Renal Function Response Research Articles

Abstract 045: Attenuated Natriuretic Response to Saline Loading in Sheep With Hypertensive Kidney Disease Following Radiofrequency Catheter-Based Renal Denervation

In the present study, we examined the chronic effect of renal denervation (RDN) on the blood pressure (BP) and renal function in response to a slow-infused isotonic saline load. Normotensive (control) and hypertensive chronic kidney disease (CKD) sheep at 10 months of age underwent either a sham (control-intact; N=6, CKD-intact; N=7) or radiofrequency catheter-based RDN (control-RDN; N=7, CKD-RDN, N=7) procedure using the Symplicity catheter system. BP and renal function were measured during 3-h saline loading (0.9% NaCl, 0.13ml/kg/min) and 3-h recovery periods in animals at 2 and 11 months post-procedure. In this cohort of sheep, as previously reported, BP was reduced and GFR increased at 11 months in the CKD-RDN group. In response to saline loading, BP increased 3-5 mmHg in all groups. In response to saline loading sodium excretion increased in all groups. At 2 months post-procedure, the control-intact group excreted 66±7% of the sodium load over the 6-h period, whereas the response was exaggerated in the CKD-intact group (92±9%; P<0.001 vs. control-intact) but blunted in the RDN groups (control-RDN 32±5%; CKD-RDN 63±5%; both P<0.01 vs. intact). However, by 11 months post-procedure, the % excretion of the sodium load was similar in the intact (53±4%) and RDN (65±5%) control groups, but remained attenuated in the CKD-RDN group (33±6% P<0.001 vs. CKD-intact, 63±14%). Together these data indicate that (1) the normal suppression of RSNA activity during saline loading contributes to the rapid elimination of excess sodium and water, (2) following RDN the excretion of a saline load is attenuated and (3) this effect was maintained for 11 months in the CKD-RDN group indicating nerve regrowth is not complete. In conclusion, RDN in patients with hypertensive CKD may slow the return of extracellular fluid homeostasis in response to physiological challenges such as volume expansion.

Antibiotic Dosing for Critically Ill Adult Patients Receiving Intermittent Hemodialysis, Prolonged Intermittent Renal Replacement Therapy, and Continuous Renal Replacement Therapy: An Update.

Objective: To summarize current antibiotic dosing recommendations in critically ill patients receiving intermittent hemodialysis (IHD), prolonged intermittent renal replacement therapy (PIRRT), and continuous renal replacement therapy (CRRT), including considerations for individualizing therapy. Data Sources: A literature search of PubMed from January 2008 to May 2019 was performed to identify English-language literature in which dosing recommendations were proposed for antibiotics commonly used in critically ill patients receiving IHD, PIRRT, or CRRT. Study Selection and Data Extraction: All pertinent reviews, selected studies, and references were evaluated to ensure appropriateness for inclusion. Data Synthesis: Updated empirical dosing considerations are proposed for antibiotics in critically ill patients receiving IHD, PIRRT, and CRRT with recommendations for individualizing therapy. Relevance to Patient Care and Clinical Practice: This review defines principles for assessing renal function, identifies RRT system properties affecting drug clearance and drug properties affecting clearance during RRT, outlines pharmacokinetic and pharmacodynamic dosing considerations, reviews pertinent updates in the literature, develops updated empirical dosing recommendations, and highlights important factors for individualizing therapy in critically ill patients. Conclusions: Appropriate antimicrobial selection and dosing are vital to improve clinical outcomes. Dosing recommendations should be applied cautiously with efforts to consider local epidemiology and resistance patterns, antibiotic dosing and infusion strategies, renal replacement modalities, patient-specific considerations, severity of illness, residual renal function, comorbidities, and patient response to therapy. Recommendations provided herein are intended to serve as a guide in developing and revising therapy plans individualized to meet a patient's needs.

SAT-295 EVALUATION OF THE DIABETIC GLOMERULAR HEMODYNAMICS BY SGLT2 INHIBITOR EMPAGLIFLOZIN USING IN VIVO IMAGING.

In the EMPA-REG outcome trial and CANVAS program, a sodium-glucose cotransporter 2 inhibitor (SGLT2i) slowed the progression of diabetic kidney disease (DKD) in patients with type 2 diabetes. Improvement of glomerular hyperfiltration via tubuloglomerular feedback (TGF) is considered to be one of the possible pathways for renal protection with SGLT2i in diabetic kidney disease (DKD). However, the mechanisms that regulate renal function in response to SGLT2i have not been fully elucidated. We explored the renal protective mechanisms of SGLT2i with empagliflozin (EMPA), with a focus on glomerular hemodynamic effects and TGF using in vivo multiphoton microscope (MPM) imaging techniques.

SAT-109 NEW INSIGHTS INTO THE NOVEL ROLES OF ANGIOTENSIN AT1A RECEPTORS IN THE PROXIMAL TUBULES OF THE KIDNEY IN ANGIOTENSIN II-INDUCED HYPERTENSION AND KIDNEY INJURY

It is well-recognized that the renin-angiotensin system plays powerful endocrine, paracrine, and intracellular roles in the physiological regulation of blood pressure, cardiovascular and kidney function, as well as in the development of hypertension and kidney diseases. The present study tested the hypothesis that genetic deletion of AT1a receptors selectively in the proximal tubules of the kidney attenuates angiotensin II (ANG II)-induced hypertension and renal ischemia-reperfusion injury using global and proximal tubule-specific AT1a receptor knockout mouse models. Global and proximal tubule-specific AT1a receptor-knockout mice (PT-AT1a-KO) were bred, or generated in this laboratory using the standard Cre/LoxP recombination approach. The hypothesis was tested in the following experimental protocols. Three groups (n=12 per group) of age- and body wt.-matched adult male C57BL/6J (WT), global AT1a-KO (Agtr1a-/-), and PT-AT1a-KO mice were first used to measure basal systolic, diastolic, and mean arterial blood pressure using the telemetry and tail-cuff techniques. Another two groups of WT, AT1a-KO, and PT-AT1a-KO mice (n=8-12 per group) were infused with saline (control) or a pressor dose of ANG II at 1.5 mg/kg/day, i.p., for 2 weeks. Additional three groups of WT, AT1a-KO and PT-AT1a-KO mice (n=8-12 per group) were treated with sham surgery (control) or 45 min bilateral renal ischemia, followed by reperfusion for 24 h or 7 days. Blood pressure and renal functional responses, and glomerular, tubuointerstitial, and perivascular injury were determined accordingly. Under basal conditions, systolic, diastolic and mean arterial blood pressure was 23 ± 3 mmHg lower in global AT1a-KO (p<0.01 vs. WT), and 12 ± 3 mmHg lower in PT-AT1a-KO mice (p<0.01 vs. WT). 24 h urine output and urinary sodium excretion were significantly higher in AT1a-KO and PT-AT1a-KO than in WT mice (p<0.01). Urine osmolality was significantly lower in AT1a-KO mice (p<0.01), but to a much less extent in PT-AT1a-KO mice (p<0.05). The kidney wt. to body wt. ratio was smaller in AT1a-KO mice (p<0.01), but was not different between WT and PT-AT1a-KO mice. In response to ANG II infusion, systolic, diastolic and mean arterial blood pressure were significantly increased by 45 ± 5 mmHg (p<0.01 vs. baseline) in WT mice, but only by 25 ± 3 mmHg in PT-AT1a-KO mice (p<0.01 vs. baseline). The ANG II-induced hypertension was completely prevented in global AT1a-KO mice (n.s. vs. baseline). In response to induction of renal ischemia-reperfusion injury, WT mice developed significant glomerular, cortical tubulointerstitial and perivascular injury 24 h or 7 days after renal ischemia-reperfusion was induced (p<0.01), as expected. However, both acute and chronic ischemia-reperfusion renal injury was not attenuated in global AT1a-KO mice (n.s. vs. WT). Surprisingly, however, acute and chronic ischemia-reperfusion renal injury was significantly attenuated in PT-AT1a-KO mice 24 h or 7 days after renal ischemia-reperfusion was induced (p<0.01 vs. WT or AT1a-KO). The results of the present study provide the direct evidence for an important role of ANG II and AT1a receptors in the proximal tubules of the kidney in maintaining physiological blood pressure homeostasis, and in the full development of ANG II-dependent Hypertension and renal ischemia-reperfusion injury in mice.

Recombinant Human Erythropoietin Restrains Oxidative Stress in Streptozotocin-induced Diabetic Rats Exposed to Renal Ischemia Reperfusion Injury

BackgroundRenal ischemia/reperfusion (I/R) injury (RI/RI) is a common complication of diabetes mellitus (DM) in surgical practice. Oxidative stress plays a crucial role in this process. Recombinant human erythropoietin (rhEPO) is usually used to treat anemia resulting from several diseases. However, the functional involvement of rhEPO in diabetic RI/RI remains unclear. The present study was intended to investigate the antioxidant role of rhEPO on RI/RI in DM rats. MethodsThe bilateral renal arteries and veins of streptozotocin-induced diabetic rats were subjected to 45 minutes of ischemia followed by 1, 6, and 24 hours of reperfusion with or without rhEPO pretreatment at the beginning of an I/R procedure. The renal tissue pathomorphology, renal function, oxidative stress, and inflammatory response were evaluated by detection of a series of indices by hematoxylin-eosin staining, commercial kits, enzyme-linked immunosorbent assay, and spectrophotofluorometry, respectively. ResultsCompared to the I/R group, renal function was significantly advanced in the erythropoietin group, whose subjects were also subjected to renal tissue injury, oxidative stress, and inflammation. ConclusionThese results suggest that rhEPO preconditioning can attenuate diabetic RI/RI through regulating endogenous antioxidant activity.

Glycogen Synthase Kinase-3β Inhibitor Attenuates Renal Damage Through Regulating Antioxidant and Anti-inflammation in Rat Kidney Transplant With Cold Ischemia Reperfusion

BackgroudThe glycogen synthase kinase-3β inhibitor thiadiazolidinone derivative 8 (TDZD-8) has been reported to reduce renal ischemia reperfusion (I/R) injury through inhibiting cell damage. However, it is not known whether TDZD-8 could also play a role in protecting the kidney in rat kidney transplantation with renal cold I/R. The aim of the present study was to explore the possible role of TDZD-8 in protecting renal damage in a cold I/R model of rat kidney transplantation. MethodsThe rat model of kidney transplantation with renal cold I/R was established. The renal tissue pathomorphologic changes, renal function, oxidative stress, and inflammatory response were evaluated by detection of a series of indices by hematoxylin and eosin staining, commercial kits, enzyme-linked immunosorbent assay, and spectrophotofluorometry, respectively. ResultsCompared with I/R and Graft groups, renal function was significantly improved in TDZD and TDZD-G groups, which were accompanied by the reduction of renal injury, oxidative stress, and inflammation. ConclusionsThese results suggest that preconditioning with glycogen synthase kinase-3β inhibitor can attenuate kidney transplantation with renal cold I/R through regulating endogenous antioxidant activity and inflammation.

Renal Function Responses To Steady-state Moderate-intensity And High-intensity Interval Exercise In Mid-spectrum Chronic Kidney Disease

Renal Function Responses To Steady-state Moderate-intensity And High-intensity Interval Exercise In Mid-spectrum Chronic Kidney Disease

Mechanisms of Salt‐Sensitive Hypertension in a Mouse Model of ACTH‐Dependent Cushing Syndrome

Salt‐sensitive blood pressure (BP) reflects underlying renal and vascular (endothelial) dysfunction. People with abnormal glucocorticoid homeostasis, such as in Cushing syndrome and obesity, are often salt‐sensitive but the underlying mechanisms are not clearly defined1,2. Here, we used a mouse model to examine the effect of ACTH excess on blood pressure and salt‐sensitivity. To test this, radio telemetry was used to track BP longitudinally and measure the effect of high salt diet before and after chronic ACTH treatment in C57BL/6J mice (n=6). Data are mean ± SD. After 7 days of baseline measurements, mean BP was 105.8 ± 6.5mmHg before being placed on a high salt diet (3 % Na+ by weight) for a further 7 days. BP increased ~12 mmHg over the first 3 days before declining to 113.1 ± 7.2mmHg. BP returned to 107.7 ± 10.4mmHg, similar to baseline, after a 5‐day washout period. Mice were then treated with ACTH (2.5μg/day). ACTH increased mean BP to 115.5 ± 5.0mmHg with a flattening of the diurnal rhythm following 13 days infusion. When placing these mice on a high salt diet, mean BP increased and stabilised to 136.1 ± 13.4mmHg after 14 days. These data show that chronic ACTH excess contributes to salt‐sensitivity. To investigate potential mechanisms of salt‐sensitivity, the acute pressure natriuresis (PN) response of renal artery function were examined in separate cohorts of mice treated with either vehicle or ACTH (2.5μg/day; n=6 per group) for 14 days. PN response was induced in anaesthesised mice (120mg/kg Inactin) by sequential arterial ligation. BP increased ~40mmHg following ligations in both vehicle and ACTH groups. In vehicle‐treated mice, fractional sodium excretion increased from 0.2 ± 0.2 to 5.0 ± 4.2μmol/min. The natriuretic response was significantly blunted in ACTH‐treated mice, reaching 2.1 ± 1.1μmol/min at its peak. We next investigated vascular function in ACTH‐excess ex vivo by wire myography in isolated mesenteric and renal arteries. Vascular reactivity to phenylephrine (PHE), acetylcholine (ACh) and sodium nitroprusside (SNP) was assessed. ACTH‐excess caused vascular dysfunction in the renal artery but not in the mesenteric artery. ACTH‐excess resulted in a reduction in sensitivity to vasoconstrictor PHE (p=0.0005) and endothelium dependent (ACh) and endothelium independent (SNP) vasodilators (p=0.0128 and p=0.0002, respectively). These data show that chronic glucocorticoid excess contributes to salt‐sensitivity with potential mechanisms behind this being impairment of the acute natriuretic and diuretic response to increased BP and renal vascular dysfunction.Support or Funding InformationSupported by British Heart Foundation PhD studentships FS/16/54/32730 &amp; FS/15/63/32033.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Male and Female Intrauterine Growth-Restricted Offspring Differ in Blood Pressure, Renal Function, and Glucose Homeostasis Responses to a Postnatal Diet High in Fat and Sugar.

It is well established that inadequate nutrition during fetal life followed by postnatal overabundance programs adiposity and glucose intolerance. Studies addressing sexual dimorphism in developmental responses to a dietary mismatch are limited; the effect on blood pressure and renal function is understudied. Therefore, this study tested the hypothesis that a mismatch of prenatal and postnatal nutrition heightens cardiorenal and metabolic risk, outcomes that may vary by sex. Male and female offspring from sham-operated (control) or reduced uterine perfusion dams (growth restricted) were fed regular chow or a diet high in fat and sugar (enriched diet) from weaning until 6 months of age. Male and female offspring were assessed separately; 2-way ANOVA was used to investigate interactions between intrauterine growth-restricted and enriched-diet. Blood pressure was increased in all enriched-diet groups but did not differ in enriched-diet male or female growth-restricted versus same-sex control counterparts. Glomerular filtration rate was reduced in male growth-restricted regardless of diet; a decrease exacerbated by the enriched-diet suggesting the pathogenesis of increased blood pressure induced via an enriched-diet differs between male growth-restricted versus male control. An enriched diet was associated with glucose intolerance in male and female control but not male growth-restricted; the enriched diet exacerbated glucose intolerance in female growth-restricted. Thus, these findings indicate male growth-restricted are resistant to impaired glucose homeostasis, whereas female growth-restricted are susceptible to metabolic dysfunction regardless of postnatal diet. Hence, moderation of fat and sugar intake may be warranted in those born low birth weight to ensure minimal risk for chronic disease.

Evaluation of Glomerular Hemodynamic Function by Empagliflozin in Diabetic Mice Using In Vivo Imaging.

Sodium glucose cotransporter 2 inhibitors may reduce kidney hyperfiltration, thereby preventing diabetic kidney disease progression, which may in turn reduce cardiovascular risk, including heart failure. However, the mechanisms that regulate renal function responses to sodium glucose cotransporter 2 inhibition are not yet fully understood. We explored the renal protective effects of sodium glucose cotransporter 2 inhibition with empagliflozin, with a focus on glomerular hemodynamic effects and tubuloglomerular feedback using in vivo multiphoton microscopy imaging techniques. C57BL/6 mice and spontaneously diabetic Ins2+/Akita mice were studied. The mice were treated with empagliflozin (20 mg·kg-1·d-1) and insulin for 4 weeks, and the single-nephron glomerular filtration rate was measured using multiphoton microscope. A neuronal nitric oxide synthase inhibitor (7-nitroindazole, 20 mg·kg-1·d-1) or a cyclooxygenase-2 inhibitor (SC58236, 6 mg/L), or an A1 adenosine receptor antagonist (8-cyclopentyl-1,3-dipropylxanthine, 1 mg·kg-1·d-1) was administered to elucidate the mechanisms of tubuloglomerular feedback signaling and single-nephron glomerular filtration rate regulation. The urinary excretion of adenosine, nitric oxide metabolites, and the prostanoid prostaglandin E2 was also quantified. The single-nephron glomerular filtration rate in the Ins2+/Akita group was higher than in controls (C57BL/6; 4.9±1.3 nL/min versus Ins2+/Akita; 15.8±6.8 nL/min) and lower in Ins2+/Akita /empagliflozin to 8.0±3.3 nL/min (P<0.01). In vivo imaging also revealed concomitant afferent arteriolar dilation (P<0.01) and increased glomerular permeability of albumin in the Ins2+/Akita group. Empagliflozin ameliorated these changes (P<0.01). Urinary adenosine excretion in the Ins2+/Akita/empagliflozin group was higher than in Ins2+/Akita (Ins2+/Akita; 3.4±1.4 nmol/d, Ins2+/Akita/empagliflozin; 11.2±3.0 nmol/d, P<0.05), whereas nitric oxide metabolites and prostaglandin E2 did not differ. A1 adenosine receptor antagonism, but not neuronal nitric oxide synthase or cyclooxygenase-2 inhibition, blocked the effect of empagliflozin on renal function. Empagliflozin increased urinary adenosine excretion and reduced hyperfiltration via afferent arteriolar constriction, effects that were abolished by A1 adenosine receptor blockade. Adenosine/A1 adenosine receptor pathways play a pivotal role in the regulation of the single-nephron glomerular filtration rate via tubuloglomerular feedback mechanisms in response to sodium glucose cotransporter 2 inhibition, which may contribute to renal and cardiovascular protective effects reported in clinical trials.

Deregulated renal magnesium transport during lipopolysaccharide-induced acute kidney injury in mice.

Magnesium (Mg2+) abnormalities during sepsis have been reported, but the underlying mechanisms during acute inflammation are poorly understood. We hypothesized that a decrease in GFR and/or changes in transporters or channels for Mg2+ could be responsible for the observed Mg2+ abnormalities. Therefore, we studied the metabolism of Mg2+ in a murine model of endotoxemia. LPS-induced hypermagnesemia was paralleled by a decrease in creatinine clearance and an increase in the fractional excretion of Mg2+. In agreement with an altered renal Mg2+ handling, endotoxemia decreased the renal expression of claudin (Cldn) 10b, Cldn16, Cldn19, parvalbumin, and of the solute carrier family (Slc) 41a3. Further, LPS increased the renal expression of Cldn14 and Slc41a1. The renal expression of the transient receptor potential melastin (Trpm) 6, Trpm7, and of cyclin M (Cnnm) 2 was unaltered in response to LPS. In vitro studies support a direct effect on the expression of Cldn10b, Cldn14, Cldn16, and Cldn19. Further, endotoxemia increased the fractional excretion of sodium, which was paralleled by a decrease of important renal sodium transporters. In the large intestine, the expression of Trpm7 was increased in response to LPS, whereas the expression of Trpm6 was decreased. Cnnm4 mRNA levels were unchanged in the large intestine. Further, Cldn12 and Na+-H+ exchanger 3 (Slc9a3) expressions were decreased in the small intestine in response to LPS. Our findings indicate that endotoxemia is associated with hypermagnesemia and a disturbed Mg2+ handling. It seems likely that LPS-induced hypermagnesemia is due to the decrease in renal function in response to LPS.

Renal function during exercise and recovery

This review paper analyzes the response of renal function during two types of exercise: 1) exercise of increasing intensity and 2) exercise of submaximal intensity and prolonged duration. During an effort of increasing intensity there is a decrease in renal blood flow that, theoretically, could compromise renal function. However, several studies seem to show that the kidney has self-regulatory mechanisms that allow maintaining the filtration fraction. On the other hand, ultra resistance exercises, such as ironman, are becoming more frequent. Knowing the renal response to this type of exercise is essential to apply knowledge to emergency situations such as dehydration or hyponatremia.

Peroxisome Proliferator-Activated Receptor (Ppar)-ϒ Agonist, Irbesartan and Adiponectin Ameliorate Blood Pressure, Renal Excretory Function and Vasoactive Responses to Adrenergic Agonists and Angiotensin IIin Spontaneously Hypertensive Rats

Peroxisome Proliferator-Activated Receptor (Ppar)-ϒ Agonist, Irbesartan and Adiponectin Ameliorate Blood Pressure, Renal Excretory Function and Vasoactive Responses to Adrenergic Agonists and Angiotensin IIin Spontaneously Hypertensive Rats

Secondary thrombotic microangiopathy in systemic lupus erythematosus and antiphospholipid syndrome, the role of complement and use of eculizumab: Case series and review of literature

IntroductionThrombotic microangiopathy (TMA) is a life-threatening, albeit infrequent, complication of systemic lupus erythematosus (SLE) and anti-phospholipid syndrome (APS). Recommendations for the treatment of SLE- and APS-related secondary TMA are currently based solely on case reports and expert opinion. Unfortunately, interventions may not yield timely results or effectively halt the progression of TMA. Since complement activation plays a key role in the pathogenesis of secondary TMA due to SLE, APS, a therapy that targets the complement pathway is an attractive intervention. Eculizumab, a recombinant, fully humanized IgG2/IgG4 monoclonal antibody inhibits C5 activation and is FDA-approved for PNH and atypical HUS (aHUS). However, limited case reports are available on its use in treatment of secondary TMA. Case presentation and resultsWe present the largest case series to date that includes 9 patients with SLE and/or APS who were successfully treated with eculizumab for refractory secondary TMA. In this case series, we report significant responses in hematology values, renal function and other organs following treatment with eculizumab. At 4 weeks, 75% improvement in platelet counts was observed in 78% of patients. Two-thirds of patients demonstrated >75% improvement of haptoglobin and LDH at four weeks. At 4 weeks, eGFR improved by 25% in half of the patients, and 43% had reductions in proteinuria. Two of 3 patients that required hemodialysis were able to be taken off hemodialysis. ConclusionBased on these observations, we suggest that eculizumab may be a potential treatment option for acutely ill patients with secondary TMA due to SLE and/or APS who have failed standard of care. A collective approach is needed to better elucidate the role and optimal timing of eculizumab use in the management of TMA complicating SLE and/or APS.

Hepatic and renal toxicity and associated factors among HIV-infected children on antiretroviral therapy: a prospective cohort study.

The aim of the study was to investigate the prevalence of renal function and liver enzyme abnormalities among HIV-infected children, changes in prevalence with time on combination antiretroviral therapy (cART), and the factors associated with these abnormalities. A prospective cohort study was conducted among HIV-infected children < 18 years old (n = 705) who were on first-line cART. Liver enzymes, renal function, haematology, immunology and virological response were assessed at enrolment and followed bi-annually for 18 months. Liver fibrosis and cirrhosis were assessed using noninvasive markers including the aspartate aminotransferase (AST) to platelet ratio index (APRI) and fibrosis score (FIB-4). The median age was 12 [interquartile range (IQR) 8-14] years; 53.3% of patients were male. At enrolment, the median cART duration was 3.3 (IQR 1.1-6.1) years; 177 (25.1%) and 83 (11.8%) patients had elevated AST and alanine aminotransferase (ALT), respectively. A tenth of the children had an APRI score > 0.5, suggesting liver fibrosis. Being on a zidovudine (ZDV)- or nevirapine (NVP)-based regimen and having a viral load > 1000 HIV-1 RNA copies/mL were significantly associated with elevated ALT. Twenty-four (3.4%) and 84 (12.1%) patients had elevated creatinine and blood urea nitrogen (BUN), respectively. As cART duration increased by 6 months, median BUN increased by 1.6 [95% confidence interval (CI) 0.4-2.7] mg/dL (P = 0.01); the glomerular filtration rate (GFR) decreased by 35.6 (95% CI 17.7-53.4) mL/min/1.73 m2 (P < 0.0001); and AST and ALT decreased by 1.4 (95% CI 0.4-2.5) IU/L (P = 0.01) and 1.4 (95% CI 0.2-2.6) IU/L (P = 0.01), respectively. A high prevalence of liver enzyme and renal function abnormalities was observed at enrolment. Decreasing liver enzyme levels during follow-up are possibly reassuring, while the progressive reduction in GFR and the increase in BUN are worrisome and require further study.

Role of Absolute Reticulocyte Count in the Assessment of Renal Function and Erythropoietin Response in Adults with Sickle Cell Anemia Seen at the Lagos University Teaching Hospital

Role of Absolute Reticulocyte Count in the Assessment of Renal Function and Erythropoietin Response in Adults with Sickle Cell Anemia Seen at the Lagos University Teaching Hospital

Evaluation of Glomerular Hemodynamic Function by Empagliflozin in Diabetic Mice Using In Vivo Imaging

Improvement of glomerular hyperfiltration via tubuloglomerular feedback (TGF) is considered to be one of the possible pathways for renal protection with SGLT2 inhibition (SGLT2i) in diabetic kidney disease (DKD). However, the mechanisms that regulate renal function in response to SGLT2i have not been fully elucidated. We explored the renal protective mechanisms of SGLT2i with empagliflozin (EMPA), with a focus on glomerular hemodynamic effects and TGF using in vivo multiphoton microscope (MPM) imaging techniques. C57BL/6 mice and spontaneously diabetic Ins2 Akita (AKITA) mice were used. The mice were treated with EMPA (20mg/kg/day) and insulin for four weeks, and single-nephron GFR (SNGFR) was measured using MPM. An nNOS inhibitor (7-nitroindazole, 20mg/kg/day) or a COX2 inhibitor (SC58236, 6mg/L), or an adenosine A1 receptor (A1aR) antagonist (8-cyclopentyl-1,3-dipropylxanthine, 1mg/kg/day) were administered to elucidate mechanisms of TGF signaling and SNGFR regulation. The urinary excretion of adenosine, nitric oxide metabolites (NOx) and the prostanoid PGE2 was also quantified. SNGFR in the AKITA group was higher compared to controls (C57BL/6; 4.9±1.3 nl/min vs. AKITA; 15.8±6.8 nl/min) and decreased in AKITA/EMPA to 8.0±3.3 nl/min (p&amp;lt;0.01). In vivo imaging also revealed concomitant afferent arteriolar dilation (p&amp;lt;0.01) and increased glomerular permeability of albumin in the AKITA group. EMPA ameliorated these changes (p&amp;lt;0.01). Urinary adenosine excretion in the AKITA/EMPA group was higher compared to AKITA (AKITA; 3.4±1.4 nmol/day, AKITA/EMPA; 11.2±3.0 nmol/day, p&amp;lt;0.05), while NOx and PGE2 did not differ. A1aR antagonism, but not nNOS or COX2 inhibition, blocked the effect of EMPA on renal function. EMPA increased urinary adenosine excretion and reduced hyperfiltration via afferent arteriolar constriction, effects that were abolished by A1aR blockade. The adenosine/A1aR system plays a pivotal role in the regulation of SNGFR via TGF mechanisms in DKD. Disclosure K. Kidokoro: Research Support; Spouse/Partner; Sanwa Kagaku Kenkyusho Co., Ltd., Kyowa Hakko Kirin Co., Ltd., Chugai Pharmaceutical Co., Ltd., Pfizer Inc., MSD K.K., Boehringer Ingelheim Pharmaceuticals, Inc., Sanofi K.K., Takeda Pharmaceutical Co., Astellas Pharma Inc., TORII PHARMACEUTICAL Co.. Y. Sogawa: None. D. Cherney: Consultant; Self; AbbVie Inc.. Other Relationship; Self; AstraZeneca, Boehringer Ingelheim GmbH, Eli Lilly and Company. Consultant; Self; Sanofi. Other Relationship; Self; Merck &amp; Co., Inc.. Consultant; Self; Mitsubishi Tanabe Pharma Corporation. Other Relationship; Self; Janssen Pharmaceuticals, Inc.. V. Kulasingam: None. H. Nagasu: None. M. Satoh: None. T. Sasaki: None. N. Kashihara: None.

A Novel Dorsal Slit Approached Non-Ischemic Partial Nephrectomy Method for a Renal Tissue Regeneration in a Mouse Model.

Kidney ischemia-reperfusion (IR) via laparotomy is a conventional method for kidney surgery in a mouse model. However, IR, an invasive procedure, can cause serious acute and chronic complications through apoptotic and inflammatory pathways. To avoid these adverse responses, a Non-IR and dorsal slit approach was designed for kidney surgery. Animals were divided into three groups, 1) sham-operated control; 2) IR, Kidney IR via laparotomy; and 3) Non-IR, Non-IR and dorsal slit. The effects of Non-IR method on renal surgery outcomes were verified with respect to animal viability, renal function, apoptosis, inflammation, fibrosis, renal regeneration, and systemic response using histology, immunohistochemistry, real-time polymerase chain reaction, serum chemistry, terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining, and Masson's trichrome staining. The Non-IR group showed 100% viability with mild elevation of serum blood urea nitrogen and creatinine values at day 1 after surgery, whereas the IR group showed 20% viability and lethal functional abnormality. Histologically, renal tubule epithelial cell injury was evident on day 1 in the IR group, and cellular apoptosis enhanced TUNEL-positive cell number and Fas/caspase-3 and KIM-1/NGAL expression. Inflammation and fibrosis were high in the IR group, with enhanced CD4/CD8-positive T cell infiltration, inflammatory cytokine secretion, and Masson's trichrome stain-positive cell numbers. The Non-IR group showed a suitable microenvironment for renal regeneration with enhanced host cell migration, reduced immune cell influx, and increased expression of renal differentiation-related genes and anti-inflammatory cytokines. The local renal IR influenced distal organ apoptosis and inflammation by releasing circulating pro-inflammatory cytokines. The Non-IR and dorsal slit method for kidney surgery in a mouse model can be an alternative surgical approach for researchers without adverse reactions such as apoptosis, inflammation, fibrosis, functional impairment, and systemic reactions.

Safety of Direct-Acting Antiviral Therapy Regarding Renal Function in Post–Liver Transplant Patients Infected with Hepatitis C Virus and a 100% 12-Week Sustained Virologic Response—A Single-Center Study

BackgroundPatients after liver transplantation (LT) with hepatitis C virus (HCV) infection often suffer from renal or hepatic impairment. Treating patients after LT with direct-acting antivirals (DAA) might result in decreasing renal function due to interaction of DAA and immunosuppressive therapy. In this single-center study we analyzed clinical parameters of 18 HCV-infected patients treated with DAA therapy after LT. MethodsThe primary end points were change of renal function (glomerular filtration rate) and sustained virologic response 12 weeks after therapy (SVR12). For secondary end points, we investigated the influence of DAA therapy on transaminases, bilirubin, international normalized ratio, noninvasive fibrosis measurement, and Model for End-Stage Liver Disease (MELD) score. ResultsFive out of 18 patients treated with DAA suffered from renal impairment stage 2, and 7 patients of renal impairment stage 3. Renal function at SVR12 was not influenced by preexisting renal impairment (P > .5), type of immunosuppressant (P > .5), or type of DAA regimen (P > .5). All patients reached SVR12. The levels of transaminases and bilirubin declined rapidly, as expected. Ten out of 18 patients already suffered from cirrhosis or liver fibrosis >F3 according to noninvasive measurement before initiation of treatment. Single-point acoustic radiation force impulse imaging improved in 9 patients (P = .012). In 7 patients, MELD score improved owing to the decrease of bilirubin levels. In 6 patients it worsened. ConclusionsDAA therapy in LT patients was effective and safe in this single-center real-life cohort. Renal function was not influenced by the administered drug combinations, even in patients with preexisting renal impairment.

Haemodynamic or metabolic stimulation tests to reveal the renal functional response: requiem or revival?

ABSTRACTRenal stimulation tests document the dynamic response of the glomerular filtration rate (GFR) after a single or a combination of stimuli, such as an intravenous infusion of dopamine or amino acids or an oral protein meal. The increment of the GFR above the unstimulated state has formerly been called the renal functional reserve (RFR). Although the concept of a renal reserve capacity has not withstood scientific scrutiny, the literature documenting renal stimulation merits renewed interest. An absent or a blunted response of the GFR after a stimulus indicates lost or diseased nephrons. This information is valuable in preventing, diagnosing and prognosticating acute kidney injury and pregnancy-related renal events as well as chronic kidney disease. However, before renal function testing is universally practiced, some shortcomings must be addressed. First, a common nomenclature should be decided upon. The expression of RFR should be replaced by renal functional response. Second, a simple protocol must be developed and propagated. Third, we suggest designing prospective studies linking a defective stimulatory response to emergence of renal injury biomarkers, to histological or morphological renal abnormalities and to adverse renal outcomes in different renal syndromes.