Refined protocol for newly onset identification in non-obese diabetic mice: an animal-friendly, cost-effective, and efficient alternative.

BACKGROUND: Therapeutic interventions for diabetes are most effective when administered in the newly onset phase, yet determining the exact onset moment can be elusive in practice. Spontaneous autoimmune diabetes among NOD mice appears randomly between 12 and 32 weeks of age with an incidence range from 60 to 90%. Furthermore, the disease often progresses rapidly to severe diabetes within days, resulting in a very short window of newly onset phase, that poses significant challenge in early diagnosis. Conventionally, extensive blood glucose (BG) testing is typically required on large cohorts throughout several months to conduct prospective survey. We incorporated ultrasensitive urine glucose (UG) testing into an ordinary BG survey process, initially aiming to elucidate the lag period required for excessive glucose leaking from blood to urine during diabetes progression in the mouse model. RESULTS: The observations unexpectedly revealed that small amounts of glucose detected in the urine often coincide with, sometimes even a couple days prior than elevated BG is diagnosed. Accordingly, we conducted the UG-based survey protocol in another cohort that was validated to accurately identified every individual near onset, who could then be confirmed by following few BG tests to fulfill the consecutive BG + criteria. This approach required fewer than 95 BG tests, compared to over 700 tests with traditional BG survey, to diagnose all the 37-38 diabetic mice out of total 60. The average BG level at diagnosis was slightly below 350 mg/dl, lower than the approximately 400 mg/dl observed with conventional BG monitoring. CONCLUSIONS: We demonstrated a near perfect correlation between BG + and ultrasensitive UG + results in prospective survey with no lag period detected under twice weekly of testing frequency. This led to the refined protocol based on surveying with noninvasive UG testing, allowing for the early identification of newly onset diabetic mice with only a few BG tests required per mouse. This protocol significantly reduces the need for extensive blood sampling, lancet usage, labor, and animal distress, aligning with the 3Rs principle. It presents a convenient, accurate, and animal-friendly alternative for early diabetes diagnosis, facilitating research on diagnosis, pathogenesis, prevention, and treatment.

High Incidence of Antibiotic Resistance in the Uropathogenic Bacteria Associated with Different Urological Diseases and Metabolic Complications: A Single Center Cross-Sectional Study.

Urological diseases affect all age groups and are associated with different urinary complications. Presence of pathogenic bacteria complicates the urological diseases such as chronic kidney disease (CKD), kidney stone disease (KSD), emphysematous pyelonephritis (EPN), and urological cancers (UCs) coinciding with urinary metabolic complications. The One Health concept for preventing the spread of antibiotic resistant opportunistic pathogens necessitates detailed investigation on the virulence and the antibiotic sensitivity patterns of the pathogens from the urinary tract infections (UTIs). This cross-sectional study was aimed to profile the pathogenic bacteria associated with different urological diseases that included urine samples from the patients from a tertiary care hospital. The study included 258 patients representing CKD (15.1%), KSD (28.7%), EPN (15.5%), UC (12.0%), and UTI patients without any urological diseases (28.7%) with overall 70.5% patients showing positive urine culture. Furthermore, other than UTI in patients without any urological diseases (100%), higher culture positive cases were seen in KSD (64.9%), followed by CKD (61.5%), EPN (52.5%), and UC (48.4%). Escherichia coli was the most predominant bacteria in UTI (35.1%) and EPN (66.7%). In KSD, Pseudomonas aeruginosa (41.7%), Staphylococcus aureus (18.8%), and Proteus mirabilis (14.6%) were more common. S. aureus (86.7%) was the most isolated bacteria from the UC cases. Overall rate of multidrug resistance (MDR) was 77.8%. All (100%) E. coli, K. pneumoniae, P. mirabilis, and S. aureus strains were MDR. Among the strains, strong biofilm formation was observed in 73.6%, and 66.7% strains were urease positive. Biofilm was positively correlated with MDR and urease activity. The abundance and distribution of bacteria differed among the urological diseases suggesting their association with the urine metabolite profile. Colonization of MDR pathogens in patients with urological diseases is a serious concern requiring steps to control the emergence of drug resistance and their further spread into the ecosystem.

Intrarenal Mechanisms of Sodium-Glucose Cotransporter-2 Inhibitors on Tubuloglomerular Feedback and Natriuresis.

When sodium-glucose cotransporter-2 (SGLT2) inhibitors were first introduced a decade ago, no one expected them to have substantial effects beyond their known glucose-lowering effects, until the emergence of evidence of their robust renal and cardiovascular benefits showing that they could attenuate progression of kidney disease, irrespective of diabetes, as well as prevent the development of acute kidney injury. Still, the precise and elaborate mechanisms underlying the major organ protection of SGLT2 inhibitors remain unclear. SGLT2 inhibitors inhibit the reabsorption of sodium and glucose in the proximal tubule of the kidney and then recovers tubuloglomerular feedback, whereby SGLT2 inhibitors reduce glomerular hyperfiltration. This simple demonstration of their beneficial effects has perplexed experts in seeking more plausible and as yet undisclosed explanations for the whole effects of SGLT2 inhibitors, including metabolism reprogramming and the modulation of hypoxia, inflammation, and oxidative stress. Given that the renal benefits of SGLT2 inhibitors in patients with kidney disease but without diabetes were comparable to those seen in patients with diabetes, it may be reasonable to keep the emphasis on their hemodynamic actions. In this context, the aim of the present review is to provide a comprehensive overview of renal hemodynamics in individuals with diabetes who are treated with SGLT2 inhibitors, with a focus on natriuresis associated with the regulation of tubuloglomerular feedback and potential aquaresis. Throughout the discussion of alterations in renal sodium and water transports, particular attention will be given to the potential enhancement of adenosine and its receptors following SGLT2 inhibition.

Performance of the ACMG-AMP criteria in a large familial renal glucosuria cohort with identified SLC5A2 sequence variants.

Familial Renal Glucosuria (FRG) is a co-dominantly inherited trait characterized by orthoglycaemic glucosuria. From 2003 to 2015 we have reported several cohorts validating SLC5A2 (16p11.2), encoding SGLT2 (Na+/glucose cotransporter family member 2), as the gene responsible for FRG. The aim of this work was to validate the variants identified in our extended FRG cohort of published, as well more recent unreported cases, according to the ACMG-AMP 2015 criteria. Forty-six variants were evaluated, including 16 novel alleles first described in this study. All are rare, ultra-rare or absent from population databases and most are missense changes. According to the ACMG-AMP standards, only 74% of the variants were classified as P/LP. The lack of descriptions of unrelated patients with similar variants or failing to test additional affected family members, averted a conclusion for pathogenicity in the alleles that scored VUS, highlighting the importance of both family testing and variant reporting. Finally, the cryo-EM structure of the hSGLT2-MAP17 complex in the empagliflozin-bound state improved the ACMG-AMP pathogenicity score by identifying critical/functional protein domains.

Unexpected associations of long-term and excessive exposure to trivalent chromium with hypertension and glycosuria in male tannery workers.

Serious health hazards including renal, skin and hearing disorders have been reported in Bangladeshi tannery workers (TWs) who were chronically exposed to a large amount of trivalent chromium [Cr(III)]. However, the effects of Cr(III) exposure on the prevalence of hypertension and the prevalence of glycosuria in TWs remain unknown. Since the Cr level in toenails is an established marker reflecting long-term exposure to Cr(III) in humans, the associations of Cr levels in toenails with the prevalence of hypertension and the prevalence of glycosuria in male tannery and non-tannery office workers (non-TWs) in Bangladesh were investigated in this study. The mean toenail Cr level in non-TWs (0.5 µg/g, n = 49) was comparable to that in the general population reported previously. Mean Cr levels in TWs with a low toenail Cr level (5.7 µg/g, n = 39) and those with a high toenail Cr level (298.8 µg/g, n = 61) were >10-fold and >500-fold higher, respectively, than that in non-TWs. Our univariate and multivariate analyses indicated that the prevalence of hypertension and the prevalence of glycosuria in TWs with a high toenail Cr level, but not in TWs with a low toenail Cr level, were significantly lower than those in non-TWs. This study showed for the first time that long-term and excessive exposure to Cr(III) that is more than >500-fold but not >10-fold higher than the usual exposure level could decrease the prevalence of hypertension and the prevalence of glycosuria in TWs. Thus, this study revealed unexpected effects of exposure to Cr(III) on health.

Inhibition of SGLT2 co-transporter by dapagliflozin ameliorates tubular proteinuria and tubule-interstitial injury at the early stage of diabetic kidney disease.

Diabetic kidney disease (DKD) is characterized by progressive impairment of kidney function. It has been postulated that tubule-interstitial injury, associated with tubular albuminuria, precedes glomerular damage in the early stage of DKD. Here, we wanted to determine if the development of tubule-interstitial injury at the early stage of DKD implies modulation of megalin-mediated protein reabsorption in proximal tubule epithelial cells (PTECs) by SGLT2-dependent high glucose influx. Rats with streptozotocin (STZ)-induced diabetes were treated or not with dapagliflozin (DAPA) for 8 weeks. Four experimental groups were generated: (1) CONT, control; (2) DAPA, rats treated with DAPA; (3) STZ, diabetic rats; (4) STZ + DAPA, diabetic rats treated with DAPA. No changes in glomerular structure and function were observed. The STZ group presented proteinuria and albuminuria associated with an increase in the fractional excretion of proteins. A positive correlation between glycemia and proteinuria was found. These phenomena were linked to a decrease in luminal and total megalin expression and, consequently, in albumin reabsorption in PTECs. We also observed tubule-interstitial injury characterized by an increase in urinary tubular injury biomarkers and changes in tubular histomorphometry parameters. In addition, inverse correlations were found between cortical albumin uptake and tubule-interstitial injury or glycemia. All these modifications were attenuated in the STZ + DAPA group. These results suggest that SGLT2-dependent high glucose influx into PTECs promotes a harmful effect on the PTECs, leading to the development of tubular albuminuria and tubule-interstitial injury preceding glomerular damage. These results expand current knowledge on the renoprotective effects of gliflozins.

Rhabdomyolysis and myoglobinuria following single induction dose of propofol in a dog.

OBJECTIVE: To report a case of rhabdomyolysis and myoglobinuria following single induction dose of propofol in a dog. CASE SUMMARY: A 5-year-old intact male Shih-Tzu dog was presented for pigmenturia occurring a few hours following anesthesia for comprehensive oral health assessment and treatment. After premedication with IV diazepam (0.5 mg/kg), anesthesia was induced with IV propofol (4 mg/kg) and maintained with isoflurane vaporized in oxygen. A few hours following recovery from anesthesia, the dog developed rhabdomyolysis and myoglobinuria associated with increased serum alanine aminotransferase and C-reactive protein concentrations, as well as mild hypokalemia and euglycemic glycosuria. Approximately 48 hours after IV fluid therapy, the dog was clinically normal, and myoglobinuria progressively resolved. NEW OR UNIQUE INFORMATION PROVIDED: This is the first case description of rhabdomyolysis and myoglobinuria following a single dose of injectable propofol.

Gestational glycosuria, proteinuria, and borderline hypertension in pregnancy are predictors for the later onset of maternal chronic disease.

AIM: Although hypertensive disorders of pregnancy and gestational diabetes mellitus (DM) are risk factors for hypertension, DM, and kidney disease in later life, the association of gestational glycosuria, proteinuria, and borderline hypertension with these chronic diseases has been unclear. METHODS: This cross-sectional study was conducted between April 2017 and November 2020 at a Japanese tertiary hospital. Three variables listed in the Maternal and Child Health Handbook were analyzed: glycosuria, proteinuria, and systolic blood pressure (<130, 130-139, and ≥ 140 mmHg) during pregnancy. The incidences of DM, kidney disease, and hypertension self-reported by mothers of pregnant women on a questionnaire were assessed with logistic regression analysis. RESULTS: The 312 women completed the questionnaires an average of 35.8 ± 4.2 years after delivering their daughters. Risk for DM was significantly increased among women with glycosuria (adjusted odds ratio [aOR], 3.62; 95% confidence interval [CI], 1.21-10.9), and risk for kidney disease was significantly increased among women with proteinuria (aOR, 4.07; 95% CI, 1.29-12.9). Risk for hypertension was significant in women whose blood pressures were ≥ 140 mmHg (aOR, 4.26; 95% CI, 1.96-9.24), but the association between blood pressures of 130-139 mmHg and hypertension was not significant (aOR, 1.72; 95% CI, 0.95-3.11); however, a significant positive trend (p < 0.001) between increasing blood pressure and hypertension was observed. CONCLUSIONS: Gestational glycosuria, proteinuria, and increased blood pressure were associated with the development of maternal chronic diseases. These standard and inexpensive assessments may improve lifelong health management in women.

Sodium Glucose Co-Transporter 2 Inhibitors and the Cardiovascular System: Current Knowledge and Future Expectations.

Diabetic cardiomyopathy is a well-recognized clinical entity and reflects a complex relationship between metabolic substrates and myocardial function. Sodium glucose co-transporter 2 (SGLT2) inhibitors are antidiabetic agents that are found to exert multiple cardioprotective effects. Large clinical trials showed their beneficial effects on patients with heart failure, reducing the rates of rehospitalizations and improving kidney function. The aim of this review is to summarize the latest evidence in the literature regarding the multiple effects of SGLT2 inhibitors on patients across the spectrum of cardiovascular diseases.

Outcome of Acquired Fanconi Syndrome Associated with Ingestion of Jerky Treats in 30 Dogs.

Acquired canine proximal renal tubulopathy (Fanconi syndrome) related to excessive ingestion of jerky treats has been recognized since 2007. This study aimed to improve knowledge about the syndrome's characteristics, especially long-term outcome. By reaching out to veterinarians and dog owners, dogs suspected of jerky induced Fanconi syndrome were identified. The dog's medical records were reviewed, and owners interviewed. Data was analyzed using linear mixed models (p < 0.05 was considered statistically significant) and descriptive statistics are reported. Thirty dogs, median body weight 6.8 (range 1.2−59) kg and age 6.5 (0.5−14) years, were enrolled as suspected cases based on history of jerkey ingestion and confirmed normoglycemic/hypoglycemic glycosuria. Clinical signs included polydipsia (23/30), polyuria (21/30), lethargy (19/30), weight loss (15/30), hyporexia (11/30), vomiting (7/30), diarrhea (7/30) and no clinical signs (2/30). Para-clinical findings included azotemia (6/28), hypophosphatemia (9/25), metabolic acidosis (3/8), hypokalemia (6/20), proteinuria (13/26), aminoaciduria (4/4), hematuria (22/29) and ketonuria (7/27). Clinical signs resolved in 22/28 within 11 (0.3−52) weeks and glycosuria resolved in 28/30 within 6.5 (1−31) weeks. There were no associations between serum creatinine and urea and the amount/duration of jerky ingestion. Serum symmetric dimethylarginine concentrations were only available for a few dogs, therefore no conclusion was achieved on a possible association with duration of jerky ingestion. Apart from a larger percentage of dogs achieving complete recovery, the current findings are in agreement with previous reports.

Renal Deletion of LRRC8/VRAC Channels Induces Proximal Tubulopathy.

BACKGROUND: Volume-regulated anion channels (VRACs) are heterohexamers of LRRC8A with LRRC8B, -C, -D, or -E in various combinations. Depending on the subunit composition, these swelling-activated channels conduct chloride, amino acids, organic osmolytes, and drugs. Despite VRACs' role in cell volume regulation, and large osmolarity changes in the kidney, neither the localization nor the function of VRACs in the kidney is known. METHODS: Mice expressing epitope-tagged LRRC8 subunits were used to determine the renal localization of all VRAC subunits. Mice carrying constitutive deletions of Lrrc8b-e, or with inducible or cell-specific ablation of Lrrc8a, were analyzed to assess renal functions of VRACs. Analysis included histology, urine and serum parameters in different diuresis states, and metabolomics. RESULTS: The kidney expresses all five VRAC subunits with strikingly distinct localization. Whereas LRRC8C is exclusively found in vascular endothelium, all other subunits are found in the nephron. LRRC8E is specific for intercalated cells, whereas LRRC8A, LRRC8B, and LRRC8D are prominent in basolateral membranes of proximal tubules. Conditional deletion of LRRC8A in proximal but not distal tubules and constitutive deletion of LRRC8D cause proximal tubular injury, increased diuresis, and mild Fanconi-like symptoms. CONCLUSIONS: VRAC/LRRC8 channels are crucial for the function and integrity of proximal tubules, but not for more distal nephron segments despite their larger need for volume regulation. LRRC8A/D channels may be required for the basolateral exit of many organic compounds, including cellular metabolites, in proximal tubules. Proximal tubular injury likely results from combined accumulation of several transported molecules in the absence of VRAC channels.

Glycosuria Alters Uropathogenic Escherichia coli Global Gene Expression and Virulence.

Uropathogenic Escherichia coli (UPEC) is the principal etiology of more than half of urinary tract infections (UTI) in humans with diabetes mellitus. Epidemiological data and studies in mouse model of ascending UTI have elucidated various host factors responsible for increasing the susceptibility of diabetic hosts to UPEC-UTI. In contrast, diabetic urinary microenvironment-mediated alterations in UPEC physiology and its contributions to shaping UPEC-UTI pathogenesis in diabetes have not been examined. To address our central hypothesis that glycosuria directly induces urinary virulence of UPEC, we compared virulence characteristics and gene expression in human UPEC strains UTI89 (cystitis) and CFT073 (pyelonephritis), exposed for 2 h in vitro to urine from either male or female donors that was either plain or supplemented with glucose to mimic glycosuria. Compared to control UPEC exposed to nutrient-rich culture medium, lysogeny broth, glycosuria-exposed UPEC exhibited significant increase in biofilm formation and reduction in the hemagglutination of Guinea pig erythrocytes (a measure of type 1 piliation). In addition, the analysis of UTI89 transcriptome by RNA sequencing revealed that 2-h-long, in vitro exposure to glycosuria also significantly alters expression of virulence and metabolic genes central to urinary virulence of UPEC. Addition of galactose as an alternative carbon source affected biofilm formation and gene expression profile of UPEC to an extent similar to that observed with glucose exposure. In summary, our results provide novel insights into how glycosuria-mediated rapid changes in UPEC fitness may facilitate UTI pathogenesis in the diabetic urinary microenvironment. IMPORTANCE Uropathogenic Escherichia coli (UPEC) is an important causative agent of urinary tract infections in diabetic humans. We examined the effects of in vitro exposure to glycosuria (presence of glucose in urine) on the virulence and gene expression by UPEC. Our results show that glycosuria rapidly (in 2 h) alters UPEC gene expression, induces biofilm formation, and suppresses type 1 piliation. These results offer novel insights into the pathogenesis of UPEC in the urinary tract.

Clinical algorithms for the management of intrapartum maternal urine abnormalities.

AIM: To develop evidence-based clinical algorithms for management of common intrapartum urinary abnormalities. POPULATION: Women with singleton, term pregnancies in active labour and immediate postnatal period, at low risk of complications. SETTING: Healthcare facilities in low- and middle-income countries. SEARCH STRATEGY: A systematic search and review were conducted on the current guidelines from WHO, NICE, ACOG and RCOG. Additional search was done on PubMed and The Cochrane Database of Systematic Reviews up to May 2020. CASE SCENARIOS: Four common intrapartum urinary abnormalities were selected: proteinuria, ketonuria, glycosuria and oliguria. Using reagent strip testing, glycosuria was defined as ≥2+ on one occasion or of ≥1+ on two or more occasions. Proteinuria was defined as ≥2+ and presence of ketone indicated ketonuria. Oliguria was defined as hourly urine output ≤30 ml. Thorough initial assessment using history, physical examination and basic investigations helped differentiate most of the underlying causes, which include diabetes mellitus, dehydration, sepsis, pre-eclampsia, shock, anaemia, obstructed labour, underlying cardiac or renal problems. A clinical algorithm was developed for each urinary abnormality to facilitate intrapartum management and referral of complicated cases for specialised care. CONCLUSIONS: Four simple, user-friendly and evidence-based clinical algorithms were developed to enhance intrapartum care of commonly encountered maternal urine abnormalities. These algorithms may be used to support healthcare professionals in clinical decision-making when handling normal and potentially complicated labour, especially in low resource countries. TWEETABLE ABSTRACT: Evidence-based clinical algorithms developed to guide intrapartum management of commonly encountered urinary abnormalities.

Effects of Sodium-Glucose Cotransporter 2 Inhibitors on Water and Sodium Metabolism.

Sodium-glucose cotransporter 2 (SGLT2) inhibitors exert hypoglycemic and diuretic effects by inhibiting the absorption of sodium and glucose from the proximal tubule. Currently available data indicate that SGLT2 inhibitors transiently enhance urinary sodium excretion and urinary volume. When combined with loop diuretics, SGLT2 inhibitors exert a synergistic natriuretic effect. The favorable diuretic profile of SGLT2 inhibitors may confer benefits to volume management in patients with heart failure but this natriuretic effect may not be the dominant mechanism for the superior long-term outcomes observed with these agents in patients with heart failure. The first part of this review explores the causes of transient natriuresis and the diuretic mechanisms of SGLT2 inhibitors. The second part provides an overview of the synergistic effects of combining SGLT2 inhibitors with loop diuretics, and the third part summarizes the mechanisms of cardiovascular protection associated with the diuretic effects of SGLT2 inhibitors.

Hereditary renal glycosuria, diabetes and responses to SGLT2 inhibitor.

AIMS: To present the clinical features of two rare cases with hereditary renal glycosuria and diabetes, explore their responses to sodium-glucose cotransporter 2 (SGLT2) inhibitor, and summarize the reported solute carrier family 5 member 2 (SLC5A2) mutations and related phenotypes. METHODS: Two patients were followed up for 6.5 and 3 years respectively. SLC5A2 and hepatocyte nuclear factor 1-alpha (HNF1A) gene were sequenced. We used the flash glucose monitoring system to evaluate the efficacy of SGLT2 inhibitor treatment. Then we retrieved all the literature and analyzed SLC5A2 gene mutations and the phenotypes. RESULTS: During long-time follow up, the two patients had frequent unproportional renal glycosuria in the morning even when their fasting serum glucose was only slightly increased. A novel rare mutation V359G and a pathogenic rare mutation ivs7 + 5G > A in SLC5A2 gene were found respectively. In Case 1, the 24 h glucose excretion was 2.2 g/d and increased to 103 g/d after dapaglifozin treatment, whereas the average glucose (6.33 ± 1.56 vs. 6.28 ± 1.74 mmol/L), and time in range (TIR) (95% vs. 93%) were similar. In Case 2, the 24 h glycosuria was 121.4 g/d and increased to 185.8 g/day after dapaglifozin add-on therapy, with a further reduction of average glucose (9.11 ± 2.63 vs. 7.54 ± 2.39 mmol/L, p < 0.001) and better TIR (70% vs. 84%). We reviewed 139 cases with hereditary renal glycosuria and SLC5A2 gene mutation. The urine glucose was highest in patients with homozygous mutations [64.0(36.6-89.6)g/24 h] compared with compound heterozygous mutations [25.9(14.4-41.2)g/24 h] and heterozygous mutations [3.45(1.41-7.50)g/24 h] (p < 0.001). CONCLUSIONS: Genetic renal glycosuria could not protect individuals completely from developing diabetes. Patients with SGLT2 gene mutations are still responsive to the SGLT2 inhibitor treatment.

Frequency of Urinary Tract Infections in Type 2 Diabetic Patients Taking Dapagliflozin.

Background Urinary tract infections (UTIs) are common in patients with diabetes. The use of sodium-glucose cotransporter-2 inhibitors (SGLT2i) to achieve good glycemic control increases glucose levels in urine. This glycosuria further enhances the risk of UTIs. This study aimed to evaluate the frequency of UTIs in patients with type 2 diabetes receiving the SGLT2i dapagliflozin as an add-on therapy. Methods We conducted this cross-sectional study at the Endocrinology Department of Hayatabad Medical Complex in Peshawar from April 2020 to September 2020. A total of 400 patients with diabetes receiving either 5 mg or 10 mg of dapagliflozin as an add-on therapy for the treatment of type 2 diabetes were included in this study. We collected blood and urine samples from participants and measured glycosylated hemoglobin levels. Urine samples were cultured on cysteine lactose electrolyte deficient agar. We used IBM SPSS Statistics for Windows, version 25.0 (IBM Corp., Armonk, NY) to analyze our data. Results The prevalence of UTIs in diabetic patients receiving 5 mg or 10 mg of dapagliflozin was 5.3%. Women were more affected (76.2%) than men (p < 0.05). UTIs were more prevalent in patients older than 50 years (85.7%) than in any other age group. The dose strength of dapagliflozin was not associated with UTIs (p > 0.05). Conclusion This study examined UTIs in patients taking dapagliflozin for the treatment of type 2 diabetes. These infections were mild to moderate and were treated easily. None of these infections caused the patient to discontinue the treatment. Dapagliflozin is well-tolerated in patients with diabetes but should be used with appropriate caution and monitoring.

Glycosuria in primary glomerulopathies: prevalence and prognostic significance / Glicosúria nas doenças glomerulares primárias: prevalência e significância prognóstica

Abstract Introduction: Tubular damage is common in glomerular diseases (GD). Glycosuria is a marker of tubular dysfunction and may be used to detect tubular lesion and CKD progression. The aim of this study was to evaluate the prevalence and prognostic value of glycosuria at the time of diagnosis in primary glomerulopathies (PG). Methods: We conducted a 24-month retrospective study in patients diagnosed with PG in our center between 2009 and 2020. We excluded diabetic patients, use of SGLT2 inhibitors, transplant patients, and secondary GD. Patients were divided in two groups according to their glycosuria status at diagnosis. Results: We studied 115 patients. Global prevalence of glycosuria was 10% (n=11) and membranous nephropathy (MN) had the highest prevalence (n=5, 17.9%). We found that patients with glycosuria had higher serum creatinine (2.4 vs. 1.2 mg/dL, p=0.030), higher albuminuria (4.8 vs. 1.9 g/g, p=0.004), and lower serum albumin (2.3 vs. 3.2 g/dL, p=0.021). We did not find association with histological prognostic factors. At the end of follow-up, patients with glycosuria had higher prevalence of the composite outcome of stage 5D CKD or 50% increase in basal SCr (45.5% vs. 17.3%, p=0.037). In patients with MN, results were similar but we were able to find an association of glycosuria with more severe interstitial fibrosis and tubular atrophy (25.0 vs. 0.0 %, p=0.032). Conclusion: Ten percent of our patients with PG have glycosuria. Glycosuria at the time of diagnosis was associated with more severe clinical presentation and worst renal outcome. The association with higher albuminuria suggests that tubular function has an impact on the severity and outcomes of PG.

Resumo Introdução: Danos tubulares são comuns em doenças glomerulares (DG). Glicosúria é um marcador de disfunção tubular e pode detectar lesão tubular e progressão da DRC. O objetivo deste estudo foi avaliar a prevalência e o valor prognóstico da glicosúria no diagnóstico em glomerulopatias primárias (GP). Métodos: Realizamos estudo retrospectivo de 24 meses em pacientes diagnosticados com GP em nosso centro entre 2009-2020. Excluímos pacientes diabéticos, uso de inibidores de SGLT2, pacientes transplantados e DG secundárias. Os pacientes dividiram-se em dois grupos de acordo com seu estado de glicosúria no diagnóstico. Resultados: Estudamos 115 pacientes. A prevalência global de glicosúria foi de 10% (n=11) e a nefropatia membranosa (NM) teve maior prevalência (n=5, 17,9%). Constatamos que pacientes com glicosúria apresentavam creatinina sérica mais elevada (2,4 vs. 1,2 mg/dL, p=0,030), albuminúria mais alta (4,8 vs. 1,9 g/g, p=0,004), e albumina sérica mais baixa (2,3 vs. 3,2 g/dL, p=0,021). Não encontramos associação com fatores prognósticos histológicos. Ao final do acompanhamento, pacientes com glicosúria tiveram maior prevalência do desfecho composto de DRC estágio 5D ou aumento de 50% na CrS basal (45,5% vs. 17,3%, p=0,037). Em pacientes com NM, os resultados foram semelhantes, mas encontramos uma associação de glicosúria com fibrose intersticial mais grave e atrofia tubular (25,0 vs. 0,0 %, p=0,032). Conclusão: 10% de nossos pacientes com GP têm glicosúria. A glicosúria no diagnóstico foi associada a uma apresentação clínica mais grave e pior desfecho renal. A associação com albuminúria mais elevada sugere que a função tubular tem um impacto na gravidade e nos desfechos da GP.

Zoledronic Acid-Associated Fanconi Syndrome in Patients With Cancer.

Zoledronic acid (ZA) is an antiresorptive agent typically used for fracture prevention in postmenopausal osteoporosis, malignancy-associated metastatic bone lesions, and as a treatment for hypercalcemia. ZA is excreted almost entirely by the kidney; as a result, a reduction in renal clearance can lead to its accumulation and potential renal toxicity. Although uncommon, acute kidney injury (AKI) from intravenous bisphosphonates has been described, with different patterns including tubulointerstitial nephritis, acute tubular necrosis, as well as focal segmental glomerulosclerosis. Here we present 4 patients with an underlying malignancy who each developed evidence of generalized proximal tubular dysfunction, also known as Fanconi syndrome, approximately 1 week after receiving treatment with ZA. On presentation, all patients had AKI, low serum bicarbonate levels, abnormal urinary acidification, hypophosphatemia, hypokalemia, and increased urine amino acid excretion or renal glycosuria. Based on the temporal association between ZA infusion and the development of these electrolyte abnormalities, each case is highly suggestive of ZA-associated Fanconi syndrome. Due to the severity of presentation, all required discontinuation of ZA and ongoing electrolyte repletion. Nephrologists and oncologists should be aware of this complication and consider ZA as a possible trigger of new-onset Fanconi syndrome.

"The Bitter Truth of Sugar"-Euglycemic Diabetic Ketoacidosis due to Sodium-glucose Cotransporter-2 Inhibitors: A Case Series.

Diabetic ketoacidosis (DKA) is an acute and major complication of diabetes mellitus (DM), both type I and type II. Biochemically, DKA consists of a triad of blood sugar levels greater than 250 mg/dL, ketonemia of greater than 3 mmol/L and/or significant ketonuria, and a blood pH less than 7.3 with an increased anion gap. Currently, the sodium-glucose cotransporter-2 inhibitors (SGLT-2i) are widely used in management of type II diabetes. There have been several reports of an association between euglycemic diabetic ketoacidosis (EuDKA) and SGLT-2i agents. We present three different patients who were on SGLT-2i therapy who developed recurrent EuDKA postprocedure or sepsis. We believe that prolonged treatment (5-6 days) with intravenous (IV) insulin with glucose until resolution of glycosuria can be considered as an inexpensive marker of resolution of EuDKA. Moreover, the recommended duration for discontinuation of these drugs prior to elective procedures should be longer than 3 days. How to cite this article: Shah M, Pathrose E, Bhagwat NM, Chandy D. "The Bitter Truth of Sugar"-Euglycemic Diabetic Ketoacidosis due to Sodium-glucose Cotransporter-2 Inhibitors: A Case Series. Indian J Crit Care Med 2022;26(1):123-126.