Clinical profile of patients with diabetic ketoacidosis and hyperglycemic hyperosmolar syndrome in Japan: a multicenter retrospective cohort study.

INTRODUCTION: Diabetic ketoacidosis (DKA) and hyperglycemic hyperosmolar syndrome (HHS) are life-threatening complications of diabetes mellitus. Their clinical profiles have not been fully investigated. METHODS: A multicenter retrospective cohort study was conducted in 21 acute care hospitals in Japan. Patients included were adults aged 18 or older who had been hospitalized from January 1, 2012, to December 31, 2016 due to DKA or HHS. The data were extracted from patient medical records. A four-group comparison (mild DKA, moderate DKA, severe DKA, and HHS) was performed to evaluate outcomes. RESULTS: A total of 771 patients including 545 patients with DKA and 226 patients with HHS were identified during the study period. The major precipitating factors of disease episodes were poor medication compliance, infectious diseases, and excessive drinking of sugar-sweetened beverages. The median hospital stay was 16 days [IQR 10-26 days]. The intensive care unit (ICU) admission rate was 44.4% (mean) and the rate at each hospital ranged from 0 to 100%. The in-hospital mortality rate was 2.8% in patients with DKA and 7.1% in the HHS group. No significant difference in mortality was seen among the three DKA groups. CONCLUSIONS: The mortality rate of patients with DKA in Japan is similar to other studies, while that of HHS was lower. The ICU admission rate varied among institutions. There was no significant association between the severity of DKA and mortality in the study population. TRIAL REGISTRATION: This study is registered in the UMIN clinical Trial Registration System (UMIN000025393, Registered 23th December 2016).

Epidemiology, microbiology, and diagnosis of infection in diabetic ketoacidosis and hyperosmolar hyperglycemic syndrome: A multicenter retrospective observational study.

AIMS: We investigated the characteristics of infection and the utility of inflammatory markers in diabetic ketoacidosis (DKA) and hyperosmolar hyperglycemic syndrome (HHS). METHODS: A multicenter, retrospective observational study in 21 acute-care hospitals was conducted in Japan. This study included adult hospitalized patients with DKA and HHS. We analyzed the diagnostic accuracy of markers including C-reactive protein (CRP) and procalcitonin (PCT) for bacteremia. Multiple regression models were created for estimating bacteremia risk factors. RESULTS: A total of 771 patients, including 545 patients with DKA and 226 patients with HHS, were analyzed. The mean age was 58.2 (SD, 19.3) years. Of these, 70 tested positive for blood culture. The mortality rates of those with and without bacteremia were 14 % and 3.3 % (P-value < 0.001). The area under the curve (AUC) of CRP and PCT for diagnosis of bacteremia was 0.85 (95 %CI, 0.81-0.89) and 0.76 (95 %CI, 0.60-0.92), respectively. Logistic regression models identified older age, altered level of consciousness, hypotension, and higher CRP as risk factors for bacteremia. CONCLUSIONS: The mortality rate was higher in patients with bacteremia than patients without it. CRP, rather than PCT, may be valid for diagnosing bacteremia in hyperglycemic emergencies. TRIAL REGISTRATION: This study is registered in the UMIN clinical trial registration system (UMIN000025393, Registered December 23, 2016).

High versus low chloride load in adult hyperglycemic emergencies with acute kidney injury: a multicenter retrospective cohort study.

Hyperglycemic emergencies frequently lead to acute kidney injury (AKI) and require treatment with large amount of intravenous fluids. However, the effects of chloride loading on this population have not yet been investigated. We conducted a multicenter, retrospective, cohort study in 21 acute-care hospitals in Japan. The study included hospitalized adult patients with diabetic ketoacidosis (DKA) and hyperosmolar hyperglycemic syndrome (HHS) who had AKI upon arrival. The patients were classified into high and low chloride groups based on the amount of chloride administered within the first 48 h of their arrival. The primary outcome was recovery from AKI; secondary outcome was major adverse kidney events within 30 days (MAKE30), including mortality and prolonged renal failure. A total of 390 patients with AKI, including 268 (69%) with DKA and 122 (31%) with HHS, were included in the study. Using the criteria of Kidney Disease Improving Global Outcomes, the severity of AKI in the patients was Stage 1 (n = 159, 41%), Stage 2 (n = 121, 31%), and Stage 3 (n = 110, 28%). The analysis showed no significant difference between the two groups in recovery from AKI (adjusted hazard ratio, 0.96; 95% CI 0.72-1.28; P = 0.78) and in MAKE30 (adjusted odds ratio, 0.91; 95% CI 0.45-1.76; P = 0.80). Chloride loading with fluid administration had no significant impact on recovery from AKI in patients with hyperglycemic emergencies.Trial Registration This study was registered in the UMIN clinical trial registration system (UMIN000025393, registered December 23, 2016).

A case of severe acute hyponatremia after colonoscopy with polyethylene glycol plus ascorbic acid bowel preparation.

Previous reports have shown that bowel preparation can, in extremely rare circumstances, induce severe acute hyponatremia. Polyethylene glycol plus ascorbic acid as a bowel preparation is considered relatively safe with a smaller amount of free water load and a more pleasant taste with additives.We present the case of an 86-year-old man who developed severe acute hyponatremia presenting with tremor and impaired consciousness after colonoscopy, which is life-threatening. The severe hyponatremia in our case was not caused by free water loads from drinking large amounts of water during bowel preparation or hypovolemia due to bowel preparation-induced nausea, vomiting, and diarrhea, but might have been due to non-osmotic stimuli of antidiuretic hormone (ADH) release (i.e., pre-existing nausea, stress, anxiety, pain, stress, or the colonoscopy itself). Our study indicates that it is important to choose safer bowel preparation solutions, to be aware of ingested water volumes, to assess volume status, and also remain aware of other coexisting risk factors for acute hyponatremia, such as medical history, medication, and ADH release, especially in elderly patients.

Non-occlusive Mesenteric Ischemia with Significant Hyperphosphatemia.

An 86-year-old Japanese woman was referred to our hospital due to the sudden onset of abdominal pain. Abdominal contrast-enhanced computed tomography (CT) revealed no signs of ischemic bowel; however, laboratory investigations revealed metabolic lactic acidosis, elevation of inflammatory markers, and a remarkable elevation in the serum phosphate level. A prompt surgical evaluation revealed non-occlusive mesenteric ischemia (NOMI). Elevated serum phosphate levels may suggest extensive bowel ischemia or infarction, which can lead to a prompt surgical evaluation, even in the absence of specific radiological findings.

Case report of acute myocarditis after administration of coronavirus disease 2019 vaccine in Japan.

BACKGROUND: The worldwide spread of coronavirus disease 2019 (COVID-19) is still not under control and vaccination in Japan started in February 2021, albeit later than in Europe and the USA. The COVID-19 vaccination frequently leads to minor adverse reactions, which may be more intense after the second dose. The number of case reports of myocarditis following COVID-19 vaccination have been recently increased. CASE SUMMARY: We report a case of a 26-year-old healthy man who presented to our hospital with chest pain on 24 May 2021, 4 days after his second COVID-19 vaccination. The electrocardiogram showed ST elevation with upward concavity in I, II, aVL, aVF, V4 to V6, and small Q wave in II, III, aVF. Laboratory studies revealed elevation of troponin I, creatine kinase, C-reactive protein, and negative viral serologies. Acute aortic dissection and pulmonary thromboembolism were ruled out by contrast-enhanced thoracoabdominal computed tomography. An urgent coronary angiogram was performed because an acute coronary syndrome was suspected, but no significant stenosis was found. Cardiac magnetic resonance imaging demonstrated oedema and late gadolinium enhancement of the left ventricle in a mid-myocardial and epicardial distribution. DISCUSSION: Although the temporal association does not prove causation, the very short span between the second vaccination and the onset of myocarditis suggests that this acute myocarditis seemed to be an adverse reaction to COVID-19 vaccine. To the best of our knowledge, this is the first published case of acute myocarditis following COVID-19 vaccine in Asia.

Fenofibrate, a PPARα agonist, has renoprotective effects in mice by enhancing renal lipolysis.

As renal lipotoxicity can lead to chronic kidney disease (CKD), we examined the role of peroxisome proliferator-activated receptor (PPAR)-α, a positive regulator of renal lipolysis. Feeding mice a high-fat diet induced glomerular injury, and treating them with fenofibrate, a PPARα agonist, increased the expression of lipolytic enzymes and reduced lipid accumulation and oxidative stress in glomeruli, while inhibiting the development of albuminuria and glomerular fibrosis. In mice given an overload of free fatty acid-bound albumin to induce tubulointerstitial injury, fenofibrate attenuated the development of oxidative stress, macrophage infiltration, and fibrosis, and enhanced lipolysis in the renal interstitium. Fenofibrate inhibited palmitate-induced expression of profibrotic plasminogen activator inhibitor-1 (PAI-1) in cultured mesangial cells, and the expression of both monocyte chemoattractant protein-1 and PAI-1 in proximal tubular cells along with the overexpression of lipolytic enzymes. Thus, fenofibrate can attenuate lipotoxicity-induced glomerular and tubulointerstitial injuries, with enhancement of renal lipolysis. Whether amelioration of renal lipotoxicity by PPARα agonists will turn out to be a useful strategy against CKD will require direct testing.

Cerebral microvascular disease predicts renal failure in type 2 diabetes.

Abnormalities in small renal vessels may increase the risk of developing impaired renal function, but methods to assess these vessels are extremely limited. We hypothesized that the presence of small vessel disease in the brain, which manifests as silent cerebral infarction (SCI), may predict the progression of kidney disease in patients with type 2 diabetes. We recruited 608 patients with type 2 diabetes without apparent cerebrovascular or cardiovascular disease or overt nephropathy and followed them for a mean of 7.5 years. At baseline, 177 of 608 patients had SCI, diagnosed by cerebral magnetic resonance imaging. The risk for the primary outcome of ESRD or death was significantly higher for patients with SCI than for patients without SCI [hazard ratio, 2.44; 95% confidence interval (CI) 1.36 to 4.38]. The risk for the secondary renal end point of any dialysis or doubling of the serum creatinine concentration was also significantly higher for patients with SCI (hazard ratio, 4.79; 95% CI 2.72 to 8.46). The estimated GFR declined more in patients with SCI than in those without SCI; however, the presence of SCI did not increase the risk for progression of albuminuria. In conclusion, independent of microalbuminuria, cerebral microvascular disease predicted renal morbidity among patients with type 2 diabetes.

Oleate and eicosapentaenoic acid attenuate palmitate-induced inflammation and apoptosis in renal proximal tubular cell.

Free fatty acid (FFA)-bound albumin, which is filtrated through the glomeruli and reabsorbed into proximal tubular cells, is one of the crucial mediators of tubular damage in proteinuric kidney disease. In this study, we examined the role of each kind of FFA on renal tubular damage in vitro and tried to identify its molecular mechanism. In cultured proximal tubular cells, a saturated fatty acid, palmiate, increased the expression of monocyte chemoattractant protein-1 (MCP-1), but this effect was abrogated by co-incubation of monounsaturated fatty acid, oleate, or ω-3 polyunsaturated fatty acid, eicosapentaenoic acid (EPA). Palmitate led to intracellular accumulation of diacylglycerol (DAG) and subsequent activation of protein kinase C protein family. Among the several PKC inhibitors, rottlerin, a PKCθ inhibitor, prevented palmitate-induced MCP-1 expression via inactivation of NFB pathway. Overexpression of dominant-negative PKCθ also inhibited palmitate-induced activation of MCP-1 promoter. Furthermore, palmitate enhanced PKCθ-dependent mitochondrial apoptosis, which was also prevented by co-incubation with oleate or EPA through restoration of pro-survival Akt pathway. Moreover, oleate and EPA inhibited palmitate-induced PKCθ activation through the conversion of intracellular DAG to triglyceride with the restoration of diacylglycerol acyltransferase 2 expression. These results suggest that oleate and EPA have protective effects against the palmitate-induced renal tubular cell damage by inhibiting PKCθ activation.

Renoprotective effects of asialoerythropoietin in diabetic mice against ischaemia-reperfusion-induced acute kidney injury.

AIM: Diabetic patients are at higher risk of failure to recover after acute kidney injury, however, the mechanism and therapeutic strategies remain unclear. Erythropoietin is cytoprotective in a variety of non-haematopoietic cells. The aim of the present study was to clarify the mechanism of diabetes-related acceleration of renal damage after ischaemia-reperfusion injury and to examine the therapeutic potential of asialoerythropoietin, a non-haematopoietic erythropoietin derivative, against ischaemia-reperfusion-induced acute kidney injury in diabetic mice. METHODS: C57BL/6J mice with and without streptozotocin-induced diabetes were subjected to 30 min unilateral renal ischaemia-reperfusion injury at 1 week after induction of diabetes. They were divided into four group: (i) non-diabetic plus ischaemia-reperfusion injury; (ii) non-diabetic plus ischaemia-reperfusion injury plus asialoerythropoietin (3000 IU/kg bodyweight); (iii) diabetic plus ischaemia-reperfusion injury; and (iv) diabetic plus ischemia-reperfusion injury plus asialoerythropoietin. Experiments were conducted at the indicated time periods after ischaemia-reperfusion injury. RESULTS: Ischaemia-reperfusion injury of diabetic kidney resulted in significantly low protein expression levels of bcl-2, an anti-apoptotic molecule, and bone morphogenetic protein-7 (BMP-7), an anti-fibrotic and pro-regenerative factor, compared with non-diabetic kidneys. Diabetic kidney subsequently showed severe damage including increased tubular cell apoptosis, tubulointerstitial fibrosis and decreased tubular proliferation, compared with non-diabetic kidney. Treatment with asialoerythropoietin induced bcl-2 and BMP-7 expression in diabetic kidney and decreased tubular cell apoptosis, tubulointerstitial fibrosis and accelerated tubular proliferation. CONCLUSION: Reduced induction bcl-2 and BMP-7 may play a role in the acceleration of renal damage after ischaemia-reperfusion injury in diabetic kidney. The renoprotective effects of asialoerythropoietin on acute kidney injury may be mediated through the induction of bcl-2 and BMP-7.

[Case of minocycline-induced vasculitic neuropathy].

A 70-year-old woman was admitted to our hospital because of fever, numbness in her extremities and right drop foot. Because her hip prosthesis had loosened as a result of infection, she had been taking 100 mg of minocycline orally for eight months. Three months before admission, she had had melena several times and body weight loss and pyrexia developed. A month before admission, asymmetrical paresthesia and numbness appeared in her extremities and finally right drop foot developed. Laboratory tests showed elevated C-reactive protein and positive anti-nuclear antibody. Abnormalities found in nerve conduction study were compatible with mononeuritis multiplex. Sural nerve biopsy revealed an occluded medium-size artery in the epineurium and axonal degeneration in the nerve fascicles, confirming the diagnosis of vasculitic neuropathy. These manifestations met the American Congress Rheumatology criteria for polyarteritis nodosa. However, her clinical conditions markedly improved after discontinuing minocycline and therefore she was diagnosed as having minocycline-induced vasculitic neuropathy. Although minocycline-induced vasculitis is a well known adverse effect of the drug, peripheral neuropathy with biopsy findings has rarely been reported. Drug induced-vasculitis is important as a differential diagnosis for mononeuritis multiplex because the symptoms can be improved by the discontinuation of an offending drug.

Exendin-4 has an anti-hypertensive effect in salt-sensitive mice model.

The improvement of salt-sensitive hypertension is a therapeutic target for various vascular diseases. Glucagon-like peptide 1 (GLP-1), an incretin peptide, has been reported to have natriuretic effect as well as blood glucose lowering effect, although its exact mechanism and clinical usefulness remain unclear. Here, we examined anti-hypertensive effect of exendin-4, a GLP-1 analog, in salt-sensitive obese db/db mice and angiotensin II (angII)-infused C57BLK6/J mice. The treatment of exendin-4 for 12 weeks inhibited the development of hypertension in db/db mice. In db/db mice, the urinary sodium excretion was delayed and blood pressure was elevated in response to a high-salt load, whereas these were attenuated by exendin-4. In db/db mice, intra-renal angII concentration was increased. Furthermore, exendin-4 prevented angII-induced hypertension in non-diabetic mice and inhibited angII-induced phosphorylation of ERK1/2 in cultured renal cells. Considered together, our results indicate that exendin-4 has anti-hypertensive effects through the attenuation of angII-induced high-salt sensitivity.

Asialoerythropoietin prevents contrast-induced nephropathy.

Strategies to prevent contrast-induced nephropathy (CIN) are suboptimal. Erythropoietin was recently found to be cytoprotective in a variety of nonhematopoietic cells, so it was hypothesized that the nonhematopoietic erythropoietin derivative asialoerythropoietin would prevent CIN. Nephropathy was induced in rats by injection of the radiocontrast medium Ioversol in addition to inhibition of prostaglandin and nitric oxide synthesis. Administration of a single dose of asialoerythropoietin before the induction of nephropathy significantly attenuated the resulting renal dysfunction and histologic renal tubular injury. Contrast-induced apoptosis of renal tubular cells was inhibited by asialoerythropoietin both in vivo and in vitro, and this effect was blocked by a Janus kinase 2 (JAK2) inhibitor in vitro. Furthermore, phospho-JAK2/signal transducer and activator of transcription 5 (STAT5) and heat-shock protein 70 increased after injection of asialoerythropoietin, suggesting that the effects of asialoerythropoietin may be mediated by the activation of the JAK2/STAT5 pathway. Overall, these findings suggest that asialoerythropoietin may have potential as a new therapeutic approach to prevent CIN given its ability to preserve renal function and directly protect renal tissue.

A case of Castleman's disease complicated with nephrotic syndrome due to glomerulopathy mimicking membranoproliferative glomerulonephritis.

Castleman's disease is a rare atypical lymphoproliferative disorder. Renal manifestations, such as proteinuria, hematuria, and renal dysfunction, are common in Castleman's disease; however, a nephrotic syndrome rarely occurs. We have encountered an unusual case of Castleman's disease of the plasma cell type characterized by nephrotic syndrome because of glomerulopathy mimicking membranoproliferative glomerulonephritis. Our patient showed higher levels of circulating cytokines (interleukin-6/vascular endothelial cell-derived growth factor), the glomerular lesions not associated with immunocomplex deposition, and the resolution of nephrotic syndrome after successful corticosteroids therapy resulting in a decline in cytokines levels, thereby implicating a cytokine-induced glomerular cell injury/activation as a possible cause of the glomerular pathological changes in this case.

Emerging lupus-like manifestations in acute parvovirus B19 infection.

We encountered an adult patient with acute parvovirus B19 infection who presented with transient lupus-like symptoms (i.e., polyarthritis, fever, myalgia, pancytopenia, hypocomplementemia, and nephritis). Our case is characterized by the demonstration of acute nephritis as a complication of this infection, making it difficult to distinguish between a viral infection and the first episode of systemic lupus erythematosus.

Legumain/asparaginyl endopeptidase controls extracellular matrix remodeling through the degradation of fibronectin in mouse renal proximal tubular cells.

Legumain/asparaginyl endopeptidase (EC 3.4.22.34) is a novel cysteine protease that is abundantly expressed in the late endosomes and lysosomes of renal proximal tubular cells. Recently, emerging evidence has indicated that legumain might play an important role in control of extracellular matrix turnover in various pathological conditions such as tumor growth/metastasis and progression of atherosclerosis. We initially found that purified legumain can directly degrade fibronectin, one of the main components of the extracellular matrix, in vitro. Therefore, we examined the effect of legumain on fibronectin degradation in cultured mouse renal proximal tubular cells. Fibronectin processing can be inhibited by chloroquine, an inhibitor of lysosomal degradation, and can be enhanced by the overexpression of legumain, indicating that fibronectin degradation occurs in the presence of legumain in lysosomes from renal proximal tubular cells. Furthermore, in legumain-deficient mice, unilateral ureteral obstruction (UUO)-induced renal interstitial protein accumulation of fibronectin and renal interstitial fibrosis were markedly enhanced. These findings indicate that legumain might have an important role in extracellular matrix remodeling via the degradation of fibronectin in renal proximal tubular cells.

The occurrence of systemic lupus erythematosus in an asymptomatic carrier of human T-cell lymphotropic virus type I.

A 63-year-old asymptomatic carrier of human T-cell lymphotropic virus type I (HTLV-1) infection was admitted because of chest oppression, a high-grade fever, polyarthralgia, and erythematous rashes. Laboratory examination revealed lymphocytopenia, proteinuria, and high titers of antinuclear antibodies and antidouble-stranded DNA antibody; thus, she was diagnosed as having systemic lupus erythematosus (SLE). This case indicates that HTLV-1 infection might be related with the pathogenesis of SLE.

A case of myeloperoxidase-antineutrophil cytoplasmic antibody positive-polyarteritis nodosa complicated by interstitial pneumonia and rapidly progressive renal failure.

A 73-year-old woman was admitted to our hospital because of persistent high fever and cough, generalized myalgia, and renal dysfunction. Laboratory examination revealed severe inflammatory signs, pulmonary fibrosis, progression of renal impairment with active nephritic urinary sediments, and a high titer of myeloperoxidase-antineutrophil cytoplasmic antibody, indicating that she might have microscopic polyangiitis with interstitial pneumonia and rapidly progressive glomerulonephritis. Her renal biopsy, however, showed tubulointerstitial changes with mild glomerular abnormalities, and renal angiography revealed that she had vascular lesions of medium-sized arteries, which were compatible with classical polyarteritis nodosa. Tissue biopsy of the clinically affected organ should be considered in anyone suspected to have vasculitis.

Massive pericardial effusion secondary to Hashimoto's disease.

Although relatively rare, hypothyroidism remains a significant cause of moderate to severe pericardial effusion. Pericardial effusion secondary to hypothyroidism does not usually cause symptoms since it tends to regress slowly and ultimately disappear several months after the patient has reverted to the euthyroid state. Thus, hypothyroidism must be ruled out in patients with an unexplained pericardial effusion, both to improve prognosis and to avoid unnecessary pericardiocentesis. Even when they have a massive pericardial effusion, patients should receive the standard treatment for hypothyroidism. We herein describe a 79-year-old woman with a massive pericardial effusion associated with hypothyroidism who showed a good response to standard levothyroxine replacement therapy after 5months.