A novel heterozygous mutation in the SLC5A2 gene causing severe glycosuria, mild failure to thrive, and subclinical hypoglycemia.

Highlights A novel heterozygous mutation in the SLC5A2 gene in a 2-year-old girl with severe asymptomatic glycosuria, mild failure to thrive, and subclinical hypoglycemia: Continuous glucose monitoring identified 14% hypoglycemic excursions (< 70 mg/dl), reduced at 1% with 1 g/Kg uncooked cornstarch at bed-time milk and eliminated (0%) adjusting the dose at 1.5 g/Kg, as shown by Flash technology.

Non-diabetic glycosuria as a diagnostic clue for acute tubulointerstitial nephritis in patients with azotemia.

BACKGROUND: Glycosuria is one of the manifestations of acute tubulointerstitial nephritis (ATIN), but may also be observed in other renal diseases. In this study, we investigated the value of non-diabetic glycosuria as a diagnostic clue for ATIN. METHODS: We retrospectively reviewed the medical records of adult patients who underwent a kidney biopsy as an evaluation for serum creatinine > 1.4 mg/dL. Patients with proteinuria in the nephrotic range, diabetes mellitus, or transplanted kidney were excluded. The laboratory abnormalities suggestive of tubular injury were compared between 28 patients (14 men and 14 women, mean age 48.5 ± 14.1 years) with ATIN and 116 patients (76 men and 40 women, mean age 53.1 ± 15.0 years) with other diagnoses. RESULTS: In ATIN, glycosuria (≥ 1+ on dipstick; 68%) was more frequent than hypophosphatemia (18%), hypouricemia (18%), hypokalemia (18%), and tubular proteinuria (40%). In other diagnoses, glycosuria (≥ 1+) was detected in 7 (6%) patients; 6 of them had the histological diagnosis of antineutrophil cytoplasmic antibody-associated glomerulonephritis. The presence of glycosuria (≥ 1+) had 68% sensitivity and 94% specificity for ATIN, with the positive likelihood ratio of 11.24 and the negative likelihood ratio of 0.34. Pyuria and low total CO2 were equally and more sensitive (68% and 71%, respectively) than glycosuria (≥ 1+), but had no diagnostic value due to low specificities (58% and 60%, respectively). CONCLUSION: In non-diabetic, non-nephrotic patients undergoing a kidney biopsy for azotemia, 1+ or higher glycosuria, if present, was a good predictor of the diagnosis of ATIN.

Western Diet Promotes Renal Injury, Inflammation, and Fibrosis in a Murine Model of Alström Syndrome.

INTRODUCTION: Alström syndrome is a rare recessive genetic disease caused by mutations in ALMS1, which encodes a protein that is related to cilia function and intracellular endosome trafficking. The syndrome has been linked to impaired glucose metabolism and CKD. Polymorphisms in Alms1 have likewise been linked to CKD, but little is known about the modification of the phenotype by environmental factors. METHODS: To gain further insights, the fat aussie (foz) mouse strain, a genetic murine model of Alström syndrome, was exposed to a normal chow (NC) or to a Western diet (WD, 20% fat, 34% sucrose by weight, and 0.2% cholesterol) and renal outcomes were measured. RESULTS: Body weight and albuminuria were higher in foz than in wild-type (WT) mice on both diets but WD significantly increased the difference. Measurement of plasma creatinine and cystatin C indicated that glomerular filtration rate was preserved in foz versus WT independent of diet. Renal markers of injury, inflammation, and fibrosis were similar in both genotypes on NC but significantly greater in foz than in WT mice on WD. A glucose tolerance test performed in foz and WT mice on WD revealed similar basal blood glucose levels and subsequent blood glucose profiles. CONCLUSIONS: WD sensitizes a murine model of Alström syndrome to kidney injury, inflammation, and fibrosis, an effect that may not be solely due to effects on glucose metabolism. Polymorphisms in Alms1 may induce CKD in part by modulating the deleterious effects of high dietary fat and sucrose on kidney outcome.

Nephrological disorders and neurological involvement in pediatric primary Sjogren syndrome:a case report and review of literature.

BACKGROUND: Sjögren syndrome (SS) is a rare disease in pediatrics, and little attention has been paid to the clinical feature in these patients. To date, there are few cases concern about neurological and nephrological disorders in childhood Sjögren syndrome. We describe a case of Sjögren syndrome in a 12-year-old girl who developed neurological disorders and interstitial nephritis and review the literature currently available on this topic. CASE PRESENTATION: A 12-year-old girl was admitted to our hospital for arthritis and glucosuria. She was required to do labial gland and renal biopsy, because the positive for anti-nuclear antibody and anti-Sjögren syndrome B (anti-SSB) antibody. Then the biopsy was performed revealing the lymphocytic infiltrate in the small area and renal tubular interstitial damage,thus the diagnosis of Sjögren syndrome with tubular interstitial damage was made. Three months later, she presented again with headache, fever, nausea, vomiting and was recovered without drug therapy. Based on the patient's medical history, laboratory and imaging examination, and treatment, we speculate that the disorders of the nervous system were caused by the Sjögren syndrome. The girl has stable renal function and no residual nervous system damage in the next 1.5 years, but she underwent low dose prednisone therapy because of persistent renal glucosuria. CONCLUSIONS: Nephrological disorders and neurological involvement are rare manifestations of Sjögren syndrome in children, and rarely presented as the initial symptoms. It should be suspected in children presenting with unexplained renal diseases, neurological abnormalities, or unexplained fever. Although there is no guidelines on the diagnosis and treatment of children Sjögren syndrome are currently available, early recognition and the appropriate treatment of renal damage and neurologic involvement would improve prognosis and prevent complications.

Can we contribute to the diagnosis of diabetes and regulation of blood glucose by increasing the urologists' awareness of glucosuria?

AIMS: Diabetes mellitus is a progressive, chronic, systemic, metabolic disease that must be managed effectively. Its prevalence is increasing rapidly. We investigated whether urologists' awareness and recognition of glucosuria contributed to the diagnosis of diabetes and regulation of blood glucose. METHODS: A total of 39,053 patients were retrospectively evaluated between January 2018 and February 2019. Of them, 16,211 had undergone urinalysis for varied reasons. Glucosuria was semi-quantitatively measured as (+), (++), (+++), and (++++). Patients were assessed in terms of whether they had been referred to endocrinology or internal medicine departments within the 15 days and the presence/absence of a previous or new diagnosis of diabetes mellitus by measuring blood glucose and HgbA1c levels. RESULTS: Glucosuria was detected in 665 patients (4.1%), of whom 495 were included in the study. 417 (84.2%) had been previously diagnosed with diabetes mellitus, and 56 (11.3%) newly received a diabetes mellitus diagnosis. Blood glucose and HbA1c values were normal in 22 (4.4%) patients with glucosuria. HgbA1c value was determined as 7 or above in 381 (91.3%) of 417 cases with a previous diabetes mellitus diagnosis. CONCLUSION: Referring all patients detected to have glucosuria in the spot urine test at any time regardless of fasting/non-fasting to the relevant departments can contribute to the diagnosis and treatment of diabetes mellitus disease.

Regional variance in the use of urine dipstick test for outpatients in Japan.

AIM: The urine dipstick is a simple diagnostic module for detecting proteinuria, haematuria and glycosuria and is favourably accepted in East Asia despite debates regarding its accuracy and target population, claiming that quantitative tests for a high-risk cohort should be more cost-effective. However, the current status of utilizing this test in these countries is not widely known due to lack of extensive data. We aimed to clarify the current nationwide and regional status of utilization of the urine dipstick test in an outpatient care setting and to determine the regional factors associated with adoption of this method. METHODS: This cross-sectional study used openly accessible data from the national claim database that included the health insurance claims data of the Japanese population in 2017. RESULTS: In total, 67 125 386 urine dipstick tests were performed compared with 1 862 700 quantitative urine protein tests and 17 544 949 urine sediment microscopy tests. Dipstick tests were employed principally for those who are >65 years old (60.3%) and, although the male population (52.5%) is generally larger, the female population is larger in age of 15 to 39 years and >85 years. Multivariate analysis with several regional parameters revealed that the test was performed more commonly in the areas that accommodate greater elderly population (P < .01). CONCLUSION: Despite a heated dispute, the urine dipstick test is performed even more frequently than the quantitative biochemical or microscopic sediment tests, especially in regions holding the larger elderly population, which suggests that the test forms a part of geriatric medical care.

Fatalities Due to Failure of Continuous Subcutaneous Insulin Infusion Devices: A Report of Six Cases.

Diabetes mellitus type 1 and type 2 are diseases characterized by impaired regulation of blood glucose due to decreased insulin production and insulin resistance, respectively. Management of diabetes mellitus often requires injection of exogenous insulin. Continuous subcutaneous insulin infusion (CSII or insulin pump) is a diabetes treatment modality utilizing a device to aid in regulation of glycemic control. Malfunctions in device components can have rare fatal consequences. Described in this report are six fatalities due to one such malfunction, the failure of plastic cannulas of CSII devices to penetrate the skin and deliver insulin, resulting in fatal diabetic ketoacidosis (DKA). The cases derive from four different death investigation systems. For each case, scene and autopsy findings are presented, as well as selected toxicology and histology findings. These cases illustrate the importance of careful examination of CSII devices in death investigations and introduce a discussion on discrepant manner of death classifications.

Efficacy of urinary glucose for diabetes screening: a reconsideration.

AIMS: Previous studies indicated that urinary glucose (UG) had a limited efficacy in diabetes screening. This study was designed to have a re-evaluation of its efficacy, taking into consideration the collection method of urine and the measurement approach for UG among Chinese adults. METHODS: This cross-sectional study enrolled a total of 7689 participants without known diabetes, who were fasted and asked to empty bladders before a 75 g glucose loading. Urine was collected 2 h post glucose loading, and UG was measured using quantitative and qualitative approaches. The efficacy of UG in detecting diabetes was assessed by the receiver operating characteristic (ROC) curve. RESULTS: The area under the ROC curve was 0.89 for quantitative UG and 0.87 for qualitative UG. Quantitative UG was positively correlated with fasting plasma glucose (FPG) and 2 h plasma glucose (2 h PG) (r = 0.55 and 0.56, respectively, both P < 0.001). Quantitative UG displayed a sensitivity of 82.9% and a specificity of 84.7% in detecting diabetes at the corresponding optimal cutoff of 130 mg. Qualitative UG exhibited a sensitivity of 80.2% and a specificity of 85.6% at the optimal cutoff of glycosuria + 1. In addition, the sensitivity of both quantitative and qualitative UG was significantly higher than that of HbA1c (≥ 6.5%) (P < 0.001) and had a comparable sensitivity to 2 h PG (≥ 11.1 mmol/L) (P = 0.493). CONCLUSIONS: UG, either quantitatively or qualitatively measured at 2 h post glucose loading, was effective in diabetes screening. This indicates that UG is a feasible approach for diabetes screening.

Glycemic control by the SGLT2 inhibitor empagliflozin decreases aortic stiffness, renal resistivity index and kidney injury.

BACKGROUND: Arterial stiffness is emerging as an independent risk factor for the development of chronic kidney disease. The sodium glucose co-transporter 2 (SGLT2) inhibitors, which lower serum glucose by inhibiting SGLT2-mediated glucose reabsorption in renal proximal tubules, have shown promise in reducing arterial stiffness and the risk of cardiovascular and kidney disease in individuals with type 2 diabetes mellitus. Since hyperglycemia contributes to arterial stiffness, we hypothesized that the SGLT2 inhibitor empagliflozin (EMPA) would improve endothelial function, reduce aortic stiffness, and attenuate kidney disease by lowering hyperglycemia in type 2 diabetic female mice (db/db). MATERIALS/METHODS: Ten-week-old female wild-type control (C57BLKS/J) and db/db (BKS.Cg-Dock7m+/+Leprdb/J) mice were divided into three groups: lean untreated controls (CkC, n = 17), untreated db/db (DbC, n = 19) and EMPA-treated db/db mice (DbE, n = 19). EMPA was mixed with normal mouse chow at a concentration to deliver 10 mg kg-1 day-1, and fed for 5 weeks, initiated at 11 weeks of age. RESULTS: Compared to CkC, DbC showed increased glucose levels, blood pressure, aortic and endothelial cell stiffness, and impaired endothelium-dependent vasorelaxation. Furthermore, DbC exhibited impaired activation of endothelial nitric oxide synthase, increased renal resistivity and pulsatility indexes, enhanced renal expression of advanced glycation end products, and periarterial and tubulointerstitial fibrosis. EMPA promoted glycosuria and blunted these vascular and renal impairments, without affecting increases in blood pressure. In addition, expression of "reversion inducing cysteine rich protein with Kazal motifs" (RECK), an anti-fibrotic mediator, was significantly suppressed in DbC kidneys and partially restored by EMPA. Confirming the in vivo data, EMPA reversed high glucose-induced RECK suppression in human proximal tubule cells. CONCLUSIONS: Empagliflozin ameliorates kidney injury in type 2 diabetic female mice by promoting glycosuria, and possibly by reducing systemic and renal artery stiffness, and reversing RECK suppression.

Renal tubule insulin receptor modestly promotes elevated blood pressure and markedly stimulates glucose reabsorption.

Although the cause of hypertension among individuals with obesity and insulin resistance is unknown, increased plasma insulin, acting in the kidney to increase sodium reabsorption, has been proposed as a potential mechanism. Insulin may also stimulate glucose uptake, but the contributions of tubular insulin signaling to sodium or glucose transport in the setting of insulin resistance is unknown. To directly study the role of insulin signaling in the kidney, we generated inducible renal tubule-specific insulin receptor-KO mice and used high-fat feeding and mineralocorticoids to model obesity and insulin resistance. Insulin receptor deletion did not alter blood pressure or sodium excretion in mice on a high-fat diet alone, but it mildly attenuated the increase in blood pressure with mineralocorticoid supplementation. Under these conditions, KO mice developed profound glucosuria. Insulin receptor deletion significantly reduced SGLT2 expression and increased urinary glucose excretion and urine flow. These data demonstrate a direct role for insulin receptor-stimulated sodium and glucose transport and a functional interaction of insulin signaling with mineralocorticoids in vivo. These studies uncover a potential mechanistic link between preserved insulin sensitivity and renal glucose handling in obesity and insulin resistance.

Glucosuria without diabetes: key to the diagnosis of fragility fractures due to Fanconi syndrome.

A 64-year-old woman had fragility fractures which caused her to have gross deformities and confined her to bed. These were initially ascribed to vitamin D deficiency. However, despite correction of the deficiency, she did not improve. A review of previous records already showed glucosuria in the absence of diabetes, but this finding was overlooked. Eight years into the disease, it was realised that the glucosuria despite normal blood sugar could also mean that the patient was losing other substances needed for proper bone formation. Further investigations showed hypophosphataemia, renal phosphate wasting, hypokalaemia, mild metabolic acidosis, alkaline urine pH, hypouricaemia and aminoaciduria, all compatible with a proximal renal tubular defect (Fanconi syndrome). The fragility fractures were due to poor bone mineralisation because of hypophosphataemia induced by the inability of the kidneys to conserve phosphorus.

Glycosuria and hyperglycemia in the neonatal period as the first clinical sign of Fanconi-Bickel syndrome.

Fanconi-Bickel syndrome is a rare inherited disease characterized by the combination of hepatorenal glycogen accumulation, proximal renal tubular dysfunction and impaired utilization of glucose and galactose. The first symptoms of the disorder are recognized in late infancy as clinical characteristics appear. Therapeutic approach is mainly conservative with supplements of calcium, phosphate and vitamin D and small frequent feedings to avoid hypoglycemia. We report 1 clinical case of very early diagnosis, a 19 days old baby girl, in which the first clinical sign of the disease was the detection of glycosuria and vomits. Serum alkaline phosphatase levels were very high without rickets. The patient presented postprandial hyperglycemia and fasting hypoglycemia. A complete 24-hour glucose profile was obtained using a continuous glucose monitoring system in real time, which was fundamental not only for the diagnosis but also for the prevention of hypoglycemia. She received frequent small meals, galactose-free milk diet, and oral intakes of calcium, phosphorum, bicarbonate and vitamin D supplements with good evolution and normal height and weight gain.

Sodium-Glucose Linked Cotransporter-2 Inhibition Does Not Attenuate Disease Progression in the Rat Remnant Kidney Model of Chronic Kidney Disease.

Pharmacological inhibition of the proximal tubular sodium-glucose linked cotransporter-2 (SGLT2) leads to glycosuria in both diabetic and non-diabetic settings. As a consequence of their ability to modulate tubuloglomerular feedback, SGLT2 inhibitors, like agents that block the renin-angiotensin system, reduce intraglomerular pressure and single nephron GFR, potentially affording renoprotection. To examine this further we administered the SGLT2 inhibitor, dapagliflozin, to 5/6 (subtotally) nephrectomised rats, a model of progressive chronic kidney disease (CKD) that like CKD in humans is characterised by single nephron hyperfiltration and intraglomerular hypertension and where angiotensin converting enzyme inhibitors and angiotensin receptor blockers are demonstrably beneficial. When compared with untreated rats, both sham surgery and 5/6 nephrectomised rats that had received dapagliflozin experienced substantial glycosuria. Nephrectomised rats developed hypertension, heavy proteinuria and declining GFR that was unaffected by the administration of dapagliflozin. Similarly, SGLT2 inhibition did not attenuate the extent of glomerulosclerosis, tubulointerstitial fibrosis or overexpression of the profibrotic cytokine, transforming growth factor-ß1 mRNA in the kidneys of 5/6 nephrectomised rats. While not precluding beneficial effects in the diabetic setting, these findings indicate that SGLT2 inhibition does not have renoprotective effects in this classical model of progressive non-diabetic CKD.

New-Onset Diabetes Mellitus After Transplantation in a Cynomolgus Macaque (Macaca fasicularis).

A 5.5-y-old intact male cynomolgus macaque (Macaca fasicularis) presented with inappetence and weight loss 57 d after heterotopic heart and thymus transplantation while receiving an immunosuppressant regimen consisting of tacrolimus, mycophenolate mofetil, and methylprednisolone to prevent graft rejection. A serum chemistry panel, a glycated hemoglobin test, and urinalysis performed at presentation revealed elevated blood glucose and glycated hemoglobin (HbA1c) levels (727 mg/dL and 10.1%, respectively), glucosuria, and ketonuria. Diabetes mellitus was diagnosed, and insulin therapy was initiated immediately. The macaque was weaned off the immunosuppressive therapy as his clinical condition improved and stabilized. Approximately 74 d after discontinuation of the immunosuppressants, the blood glucose normalized, and the insulin therapy was stopped. The animal's blood glucose and HbA1c values have remained within normal limits since this time. We suspect that our macaque experienced new-onset diabetes mellitus after transplantation, a condition that is commonly observed in human transplant patients but not well described in NHP. To our knowledge, this report represents the first documented case of new-onset diabetes mellitus after transplantation in a cynomolgus macaque.

Transient renal Fanconi syndrome in a Chihuahua exposed to Chinese chicken jerky treats.

Transient Fanconi syndrome without azotemia was diagnosed in a dog and was associated with ingestion of Chinese chicken jerky treats. Fanconi syndrome is a proximal renal tubular defect and a diagnosis was made based upon severe glucosuria with normoglycemia, and severe generalized aminoaciduria. The clinical signs of polyuria and polydipsia as well as the massive urinary metabolic abnormalities resolved after jerky treat withdrawal. While frequently seen in North America and Australia, this is the first report of jerky treat induced Fanconi syndrome in continental Europe. Clinicians should be aware of this potential intoxication and be vigilant for a history of jerky treat consumption in a dog with glucosuria.

Postprandial self-monitoring of urine glucose reflects glycaemic control in people with relatively well controlled Type 2 diabetes mellitus not treated with insulin: a retrospective cohort study.

AIM: To analyse the association of self-monitoring of urine glucose with HbA1c concentration in people with Type 2 diabetes not treated with insulin. METHODS: We studied the association of postprandial self-monitored urine glucose with HbA1c concentrations in 264 people with Type 2 diabetes (mean age 62.4 years, time since diagnosis of diabetes 6.8 years and HbA1c 50 mmol/l). All patients took part in a diabetes treatment and teaching programme. HbA1c values were adjusted according to the Diabetes Control and Complication Trial. RESULTS: The mean ( ± sd) HbA1c concentration for the patients with constant negative urine glucose tests (56.1% of patients) was 46 ( ± 6) mmol/mol [6.4 ( ± 0.6)%]. This was significantly lower than in patients with < 50% positive urine glucose tests (33.3% of patients): mean ( ± sd) HbA1c was 53 ( ± 8) mmol/mol [7.0( ± 0.7)%] and also lower than in patients with ≥50% positive tests (10.6% of patients): mean ( ± sd) HbA1c of 57 ( ± 8) mmol/mol [7.4 ( ± 0.7)%]; P < 0.001. There was a significant correlation between the urine glucose test results and HbA1c (r = 0.416; P < 0.001). CONCLUSION: HbA1c concentrations were observed to be in the near-normal range for people with Type 2 diabetes not receiving insulin treatment who were negative for postprandial glucosuria. Urine glucose self-monitoring is a cheap and effective method to determine the quality of glucose control.

Self-monitoring of blood glucose versus self-monitoring of urine glucose in adults with newly diagnosed Type 2 diabetes receiving structured education: a cluster randomized controlled trial.

AIMS: To compare the effectiveness and acceptability of self-monitoring of blood glucose with self-monitoring of urine glucose in adults with newly diagnosed Type 2 diabetes. METHODS: We conducted a multi-site cluster randomized controlled trial with practice-level randomization. Participants attended a structured group education programme, which included a module on self-monitoring using blood glucose or urine glucose monitoring. HbA1c and other biomedical measures as well as psychosocial data were collected at 6, 12 and 18 months. A total of 292 participants with Type 2 diabetes were recruited from 75 practices. RESULTS: HbA1c levels were significantly lower at 18 months than at baseline in both the blood monitoring group [mean (se) -12 (2) mmol/mol; -1.1 (0.2) %] and the urine monitoring group [mean (se) -13 (2) mmol/mol; -1.2 (0.2)%], with no difference between groups [mean difference adjusted for cluster effect and baseline value = -1 mmol/mol (95% CI -3, 2); -0.1% (95% CI -0.3, 0.2)]. Similar improvements were observed for the other biomedical outcomes, with no differences between groups. Both groups showed improvements in total treatment satisfaction, generic well-being, and diabetes-specific well-being, and had a less threatening view of diabetes, with no differences between groups at 18 months. Approximately one in five participants in the urine monitoring arm switched to blood monitoring, while those in the blood monitoring arm rarely switched (18 vs 1% at 18 months; P < 0.001). CONCLUSIONS: Participants with newly diagnosed Type 2 diabetes who attended structured education showed similar improvements in HbA1c levels at 18 months, regardless of whether they were assigned to blood or urine self-monitoring.

Hyperosmolar hyperglycemic state: a historic review of the clinical presentation, diagnosis, and treatment.

The hyperosmolar hyperglycemic state (HHS) is the most serious acute hyperglycemic emergency in patients with type 2 diabetes. von Frerichs and Dreschfeld described the first cases of HHS in the 1880s in patients with an "unusual diabetic coma" characterized by severe hyperglycemia and glycosuria in the absence of Kussmaul breathing, with a fruity breath odor or positive acetone test in the urine. Current diagnostic HHS criteria include a plasma glucose level >600 mg/dL and increased effective plasma osmolality >320 mOsm/kg in the absence of ketoacidosis. The incidence of HHS is estimated to be <1% of hospital admissions of patients with diabetes. The reported mortality is between 10 and 20%, which is about 10 times higher than the mortality rate in patients with diabetic ketoacidosis (DKA). Despite the severity of this condition, no prospective, randomized studies have determined best treatment strategies in patients with HHS, and its management has largely been extrapolated from studies of patients with DKA. There are many unresolved questions that need to be addressed in prospective clinical trials regarding the pathogenesis and treatment of pediatric and adult patients with HHS.