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

Brocklebank, Vicky; Kumar, Gurinder; Howie, Alexander J.; Chandar, Jayanthi; Milford, David V.; Craze, Janet; Evans, Jonathan; Finlay, Eric; Freundlich, Michael; Gale, Daniel P.; Inward, Carol; Mraz, Martin; Jones, Caroline; Wong, William; Marks, Stephen D.; Connolly, John; Corner, Bronte M.; Smith-Jackson, Kate; Walsh, Patrick R.; Marchbank, Kevin J.; Harris, Claire L.; Wilson, Valerie; Wong, Edwin K.S.; Malina, Michal; Johnson, Sally; Sheerin, Neil; Kavanagh, David

doi:10.1016/j.kint.2020.01.045

Cited by 33 publications

(27 citation statements)

References 41 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…A total of 80–94 % present with aHUS, while 6–20 % present with early-onset nephrotic syndrome and membrane proliferative glomerulonephritis (MPGN)-like features on kidney biopsy [ 3 , 4 ]. These patients who present with aHUS have a 64–70 % rate of relapse after initial remission and usually have persistent proteinuria and microscopic haematuria in between relapses [ 2 , 5 ]. For the last decade, the empirical therapy for patients diagnosed with aHUS has been eculizumab, a recombinant humanized monoclonal antibody that binds to complement component 5 (C5) to inhibit terminal complement cascade activation.…”

Section: Discussionmentioning

confidence: 99%

“…In the follow-up of these patients, it was noticed that the disease course and long-term outcome were similar with and without aHUS-specific therapy [ 4 ]. Brocklebank et al [ 5 ] recently reported the long-term outcomes of 16 patients with DGKE mutations. Six out of the 16 patients received plasma infusion/plasma exchange, and one patient received eculizumab during initial presentation.…”

Section: Discussionmentioning

confidence: 99%

“…Another 5 were given eculizumab during the course of their illness. Eculizumab was successfully withdrawn from 4 patients, and relapse occurred in one patient 6 weeks after withdrawal and was managed successfully with supportive therapy[ 5 ]. In our case, the patient presented with aHUS and low C3.…”

Section: Discussionmentioning

confidence: 99%

See 2 more Smart Citations

A patient with a homozygous diacylglycerol kinase epsilon (DGKE) gene mutation with atypical haemolytic uraemic syndrome and low C3 responded well to eculizumab: a case report

Alabdulqader

Alfakeeh

2021

BMC Nephrol

View full text Add to dashboard Cite

Background Atypical haemolytic uraemic syndrome (aHUS) is a rare systemic syndrome characterized by non-immune haemolytic anaemia, thrombocytopenia, and kidney injury. In most cases, alternative complement pathway dysregulation is the identifying cause. Recently, other genetic causes have been identified, including a mutation in the diacylglycerol kinase epsilon (DGKE) gene, which theoretically affect the coagulation pathway and does not affect the complement pathway. Data about the management of these patients are limited. Ideal management and definitive treatment protocols have not yet been established. Case presentation A three-year-old boy presented with features of atypical haemolytic uraemic syndrome (aHUS) and low complement C3. He was presumed to have complement-mediated aHUS and was managed empirically with eculizumab. Two weeks after starting eculizumab, his haemoglobin levels, platelet count, and complement C3 level normalized but he continued to have non-nephrotic range proteinuria. His genetic testing revealed a homozygous DGKE mutation, with no other mutation detected. Six months after presentation, the patient was still in remission with no features of aHUS, a trial of weaning eculizumab by increasing dose interval was followed by nephrotic range proteinuria and severe oedema. His proteinuria improved and his oedema resolved after resuming his recommended eculizumab dose. Conclusions DGKE gene mutation can lead to aHUS with theoretically no complement dysregulation. However, some patients with this mutation show alternative complement pathway activation. This case report describes a patient with aHUS due to a DGKE gene mutation and low C3 levels who responded to eculizumab, adding to the previously reported cases of patients with DGKE gene mutations who had complete remission with no relapse with C5 blockers and/or plasma exchange. A randomized controlled study on patients with DGKE mutations might be beneficial in understanding the disease and generating a management protocol.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

A patient with a homozygous diacylglycerol kinase epsilon (DGKE) gene mutation with atypical haemolytic uraemic syndrome and low C3 responded well to eculizumab: a case report

Alabdulqader

Alfakeeh

2021

BMC Nephrol

View full text Add to dashboard Cite

show abstract

“…Brocklebank et al outlined the genotype, phenotype, and pathophysiology of DGKE mutations associated with aHUS in 16 patients (median age 9 months) [ 50 ]. The phenotype of DGKE mutations was characterized by persistent proteinuria, at least one relapse in children, and hypertension with hematuria leading to chronic kidney failure.…”

Section: Selected Mutations and Anti-complement Factor Antibodiesmentioning

confidence: 99%

Pediatric Atypical Hemolytic Uremic Syndrome Advances

Raina

Vijayvargiya

Khooblall

et al. 2021

Cells

View full text Add to dashboard Cite

Atypical hemolytic uremic syndrome (aHUS) is a rare disorder characterized by dysregulation of the alternate pathway. The diagnosis of aHUS is one of exclusion, which complicates its early detection and corresponding intervention to mitigate its high rate of mortality and associated morbidity. Heterozygous mutations in complement regulatory proteins linked to aHUS are not always phenotypically active, and may require a particular trigger for the disease to manifest. This list of triggers continues to expand as more data is aggregated, particularly centered around COVID-19 and pediatric vaccinations. Novel genetic mutations continue to be identified though advancements in technology as well as greater access to cohorts of interest, as in diacylglycerol kinase epsilon (DGKE). DGKE mutations associated with aHUS are the first non-complement regulatory proteins associated with the disease, drastically changing the established framework. Additional markers that are less understood, but continue to be acknowledged, include the unique autoantibodies to complement factor H and complement factor I which are pathogenic drivers in aHUS. Interventional therapeutics have undergone the most advancements, as pharmacokinetic and pharmacodynamic properties are modified as needed in addition to their as biosimilar counterparts. As data continues to be gathered in this field, future advancements will optimally decrease the mortality and morbidity of this disease in children.

show abstract

“…PGE 2 suppresses the expression of MMP-2 in Tie2Cre Dgke fl/fl mouse kidneys. DGKE nephropathy is invariably associated with proteinuria (3,25,58). Proteinuria was also present in 100% of endothelial specific Tie2-Cre Dgke fl/fl knockout mice at a later time compared with the appearance of the hematologic signs, which suggests that the filtration barrier is secondarily affected by primary endothelial abnormalities.…”

Section: Vegfr2-dependent Akt Activation Is Compromised In Dgke-knockdown Human Umbilical Vein Endothelial Cells and In Human Microvasculmentioning

confidence: 99%

Loss of diacylglycerol kinase ε causes thrombotic microangiopathy by impairing endothelial VEGFA signaling

Liu¹,

Ding²,

Dai³

et al. 2021

JCI Insight

View full text Add to dashboard Cite

Loss of function of the lipid kinase diacylglycerol kinase ε (DGKε), encoded by the gene DGKE , causes a form of atypical hemolytic uremic syndrome that is not related to abnormalities of the alternative pathway of the complement, by mechanisms that are not understood. By generating a potentially novel endothelial specific Dgke -knockout mouse, we demonstrate that loss of Dgke in the endothelium results in impaired signaling downstream of VEGFR2 due to cellular shortage of phosphatidylinositol 4,5-biphosphate. Mechanistically, we found that, in the absence of DGKε in the endothelium, Akt fails to be activated upon VEGFR2 stimulation, resulting in defective induction of the enzyme cyclooxygenase 2 and production of prostaglandin E 2 (PGE 2 ). Treating the endothelial specific Dgke -knockout mice with a stable PGE 2 analog was sufficient to reverse the clinical manifestations of thrombotic microangiopathy and proteinuria, possibly by suppressing the expression of matrix metalloproteinase 2 through PGE 2 -dependent upregulation of the chemokine receptor CXCR4. Our study reveals a complex array of autocrine signaling events downstream of VEGFR2 that are mediated by PGE 2 , that control endothelial activation and thrombogenic state, and that result in abnormalities of the glomerular filtration barrier.

show abstract

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

Cited by 33 publications

References 41 publications

A patient with a homozygous diacylglycerol kinase epsilon (DGKE) gene mutation with atypical haemolytic uraemic syndrome and low C3 responded well to eculizumab: a case report

A patient with a homozygous diacylglycerol kinase epsilon (DGKE) gene mutation with atypical haemolytic uraemic syndrome and low C3 responded well to eculizumab: a case report

Pediatric Atypical Hemolytic Uremic Syndrome Advances

Loss of diacylglycerol kinase ε causes thrombotic microangiopathy by impairing endothelial VEGFA signaling

Contact Info

Product

Resources

About