PET [11C]acetate is also a perfusion tracer for kidney evaluation purposes.

RATIONALE: Renal positron emission tomography (PET) functional imaging allows non-invasive and dynamic measurements of functional and metabolic parameters. [15O]H2O is used as a perfusion tracer, and [11C]acetate as an oxidative metabolism in this purpose, requiring two injections to assess those fundamental parameters. Yet, in cardiac physiology study, the high first-pass myocardial extraction fraction of [11C]acetate allowed to use its influx rate as a blood flow marker too. Since [11C]acetate has been characterized by a 20-25% single pass renal extraction in dogs, it could be used as a potential tracer for renal perfusion. The aim of this study was to determine whether [11C]acetate influx rate can be used as quantitative in vivo marker of kidney perfusion in human. METHODS: In 10 healthy subjects, dynamic PET acquisitions were performed after [15O]H2O and [11C]acetate injections spaced by a 15-minute interval. As previously validated, with compartmental modeling of kinetics, renal perfusion and oxidative metabolism were estimated respectively with influx rate of [15O]H2O and efflux rate of [11C]acetate. Additionally, influx rate of [11C]acetate was regressed to influx rate of [15O]H2O. RESULTS: Renal time activity curves of [11C]-acetate was best fitted with a mono compartmental model compared to a bi-compartmental model (p < 0.0001). [11C]acetate influx rate was significantly correlated with perfusion quantified with [15O]H2O (r2 = 0.37, p < 0.001) at baseline. This regression allowed the computation of a renal [11C]acetate extraction fraction (EF), and further the computation of renal blood flow from its influx rate. CONCLUSION: In healthy subjects, over a wide range of renal perfusion, direct estimates of renal oxygen consumption as well as tissue perfusion can be obtained by PET with a single tracer [11C]acetate. This approach needs to be validated in CKD patients, and would be of great interest to design clinical protocol aiming at evaluating ischemic nephropathies candidate to revascularization.

Estimated Glomerular Filtration Rate Bias in Participants with Severe Obesity Regardless of Deindexation.

OBJECTIVE: Morbid obesity is associated with a higher independent risk of chronic kidney disease (CKD). Estimated glomerular filtration rate (eGFR) has been evaluated in a limited number of study participants with severe obesity. METHODS: A total of 706 measured GFR (mGFR) results from 598 participants with obesity (BMI ≥ 35 kg/m2 ) were retrospectively collected. The performance of the Modification of Diet in Renal Disease (MDRD) equation, Chronic Kidney Disease-Epidemiology (CKD-EPI) equation, and deindexed eGFR were compared with mGFR from the gold standard technique (inuline or iohexol), adjusted (mGFRr) or nonadjusted (mGFR) to body surface area. Absolute bias, precision, and accuracy were calculated. RESULTS: Mean mGFRr (58 ± 31 mL/min/1.73 m2 ) was significantly different from CKD-EPI and MDRD (P < 0.001). Mean mGFR (nonindexed) (70 ± 40 mL/min) was significantly higher than mGFRr (P < 0.001). eGFR showed important biases and low accuracies for CKD-EPI and MDRD (10.7 ± 10.7 and 12.2 ± 13.7 mL/min/1.73 m2 ; 78% vs. 75% respectively). Deindexation worsened bias and accuracy 30% (percentage of GFR estimates within 30% of mGFRr or mGFR) between eGFR and mGFR. CONCLUSIONS: eGFR overestimates mGFR and is associated with important biases and inaccuracies in patients with severe obesity, and deindexing eGFR worsens the overestimation. These findings may have important implications in examining kidney function in patients with obesity.

Blood pressure decreases after revascularization in atherosclerotic renal artery disease: A cohort study based on a multidisciplinary meeting.

BACKGROUND: In atherosclerotic renal artery disease, the benefit of revascularization is controversial. A clinical decision-making process based on a multidisciplinary meeting was formalized in the Lyon university hospital. OBJECTIVES: To investigate whether this decisional process ensured a clinical benefit to patients assigned to renal revascularization. METHODS: Single-centre retrospective cohort study, including patients diagnosed from April 2013 to February 2015 with an atherosclerotic renal artery disease with a peak systolic velocity >180cm/s. For each patient, the decision taken in multidisciplinary meeting (medical treatment or revacularization) was compared to the one guided by international guidelines. Blood pressure values, number of antihypertensive medications, presence of an uncontrolled or resistant hypertension, and glomerular filtration rate at one-year follow-up were compared to baseline values. Safety data were collected. RESULTS: Forty-nine patients were included: 26 (53%) were assigned to a medical treatment and 23 (47%) to a renal revascularization. Therapeutic decision was in accordance with the 2013 American Health Association guidelines and with the 2017 European Society of Cardiology guidelines for 78% and 22% of patients who underwent revascularization, respectively. Patients assigned to revascularization presented a significant decrease in systolic blood pressure (-23±34mmHg, p = 0.007), diastolic blood pressure (-12±18mmHg, p = 0.007), number of antihypertensive medications (-1.00±1.03, p = 0.001), and number of uncontrolled or resistant hypertension (p = 0.022 and 0.031) at one-year follow-up. Those parameters were not modified among patients assigned to medical treatment alone. There was no grade 3 adverse event. CONCLUSION: Based on a multidisciplinary selection of revascularization indications, patients on whom a renal revascularization was performed exhibited a significant improvement of blood pressure control parameters with no severe adverse events.

AGE Content of a Protein Load Is Responsible for Renal Performances: A Pilot Study.

OBJECTIVE: Chronic kidney disease is associated with higher morbidity and mortality in patients with diabetes. A low-protein diet is recommended to slow diabetic nephropathy progression because each protein load leads to renal hemodynamic variations. The aim of our study was to evaluate whether the advanced glycation end products (AGE) content of a protein load is responsible for the protein-induced renal hemodynamic variations in humans. RESEARCH DESIGN AND METHODS: Ten healthy subjects were assigned to a high-protein (1 g/kg) low-AGE (3,000 kU AGE) versus high-AGE (30,000 kU AGE) meal. Renal perfusion, oxygen consumption, and oxygen content were measured before and 120 min after each meal. RESULTS: Renal perfusion (3.2 ± 0.5 vs. 3.8 ± 0.4 mL/min/g; P = 0.0002) and oxygen consumption (0.3 ± 0.04 vs. 0.4 ± 0.08 min-1; P = 0.005) increased significantly after the high-AGE meal compared with the low-AGE meal. CONCLUSIONS: Our results suggest that the AGE content of a protein load is responsible for renal hemodynamic modifications. Therefore, prevention of diabetic nephropathy progression could aim predominantly at reducing food AGE content.

Pregnancy Outcomes in French Hemodialysis Patients.

BACKGROUND: Pregnancy in hemodialysis (HD) women is a rare event and often associated with maternal and fetal complications. Scarcity of available data from large cohorts impedes fair medical counseling. METHODS: This is a descriptive, retrospective, multi-centric study. Pregnant women on HD during the period from 1985 to 2015 in France were included. The primary outcome was a living infant discharged from hospital, while secondary outcomes included gestational age and birth weight. RESULTS: We identified 100 pregnancies in 84 women on HD, from 41 centers. Chronic HD was initiated during pregnancy for 17.7% (14/79) of patients explaining a 19.8% prevalence of catheter (19/96) and a preserved residual diuresis for 50% of pregnancy (43/86). Seventy-six (89.4%) women performed daily dialysis during the third trimester (6 times per week). Our primary outcome was met for 78% of newborns with a mean gestational age of 33.2 ± 3.9 weeks and a mean birth weight of 1,719 ± 730 g. CONCLUSIONS: Our study is one of the largest series of -pregnancies in HD patients. Despite recent progresses, these pregnancies remain at high risk, reinforcing the need for an early nephrologist-obstetrician skilled team co-management.

Dose and timing of injections for effective cyclosporine A pretreatment before renal ischemia reperfusion in mice.

BACKGROUND: There is experimental evidence that lethal ischemia-reperfusion injury (IRI) is largely due to mitochondrial permeability transition pore (mPTP) opening, which can be prevented by cyclosporine A (CsA). The aim of our study is to show that a higher dose of CsA (10 mg/kg) injected just before ischemia or a lower dose of CsA (3 mg/kg) injected further in advance of ischemia (1 h) protects the kidneys and improves mitochondrial function. METHODS: All mice underwent a right unilateral nephrectomy followed by 30 min clamping of the left renal artery. Mice in the control group did not receive any pharmacological treatment. Mice in the three groups treated by CsA were injected at different times and with different doses, namely 3 mg/kg 1 h or 10 min before ischemia or 10 mg/kg 10 min before ischemia. After 24 h of reperfusion, the plasma creatinine level were measured, the histological score was assessed and mitochondria were isolated to calculate the calcium retention capacity (CRC) and level of oxidative phosphorylation. RESULTS: Mortality and renal function was significantly higher in the CsA 10 mg/kg-10 min and CsA 3mg/kg-1 h groups than in the CsA 3mg/kg-10 min group. Likewise, the CRC was significantly higher in the former two groups than in the latter, suggesting that the improved renal function was due to a longer delay in the opening of the mPTP. Oxidative phosphorylation levels were also higher 24 h after reperfusion in the protected groups. CONCLUSIONS: Our results suggest that the protection afforded by CsA is likely limited by its availability. The dose and timing of the injections are therefore crucial to ensure that the treatment is effective, but these findings may prove challenging to apply in practice.

Pregnancy outcomes in simultaneous pancreas and kidney transplant recipients: a national French survey study.

Simultaneous pancreas and kidney transplantation (SPK) is currently the best therapeutic option for patients with type 1 diabetes and terminal renal failure. Renal transplantation restores fertility enabling women to pursue pregnancies. However, scarcity of available data on pregnancy outcomes in SPK impedes fair medical counseling. Medical files of all pregnancies that lasted ≥3 months among recipients of functional SPK performed between 1990 and 2015 in France were retrospectively analyzed. Twenty-six pregnancies in 22 SPK recipients were identified. Main maternal complications included gestational hypertension (53.8%) and infections (50%). Cesarean section was performed in 73% of cases. Overall fetal survival was 92.6% with a mean gestational age of 34.2 ± 3 weeks. Four children (16.7% of live births) had a birth weight <10th percentile. Endocrine pancreas graft function remained stable during pregnancy. An acute kidney rejection occurred in two patients, one of which resulting in graft loss. Kidney and pancreas graft survival was, respectively, 96% and 100% at 1 year postconception and did not differ from controls. Pregnancy in SPK is feasible, but patients should be informed of the risks for the fetus, the mother, and the grafts. Planning of pregnancy in SPK women is key to allow a personalized multidisciplinary monitoring, which represents the most straightforward approach to optimize outcomes.

Paraneoplastic fibrillary glomerulonephritis associated with intrahepatic cholangiocarcinoma: When diagnosis of a rare kidney disease leads to successful hepatic cancer treatment.

A 50-year-old man presented with nephrotic syndrome. Electron microscopy analysis of a kidney biopsy specimen showed fibrillary glomerulonephritis, a rare glomerular disease, while histological analysis of a liver tumor biopsy confirmed an intrahepatic cholangiocarcinoma. The paraneoplastic nature of fibrillary glomerulonephritis is debated but after curative treatment of the hepatic nodule, remission of nephrotic syndrome was confirmed at 6-, 12- and 24-months follow-up. To our knowledge, this is the first description of a paraneoplastic fibrillary glomerulonephritis associated with a cholangiocarcinoma, supported by complete remission achieved following cancer treatment.

Intracellular Phosphate Dynamics in Muscle Measured by Magnetic Resonance Spectroscopy during Hemodialysis.

Of the 600-700 mg inorganic phosphate (Pi) removed during a 4-hour hemodialysis session, a maximum of 10% may be extracted from the extracellular space. The origin of the other 90% of removed phosphate is unknown. This study tested the hypothesis that the main source of phosphate removed during hemodialysis is the intracellular compartment. Six binephrectomized pigs each underwent one 3-hour hemodialysis session, during which the extracorporeal circulation blood flow was maintained between 100 and 150 ml/min. To determine in vivo phosphate metabolism, we performed phosphorous ((31)P) magnetic resonance spectroscopy using a 1.5-Tesla system and a surface coil placed over the gluteal muscle region. (31)P magnetic resonance spectra (repetition time =10 s; echo time =0.35 ms) were acquired every 160 seconds before, during, and after dialysis. During the dialysis sessions, plasma phosphate concentrations decreased rapidly (-30.4 %; P=0.003) and then, plateaued before increasing approximately 30 minutes before the end of the sessions; 16 mmol phosphate was removed in each session. When extracellular phosphate levels plateaued, intracellular Pi content increased significantly (11%; P<0.001). Moreover, ßATP decreased significantly (P<0.001); however, calcium levels remained balanced. Results of this study show that intracellular Pi is the source of Pi removed during dialysis. The intracellular Pi increase may reflect cellular stress induced by hemodialysis and/or strong intracellular phosphate regulation.

ABCA2 transporter deficiency reduces incidence of TRAMP prostate tumor metastasis and cellular chemotactic migration.

In order to study the effects of ATP-binding cassette transporter 2 (ABCA2) deficiency on the progression of prostate cancer, congenic Abca2 knockout (KO) mice were crossed to the transgenic adenocarcinoma of the mouse prostate (TRAMP) model. ABCA2 expression was elevated in wild-type/TRAMP (WT/Tg) dorsal prostate, a region comprising the most aggressive tumors in this model, compared to non-transgenic WT mice. Primary prostate tumor progression was similar in KO/Tg and WT/Tg mice with respect to pathological score, prostate tumor growth, as calculated using MRI volumetry, and proliferative index, as determined by PCNA immunostaining. Vimentin, a marker of the epithelial-mesenchymal transition, was expressed at similar levels in prostate, but elevated in histologically normal seminal vesicles (SV) in KO/Tg mice (P < 0.02), concomitant with an increased SV volume (P < 0.01). These changes in the SV did not exacerbate the metastatic phenotype of this disease model; rather, KO/Tg mice aged 20-25 weeks had no detectable metastases while 38% of WT/Tg developed metastases to lung and/or lymph nodes. The absence of a metastatic phenotype in KO/Tg mice was reprised in stable ABCA2 knockdown (KD) cells where chemotactic, but not random, migration was impaired (P = 0.0004). Expression levels of sphingolipid biosynthetic enzymes were examined due to the established link of the transporter with sphingolipid homeostasis. Galactosylceramide synthase (GalCerS) mRNA levels were over 8-fold higher in KD cells (P = 0.001), while lactosylceramide synthase (LacCerS) and CTP:choline cytidylyltransferase (CCT) were significantly reduced (P < 0.0001 and 0.03, respectively). Overall, we demonstrate that ABCA2-deficiency inhibits prostate tumor metastasis in vivo and decreases chemotactic potential of cells, conceivably due to altered sphingolipid metabolism.

Biomarkers of selenium status in the Amazonian context: blood, urine and sequential hair segments.

Selenium (Se) is an essential element and deficit or excess of dietary Se is associated with health disorders. Relatively elevated Se levels have been reported in the Brazilian Amazon, where there are also important annual variations in the availability of different foods. The present study was conducted among six riparian communities of the Tapajós River to evaluate seasonal variations in blood and sequential hair cm Se concentrations, and to examine the relationships between Se in blood and hair, and blood and urine. Two cross-sectional studies were conducted, at the descending water (DWS, n=259) and the rising water (RWS, n=137) seasons, with repeated measures for a subgroup (n=112). Blood Se (B-Se), hair Se (H-Se) and urine Se (U-Se) were determined. Match-paired analyses were used for seasonal comparisons and the method of best fit was used to describe the relationships between biomarkers. B-Se levels presented a very large range (142-2447 microg/l) with no overall seasonal variation (median 284 and 292 microg/l, respectively). Sequential analysis of 13 cm hair strands showed significant variations over time: Se concentrations at the DWS were significantly lower compared with the rising water season (medians: 0.7 and 0.9 microg/g; ranges: 0.2-4.3 microg/g and 0.2-5.4 microg/g, respectively). At both seasons, the relationships between B-Se and H-Se were linear and highly significant (r(2)=67.9 and 63.6, respectively), while the relationship between B-Se and U-Se was best described by a sigmoid curve. Gender, age, education and smoking did not influence Se status or biomarker relationships. Variations in H-Se suggest that there may be seasonal availability of Se sources in local food. For populations presenting a large range and/or elevated Se exposure, sequential analyses of H-Se may provide a good reflection of variations in Se status.