Blockade of sodium-glucose co-transporters improves peritoneal ultrafiltration in uraemic rodent models.

BACKGROUND: The most used PD fluids contain glucose as a primary osmotic agent. Glucose peritoneal absorption during dwell decreases the osmotic gradient of peritoneal fluids and causes undesirable metabolic consequences. Inhibitors of sodium-glucose co-transporter (SGLT) type 2 are wildly used for the treatment of diabetes, heart and kidney failure. Previous attempts to use SGLT2 blockers in experimental peritoneal dialysis yielded contrasting results. We studied whether peritoneal SGLTs blockade may improve ultrafiltration (UF) via partial inhibition of glucose uptake from dialysis fluids. METHODS: Kidney failure was induced in mice and rats by bilateral ureteral ligation, and dwell was performed by injection of glucose-containing dialysis fluids. The effect of SGLT inhibitors on glucose absorption during fluid dwell and UF was measured in vivo. RESULTS: Diffusion of glucose from dialysis fluid into the blood appeared to be sodium-dependent, and blockade of SGLTs by phlorizin and sotagliflozin attenuated blood glucose increment thereby decreasing fluid absorption. Specific SGLT2 inhibitors failed to reduce glucose and fluid absorption from the peritoneal cavity in a rodent kidney failure model. CONCLUSIONS: Our study suggests that peritoneal non-type 2 SGLTs facilitate glucose diffusion from dialysis solutions, and we propose that limiting glucose reabsorption by specific SGLT inhibitors may emerge as a novel strategy in PD treatment to enhance UF and mitigate the deleterious effects of hyperglycaemia.

Neutrophil to lymphocyte ratio as an early indicator for ureteral catheterization in patients with renal colic due to upper urinary tract lithiasis.

PURPOSE: To evaluate whether the neutrophil-to-lymphocyte ratio (NLR) can predict the need for ureteral catheterization in patients with renal colic. MATERIALS AND METHODS: We retrospectively studied 15,887 patients with renal colic between 2005 and 2019. Patients with prior antibiotics treatment (156), with hematological diseases (15), with negative computerized tomography scan (CTS) for stone disease (473) or with no available laboratory findings (1750) were excluded. A ureteral double J stent (DJS) was inserted in case of ongoing pain, fever, sepsis, single kidney and elevated blood creatinine levels concomitant with hydronephrosis. A cut-off value of 2.1 NLR was determined to stratify and to compare patients using multivariable logistic regression models. A locally weighted scatterplot smoothing (LOWESS) plot was also applied to show the relationship between NLR and predicted probability for DJS insertion. RESULTS: Thirteen-thousand and 493 patients with a mean age of 42.7 years (30% females and 70% males) were included in the study. Five-hundred and 57 patients (4.1%) underwent early DJS insertion: 5.3% vs. 1.5% of patients with high vs. low NLR, respectively, (p<0.001). High NLR was significantly associated with longer hospitalization time, admission to the intensive care unit and overall mortality within a month from admission (p<0.05). LOWESS plot showed that NLR value >2.1 escalates progressively the probability for DJS insertion. CONCLUSIONS: A high NLR is associated with the need for early internal DJS insertion due to urolithiasis. The NLR is easily calculated from simple blood tests and based on our results can be used for clinical decision making in patients with renal colic needing renal decompression.

The stressed bird in the hand: Influence of sampling design on the physiological stress response in a free-living songbird.

Despite the widely used application of standardized capture-handling protocols to collect blood and assess the physiological stress response, the actual sampling design (e.g., timing and the number of blood samples) often differs between studies, and the potential implications for the measured physiological endpoints remain understudied. We, therefore experimentally tested the effects of repeated handling and multiple blood sampling on the stress response in wintering free-living great tits (Parus major). We modified a well-established sampling protocol of avian studies by adding either an additional blood sample or a "sham-manipulation" (i.e., handling associated with the blood sampling procedure without venepuncture), to disentangle the effects of handling stress and blood loss. We combined three different stress metrics along the endocrine-immune interface to investigate the acute short-term stress response: total corticosterone concentrations (Cort), the heterophil/lymphocyte ratio (H:L), and the Leucocyte Coping Capacity (LCC). Our study provided three key results: i) no relationship between Cort levels, LCC and H:L, confirming that these three parameters represent different physiological endpoints within the stress response; ii) contrasting dynamics in response to stress by the measured parameters and iii) no difference in physiological stress levels 30 min after capture due to one additional blood sampling or handling event. By optimising the sampling design, our results provide implications for animal welfare and planning experimental procedures on stress physiology in passerine species.

Circulating Cell-Free DNA Levels in Patients with Metastatic Renal Cell Carcinoma.

BACKGROUND: Limited data about biomarkers are available to predict the outcomes of targeted therapy in metastatic renal cell carcinoma (mRCC). Circulating cell-free DNA (CFD) is elevated in various cancers. PATIENTS AND METHODS: We performed a prospective study of patients with mRCC who received targeted therapy in the Soroka Medical Center between 2013 and 2015. CFD levels were measured using a simple fluorometric assay. Blood samples for CFD were collected before treatment and at weeks 1, 4, 12, 18, and 24 of treatment. The normal cut-off level of CFD was defined as 800 ng/ml. The association of CFD with objective response, progression-free survival (PFS), and overall survival was tested, with adjustment for known confounding risk factors. RESULTS: A total of 23 patients were included; 18 were treated with first-line therapy and 5 with second- and third-line therapies. Patients with normal pretreatment CFD level had a better PFS versus patients with increased levels (p = 0.023). In multivariate analysis, factors associated with PFS were pretreatment CFD levels (p = 0.020) and Heng risk (p = 0.006). CONCLUSIONS: Elevated pretreatment CFD levels measured using a simple fluorometric assay may be associated with a worse PFS in patients with mRCC. A larger prospective study is warranted in order to validate our observation.

Testicular Metastasis from Renal Cell Carcinoma: A Case Report and Review of the Literature.

Testicular metastases from renal cell carcinoma (RCC) are extremely rare. To the best of our knowledge, only 33 cases have been described in the literature. Most of the reported cases are of unilateral testicular metastasis from RCC. We report a case of metachronous ipsilateral testicular metastasis from RCC in a 78-year-old man 6 years after nephrectomy. Scrotal ultrasonography showed a 4 × 5 cm mass in the right testis. Right inguinal orchiectomy was performed for diagnosis. Computed tomography revealed liver and lung metastases. First-line therapy with sunitinib was started in November 2016 for metastatic RCC.

Monitoring treatment of acute kidney injury with damage biomarkers.

BACKGROUND: Damage biomarkers may identify mechanisms and sites of acute kidney injury (AKI). However, the utility of novel AKI biomarkers differs by context, and their utility for monitoring treatment of AKI is unknown. We hypothesized that selected AKI biomarkers would facilitate monitoring of mechanism-specific treatment. We examined this using a panel of biomarkers to monitor cisplatin-induced AKI treatment with alpha-lipoic acid (α-LA) that has previously been demonstrated to ameliorate cisplatin induced AKI. METHODS: AKI was induced in male Sprague Dawley rats using cisplatin (6mg/kg) in the presence or absence of a single dose of α-LA (100mg/kg). A panel of 12 urinary kidney damage biomarkers (CystatinC, NGAL albumin, alpha-1-acid glycoprotein, clusterin, KIM-1, osteopontin, total protein, cytochrome C, epidermal growth factor, interleukin-18 and malondialdehyde was examined as well as histological injury, serum creatinine and cystatin C, and clinical parameters. RESULTS: Cisplatin treatment modified all parameters, except interleukin-18 and malondialdehyde, with each parameter demonstrating a different temporal profile. α-LA treatment attenuated renal tubular injury scores (P <0.05), decreased peak serum creatinine (p=0.004) and cystatin C (p=0.04), and urinary damage biomarkers of proximal tubular injury (CystatinC, NGAL, albumin, and alpha-1-acid glycoprotein). Other urinary biomarkers were not modified. Neither α-LA alone, nor the cisplatin vehicle (DMSO) modified biomarker profiles. CONCLUSIONS: α-LA treatment ameliorated cisplatin-induced AKI. Protection was demonstrated by reduced structural damage, improved glomerular filtration and reduced excretion of urinary biomarkers of proximal tubular damage. Effective treatment of AKI can be monitored by site and perhaps by mechanism-specific kidney damage biomarkers.

Removal of body surface area normalisation improves raw-measured glomerular filtration rate estimation by the Chronic Kidney Disease Epidemiology Collaboration equation and drug dosing in the obese.

BACKGROUND/AIM: We aimed to compared estimated glomerular filtration rate (eGFR) according to the Chronic Kidney Disease Epidemiology Collaboration equation (CKD-EPI), with (mL/min/1.73 m(2) ) and without body surface area (BSA) normalisation (CKD-EPI_noBSA, mL/min) against measured (99m) Technetium - diethylenepentaacetic acid (Tc-DTPA GFR) (mL/min) in 222 individuals, including 80 with malignancy. METHODS: BSA was calculated for each individual using the Du Bois equation. The CKD-EPI and CKD-EPI_noBSA equations were compared with measured Tc-DTPA GFR with respect to bias, proportion within 30% of GFR (P30) and root mean square error for predicting levels of GFR, and concordance in relation to carboplatin dosing. RESULTS: The mean (SD) for BSA and measured GFR for the entire group was 1.99 (0.25) m(2) and 127 (41) mL/min respectively. The P30 for Tc-DTPA GFR was significantly higher with the CKD-EPI_noBSA (80%) than with the CKD-EPI equation (63%, P = 0.0001). In those with body mass index (BMI) > 30 kg/m(2) , the P30 values for the CKD-EPI_noBSA and CKD-EPI were 74% and 42% respectively (P < 0.0001). Carboplatin dosing concordance for the cancer patients using the CKD-EPI and CKD-EPI_noBSA equation was 71% and 56% respectively (P = 0.07). In 78 individuals with BMI > 30 kg/m(2) , concordance in relation to carboplatin dosing using CKD-EPI_noBSA was 65% compared with 26% with the CKD-EPI (P < 0.0001). CONCLUSION: The CKD-EPI without normalisation (CKD-EPI_noBSA) equation was superior to the CKD-EPI equation in estimating raw-measured Tc-DTPA GFR (mL/min).

Lean mass modulates glomerular filtration rate in males of normal and extreme body composition.

BACKGROUND: Understanding determinants of glomerular filtration rate (GFR) is important in aiding prediction and interpretation of kidney function. Body composition is known to affect GFR but is not included in current screening of kidney disease. We investigated the association between GFR and body composition in healthy young men with differing body mass but without known diabetes or kidney injury. METHODS: Three groups were recruited: normal BMI (n = 22) with a body mass index (BMI) <25 kg/m(2) , muscular (n = 23) with BMI ≥30 kg/m(2) and bioelectrical impedance body fat ≤20% and obese (n = 22) with BMI ≥30 kg/m(2) and bioelectrical impedance body fat ≥30%. Dietary analyses, GFR clearance by (99m) Tc-DTPA, urine protein and body composition by dual-energy X-ray absorptiometry were measured in all participants. Linear and nonlinear associations of constituents of body composition with GFR were assessed. RESULTS: Muscular men had a higher GFR (mean 186.4 mL/min; 95% CI 171.7-201.1) than normal BMI and obese groups (P = 0.0007). Urine protein and albumin excretion were not elevated in any participants. On multiple regression analysis (r(2) = 0.60), the variables with strong associations with GFR were age (P = 0.0009) and lean mass (P = 0.0001). Fat mass, protein intake and smoking status were not associated. Skeletal muscle mass correlated significantly with GFR in all subgroups. CONCLUSION: Age and lean mass were strong determinants of GFR. Estimates of GFR should therefore be indexed to an estimate of lean mass.

Amelanotic malignant melanoma of the penis. A case report and literature review.

Malignant melanoma (MM) of the penis represents an uncommon form of genitourinary malignancies, which account for about 1% of all cases of melanoma. Amelanotic malignant melanoma (AMM) lacks the pigmented elements, which is the hallmark of melanoma. This is a challenging diagnosis since confusion might be made with a variety of benign lesions, causing a delay in appropriate medical treatment. Taking into consideration that prognosis is the same for melanotic and amelanotic melanoma, early diagnosis is crucial. We describe a patient with amelanotic melanoma of the penis, treated with partial penectomy.

Nephrolithiasis during pregnancy: characteristics, complications, and pregnancy outcome.

PURPOSE: To evaluate obstetric complications and birth outcome in pregnant women with nephrolithiasis. METHODS: A retrospective population-based study comparing all pregnancies of women with and without nephrolithiasis between 1989 and 2010 was conducted. Clinical characteristics were compared, and the obstetric risk factors and labor complication were analyzed. Multivariable logistic regression models were constructed in order to identify independent risk factors for nephrolithiasis. RESULTS: During the study period, there were 219,656 deliveries, of which 195 women with nephrolithiasis were identified. Nephrolithiasis in pregnant women was significantly associated with recurrent abortions, mild preeclampsia, chronic hypertension, gestational diabetes mellitus, and cesarean deliveries. Nephrolithiasis was also significantly associated with urinary tract infections, pyelonephritis, hydronephrosis, and hydroureter. Nevertheless, no higher rates of premature rupture of membranes, preterm deliveries, or adverse perinatal outcomes (birth weight, Apgar scores or perinatal mortality) were noted in patients with nephrolithisais. Using a multiple logistic regression model, obesity (odds ratio 4.4, 95% confidence interval 2.1-9.0) and hypertensive disorders (odds ratio 2.8, 95% confidence interval 1.9-4.1) were independently associated with nephrolithiasis. CONCLUSION: Maternal kidney stones are significantly associated with several pregnancy complications, including recurrent abortions, hypertensive disorders, gestational diabetes, and cesarean deliveries. Nevertheless, it is not associated with adverse perinatal outcomes. These findings raise the question regarding the proper management of small asymptomatic kidney stone in a pregnant woman.

Breath ammonia and trimethylamine allow real-time monitoring of haemodialysis efficacy.

Non-invasive monitoring of breath ammonia and trimethylamine using Selected-ion-flow-tube mass spectroscopy (SIFT-MS) could provide a real-time alternative to current invasive techniques. Breath ammonia and trimethylamine were monitored by SIFT-MS before, during and after haemodialysis in 20 patients. In 15 patients (41 sessions), breath was collected hourly into Tedlar bags and analysed immediately (group A). During multiple dialyses over 8 days, five patients breathed directly into the SIFT-MS analyser every 30 min (group B). Pre- and post-dialysis direct breath concentrations were compared with urea reduction, Kt/V and creatinine concentrations. Dialysis decreased breath ammonia, but a transient increase occurred mid treatment in some patients. Trimethylamine decreased more rapidly than reported previously. Pre-dialysis breath ammonia correlated with pre-dialysis urea in group B (r(2) = 0.71) and with change in urea (group A, r(2) = 0.24; group B, r(2) = 0.74). In group B, ammonia correlated with change in creatinine (r(2) = 0.35), weight (r(2) = 0.52) and Kt/V (r(2) = 0.30). The ammonia reduction ratio correlated with the urea reduction ratio (URR) (r(2) = 0.42) and Kt/V (r(2) = 0.38). Pre-dialysis trimethylamine correlated with Kt/V (r(2) = 0.21), and the trimethylamine reduction ratio with URR (r(2) = 0.49) and Kt/V (r(2) = 0.36). Real-time breath analysis revealed previously unmeasurable differences in clearance kinetics of ammonia and trimethylamine. Breath ammonia is potentially useful in assessment of dialysis efficacy.

Upper pole multicystic dysplasia and ureteropelvic junction obstruction associated with obstructive-refluxing megaureter in a neonate with a single kidney.

A 20-day-old male neonate presented with fever and hydronephrosis. Evaluation revealed that the patient had a single left kidney and a rare combination of multiple congenital malformations: upper pole segmental multicystic dysplasia, ureteropelvic junction obstruction, and an obstructive and refluxing megaureter (ureterovesical junction obstruction). We performed percutaneous drainage of the infected and obstructed upper collecting system and then used a sequential approach to manage the patient's anomalies. First, we performed an upper pole partial nephrectomy and pyeloplasty with a modified Y ureterostomy. Second, when the child was older, we performed ureterovesical reimplantation with ureteral tailoring. Currently, after 5 years of follow up, the patient has stable renal function.

Renal autoregulation and passive pressure-flow relationships in diabetes and hypertension.

We investigated renal hemodynamics in isolated, perfused kidneys from rat models of diabetes and hypertension. Autoregulation and passive vascular responses were measured using stepped pressure ramps in the presence of angiotensin II (pEC50) or papaverine (0.1 mM), respectively. Male diabetic heterozygote m(Ren2)27 rats were compared with three male control groups: nondiabetic, normotensive Sprague-Dawley (SD) rats; nondiabetic, hypertensive heterozygote m(Ren2)27 rats; and diabetic, normotensive SD rats. Kidney function (proteinuria, creatinine clearance) was monitored before induction and at monthly intervals. Vascular function was measured in vitro in rats of induction age (6-8 wk) and at 2 and 4 mo postinduction. Renal flow correlated with age, but not diabetes or the Ren2 gene. Kidney weight-specific and body weight-specific renal flow differed between diabetic and nondiabetic rats because diabetic rats had higher kidney but lower body weights. Kidneys from all groups showed effective autoregulation in the presence of angiotensin II. The autoregulatory pressure threshold of m(Ren2)27 rats was higher, and the autoregulation pressure range was wider, compared with SD rats. When vascular smooth muscle activity was blocked with papaverine, pressure-flow responses differed between groups and with time. The m(Ren2)27 rat groups showed higher renal vascular resistance at lower pressures, suggesting greater vascular stiffness. In contrast, diabetic SD rat kidneys demonstrated reduced vessel stiffness. Flow was impaired in diabetic m(Ren2)27 rats at 4 mo, and this correlated with a decline in creatinine clearance. The results suggest that the characteristic late decline in renal filtration function in diabetes- and hypertension-related renal disease follows changes in renal vascular compliance.