoforms of diacylglycerol kinases (DGK). All catalyze the phosphorylation of diacylglycerol (DAG) to phosphatidic acid (PA). Among DGK isoforms, DGKε has several unique features. It is the only DGK isoform with specificity for a particular species of DAG, i.e., 1-stearoyl-2-arachidonoyl glycerol. The smallest of all known DGK isoforms, DGKε, is also the only DGK devoid of a regulatory domain. DGKε is the only DGK isoform that has a hydrophobic segment that is predicted to form a transmembrane helix. As the only membrane-bound, constitutively active DGK isoform with exquisite specificity for particular molecular species of DAG, the functional overlap between DGKε and other DGKs is predicted to be minimal. DGKε exhibits specificity for DAG containing the same acyl chains as those found in the lipid intermediates of the phosphatidylinositol-cycle. It has also been shown that DGKε affects the acyl chain composition of phosphatidylinositol in whole cells. It is thus likely that DGKε is responsible for catalyzing one step in the phosphatidylinositol-cycle. Steps of this cycle take place in both the plasma membrane and the endoplasmic reticulum membrane. DGKε is likely present in both of these membranes. DGKε is the only DGK isoform that is associated with a human disease. Indeed, recessive loss-of-function mutations in DGKε cause atypical hemolytic-uremic syndrome (aHUS). This condition is characterized by thrombosis in the small vessels of the kidney. It causes acute renal insufficiency in infancy and most patients develop end-stage renal failure before adulthood. Disease pathophysiology is poorly understood and there is no therapy. There are also data suggesting that DGKε may play a role in epilepsy and Huntington disease. Thus, DGKε has many unique molecular and biochemical properties when compared to all other DGK isoforms. DGKε homologs also contain a number of conserved sequence features that are distinctive characteristics of either the rodents or specific groups of primate homologs. How cells, tissues and organisms harness DGKε's catalytic prowess remains unclear. The discovery of DGKε's role in causing aHUS will hopefully boost efforts to unravel the mechanisms by which DGKε dysfunction causes disease.

Project description:Nephrotoxicity remains the dose-limiting side effect of cisplatin, an effective chemotherapeutic agent with applications across diverse tumor types. This study presents data on renal outcomes across multiple tumor types in 821 adults. We report on incidence of AKI, initial and long-term changes in eGFR after cisplatin, and relationships between cumulative dose, initial eGFR, age, sex, and long-term renal function.This was a retrospective study of adult patients treated with cisplatin from January 1, 2000 to September 21, 2011 who had survived ?5 years after initial dose. The Modification of Diet in Renal Disease equation was used to calculate eGFR. AKI was defined as an increase from the baseline creatinine of >25% within 30 days after the first cycle of cisplatin. Chi-squared tests were done to evaluate the relationships between categorical or ordinal variables; ANOVAs or t tests were used to evaluate continuous or categorical variables. Changes in eGFR over time were evaluated in a growth curve model.Mean follow-up was 6 years (25th and 75th percentiles, 4 and 9 years). AKI occurred in 31.5% of patients, with a median initial decline in eGFR of 10 ml/min per 1.73 m(2) (25th and 75th percentiles, -41.5 and -23.3 ml/min per 1.73 m(2)). At any time point after the first cycle of cisplatin, <3% of patients progressed to eGFR<29 ml/min per 1.73 m(2), and none were known to be on dialysis. Age was associated with a higher risk for AKI after cisplatin. Compared with age <25 years old, the odds ratios for AKI versus no AKI are 1.22 for >26-44 years old (95% confidence interval [95% CI], 0.60 to 2.4), 1.54 for >45-65 years old (95% CI, 0.78 to 3), and 2.96 for >66 years old (95% CI, 1.4 to 6.1). The lowest dose categories of cisplatin (?100 and 101-250 mg/m(2)) are associated with increases in eGFR (P=0.06 and P=0.02, respectively) compared with the highest dose category (>701 mg/m(2)).This is the largest study of adult patients with cancer who received cisplatin for treatment across multiple tumor types. Most patients experience small but permanent declines in eGFR, but none progressed to ESRD requiring hemodialysis.

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Dataset Information

Long-term outcomes and response to treatment in diacylglycerol kinase epsilon nephropathy.

Publications

Long-term outcomes and response to treatment in diacylglycerol kinase epsilon nephropathy.

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