Management of diabetes-related hyperglycaemic emergencies in advanced chronic kidney disease: Review of the literature and recommendations.

AIMS: Despite the substantial progress in the management of diabetes mellitus (DM), chronic kidney disease (CKD) remains one of the most common complications. Although uncommon, diabetic emergencies [diabetic ketoacidosis (DKA), hyperosmolar hyperglycaemic state (HHS)] can still occur in stage 4 and 5 CKD, at times with less typical clinical manifestations due to the altered pathophysiology, presence of chronic metabolic acidosis and effect of haemodialysis on glycaemic control and metabolic parameters. The purpose of this article is to review the current literature and provide recommendations for the diagnosis and treatment of DKA, euglycaemic DKA and HHS in people with advanced CKD. METHODS AND RESULTS: Guidance on the management of diabetes-related emergencies mainly focuses on individuals with preserved renal function or early-stage CKD. Existing literature is limited, and recommendations are based on expert opinions and case reports. Given the clinical need for amended guidelines for this population, we are proposing a management algorithm for DKA and HHS based on clinical and metabolic parameters. CONCLUSIONS: In this review article, we propose treatment algorithms for diabetes-related hyperglycaemic emergencies in people with advanced CKD. Further research is needed to validate our proposed algorithms.

Effect of calcitriol treatment on arterial stiffness in people with type 2 diabetes and stage 3 chronic kidney disease.

AIMS: Active vitamin D deficiency is associated with increased aortic-pulse wave velocity (Ao-PWV) in people with type 2 diabetes (T2DM) and chronic kidney disease (CKD). There are no randomised controlled trials investigating the effect of active vitamin D treatment on Ao-PWV in people with T2DM and CKD. METHODS: A 48-week duration single-centre randomised double-blind parallel-group trial examined the impact of oral 1,25 dihydroxyvitamin D (calcitriol 0.25 mcg OD) as compared to placebo on a primary endpoint of Ao-PWV. People with T2DM and stable stage 3 CKD with intact parathyroid hormone (iPTH) level >30 pg/mL were eligible. RESULTS: In total, 127 (70% male) people were randomised (calcitriol n = 64 or placebo n = 63). There was no change in Ao-PWV observed, mean ± standard deviation (SD), in the calcitriol group of 11.79 (±2.5) to 12.08 (3.0) m/s as compared to 10.90 (±2.4) to 11.39 (±2.6) m/s with placebo. The between-treatment group adjusted mean (95% confidence interval [(CI]] change was 0.23 (-0.58 to 1.05) m/s, P = .57. No effect of calcitriol was observed on central arterial pressures, albuminuria, serum calcium or phosphate levels. However, iPTH fell with calcitriol treatment (mean [95% CI] between-group difference of -27.8 (-42.3 to -13.2) pg/mL, P < .001. CONCLUSION: In T2DM and stage 3 CKD, calcitriol as compared to placebo does not improve Ao-PWV or other markers of arterial stiffness. Our study does not provide evidence for the use of active vitamin D for improving arterial stiffness in T2DM with stage 3 CKD.

Prevalence of the BRAF V600E mutation in Greek adults with Langerhans cell histiocytosis.

Langerhans cell histiocytosis (LCH) is a rare inflammatory myeloid neoplasia with a broad spectrum of clinical manifestations. The activation of the MAP kinase pathway plays an integral role in its pathogenesis with genetic alterations found in the majority of cases that most frequently involve a somatic mutation of the oncogenic BRAFV600E variant. In this study we investigated the prevalence of the BRAFV600E mutation and its clinical relevance in adult Greek patients with LCH. Among 37 patients studied, the BRAFV600E mutation was identified in 12 out of 31 (38.7%), whereas in six patients (19.3%) the results were in conclusive. The presence of the mutation did not correlate with age at diagnosis, organ involvement, disease extent, response to initial treatment, development of diabetes insipidus and relapse risk. In our series the prevalence of the BRAFV600E mutation is at the lower range of the relative percentage found in children, but in line to that obtained in previous studies of adult patients with LCH that have found an up to 50% prevalence of the BRAFV600E mutation in these patients. Further studies with a larger number of adults are needed to identify the exact prevalence of mutations in the RAS-RAF-MEK-ERK pathway and their role on clinical parameters and disease outcomes.Supplemental data for this article is available online at https://doi.org/10.1080/08880018.2022.2029988 .

The annual incidence of Langerhans cell histiocytosis among adults living in Greece.

Langerhans cell histiocytosis (LCH) is a rare inflammatory myeloid neoplasia with a variable clinical course and outcome. Although there are some data regarding its incidence in children, such information in adults is lacking. To address the actual annual LCH incidence among adults, we prospectively recorded, during a 12-month period, any new case with a definitive histological diagnosis of LCH, among persons aged 18 and older living in Greece. Fourteen new cases were recorded corresponding to an annual incidence of 1.58 per million population. Female to male ratio was 1.34, and mean age at diagnosis was 43.5 years.

Minimal change disease following COVID-19 vaccination: A systematic review.

BACKGROUND: The newly developed COVID-19 vaccines are highly effective and safe. However, a small portion of vaccine recipients experience a wide range of adverse events. Recently, glomerular disease, including the development of Minimal Change Disease (MCD), has been observed after administration of different COVID-19 vaccines, although causality remains a matter of debate. AIM: The aim of this systematic review was to comprehensively examine the available literature and provide an overview of reported cases of MCD following vaccination against SARS-CoV-2. RESULTS: We identified 46 eligible articles which included 94 cases with MCD following COVID-19 vaccination of which one case was reported twice due to a second relapse. Fifty-five participants were males (59.1%, 55/93) and 38 (40.9%, 38/93) were females with a mean age of 45.02 years (SD:20.95). From the included patients 50 (50/94, 53.1%) were described as new-onset and 44 (46.9%, 44/94) as relapse. On average, symptomatology developed 16.68 days (SD: 22.85) after the administration of the vaccine irrespective of the dose. Data about symptoms was reported in 68 cases with the most common being oedema (80.8%, 55/68), followed by weight gain (26.5%, 18/68) and hypertension (16.1%, 11/68). In terms of outcome, more than half of the patients went into remission (61%, 57/94), while 18 recovered or improved post treatment (19.1%, 18/94). Two people relapsed after treatment (2.1%, 2/94) and two cases (2.1%, 2/94) were reported as not recovered. CONCLUSION: MCD is possibly a condition clinicians may see in patients receiving COVID-19 vaccines. Although this adverse event is uncommon, considering the limited published data and the absence of confirmed causality, increased clinical awareness is crucial for the early recognition and optimal management of these patients.

Presentation of new onset type 1 diabetes with diabetic ketoacidosis and hyperosmolar hyperglycaemia after a single dose of nivolumab and ipilimumab.

Summary: A Caucasian man in his 60s with recent diagnosis of metastatic renal cell carcinoma presented to the emergency department with a 5-day history of severe polyuria, polydipsia and fatigue and 1-day history of confusion, abdominal pain, nausea and vomiting. Investigations revealed an overlap of diabetic ketoacidosis (DKA) and hyperosmolar hyperglycaemic state (HHS). He had received the first dose of immunotherapy with nivolumab and ipilimumab 3 weeks prior to this attendance. New-onset type 1 diabetes (T1DM) was confirmed based on the clinical features at presentation, seropositivity for glutamic acid decarboxylase antibodies and significant insulin deficiency. He is currently on a multiple daily injections of insulin and uses intermittent-scanned glucose monitoring. Given the irreversible impact on beta-cell function and clinical response with insulin resulting in improved diabetes control, immunotherapy was resumed for his metastatic cancer with good radiological response. Although rare, new-onset T1DM can present with DKA and HSS overlap after a single dose of nivolumab/ipilimumab in individuals without pre-existing history of diabetes. Learning points: Although rare, new onset of T1DM after immunotherapy can present with DKA and HSS overlap after a single dose of nivolumab/ipilimumab in individuals without pre-existing history of diabetes and normal glycaemic parameters. Due to the irreversible destruction of beta-cells, treatment with steroids is not indicated in contrast to other settings such as immunotherapy-induced hypophysitis. Presence of low c-peptide levels post-acute presentation is indicative of an irreversible impact on beta-cell function and supports resuming immunotherapy given the significant benefits on cancer prognosis. Clinicians must maintain a high index of suspicion in regards to diagnosis and management of new-onset type 1 diabetes and advice patients on reporting symptoms suggestive of diabetes and/or diabetes-related hyperglycaemic emergencies.

Diabetes technology including automated insulin delivery systems to manage hyperglycemia in a failing pancreatic graft: Case series of people with type 1 diabetes and a pancreas kidney or pancreas-only transplant.

We share our experience of using continuous subcutaneous insulin infusion (CSII) therapy and diabetes technology in six people (5 men) with type 1 diabetes (mean duration 36 years), who developed hyperglycemia post-simultaneous kidney/pancreas (n = 5) or pancreas only (n = 1) transplant. All were on immunosuppression and multiple daily injections of insulin prior to CSII. Four people were started on automated insulin delivery, and two people on CSII and intermittently scanned continuous glucose monitoring. With diabetes technology, the median time in range glucose improved from 37% (24-49%) to 56.6% (48-62%), and similarly, glycated hemoglobin fell from 72.7 mmol/mol (72-79 mmol/mol) to 64 mmol/mol (42-67 mmol/mol; P < 0.05 for both) with no concomitant increase in hypoglycemia. Use of diabetes technology improved glycemic parameters in people with type 1 diabetes with failing pancreatic graft function. Early use of such technology should be considered to improve diabetes control in this complex cohort.

COVID-19 induced type 1 diabetes: A systematic review of case reports and series.

AIMS: To provide an overview of reported cases of new-onset type 1 diabetes mellitus (T1D) following COVID-19 infection. METHODS: PubMed and Scopus library databases were screened for relevant case reports published between January 2020 and June 2022. Study design, geographic region or language were not restricted. RESULTS: Twenty studies were identified and involved 37 patients (20 [54%] male, 17 [46%] female). Median age was 11.5 years (range 8 months-33 years) and 31 (84%) patients were aged ≤17 years. Most patients (33, 89%) presented with diabetic ketoacidosis (DKA). In total, 23 (62%) patients presented at the time of positive COVID-19 testing and 14 (38%) had symptoms consistent with COVID-19 infection or a previous positive test (1-56 days). Diabetes symptomatology was provided in 22 cases and (19, 86%) reported polyuria, polydipsia, polyphagia, fatigue, or weight loss or a combination of the aforementioned in the preceding weeks (3 days-12 weeks). Of the 28 patients that had data on acute and long-term treatment, all recovered well and most were managed with basal bolus insulin regimens. Quality assessment showed that most reports were either 'good' or 'moderate quality'. CONCLUSIONS: Although uncommon, new-onset T1D is a condition healthcare professionals may expect to see following a COVID-19 infection.

Impact of treatment with active vitamin D calcitriol on bone turnover markers in people with type 2 diabetes and stage 3 chronic kidney disease.

People with diabetes and chronic kidney disease (CKD) are predisposed to bone mineral disorders and increased fracture risk. There is limited data on the effect of calcitriol on bone turnover markers (BTMs) in people with type 2 diabetes (T2DM) and stage 3 CKD. In a pre-specified secondary endpoint analysis of a 48-week randomized placebo controlled double-blind trial, we studied the effects of oral calcitriol 0.25 µg once daily on circulating BTMs that included osteocalcin (OCN), C-terminal telopeptide of type I collagen (CTXI), procollagen type I N-propeptide (PINP) and fibroblast growth factor-23 (FGF-23). Inclusion criteria were people with T2DM with stable stage 3 CKD stage and intact parathyroid hormone (iPTH) >30 pg/ml. In total, 127 people [calcitriol (n = 64), placebo (n = 63)] were eligible for analyses. Baseline median (interquartile range) age of the cohort was 67 (60.5-70) years, iPTH (median range) 73.9 (55, 105) pg/ml and eGFR 40 (33, 48.5) ml/min. Calcitriol treatments resulted in a significant fall in iPTH, CTX, PINP and OCN levels and rise FGF-23, with mean (95 % confidence interval) between group differences in iPTH [-27.8 pg/ml; 95 % CI (-42.3 to -13.2); p < 0.001], FGF-23 [30.6 pg/ml; 95 % CI (14.8 to 46.3); p < 0.001], CTX [0.12 µg/l; 95 % CI (-0.19 to -0.06); (p < 0.001) and OCN [-4.03 ng/ml; 95 % CI (-7.8 to -0.27); p = 0.036]. Similarly we observed with calcitriol, as between treatment percentage change, a reduction of -38 % for iPTH, -34 % for CTX, and -28 % for OCN levels respectively (p < 0.05 for all). In people with T2DM and stage 3 CKD, calcitriol reduces the levels of CTX, OCN, PINP and iPTH. Further studies are needed to assess the clinical significance of our findings and the related long term impact on bone health.

Graves' disease following vaccination against SARS-CoV-2: A systematic review of the reported cases.

The newly developed COVID-19 vaccines have established a safe profile, yet some individuals experience a wide range of adverse events. Recently, thyroid dysfunction, including Graves' disease, has been observed after administration of different COVID-19 vaccines, although causality remains a matter of debate. The aim of this systematic review was to examine the available literature and provide an overview of reported cases of Graves' disease following COVID-19 vaccination. We identified 21 eligible articles which included 57 patients with Graves' disease following COVID-19 vaccination. Fourteen participants were males (25%, 14/57) and 43 (75%, 44/57) were females with a mean age of 44.3 years. The most common presenting symptom was palpitations (63%, 27/43) followed by weight loss (35%, 15/43). The majority of patients received thionamides (47%, 25/53). The clinical status after treatment was provided for 37 patients and it was improved in the majority of them (84%, 31/37). Graves' disease is possibly a condition clinicians may expect to encounter in patients receiving COVID-19 vaccines. While the above adverse event is rare, considering the scarcity of available data in scientific literature, and causality is not yet confirmed, the increased awareness of clinicians and the early recognition of the disorder are important for the optimal management of these patients.

Does Dapagliflozin influence arterial stiffness and levels of circulating anti-aging hormone soluble Klotho in people with type 2 diabetes and kidney disease? Results of a randomized parallel group clinical trial.

Objective: The mechanisms that explain the cardio-renal benefits of sodium glucose co-transporter 2 (SGLT-2) inhibitors are unknown. The effect of SGLT-2 inhibitors on arterial aging, measured by Aortic Pulse Wave Velocity (Ao-PWV) and Soluble Klotho (s-Klotho), a circulating anti-aging biomarker of arterial health are also unclear. Design/Setting: A 24-week single center randomized controlled trial (registry number/ EudraCT Number: 2013-004042-42) comparing Dapagliflozin and Ramipril (D+R) versus Ramipril (R) on the primary endpoint of urine albumin excretion rate (AER) and pre-specified secondary endpoints of Ao-PWV and biomarkers of arterial aging [s-Klotho and Fibroblast Growth Factor 23 (FGF-23)]. People with type 2 diabetes who had estimated glomerular filtration rate (eGFR) > 60 ml/min and residual microalbuminuria on maximum tolerated renin angiotensin system (RAS) inhibition were included in this study. Results: In total, 33 participants (male 73%) were randomized to either D+R (n = 17) or R (n = 16) arms. After 24 weeks of treatment, Ao-PWV (mean ± SD) did not change significantly from baseline D +R [9.06 ± 1.91 m/s to 9.13 ± 2.03 m/s], and R [9.88 ± 2.12 m/s to 10.0 ± 1.84 m/s]. AER fell significantly by 43.5% (95% CI: -57.36%, -29.56%; p < 0.01) in people in the D+ R arm only. We do not observe any significant changes in FGF-23 or s-Klotho. HbA1c and Angiotensin 1-7 fell significantly only in D + R arm. Conclusions: The combination of Dapagliflozin and Ramipril had no effects on Ao-PWV and s-Klotho which are biomarkers of arterial aging and cardio-renal risk. Our data suggest that the early cardio-renal benefits observed with SGLT-2 inhibitors are unlikely to be related to an improvement in arterial aging.