Long-term dietary nitrate supplementation does not reduce renal cyst growth in experimental autosomal dominant polycystic kidney disease.

Augmentation of endogenous nitric oxide (NO) synthesis, either by the classical L-arginine-NO synthase pathway, or the recently discovered entero-salivary nitrate-nitrite-NO system, may slow the progression of autosomal dominant polycystic kidney disease (ADPKD). To test this hypothesis, the expression of NO in human ADPKD cell lines (WT 9-7, WT 9-12), and the effect of L-arginine on an in vitro model of three-dimensional cyst growth using MDCK cells, was examined. In addition, groups of homozygous Pkd1RC/RC mice (a hypomorphic genetic ortholog of ADPKD) received either low, moderate or high dose sodium nitrate (0.1, 1 or 10 mmol/kg/day), or sodium chloride (vehicle; 10 mmol/kg/day), supplemented drinking water from postnatal month 1 to 9 (n = 12 per group). In vitro, intracellular NO, as assessed by DAF-2/DA fluorescence, was reduced by >70% in human ADPKD cell lines, and L-arginine and the NO donor, sodium nitroprusside, both attenuated in vitro cyst growth by up to 18%. In contrast, in Pkd1RC/RC mice, sodium nitrate supplementation increased serum nitrate/nitrite levels by ~25-fold in the high dose group (P<0.001), but kidney enlargement and percentage cyst area was not altered, regardless of dose. In conclusion, L-arginine has mild direct efficacy on reducing renal cyst growth in vitro, whereas long-term sodium nitrate supplementation was ineffective in vivo. These data suggest that the bioconversion of dietary nitrate to NO by the entero-salivary pathway may not be sufficient to influence the progression of renal cyst growth in ADPKD.

Effect of placental growth factor in models of experimental pre-eclampsia and trophoblast invasion.

Placental growth factor (PlGF) is decreased in early gestation of pregnant women who subsequently develop pre-eclampsia. In this study, pre-emptive treatment with PlGF to prevent pre-eclampsia was evaluated in an in vivo rodent model of experimental pre-eclampsia (EPE) induced by TNF-α and in an in vitro model of human first-trimester trophoblast invasion. Pregnant C57/BL6 mice were treated with recombinant mouse placental growth factor-2 (rmPlGF-2) 100 µg/kg/day IP from gestational day (gd) 10. Animals had EPE induced by continuous TNF-α infusion on gd 13 and were subject to either continuous blood pressure monitoring by radiotelemetry throughout pregnancy or live placenta T2 -weighted magnetic resonance imaging (MRI) to demonstrate placental function on gd 17. There was no difference in BP (P > .99), proteinuria (P = .9) or T2 values on MRI (P = .9) between control and rmPlGF-2-treated animals. On gd 13, animals treated with rmPlGF-2 demonstrated increased placenta PlGF (P = .01) and Toll-like receptor-3 (P = .03) mRNA expression as compared with controls. Fluorescent-labelled human uterine microvascular endothelial cells and HTR8/SVNeo cells were co-cultured on Matrigel™ and treated with recombinant human PlGF (rhPlGF) (10 ng/mL) and/or TNF-α (0.5 ng/mL). Trophoblast integration into endothelial networks was reduced by added TNF-α (P = .006), as was rhPlGF concentration in conditioned media (P < .0001). Cell integration was not ameliorated by addition of rhPlGF (P > .9). Although TNF-α-induced EPE was not reversed with pre-emptive rmPlGF-2, a further trial of pre-emptive rhPlGF in vivo is required to determine whether the absence of effect of rhPlGF demonstrated in vitro precludes PlGF as a preventative therapy for pre-eclampsia.

The effect of acetyl salicylic acid (Aspirin) on trophoblast-endothelial interaction in vitro.

Early administration of low dose acetyl salicylic acid (Aspirin) in high risk women reduces the risk of early onset preeclampsia. This study aims to investigate the effect of aspirin on trophoblast integration and the its effect on angiogenic and invasive pathways in an in-vitro model of preeclampsia. Red fluorescent-labeled human uterine myometrial microvascular endothelial cells (UtMVECs) were seeded on matrigel to form endothelial networks. Green fluorescent-labeled trophoblastic HTR-8/SVneo cells were co-cultured with the endothelial networks with/without TNF-a (0.5ng/mL) and/or aspirin (0.1mM) for 24h. Fluorescent images were captured and quantified by Image J to examine the effects of TNF-a and aspirin on the trophoblast-endothelial integration. Conditioned media were collected to measure free VEGF, PlGF and sFlt-1 by ELISA and PGF1a by Enzyme immunoassay (EIA). Cells were retrieved to examine mRNA expression of angiogenic factors (VEGF, PlGF and sFlt-1), invasion markers (MMP-2 and TIMP-1), endothelial cell activation markers (E-selectin and VCAM), eNOS and cyclooxygenase (COX)-2 by quantitative PCR. Aspirin reversed the inhibitory effect of TNF-a on trophoblast cell integration into endothelial cellular networks. TNF-a increased PGF1a production (128±11%, p<0.05), whilst aspirin reversed the TNF-a effect on PGF1a production (19±4%, p<0.01). TNF-a decreased the mRNA expression of PlGF, eNOS, MMP-2 and TIMP-1, and stimulated COX2, E-selectin and VCAM mRNA expression. Aspirin did not reverse the TNF-a effect on these molecules. Aspirin improves trophoblast cell integration into endothelial cellular networks by inhibiting the effect of TNF-a via PGI2 with no significant effect on antiangiogenic, invasive or endothelial activation markers.

Secondary hypertension due to concomitant aldosterone-producing adenoma and parathyroid adenoma.

There is a growing body of evidence supporting a bidirectional relationship between parathyroid hormone (PTH) and aldosterone (Aldo). We report a case of secondary hypertension due to concomitant Aldo-producing adenoma (APA) and parathyroid adenoma (PA) requiring both unilateral adrenalectomy and parathyroidectomy.

Vascular calcification in patients undergoing kidney and simultaneous pancreas-kidney transplantation.

AIM: Vascular calcification (VC) is common in patients with chronic kidney disease (CKD) on dialysis, and an inverse relationship of VC to bone mineral density (BMD) has been reported. Because elderly patients are prone to atherosclerosis and BMD artefact, we examined the prevalence and epidemiology of VC in younger patients undergoing transplantation, and its relationship to BMD. METHODS: Laboratory testing was performed immediately before kidney or simultaneous pancreas-kidney (SPK) transplantation. Within 4 weeks patients underwent BMD evaluation and lateral abdominal X-ray. Aortic calcification was scored using a validated 24-point scale. RESULTS: Of 650 consecutive patients X-rays were available for 531 (82%). Their median age was 41 years (16-71), 58% were male, dialysis vintage was 20 months (0-402) and 69% had kidney and 31% SPK transplants. VC scores were ≥1 in 47%, with the median score 6 (1-24) and was associated with age, dialysis vintage and presence of cardiovascular, cerebrovascular or peripheral vascular disease. In a multivariate analysis of patients with and without VC, those with VC were older and of longer dialysis vintage (OR 1.07 and 1.17 per 12 months respectively; P < 0.001 for both). In that analysis, VC was not significantly associated with gender, transplant type, presence of diabetes, current or former smoking or calcium or calcitriol therapy, and was not inversely related to hip, spine or forearm BMD Z-scores. CONCLUSION: VC is common in younger patients undergoing transplantation and, similar to older patients, is associated with age, dialysis vintage and cardiovascular pathology. However, in this younger patient group, there was no significant inverse association of VC to BMD.

Fluid balance, change in serum creatinine and urine output as markers of acute kidney injury post cardiac surgery: an observational study.

BACKGROUND: Acute kidney injury (AKI) is defined as oliguria or rise in serum creatinine but oliguria alone as a diagnostic criterion may over-diagnose AKI. OBJECTIVES: Given the association between fluid overload and AKI, we aimed to determine if positive fluid balance can complement the known parameters in assessing outcomes of AKI. DESIGN: Prospective observational study. SETTING: Teaching hospital in Vancouver, Canada. PATIENTS: 111 consecutive patients undergoing elective cardiac surgery from January to April 2012. MEASUREMENTS: Outcomes of cardiac surgery intensive care unit (CSICU) and hospital length of stay (LOS) in relation to fluid balance, urine output and serum creatinine. METHODS: All fluid input and output was recorded for 72 hours post-operatively. Positive fluid balance was defined as >6.5 cc/kg. Daily serum creatinine and hourly urine output were recorded and patients were defined as having AKI according to the AKIN criteria. RESULTS: Of the patients who were oliguric, those with fluid overload trended towards longer LOS than those without fluid overload [CSICU LOS: 62 and 39 hours (unadjusted p-value 0.02, adjusted p-value 0.58); hospital LOS: 13 and 9 days (unadjusted p-value: 0.05, adjusted p-value: 0.16)]. Patients with oliguria who were fluid overloaded had similar LOS to patients with overt AKI (change in serum creatinine ≥ 26.5 µmol/L), [CSICU LOS: 62 and 69 hours (adjusted p value: 0.32) and hospital LOS: 13 and 14 days (adjusted p value: 0.19)]. Patients with oliguria regardless of fluid balance had longer CSICU LOS (adjusted p value: 0.001) and patients who were fluid overloaded in the absence of AKI had longer hospital LOS (adjusted p value: 0.02). LIMITATIONS: Single centre, small sample, LOS as outcome. CONCLUSIONS: Oliguria and positive fluid balance is associated with a trend towards longer LOS as compared to oliguria alone. Fluid balance may therefore be a useful marker of AKI, in addition to urine output and serum creatinine.

CONTEXTE: L'insuffisance rénale aiguë (IRA) se définit comme une oligurie ou une élévation de la créatininémie. Par contre, l'oligurie comme unique critère diagnostique peut mener abusivement au diagnostic d'IRA. OBJECTIFS: Étant donné l'association entre l'hyperhydratation et l'IRA, nous cherchons à déterminer si une balance liquidienne positive peut complémenter les paramètres connus dans l'évaluation des résultats de l'IRA. TYPE D'ÉTUDE: Étude d'observation prospective. CONTEXTE: Hôpital universitaire à Vancouver, Canada. PARTICIPANTS: 111 patients consécutifs qui subissent une chirurgie cardiaque non urgente, entre janvier et avril 2012. MESURES: On a mis en parallèle les résultats de l'unité de soins intensifs en chirurgie cardiaque (USICC), de même que la durée de l'hospitalisation (soins actifs), avec la balance liquidienne, la diurèse et la créatininémie. MÉTHODES: On a mesuré les ingesta et excreta durant les 72 heures postopératoires. On a défini une balance liquidienne positive à >6,5 cc/kg. On a enregistré la créatininémie quotidienne et la diurèse aux heures, et on a déterminé que les patients souffraient d'IRA en nous basant sur les critères de l'Acute Kidney Injury Network (AKIN). RÉSULTATS: Parmi les patients oliguriques, ceux qui avaient une surcharge liquidienne tendaient davantage vers une hospitalisation prolongée que ceux qui n'en avaient pas [durée de soins actifs à l'USICC: 62 et 39 heures (valeur de p non ajustée: 0,02, valeur de p ajustée: 0,58); durée de soins actifs à l'hôpital: 13 et 9 jours (valeur de p non ajustée: 0,05, valeur de p ajustée: 0,16)]. Les patients présentant une oligurie qui présentaient aussi une surcharge liquidienne requéraient une durée de soins actifs similaire aux patients souffrant d'IRA (modification de la créatininémie ≥ 26,5 µmol/L), [soins actifs USICC: 62 et 69 heures (valeur de p ajustée: 0,32) soins actifs à l'hôpital: 13 et 14 jours (valeur de p ajustée: 0,19)]. Les patients présentant une oligurie, indépendamment de la balance liquidienne, bénéficiaient d'une durée de soins actifs à l'USICC prolongée (valeur p ajustée: 0,001), tandis que les patients en surcharge liquidienne, mais ne souffrant pas d'IRA bénéficiaient davantage de soins actifs à l'hôpital (valeur de p ajustée: 0,02). LIMITES DE L'ÉTUDE: Un seul centre, un échantillon restreint, les soins actifs considérés comme une issue. CONCLUSION: Les patients avec oligurie et une balance liquidienne positive ont nécessité des soins actifs prolongés à l'USICC, comparativement aux patients ne présentant qu'une oligurie. La balance liquidienne peut donc constituer un marqueur d'IRA, en plus de la diurèse et la créatininémie.

Levetiracetam-induced severe acute granulomatous interstitial nephritis.

Granulomatous interstitial nephritis (GIN) is an uncommon cause of renal failure, which may be caused by drugs. Levetiracetam is an increasingly used anti-epileptic medication that is not known to cause renal toxicity in adults. To our knowledge, levetiracetam has not previously been reported as a cause of GIN. We report the case of a 69-year-old woman who developed haemodialysis-requiring acute renal failure after commencement of treatment with levetiracetam, which was shown to be GIN by renal biopsy. She made a complete recovery with cessation of levetiracetam and treatment with steroids.