Membranoproliferative glomerulonephritis and re-nal microangiopathies may manifest similar clinical presentations and histology. Many genetic mutations that cause these diseases have been reported. Studies on mutations in the gene encoding diacylglycerol kinase epsilon identified a novel pathophysiologic mechanism leading to atypical hemolytic uremic syndrome and/or membranopro-liferative glomerulonephritis. Here, we present the different clinical presentations and treatments in 4 family members who carried the same homozygous diacylglycerol kinase epsilon mutation. The first patient (age 5 years, 3 months old at diagnosis) had nephrotic syndrome. The kidney biopsy was membranoproliferative glomerulonephritis; partial remission was achieved with cyclophosphamide, cyclosporine, and mycophenolate mofetil treatment. The second patient (age 5 years, 7 months at diagnosis) presented with overlapping atypical hemolytic uremic syndrome and membranoproliferative glomerulonephritis. Remission could not be achieved with cyclophosphamide, cyclosporine, and mycophenolate mofetil, and hemodialysis treatment was started. At 10 years from first admission, the patient had end-stage kidney disease, and kidney transplant was performed successfully. The third patient was admitted with the diagnosis of nephrotic syndrome at 13 months of age, kidney biopsy showed membranoproliferative glomerulonephritis, and spontaneous remission developed during follow-up. He presented with hemolytic uremic syndrome 15 months after the first admission, and dialysis was started. Remission was achieved with plasma infusion and eculizumab treatment. The fourth patient (a 7-month-old boy and brother of patient 3) had no clinical or laboratory findings. All patients had genetic analysis, and mutation in exon 2:c.473G>A(p.W158*) was detected. Our related patients with the same mutation showed different clinical and histological findings. However, we did not observe a clear genotype-phenotype correlation in patients with diacylglycerol kinase epsilon nephropathy, suggesting additional factors mediating phenotypic heterogeneity.
Key words : Atypical hemolytic uremic syndrome, End-stage kidney disease, Membranoproliferative glomerulonephritis, Renal failure
Hemolytic uremic syndrome (HUS), which includes typical HUS and atypical HUS (aHUS), is characterized by small-vessel thrombosis resulting in microangiopathic hemolytic anemia, thrombocytopenia, and renal failure.1,2 Typical HUS is mostly caused by a Shiga toxin-producing Escherichia coli strain. Genetic variants associated with aHUS account for approximately 60% of the cases and are mainly limited to genes encoding factors that play roles in the alternative complement pathway regulation.1,3 This form has a poor prognosis, with approximately 60% of patients progressing to end-stage renal disease and a mortality rate of between 4% and 25%.1-3 Lemaire and colleagues recently reported that recessive mutations in the gene encoding for diacylglycerol kinase epsilon (DGKE) can cause HUS.4 Diacylglycerol kinase epsilon is an intracellular lipid kinase that phosphorylates diacylglycerol to phosphatidic acid and is present in endothelial cells, platelets, and podocytes.5 Reported pathological characteristics of DGKE mutations include thrombotic microangiopathy (TMA) and/or membranoproliferative glomerulonephritis (MPGN).6
Variants of DGKE are also found in families with aHUS characterized by MPGN.7 Although most patients present with a clinical and histologic picture that is consistent with HUS, a subgroup of patients show a membranoproliferative pattern of glomerular changes without signs of HUS.8,9 Nephrotic syndrome, as reported in some individuals with DGKE mutations, is characterized by heavy proteinuria (>3.5 g/d) and is universally associated with alterations of the podocyte cytoskeleton and effacement of podocyte foot processes.10 All previously identified causes of aHUS are associated with abnormal activation of the complement system, which does not occur in individuals with DGKE-associated nephropathy, establishing for the first time an alternate pathophysiological mechanism for aHUS. Notably, mutations in DGKE are not associated with activation of the complement pathway, which is the only other identified cause of this disorder so far.4,11 Therefore, the mechanisms by which mutations in DGKE result in aHUS are complex and unclear.4,12 These findings suggest that complement-regulatory treatment will be ineffective and that renal transplant may be successful in this subset of patients with aHUS without risk of relapse.4,8,9
Here, we have presented the different clinical presen-tations and treatments of 4 individuals in a consanguineous family with the same homozygous DGKE mutation of exon 2:c.473G>A(p.W158*). This case series could provide new data on the corresponding function analysis of the DGKE protein.
We present 4 individuals from a family with DGKE nephropathy. Patient 1, a 5-year, 3-month-old boy, was admitted to our center with nephrotic syndrome. He had unaffected consanguineous parents. Laboratory analyses showed normal complete blood count, normal serum creatinine level (0.6 mg/dL), low glomerular filtration rate (GFR; 91 mL/min/1.73 m2), normal serum electrolyte, low albumin (1.7 g/dL) and low protein (3.8 g/dL) levels, and nephrotic-range proteinuria (urine protein: 4+ stick). Both the complement C3 and C4 levels were normal. The patient was considered to have steroid-resistant nephrotic syndrome (SRNS), and biopsy showed MPGN. Partial remission was obtained with cyclophosphamide, cyclosporine, and mycophenolate mofetil. At present, he is 20 years old and has chronic kidney disease stage 2 at follow-up.
Patient 2, a 5-year, 7-month-old girl, was admitted with nephrotic syndrome. Laboratory findings showed a normal complete blood count, normal serum creatinine level (0.5 mg/dL), normal GFR (115 mL/min/1.73 m2), normal serum electrolyte, normal complement C3 and C4 levels, low albumin (3.8 g/dL) and protein (6.1 g/dL) levels, and nephrotic-range proteinuria (urine protein: 2+ stick). She was diagnosed with SRNS. Biopsy showed MPGN. The patient did not achieve remission with cyclophosphamide, cyclosporine, and mycophenolate mofetil. Persistent proteinuria was observed, GFR decreased below 15 mL/min/1.73 m2, and consequently hemodialysis was started. End-stage renal disease developed 10 years after the first admission. Kidney transplant was performed, and no relapse was observed at follow-up.
Patient 3, a 13-month-old girl, was admitted with nephrotic syndrome. Laboratory analyses showed normal complete blood count, normal serum creatinine level (0.48 mg/dL), normal GFR (111 mL/min/1.73 m2), normal serum electrolyte, low albumin (2.5 g/dL) and low protein (4.4 g/dL) levels, and nephrotic-range proteinuria (urine protein: 3+ stick). Because of the positive family history, kidney biopsy was performed. Biopsy showed MPGN, and spontaneous remission was obtained. Fifteen months after the first admission, the patient was referred to the hospital with aHUS. Laboratory findings showed high creatinine and blood urea nitrogen levels. Anemia, thrombocytopenia, and increased lactate dehydrogenase were also observed. However, serum complement C3 and C4 levels were both normal. Antinuclear antibody, anti-double-stranded DNA, cytoplasmic antineutrophil cytoplasmic antibody, perinuclear antineutrophil cytoplasmic antibody, and anti-ADAMTS13 antibody tests were all negative (ADAMTS13 activity was >10%). Complement factor antibody CFH, CFI, and CFB plasma levels was normal. Blood smears showed hemolysis. Histopathological findings were consistent with HUS. Stool tests were normal for Shiga toxin-producing Escherichia coli. Hemodialysis was performed because of hypervolemia. Partial remission was achieved with eculizumab treatment, and complete remission was achieved with combined treatment of plasma infusion and eculizumab, with treatment continued with plasma infusion.
Patient 4, a 7-month-old-boy who is the brother of patient 3, was screened for the mutation. Although genetic analysis showed the same mutation, he had no symptoms and no abnormal laboratory findings at first. However, proteinuria (18 mg/kg/d) and microscopic hematuria were detected during follow-up, and renal biopsy was performed. Biopsy showed MPGN and TMA in arterioles. Angiotensin-converting enzyme inhibitors were started, which have continued in follow-up (Table 1).
In 4 individuals in the same family with the same mutation, 2 patients exhibited clinical and histological MPGN without TMA, 1 patient progressed with clinical and histological HUS/MPGN overlap, and 1 patient showed nonnephrotic proteinuria but MPGN with TMA at biopsy at an early age. We did not observe a clear genotype-phenotype correlation, suggesting additional factors may mediate phenotypic heterogeneity for nephropathy of the DGKE.
We considered that DGKE-mediated HUS can res-pond to eculizumab treatment. With the benefits of anticomplement therapy being controversial. kidney transplant may be a viable option for these patients.
Among patients with DGKE nephropathy, 80% of patients have clinical association with aHUS accompanied by hypertension and nephrotic-range proteinuria with renal histological findings showing TMA.11 In 2013, Lemaire and colleagues reported that recessive mutations in DGKE cause aHUS and nephrotic syndrome and identified that recessive mutations in DGKE segregated with aHUS in unrelated individuals. In 86% of patients, DGKE-associated aHUS manifests in the first year of life, with a high risk of relapse in the first 5 years of life.4 About one-third of DGKE-associated aHUS patients show only mild alternative complement pathway dysregulation (low C3 and/or increased C5b-9 levels).11 Steroid-resistant nephrotic syndrome in children and young adults shows a different etiology, with monogenic disease accounting for 2.9% to 30% in selected series. There are also patients carrying pathogenic DGKE variants associated with MPGN or SRNS who present generally after 1 year of age with persistent nephrotic proteinuria and without complement abnormalities.7,11,13 Although 2 of our patients started as SRNS and were diagnosed as MPGN histopathologically, the result of a recurrent renal biopsy was compatible with focal segmental glomerulosclerosis at follow-up. One of our 2 patients was clinically asymptomatic in the early period, and the other patient exhibited the features of aHUS/MPGN. We performed genetic analysis, and the mutation exon 2:c.473G>A(p.W158*) was detected in all patients. As mentioned, DGKE-associated SRNS or MPGN usually manifests in patients after 1 year of age.7 A DGKE nephropathy associated with focal segmental glomerulosclerosis has been described in a patient who presented at 3 years of age, but there were no abnormalities in his blood count.13 In another report, 3 patients with in DGKE-associated aHUS developed nephrotic syndrome approximately 5 years after aHUS onset.4 Our cases are compatible with the literature and showed the common clinical features described in some patients with nephropathies associated with mutated DGKE.4,11 These patients presented with nephrotic proteinuria.
In conclusion, we presented patients with the mutated DGKE gene associated with different phenotypes. Our finding of a unique SRNS/aHUS overlap in 1 patient is remarkable and may contribute to the understanding of the clinical course in children with DGKE nephropathy. Unfortunately, we cannot fully clarify the causes of different disease manifestations based on clinical data only. Further functional studies are needed to understand the pathogenesis of various DGKE-associated nephropathies.
Volume : 20
Issue : 5
Pages : 45 - 48
DOI : 10.6002/ect.PediatricSymp2022.O13
From the 1Department of Pediatric Nephrology, Dr. Sami Ulus Maternity and Child Health and Diseases Training and Research Hospital; and the 2Departments of Pediatric Nephrology and Rheumatology and Medical Genetics, Hacettepe University Faculty of Medicine, Ankara, Turkey
Acknowledgements: The authors have not received any funding or grants in support of the presented research or for the preparation of this work and have no declarations of potential conflicts of interest.
Corresponding author: Evra Çelikkaya, Department of Pediatric Nephrology, Dr. Sami Ulus Maternity and Child Health and Diseases Training and Research Hospital, Ankara, Turkey
Phone: +90 5064713027
Table 1. Clinical Characteristics of the Patients Carrying the Diacylglycerol Kinase Epsilon Mutation