Reno-protective effect of protocatechuic acid is independent of sex-related differences in murine model of UUO-induced kidney injury.

BACKGROUND: Obstructive nephropathy is a condition often caused by urinary tract obstruction either anatomical (e.g., tumors), mechanical (e.g., urolithiasis), or compression (e.g., pregnancy) and can progress to chronic kidney disease (CKD). Studies have shown sexual dimorphism in CKD, where males were found to have a more rapid decline in kidney function following kidney injury compared to age-matched females. Protocatechuic acid (PCA), an anti-oxidant and anti-inflammatory polyphenolic compound, has demonstrated promising effects in mitigating drug-induced kidney injuries. The current study aims to explore sexual dimorphism in kidney injury after unilateral ureteral obstruction (UUO) and assess whether PCA treatment can mitigate kidney injury in both sexes. METHODS: UUO was induced in 10-12 weeks old male and female C57BL/6J mice. Mice were categorized into four groups (n = 6-8/group); Sham, Sham plus PCA (100 mg/kg, I.P daily), UUO, and UUO plus PCA. RESULTS: After 2 weeks of induction of UUO, markers of kidney oxidative stress (TBARs), inflammation (IL-1α and IL-6), tubular injury (neutrophil gelatinase-associated lipocalin, NGAL and urinary kidney injury molecule-1, KIM-1), fibrosis (Masson's trichrome staining, collagen IV expression, MMP-2 and MMP-9) and apoptosis (TUNEL+ cells, active caspase-1 and caspase-3) were significantly elevated in both males and females relative to their sham counterparts. Males exhibited significantly greater kidney oxidative stress, inflammation, fibrosis, and apoptosis after induction of UUO when compared to females. PCA treatment significantly attenuated UUO-induced kidney injury, inflammation, fibrosis, and apoptosis in both sexes. CONCLUSION: Our findings suggest a differential gender response to UUO-induced kidney injury with males being more sensitive to UUO-induced kidney inflammation, fibrosis, and apoptosis than age-matched females. Importantly, PCA treatment reduced UUO-induced kidney injury in a sex-independent manner which might be attributed to its anti-oxidant, anti-inflammatory, anti-fibrotic, and anti-apoptotic properties.

Endogenous estradiol contributes to vascular endothelial dysfunction in premenopausal women with type 1 diabetes.

BACKGROUND: Endogenous estrogen is cardio-protective in healthy premenopausal women. Despite this favorable action of estrogen, animal models depict a detrimental effect of estradiol on vascular function in the presence of diabetes. The present study sought to determine the role of endogenous estradiol on endothelial function in women with type 1 diabetes. METHOD: 32 women with type 1 diabetes (HbA1c = 8.6 ± 1.7%) and 25 apparently healthy women (HbA1c = 5.2 ± 0.3%) participated. Flow-mediated dilation (FMD), a bioassay of nitric-oxide bioavailability and endothelial function was performed during menses (M) and the late follicular (LF) phase of the menstrual cycle to represent low and high concentrations of estrogen, respectively. In addition, a venous blood sample was collected at each visit to determine circulating concentrations of estradiol, thiobarbituric acid reactive substances (TBARS), and nitrate/nitrite (NOx), biomarkers of oxidative stress and nitric oxide, respectively. Data were collected in (1) 9 additional women with type 1 diabetes using oral hormonal birth control (HBC) (HbA1c = 8.3 ± 2.1%) during the placebo pill week and second active pill week, and (2) a subgroup of 9 demographically matched women with type 1 diabetes not using HBC (HbA1c = 8.9 ± 2.1%). RESULTS: Overall, estradiol was significantly increased during the LF phase compared to M in both type 1 diabetes (Δestradiol = 75 ± 86 pg/mL) and controls (Δestradiol = 71 ± 76 pg/mL); however, an increase in TBARS was only observed in patients with type 1 diabetes (ΔTBARS = 3 ± 13 µM) compared to controls (ΔTBARS = 0 ± 4 µM). FMD was similar (p = 0.406) between groups at M. In addition, FMD increased significantly from M to the LF phase in controls (p = 0.024), whereas a decrease was observed in type 1 diabetes. FMD was greater (p = 0.015) in patients using HBC compared to those not on HBC, independent of menstrual cycle phase. CONCLUSION: Endogenous estradiol increases oxidative stress and contributes to endothelial dysfunction in women with diabetes. Additionally, HBC use appears to be beneficial to endothelial function in type 1 diabetes.

Acute nitric oxide synthase inhibition induces greater increases in blood pressure in female versus male Wistar Kyoto rats.

Nitric oxide (NO) contributes to blood pressure (BP) regulation via its vasodilatory and anti-inflammatory properties. We and others previously reported sex differences in BP in normotensive and hypertensive rat models where females have lower BP than age-matched males. As females are known to have greater NO bioavailability than age-matched males, the current study was designed to test the hypothesis that anesthetized female normotensive Wistar Kyoto rats (WKY) are more responsive to acute NOS inhibition-induced increases in BP compared to male WKY. Twelve-week-old male and female WKY were randomized to infusion of the nonspecific NOS inhibitor NG -nitro-L-arginine methyl ester (L-NAME, 1 mg/kg/min) or selective NOS1 inhibition with vinyl-L-NIO (VNIO, 0.5 mg/kg/min) for 60 min. Mean arterial BP, glomerular filtration rate (GFR), urine volume, and electrolyte excretion were assessed before, and during L-NAME or VNIO infusion. L-NAME and VNIO significantly increased BP in both sexes; however, the increase in BP with L-NAME infusion was greater in females versus males compared to baseline BP values. Acute infusion of neither L-NAME nor VNIO for 60 min altered GFR in either sex. However, urine volume, sodium, chloride and potassium excretion levels increased comparably in male and female WKY with L-NAME and VNIO infusion. Our findings suggest sex differences in BP responses to acute non-isoform-specific NOS inhibition in WKY, with females being more responsive to L-NAME-induced elevations in BP relative to male WKY. However, sex differences in the BP response did not coincide with sex differences in renal hemodynamic responses to acute NOS inhibition.

Planned percutaneous nephrolithotomy in patients who initially presented with urosepsis: Analysis of outcomes and complications.

OBJECTIVE: To compare the outcomes and complications of planned percutaneous nephrolithotomy (PCNL) in patients with a prior urosepsis episode to those without. PATIENTS AND METHODS: We recorded patients who presented initially with obstructive urosepsis, as identified by systemic inflammatory response syndrome and obstructing kidney stones. We compared the surgical outcomes and complications among those patients who had planned PCNL after control of prior urosepsis with urgent decompression and antibiotics (Group A) to a group who presented for PCNL with no previous history of a septic presentations (Group B). A 1:1 matched-pair analysis was performed using four parameters (age, gender, body mass index, and American Society of Anesthesiologists classification) to eliminate potential allocation bias. Primary outcomes included were stone-free rate (SFR) and complication rate. Secondary outcomes included were operative time, estimated blood loss, and duration of postoperative hospital stay. RESULTS: A total of 80 patients underwent PCNL (48 male and 32 females) divided equally between both treatment groups, with a mean (interquartile range) age of 47 (19-75) years. There were no differences in demographic data or stone characteristics between both groups. Both groups had comparable SFRs (92.5% vs 97.5%, P = 0.212) and mean operative time (77 vs 74 min, P = 0.728) (Table 2). Patients in Group A had a significantly higher overall complications rate (35% vs 10%, P = 0.03) . There were no postoperative mortalities and the mean length of hospital stay was significantly longer in Group A patients compared to group B (4.2 vs 1.5 days, P = 0.042). CONCLUSIONS: : Planned PCNL after decompression for urolithiasis-related sepsis has comparable operative time and SFR but higher complication rates and longer postoperative hospital stay. This is critical in counselling patients prior to definitive treatment of kidney stones after urgent decompression for urosepsis and for adequate preoperative planning and preparation.Abbreviations: ASA: American Society of Anesthesiologists; BMI: body mass index; ICU: intensive care unit; IQR: interquartile range; KUB: plain abdominal radiograph of the kidneys, ureters and bladder; PCN: percutaneous nephrostomy; PCNL: percutaneous nephrolithotomy; SFR: stone-free rate; URS; ureteroscopy; US: ultrasonography.

Percutaneous Nephrolithotomy vs Retrograde Intrarenal Surgery for Large Renal Stones in Pediatric Patients: A Randomized Controlled Trial.

PURPOSE: We compared outcomes of percutaneous nephrolithotomy and retrograde intrarenal surgery in the treatment of children with renal calculi larger than 2 cm. MATERIALS AND METHODS: A total of 38 patients younger than 16 years with renal calculi larger than 2 cm were randomized to undergo percutaneous nephrolithotomy or retrograde intrarenal surgery between May 2011 and February 2014. Demographic data, stone criteria, operative technique, radiation time, complications, blood transfusion, hemoglobin decrease, stone-free rate and length of hospital stay were compared between the groups. Stone-free status was documented if there were no residual stones after 1 month. RESULTS: The study included 43 renal units, of which 21 were subjected to retrograde intrarenal surgery and 22 to percutaneous nephrolithotomy. Operative time was comparable for both groups. Mean radiation time and hospital stay were longer after percutaneous nephrolithotomy (p<0.001). Stone-free rate was significantly lower after retrograde intrarenal surgery monotherapy vs percutaneous nephrolithotomy monotherapy (71% vs 95.5%, p=0.046). Patients in the percutaneous nephrolithotomy group had significantly more complications compared to the retrograde intrarenal surgery group (p=0.018). Three patients in the percutaneous nephrolithotomy group received blood transfusions, compared to none in the retrograde intrarenal surgery group (p=0.015). CONCLUSIONS: For treatment of large or complex renal stones in pediatric patients percutaneous nephrolithotomy monotherapy has the advantage of better stone-free rates, while retrograde intrarenal surgery has the advantages of decreased radiation exposure, fewer complications and shorter hospital stay.

Injury of the ileum during percutaneous nephrolithotomy in a pediatric patient.

Ileum injury during percutaneous nephrolithotomy (PCNL) is an extremely rare complication. We describe the successful management of an inadvertently injured ileum during subcostal PCNL in a 12-year-old boy. Mechanism of injury, presentation and management will be discussed.

Public health guidance to facilitate timely diagnosis of dementia: ALzheimer's COoperative Valuation in Europe recommendations.

OBJECTIVE: ALzheimer's COoperative Valuation in Europe (ALCOVE) was a Joint Action co-financed by the European Commission to produce a set of evidence-based recommendations for policymakers on dementia. This paper reports on timely diagnosis. METHODS: Evidence was reviewed from scientific, policy and qualitative research. An online questionnaire was completed by experts from 24 European Union countries detailing current practice. An iterative process with people with dementia, family carers and professionals was utilised to develop recommendations. RESULTS: Advances in the technical aspects of diagnosis have changed what is understood by early diagnosis. Although research into preclinical stages is crucial, diagnosing at these very earliest stages is not recommended as regular practice. On balance, it is suggested that citizens should have access to accurate diagnosis at a time in the disease process when it can be of most benefit to them. The term timely diagnosis is used to reflect this. The diagnosis can help citizens and their families make sense of what is happening and make lifestyle changes and plans for the future. The central principles identified to maximise benefit and to reduce harm associated with diagnosis at an earlier stage included reducing stigma about dementia; respecting the rights of the individual; recognising that how the diagnosis is given will impact on subsequent adjustment and that post diagnostic support are required for the person and their family. Detailed recommendations are provided for timely detection, the diagnostic process, complex diagnoses, response to early cognitive changes and workforce. CONCLUSIONS: The recommendations can be utilised at a local, national and European level to benchmark progress.