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An increase of glomerular filtration rate (GFR) is a common observation in early diabetes and is considered a key risk factor for subsequent kidney injury. However, the mechanisms underlying diabetic hyperfiltration have not been fully clarified. Here, we tested the hypothesis that macula densa neuronal nitric oxide synthase (NOS1) is upregulated via sodium glucose cotransporter type 1 (SGLT1) in diabetes, which then inhibits tubuloglomerular feedback (TGF) promoting glomerular hyperfiltration. Therefore, we examined changes in cortical NOS1 expression and phosphorylation, nitric oxide production in the macula densa, TGF response, and GFR during the early stage of insulin-deficient (Akita) diabetes in wild-type and macula densa-specific NOS1 knockout mice. A set of sophisticated techniques including microperfusion of juxtaglomerular apparatus in vitro, micropuncture of kidney tubules in vivo, and clearance kinetics of plasma fluorescent-sinistrin were employed. Complementary studies tested the role of SGLT1 in SGLT1 knockout mice and explored NOS1 expression and phosphorylation in kidney biopsies of cadaveric donors. Diabetic mice had upregulated macula densa NOS1, inhibited TGF and elevated GFR. Macula densa-selective NOS1 knockout attenuated the diabetes-induced TGF inhibition and GFR elevation. Additionally, deletion of SGLT1 prevented the upregulation of macula densa NOS1 and attenuated inhibition of TGF in diabetic mice. Furthermore, the expression and phosphorylation levels of NOS1 were increased in cadaveric kidneys of diabetics and positively correlated with blood glucose as well as estimated GFR in the donors. Thus, our findings demonstrate that the macula densa SGLT1-NOS1-TGF pathway plays a crucial role in the control of GFR in diabetes.

Hypertension is a common comorbid condition in patients with diabetes. The pathogenesis of hypertension in diabetes has not been fully clarified. Primary tubular hyperreabsorption may contribute, which may be counteracted by glomerular hyperfiltration in the early diabetic kidney. In this study, we hypothesize that in early diabetes, the macula densa neuronal nitric oxide synthase (NOS1)-derived nitric oxide (NO) production is enhanced, which blunts tubuloglomerular feedback (TGF) response, promotes glomerular hyperfiltration, and maintains normal blood pressure; conversely, insufficient NO generation by the macula densa induces hypertension by lowering glomerular filtration rate and thus inhibiting natriuresis. To test this hypothesis, we examined the changes of macula densa NOS1 expression and phosphorylation as well as NO production, TGF response, glomerular filtration rate, sodium excretion, and blood pressure in a murine model of leptin receptor-deficient (db/db) diabetes with or without macula densa-specific NOS1 deletion. We found that db/db mice presented reduced fractional renal sodium excretion and only a small increase in blood pressure, associated with upregulated expression and activity of macula densa NOS1, inhibited TGF response, and glomerular hyperfiltration. Genetic knockout of macula densa NOS1 restored the TGF response and attenuated glomerular hyperfiltration in db/db mice but also further reduced fractional renal sodium excretion and substantially increased blood pressure. In conclusion, the present study demonstrates that in the early stage of leptin receptor-deficient diabetes, the upregulation of macula densa NOS1 inhibits TGF and increases glomerular filtration rate, which counteracts renal sodium retention and limits the rise in blood pressure.

Renal ischemia-reperfusion injury is an important contributor to the development of delayed graft function after transplantation, which is associated with higher rejection rates and poorer long-term outcomes. One of the earliest impairments during ischemia is Na + /K + -ATPase (Na/K pump) dysfunction due to insufficient ATP supply, resulting in subsequent cellular damage. Therefore, strategies that preserve ATP or maintain Na/K pump function may limit the extent of renal injury during ischemia-reperfusion. Here, we applied a synchronization modulation electric field to activate Na/K pumps, thereby maintaining cellular functions under ATP-insufficient conditions. We tested the effectiveness of this technique in two models of ischemic renal injury: an in situ renal ischemia-reperfusion injury model (predominantly warm ischemia) and a kidney transplantation model (predominantly cold ischemia). Application of the synchronization modulation electric field to a renal ischemia-reperfusion injury mouse model preserved Na/K pump activity, thereby reducing kidney injury, as reflected by 40% lower plasma creatinine (1.17 ± 0.03 mg/dl) in the electric field–treated group as compared to the untreated control group (1.89 ± 0.06 mg/dl). In a mouse kidney transplantation model, renal graft function was improved by more than 50% with the application of the synchronization modulation electric field according to glomerular filtration rate measurements (85.40 ± 12.18 μl/min in the untreated group versus 142.80 ± 11.65 μl/min in the electric field–treated group). This technique for preserving Na/K pump function may have therapeutic potential not only for ischemic kidney injury but also for other diseases associated with Na/K pump dysfunction due to inadequate ATP supply.

Background The incidence of alcoholic liver disease (ALD) has increased, causing it to become a primary indication for liver transplantation in the United States. We hypothesized an association between alcohol taxation and prevalence of ALD. Methods We conducted a retrospective study of united network for organ sharing (UNOS) waitlist additions for liver transplantation between January 2007 and December 2016. We also analyzed the average excise tax (2007-2016) for beer, wine, and spirits in listing states of liver transplant waitlist additions (LTWA). Results There were 104 805 adult UNOS LTWA with assigned diagnoses, an annual increase from 22% to 28%. There were 24 316 LTWA with ALD diagnosis. The mean value for beer tax was significantly lower for ALD patients than for non-ALD patients across all age groups ( P < .001). The analysis demonstrated significantly more ALD in waitlisted patients 35-54 years of age (30%), compared with 18-34 years (10%) and ≥55 years (20%), P < .001. The data confirmed significantly more ALD Medicaid patients in the 35-54 year age group (28%) compared with other age groups, P < .001. Discussion Our research demonstrated an association between lower beer tax and higher ALD prevalence across all age groups. We found a larger percentage of middle-aged (35-54 years) Medicaid patients listed with ALD. These findings raise the need for further investigation of a potential public health concern for an association between ALD and beer tax, especially for middle-aged patients of lower socioeconomic status.

Background Studies have shown significant improvement in hepatocellular carcinoma (HCC) recurrence rates after liver transplantation since the united network of organ sharing (UNOS) implementation of a 6-month wait period prior to accrued exception model for end-stage liver disease (MELD) points enacted on October 8, 2015. However, few have examined the impact on HCC dropout rates for patients awaiting liver transplant. Our objective is to evaluate the outcomes of HCC dropout rates before and after the mandatory 6-month wait policy enacted. Methods We conducted a retrospective cohort study on adult patients added to the liver transplant wait list between January 1, 2012, and March 8, 2019 (n = 767). Information was obtained through electronic medical records and organ procurement and transplant network (OPTN) publicly available national data reports. Results In response to the 2015 UNOS-mandated 6-month wait time, dropout rates in the HCC patient population at our center increased from 12% pre-mandate to 20.8% post-mandate This increase was similarly reflected in the national dropout rate, which also increased from 26.3% pre-mandate to 29.0% post-mandate. Discussion From these changes, it is evident that the UNOS mandate achieved its goal of increasing equity of liver organ allocation, but HCC patients are nonetheless dropping off of the wait list at an increased rate and are therefore disadvantaged.

Background In 2014, direct-acting antivirals (DAAs) became available for hepatitis C virus (HCV) with successful results. Since their implementation, the rate of HCV waitlist (WL) for liver transplantation (LT) has decreased, but significant ethnic disparities exist. We hypothesized that the rate of decline for HCV WL for LT is different across the various racial groups. Methods We conducted a retrospective cohort study using Organ Procurement and Transplantation Network data reports of adult LT candidates from 2014 to 2018. Results Overall, there was a decline in HCV WL rates for all ethnic groups (Caucasians, African Americans [AA], and Hispanics). However, the WL rates were significantly higher in AA compared with Caucasians each year, and this trend was continuous across the 5-year period. There were no differences in WL rates between Caucasians and Hispanics. Discussion The results show that health care disparities related to HCV disproportionately affect AA. The factors associated with this disparity need to be explored further to develop mechanisms to address these differences. By understanding the HCV treatment disparities across racial groups, modifications to HCV treatment nationwide can be adopted. Additional emphasis should be placed on AA to help reduce their WL rate, as well as redistributing resources to promote health care equity.

Introduction Interteam performance and Clavien-Dindo (C-D) complications in renal cell carcinoma with inferior vena cava thrombectomy (RCC-IVCT) have not been reported. We aimed to describe complications by the degree of complexity and surgical teams in a collaborative effort between a National Cancer Institute-designated Comprehensive Cancer Center and a Quaternary Care Teaching Hospital. Methods Between January 2011 and May 2019, 73 consecutive RCC-IVCT were included. C-D grades III or higher were captured. Teams involved were urologic-oncology, vascular, hepatobiliary/transplant, and cardiothoracic. The Mayo Clinic tumor thrombus classification was used. Results Overall complication rate was 42% (n = 31). Nineteen percent had grade III, 18% had grade IV, and 6% had grade V complications. Patients with level IV thrombus had the highest in-hospital mortality rate (75%). Thrombus level did not show a correlation to complication rates (14% level I, 45% level II, 32% level III, 42% level IV). A positive correlation found between the number of teams involved and complication rates (35% with 2-team, 59% with 3-team, P = .059). Thromboembolic events (6% vs 24%, P = .02) and disposition other than home (22% vs 48%, P = .01) were statistically lower for the 2-team groups. Two-team in-hospital mortality was 1/51 (2%) versus 3-team (3/22,14%, ( P = .07). No statistical differences were found in infections, thromboembolic events, and grades of complications between surgical teams. Conclusions Despite similar interteam performance, the consistency of surgeons in high complexity cases could improve outcomes further. Complexity was higher for hepatobiliary/transplant and cardiothoracic teams. A combination of intraoperative events and patient selection (comorbidities and age) contributed to death. Overall, in-hospital mortality was lower than in most reported series.

Background Coronary artery disease (CAD) is a leading cause of mortality following orthotopic liver transplant, yet there is no standardized protocol for pre-liver-transplant coronary artery disease assessment. The main objective of this study was to determine the agreement between 2 methods of cardiac risk assessment: dobutamine stress echocardiogram (DSE) and coronary calcium score (CCS) and to determine which test was best able to predict coronary calcification in low-risk patients. Methods A retrospective study was performed using the medical records of 436 patients who received cardiac clearance for a liver transplant. A total of 152 patients’ medical records were included based on the inclusion of patients who had received both DSE and CCS. A kappa coefficient was calculated to determine the agreement between the DSE and CCS results. In addition, the positive predictive values (PPVs) of both the CCS and DSE along with cardiac catheterization indicating abdominal occlusion were analyzed to compare the accuracy of the 2 tests. Results It was determined that there was a 12% agreement between DSE results and CCS. It was found that the DSE had a PPV of 56% and the CCS had a PPV of 80%. Conclusion From this data, it was concluded that there was no agreement between the results of the CCS and the DSE. While neither the CCS nor the DSE presents an optimal method of risk assessment, the CCS had a much higher PPV and was therefore determined to be the more accurate test.

Background: Regulation of renal hemodynamics and blood pressure (BP) via tubuloglomerular feedback (TGF) may be an important adaptive mechanism during pregnancy. Because the β-splice variant of nitric oxide synthase 1 (NOS1β) in the macula densa is a primary modulator of TGF, we evaluated its role in normal pregnancy and gestational hypertension in a mouse model. We hypothesized that pregnancy upregulates NOS1β in the macula densa, thus blunting TGF, allowing glomerular filtration rate (GFR) to increase and BP to decrease. Methods: We employed sophisticated techniques, including microperfusion of juxtaglomerular apparatus in vitro, micropuncture of renal tubules in vivo, clearance kinetics of plasma FITC-sinistrin, and radio-telemetry BP monitoring, to determine the effects of normal pregnancy or reduced uterine perfusion pressure (RUPP) on macula densa NOS1β/NO levels, TGF responsiveness, GFR, and BP in wild-type and macula densa-specific NOS1 knockout (MD-NOS1KO) mice. Results: Macula densa NOS1β was upregulated during pregnancy, resulting in blunted TGF, increased GFR, and decreased BP. These pregnancy-induced changes in TGF and GFR were largely diminished, with a significant rise in BP, in MD-NOS1KO mice. In addition, RUPP resulted in a downregulation in macula densa NOS1β, enhanced TGF, decreased GFR, and hypertension. The superimposition of RUPP into MD-NOS1KO mice only caused a modest further alteration in TGF and its associated changes in GFR and BP. Finally, in African green monkeys, renal cortical NOS1β expression increased in normotensive pregnancies but decreased in spontaneous gestational hypertensive pregnancies. Conclusions: Macula densa NOS1β plays a critical role in control of renal hemodynamics and BP during pregnancy.

Acute kidney injury (AKI) significantly increases the risk of development of chronic kidney disease (CKD), which is closely associated with the severity of AKI. However, the underlying mechanisms for the AKI to CKD transition remain unclear. Several animal models with AKI to CKD transition have been generated and widely used in research; however, none of them exhibit the typical changes in glomerular filtration rate or plasma creatinine, the hallmarks of CKD. In the present study, we developed a novel model with a typical phenotype of AKI to CKD transition in C57BL/6 mice. In this model, life-threatening ischemia-reperfusion injury was performed in one kidney, whereas the contralateral kidney was kept intact to maintain animal survival; then, after 2 wk of recovery, when the renal function of the injured kidney restored above the survival threshold, the contralateral intact kidney was removed. Animals of this two-stage unilateral ischemia-reperfusion injury model with pedicle clamping of 21 and 24 min exhibited an incomplete recovery from AKI and subsequent progression of CKD with characteristics of a progressive decline in glomerular filtration rate, increase in plasma creatinine, worsening of proteinuria, and deleterious histopathological changes, including interstitial fibrosis and glomerulosclerosis. In conclusion, a new model of the AKI to CKD transition was generated in C57BL/6 mice.

Background Glomerular hyperfiltration is common in early diabetes and is considered a risk factor for later diabetic nephropathy. We propose that sodium-glucose cotransporter 1 (SGLT1) senses increases in luminal glucose at the macula densa, enhancing generation of neuronal nitric oxide synthase 1 (NOS1)–dependent nitric oxide (NO) in the macula densa and blunting the tubuloglomerular feedback (TGF) response, thereby promoting the rise in GFR. Methods We used microperfusion, micropuncture, and renal clearance of FITC–inulin to examine the effects of tubular glucose on NO generation at the macula densa, TGF, and GFR in wild-type and macula densa–specific NOS1 knockout mice. Results Acute intravenous injection of glucose induced hyperglycemia and glucosuria with increased GFR in mice. We found that tubular glucose blunts the TGF response in vivo and in vitro and stimulates NO generation at the macula densa. We also showed that SGLT1 is expressed at the macula densa; in the presence of tubular glucose, SGLT1 inhibits TGF and NO generation, but this action is blocked when the SGLT1 inhibitor KGA-2727 is present. In addition, we demonstrated that glucose increases NOS1 expression and NOS1 phosphorylation at Ser1417 in mouse renal cortex and cultured human kidney tissue. In macula densa–specific NOS1 knockout mice, glucose had no effect on NO generation, TGF, and GFR. Conclusions We identified a novel mechanism of acute hyperglycemia–induced hyperfiltration wherein increases in luminal glucose at the macula densa upregulate the expression and activity of NOS1 via SGLT1, blunting the TGF response and promoting glomerular hyperfiltration.

Females are protected against the development of angiotensin II (ANG II)-induced hypertension compared with males, but the mechanisms have not been completely elucidated. In the present study, we hypothesized that the effect of ANG II on the macula densa nitric oxide (NO) synthase 1β (NOS1β)-mediated tubuloglomerular feedback (TGF) mechanism is different between males and females, thereby contributing to the sexual dimorphism of ANG II-induced hypertension. We used microperfusion, micropuncture, clearance of FITC-inulin, and radio telemetry to examine the sex differences in the changes of macula densa NOS1β expression and activity, TGF response, natriuresis, and blood pressure (BP) after a 2-wk ANG II infusion in wild-type and macula densa-specific NOS1 knockout mice. In wild-type mice, ANG II induced higher expression of macula densa NOS1β, greater NO generation by the macula densa, and a lower TGF response in vitro and in vivo in females than in males; the increases of glomerular filtration rate, urine flow rate, and Na+ excretion in response to an acute volume expansion were significantly greater and the BP responses to ANG II were significantly less in females than in males. In contrast, these sex differences in the effects of ANG II on TGF, natriuretic response, and BP were largely diminished in knockout mice. In addition, tissue culture of human kidney biopsies (renal cortex) with ANG II resulted in a greater increase in NOS1β expression in females than in males. In conclusion, macula densa NOS1β-mediated TGF is a novel and important mechanism for the sex differences in ANG II-induced hypertension.

Background Prolonged cold ischemic time (CIT) in deceased donor kidney transplantation (DDKT) has been associated with adverse graft outcomes. Virtual crossmatch (VXM) facilitates reliable prediction of crossmatch results based on the profile of human leukocyte antigen antibodies of the recipient and the donor in reduced time compared with a physical crossmatch (PXM). We hypothesized a shorter CIT since the implementation of the VXM in recipients of DDKT. Methods We conducted a retrospective cohort study of consecutive adult recipients of DDKT. The data were analyzed for differences in CIT before and after the implementation of VXM. Results After the exclusion of 59 recipients (age less than 18 years and/or CIT ≥ 20 hours), our study compared outcomes of 81 PXMs from February to June 2018 against 68 VXMs from February to June 2019. There were no statistical differences between groups based on donor age ( P = .09), donor type ( P = .38), kidney donor profile index ( P = .43), or delayed graft function ( P = .20). Recipients with VXM were older (58 vs 51 years , P = .002) and had a higher estimated post-transplant survival score (59% vs 46% , P = .01). The CIT was significantly lower for the VXM group ( P = .04). Conclusion Our study demonstrated a significantly shorter CIT with VXM in DDKT recipients. Our study was limited with small sample size, but the trend of increased graft survival with higher estimated post-transplant scores and older recipients is encouraging as the donor pool expands with marginal kidneys and national sharing.

Recurrent toxic shock syndrome (TSS) is uncommon. A certain level of clinical suspicion is indicated with a complex sepsis presentation in the postoperative kidney transplant patient. We present a case of presumed recurrent postoperative TSS in a living kidney transplant recipient. The patient was a 19-year-old Caucasian female with a 4-year prior single episode of toxin-mediated sepsis and chronic kidney disease (CKD) secondary to autosomal recessive Alport’s syndrome (confirmed via renal biopsy and genetic testing). She received a human leukocyte antigen (HLA) 2A 2B 1DR MM, CMV -D/-R kidney from her 21-year-old friend. The patient received Campath and IV steroid induction after total cold ischemic time of 170 minutes with 40 minutes of revascularization. On postoperative day (POD) 5, she required re-exploration with reimplantation and stenting of the transplanted ureter. The patient subsequently spiked a fever of 101.6° with a generalized rash prompting collection of blood cultures which demonstrated no growth. Infectious Disease was consulted due to persistent fevers despite IV antibiotics. On POD 12, the patient returned to the operating room (OR) for evacuation of hematoma after decline in Hgb to 5.8 and CT confirmed perinephric hematomas. Kidney biopsy showed no rejection and donor specific antibodies (DSAs) were unremarkable. The patient underwent 1 treatment of empiric plasmapheresis for possible non-HLA antibodies followed by initiation of clindamycin. The patient’s condition improved, and she was discharged home with a normal creatinine. Recurrent TSS is rare but should be added to the differential diagnoses of immuno-compromised patients undergoing kidney transplantation with a history of prior toxin-mediated sepsis.

Background Pulmonary function tests (PFTs) are currently recommended for liver transplant candidates. We hypothesized that PFTs may not provide added clinical value to the evaluation of liver transplant patients. Methods We conducted a retrospective cohort study of adult cadaveric liver transplants from 2012 to 2018. Abnormal PFTs were defined as restrictive disease of diffusing capacity of the lungs for carbon monoxide (DLCO) Results We analyzed data on 415 liver transplant patients (358 abnormal PFT results and 57 normal results). The liver transplant patients with abnormal PFTs had no difference in number of intensive care unit (ICU) days ( P = .68), length of stay ( P = .24), or intubation days ( P = .33). There were no differences in pulmonary complications including pleural effusion ( P = .30), hemo/pneumothorax ( P = .74), pneumonia ( P = .66), acute respiratory distress syndrome ( P = .57), or pulmonary edema ( P = .73). The significant finding between groups was a higher rate of reintubation in liver transplant patients with normal PFTs ( P = .02). There was no difference in graft survival ( P = .53) or patient survival ( P = .42). Discussion Abnormal PFTs, found in 86% of liver transplant patients, did not correlate with complications, graft failure, or mortality. PFTs contribute to the high cost of liver transplants but do not help predict which patients are at risk of postoperative complications.

Background Postoperative hemorrhage has been described at rates of 14% in kidney transplant (KT) literature. The preferred management of postoperative hemorrhage in this population is not well described. We hypothesized a difference in outcomes with operative versus nonoperative management of hemorrhage after kidney transplantation. Methods We conducted a retrospective cohort study of consecutive KTs from 2012 to 2019 (living and deceased donors). We defined hemorrhage based on the objective finding of hematoma on either ultrasound or CT scan. Management was defined as operative (surgical intervention with or without transfusion) or nonoperative (with or without transfusion). Results We performed 1758 KTs of which 135 (8%) demonstrated hematoma on ultrasound or CT scan (66 operative vs 69 nonoperative management). The clinical signs and symptoms of low urine output ( P = .044), drop in hemoglobin ( P < .001), abdominal pain ( P = .005), and MAP < 70 mm Hg ( P = .034) were 92.5% predictive of postoperative hemorrhage in our KT patients. There were no differences between groups based on medical history, preop anticoagulation, anastomosis type, cold ischemic time, lowest hemoglobin, delayed graft function, or complications. Patients with nonoperative treatment of postoperative hemorrhage had shorter lengths of stay ( P = .003), better graft survival ( P = .01), and better patient survival ( P = .01). Discussion We found better outcomes of graft and patient survival with shorter lengths of stay when we utilized nonoperative management of postoperative hemorrhage in KT patients. Our findings suggest a role for conservative nonoperative management in select patients. Ultimately, it is the surgeon’s choice on how best to manage postoperative hemorrhage.

Introduction Reevaluation of donor criteria, including age, is needed to combat organ shortages, lengthy wait times, and anticipated recipient mortality rates. The purpose of this study was to evaluate donor and recipient (D/R) age combinations and patient and graft survival outcomes. Methods Single-organ, living donor kidney transplantations (LDKTs) from 2012 to 2018 were retrospectively reviewed. Donors and recipients were placed into “older” and “younger” age categories of 50 years and above or below age 50, then analyzed with SPSS version 25. Results We performed 347 LDKTs. Younger-to-older pairings had significantly higher rates of smoking in recipient (53.6%) and hepatitis C (5.5%), but shorter hospital stays (5.3 days). Older-to-younger pairings had the longest hospital stays (7.4 days) but the shortest cold ischemic time (2.3 hours). Notably, there was no significant variance in delayed graft function (first-week dialysis) between groups. Regarding complication rates, only bleeding within 30 days, highest in older-to-older pairings (7.7%), and renal complications, highest in older-to-younger pairings, significantly varied between groups. Interestingly, though younger-to-older cases had the longest mean graft survival time, older kidneys lasted 537 days longer in older recipients than in younger recipients. Discussion These results indicate there is not a one-size-fits-all approach when considering outcomes of donor/recipient age-pairings in LDKT, as significant correlations did not consistently favor one age-pairing over others. Regardless of age-pairing, LDKT provides gold standard treatment and expands the availability of organs. Future research into the impact of age-pairing on specific variables, national or multicenter studies, and protocol development for evaluating donor/recipient age-pairings is needed.

Acute kidney injury (AKI) significantly increases the risk of development of chronic kidney disease (CKD). Recently, our laboratory generated a mouse model with the typical phenotypes of AKI to CKD transition in the unilateral kidney. However, AKI, CKD, and even the transition from AKI to CKD usually occur bilaterally rather than unilaterally in patients. Therefore, in the present study, we further modified the strategy and developed a new model of CKD transitioned from bilateral ischemia-reperfusion injury (IRI) in C57BL/6 mice. In this new model, unilateral severe IRI was performed in one kidney while the contralateral kidney was kept intact to maintain animal survival; then, following 14 days of recovery, when the renal function of the injured kidney restored above the survival threshold, the contralateral intact kidney was subjected to a similar IRI. Animals of these two-stage bilateral IRI models with pedicle clamping of 21 and 24 min at a body temperature of 37°C exhibited incomplete recovery from AKI and subsequent development of CKD with characteristics of progressive decline in glomerular filtration rate, increases in plasma creatinine, worsening of proteinuria, and deleterious histopathological changes, including interstitial fibrosis and glomerulosclerosis, in both kidneys. In conclusion, a new bilateral AKI to CKD transition animal model with a typical phenotype of CKD was generated in C57BL/6 mice.

Females are relatively resistant to salt-sensitive hypertension than males, but the mechanisms are not completely elucidated. We recently demonstrated a decisive role of macula densa neuronal NOS1β (nitric oxide synthase β)-mediated tubuloglomerular feedback (TGF) in the long-term control of glomerular filtration rate, sodium excretion, and blood pressure. In the present study, we hypothesized that the macula densa NOS1β-mediated TGF mechanism is different between male and female, thereby contributing to the sexual dimorphism of salt-sensitive hypertension. We used microperfusion, micropuncture, clearance of fluorescein isothiocyanate-inulin, and radio telemetry to examine the sex differences in the changes of macula densa NOS1β expression and activity, TGF response, natriuresis, and blood pressure after salt loading in wild-type and macula densa-specific NOS1 knockout mice. In wild-type mice, a high-salt diet induced greater increases in macula densa NOS1β expression and phosphorylation at Ser 1417, greater nitric oxide generation by the macula densa, and more inhibition in TGF response in vitro and in vivo in females than in males. Additionally, the increases of glomerular filtration rate, urine flow rate, and sodium excretion in response to an acute volume expansion were significantly greater in females than in males. The blood pressure responses to angiotensin II plus a high-salt diet were significantly less in females than in males. In contrast, these sex differences in TGF, natriuretic response, and blood pressure were largely diminished in knockout mice. In conclusion, macula densa NOS1β-mediated TGF is a novel and important mechanism for the sex differences in salt-sensitive hypertension.

Impaired renal autoregulation permits more transmission of disturbance in systemic blood pressure, which initiates barotrauma in intrarenal microvasculatures such as glomerular and tubulointerstitial capillaries, contributing to the development of kidney damage and deterioration in renal function, especially under the conditions with high blood pressure. Although it has been postulated that autoregulatory efficiency is attenuated in the aging kidney, direct evidence remains lacking. In the present study, we measured the autoregulation of renal blood flow, myogenic response of afferent arteriole (Af-Art), tubuloglomerular feedback in vivo with micropuncture, as well as tubuloglomerular feedback in vitro in isolated perfused juxtaglomerular apparatus in young and aged C57BL/6 mice. We found that renal blood flow was not significantly changed in response to a defined elevation of renal arterial pressure in young mice but significantly increased in aged mice. Additionally, myogenic response of Af-Art measured by microperfusion with a stepwise increase in perfusion pressure was significantly blunted in the aging kidney, which is associated with the attenuation of intraluminal pressure-induced intracellular calcium increases, as well as the reduced expression of integrin α5 (Itga5) in Af-Art. Moreover, both tubuloglomerular feedback in vivo and in vitro were nearly inactive in the aging kidney, which is associated with the significantly reduced expression of adenosine A1 receptor (A1AR) and suppressed vasoconstrictor response to adenosine in Af-Art. In conclusion, this study demonstrates that aging impairs renal autoregulation with blunted myogenic response and inhibited tubuloglomerular feedback response. The underlying mechanisms involve the downregulations of integrin α5 and A1AR in the Af-Art.

The United Network for Organ Sharing (UNOS) implemented a policy that requires patients with hepatocellular carcinoma seeking liver transplantation to wait six months before being granted Model for End-Stage Liver Disease exception points. We investigated the difference in resource utilization between patients who underwent liver transplantation before and after the present policy. We conducted a retrospective cohort study of adult liver transplants from 2013 to 2018. Patients were classified into prepolicy or postpolicy groups based on 964 days before or after the wait-time policy. We also retrieved national survival outcome data from United Network for Organ Sharing. Differences across compared groups for continuous variables were assessed using the independent sample t test, and the chi-squared test was used for binary variables. We found statistical differences in recipient age ( P = 0.005), days on wait-list ( P = 0.001), sustained viro-logical response ( P < 0.001), and hepatocellular carcinoma recurrence one year posttransplant ( P = 0.04). There were statistically significant differences in the number of treatment days pretransplant and length of transplant admission stay, indicating an increase in resource utilization in the postpolicy group. No statistically significant differences were found between groups in one-year graft or patient survival despite an observed increase in resource utilization by the hepatocellular carcinoma postpolicy group.

Incisional hernias occur after abdominal organ transplantation with rates of 1.6 per cent to 18 per cent in kidney transplants (KTs) and 1.7 to 32.4 per cent in liver transplants (LTs). We hypothesized a difference in KTand LToutcomes in patients with and without repair of incisional hernias. We conducted a retrospective cohort study of abdominal transplants from 2012 through 2016. The difference across compared groups for continuous variables was assessed using the independent sample t test, and for binary variables, using the chi-squared test. A total of 1518 transplants were performed, including 1138 KTs and 380 LTs. There were 83 KT incisional hernias (67 repaired) and 59 LT incisional hernias (48 repaired). There was no difference between groups with regard to smoking, diabetes, age, BMI, days on dialysis (KTs), pretransplant Model for End-Stage Liver Disease (MELD) (LTs), cold ischemic time, graft survival, or recurrence rate by repair method. In the LT population, there was a statistically significant difference in days on the waitlist ( P = 0.02), drain placement ( P = 0.04), and cytomegalovirus (CMV) mismatch ( P = 0.02). Patient survival was also statistically significant for KTs ( P = 0.04) and LTs ( P = 0.01). KT and LT patients who have their incisional hernias repaired have better overall survival, regardless of the repair technique.

The significance of kidneys in regulation of sodium and water balance and hemodynamics has been demonstrated both in patients and animal models. In the present study, we tested our hypothesis that kidneys play an essential role in control of sex differences in angiotensin II (Ang II)–dependent hypertension. Kidney transplantations (KTXs) were performed between male (M) and female (F) C57BL/6 mice (donor→recipient: F→F, M→M, F→M, and M→F). Radiotelemetry transmitters were implanted for measurement of mean arterial pressure during the infusion of Ang II (600 ng·kg −1 ·min −1 ). Gene expressions and inflammatory responses in the transplanted grafts were assessed. We found that same-sex–KTX mice still exhibited sex differences in Ang II–dependent hypertension (31.3±0.8 mm Hg in M→M versus 12.2±0.6 mm Hg in F→F), which were reduced between males and females when they received kidneys of the opposite sex (32.9±1 mm Hg in M→F versus 22.3±0.7 mm Hg in F→M). The sex differences in gene expressions, including AT 1 R (angiotensin II receptor, type 1), AT 1 R/AT 2 R, ET-1 (endothelin-1), ETA (endothelin receptor type A), NHE3 (sodium–hydrogen exchanger 3), α-ENaC (α-epithelial sodium channel), and γ-ENaC, were unaltered in same-sex KTXs and much lessened in cross-sex KTXs. In addition, the cross-sex KTXs exhibited more robust inflammatory responses reflected by higher expression of IL-6 (interleukin 6), TNFα (tumor necrosis factor α), and KC (keratinocyte-derived chemokine) than same-sex KTX. Our results indicate that kidneys play an essential role in sex differences of Ang II–dependent hypertension. KTX of male kidneys to females augmented the blood pressure response, whereas KTX of female kidneys to males attenuated the blood pressure response. The host’s extrarenal systems modulate expressions of many genes and inflammatory response, which may also contribute to the sex differences in blood pressure regulation.

The prevalence of hypertension is about twofold higher in diabetic than in nondiabetic subjects. Hypertension aggravates the progression of diabetic complications, especially diabetic nephropathy. However, the mechanisms for the development of hypertension in diabetes have not been elucidated. We hypothesized that enhanced constrictive responsiveness of renal afferent arterioles (Af-Art) to angiotensin II (ANG II) mediated by ANG II type 1 (AT1) receptors contributes to the development of hypertension in diabetes. In response to an acute bolus intravenous injection of ANG II, alloxan-induced diabetic mice exhibited a higher mean arterial pressure (MAP) (119.1 ± 3.8 vs. 106.2 ± 3.5 mmHg) and a lower renal blood flow (0.25 ± 0.07 vs. 0.52 ± 0.14 ml/min) compared with nondiabetic mice. In response to chronic ANG II infusion, the MAP measured with telemetry increased by 55.8 ± 6.5 mmHg in diabetic mice, but only by 32.3 ± 3.8 mmHg in nondiabetic mice. The mRNA level of AT1 receptor increased by ~10-fold in isolated Af-Art of diabetic mice compared with nondiabetic mice, whereas ANG II type 2 (AT2) receptor expression did not change. The ANG II dose-response curve of the Af-Art was significantly enhanced in diabetic mice. Moreover, the AT1 receptor antagonist, losartan, blocked the ANG II-induced vasoconstriction in both diabetic mice and nondiabetic mice. In conclusion, we found enhanced expression of the AT1 receptor and exaggerated response to ANG II of the Af-Art in diabetes, which may contribute to the increased prevalence of hypertension in diabetes.

Kidney transplantation (KTX) is a life-saving procedure for patients with end-stage renal disease. Expression levels of many genes in the kidney vary between males and females, which may play an essential role in the sex differences in graft function. However, whether these differences are affected after cross-sex-KTX is unknown. In the present study, we assessed postoperative changes in genotype, function, and inflammatory responses of the grafts in same-sex- and cross-sex-KTX. Single kidney transplants were performed between same and different sex C57BL/6 mice paired into four combination groups: female donor/female recipient (F/F); male donor/male recipient (M/M); female donor/male recipient (F/M); and male donor/female recipient (M/F). The remnant native kidney was removed 4 days posttransplant. Expression levels of genes related to the contractility of the afferent arteriole and tubular sodium reabsorption were assessed. Same-sex-KTX did not significantly alter the magnitude or sex difference pattern of gene expression in male or female grafts. Cross-sex-KTX showed an attenuated sex difference in gene expressions. The measurements of endothelin 1, endothelin ETA receptor, Na+-K−-2Cl cotransporter 2 (NKCC2), and epithelial Na+ channels (ENaC) subunits exhibited decreases in M/F compared with M/M and increases in F/M compared with F/F. There were no significant differences in hemodynamics or sodium excretion in response to acute volume expansion for any sex combinations. Cross-sex-KTX stimulated more robust inflammatory responses than same-sex-KTX. IL-6 and KC mRNA levels elevated 5- to 20-fold in cross-sex-KTX compared with same-sex-KTX. In conclusion, cross-sex-KTX alters gene expression levels and induces inflammatory responses, which might play an important role in long-term graft function.

Acute kidney injury (AKI) induced by clamping of renal vein or pedicle is more severe than clamping of artery, but the mechanism has not been clarified. In the present study, we tested our hypothesis that increased proximal tubular pressure (Pt) during the ischemic phase exacerbates kidney injury and promotes the development of AKI. We induced AKI by bilateral clamping of renal arteries, pedicles, or veins for 18 min at 37°C, respectively. Pt during the ischemic phase was measured with micropuncture. We found that higher Pt was associated with more severe AKI. To determine the role of Pt during the ischemic phase on the development of AKI, we adjusted the Pt by altering renal artery pressure. We induced AKI by bilateral clamping of renal veins, and the Pt was changed by adjusting the renal artery pressure during the ischemic phase by constriction of aorta and mesenteric artery. When we decreased renal artery pressure from 85 ± 5 to 65 ± 8 mmHg, Pt decreased from 53.3 ± 2.7 to 44.7 ± 2.0 mmHg. Plasma creatinine decreased from 2.48 ± 0.23 to 1.91 ± 0.21 mg/dl at 24 h after renal ischemia. When we raised renal artery pressure to 103 ± 7 mmHg, Pt increased to 67.2 ± 5.1 mmHg. Plasma creatinine elevated to 3.17 ± 0.14 mg·dl·24 h after renal ischemia. Changes in KIM-1, NGAL, and histology were in the similar pattern as plasma creatinine. In summary, we found that higher Pt during the ischemic phase promoted the development of AKI, while lower Pt protected from kidney injury. Pt may be a potential target for treatment of AKI.

Transplanted kidneys usually experience several episodes of ischemia, including cold ischemia during allograft storage in preservation solution. However, previous studies focusing on cold renal ischemia were only carried out in vitro or ex vivo. In the present study, we developed and characterized an in vivo mouse model of renal ischemia-reperfusion injury (IRI) induced exclusively by cold ischemia. C57BL/6 mice underwent right kidney nephrectomy, and the left kidney was kept cool with circulating cold saline in a kidney cup, while body temperature was maintained at 37°C. We clamped the renal pedicle and flushed out the blood inside the kidney with cold saline via an opening on the renal vein. The severity of renal IRI was examined with different ischemic durations. We found that the mice with

Long-term outcomes in liver transplantation for acute liver failure (ALF) are poorly studied. The aim of the study was to identify psychosocial variables that affect adherence and late survival. Retrospective review of ALF liver transplant (LTx) patients between 1997 and 2017 (n = 47) was conducted. Psychosocial history, life stressors, and ability to participate in transplant were recorded. Survival was calculated using Kaplan-Meier and logistic regression. Eleven patients (31.5%) had poor adherence, four died, all from graft failure. Of 13 with fair and 12 with good adherence, two died, no adherence related. Poor adherence was associated with higher mortality (P = 0.04), but by Kaplan-Meier, their five- and 10-year survival was 78 and 54 per cent, versus fair and good adherence (five years, 83% P = 0.3). Participating in transplant decision improved survival (five years, 80%) versus not participating (five years, 61%; P = 0.03). Of 10 early deaths, three were neurologic and five of sepsis. Overall, one- and five-year survival was 78 and 69 per cent. ALF represents the nemesis of LTx programs. Psychosocial aspects pre-LTx, stressors, and poor adherence affected survival in this series. No improvement over two decades of ALF LTxs was observed. The ethics of transplanting these high-risk patients will be the subject of our future research.

Animal models of kidney transplantation (KTX) are widely used in studying immune response of hosts to implanted grafts. Additionally, KTX can be used in generating kidney-specific knockout animal models by transplantation of kidneys from donors with global knockout of a gene to wild-type recipients or vice versa. Dual-kidney transplantation (DKT) provides a more physiological environment for recipients than single-kidney transplantation (SKT). However, DKT in mice is rare due to technical challenges. In this study, we successfully performed DKT in mice and compared the hemodynamic response and graft function with SKT. The surgical time, complications, and survival rate of DKT were not significantly different from SKT, where survival rates were above 85%. Mice with DKT showed less injury and quicker recovery with lower plasma creatinine (Pcr) and higher glomerular filtration rate (GFR) than SKT mice (Pcr = 0.34 and 0.17 mg/dl in DKT vs. 0.50 and 0.36 mg/dl in SKT at 1 and 3 days, respectively; GFR = 215 and 131 µl/min for DKT and SKT, respectively). In addition, the DKT exhibited better renal functional reserve and long-term outcome of renal graft function than SKT based on the response to acute volume expansion. In conclusion, we have successfully generated a mouse DKT model. The hemodynamic responses of DKT better mimic physiological situations with less kidney injury and better recovery than SKT because of reduced confounding factors such as single nephron hyperfiltration. We anticipate DKT in mice will provide an additional tool for evaluation of renal significance in physiology and disease.

Background The use of autologous arteriovenous fistulae (AVF) for hemodialysis (HD) is the gold standard; however, for many patients at tertiary referral centers, this is not an option. Methods We conducted a four year retrospective cohort study to evaluate HD access outcomes with AVF, bovine carotid artery (BCA), and polytetrafluoroethylene arteriovenous graft (PTFE). Results The study contained 416 AVF, 175 BCA, and 58 PTFE, N = 649. There was statistical difference between rates of infection (AVF 3.4%, BCA 2.9%, PTFE 11.9%), P = 0.02. Maturation failed in 7.5% of AVF but in none of the BCA or PTFE (P = 0.001). Accesses were abandoned with AVF (1.9%), BCA (1.5%), and PTFE (9.5%), P = 0.01. Conclusion Bovine carotid artery can be an effective alternative form of HD access with lower infection, abandonment, and failure to maturation rates when autologous arteriovenous fistula is not an option.

Hyperfiltration is common in early diabetes and considered a risk factor for diabetic nephropathy. Inhibited tubuloglomerular feedback (TGF) mediated by less NaCl delivery at the macula densa contributes to the diabetic hyperfiltration. Nitric oxide (NO) released from macula densa via neuronal nitric oxide synthase (NOS1) inhibits TGF response. We recently demonstrated the significance of TGF response in the long-term control of GFR, sodium excretion and blood pressure, mediated by macula densa NOS1β. However, whether the NOS1β-mediated TGF response play an important role in the diabetic hyperfiltration is unknown. We hypothesized that macula densa NOS1β is upregulated in diabetes, which blunts TGF response and contributes to the diabetic hyperfiltration. The mice with deletion of NOS1 specifically from the macula densa (MD-NOS1KO) and wild-type C57BL/6 (WT) mice were used. Diabetes was induced by alloxan (55 mg/kg i.v.) with blood glucose from 350 to 450 mg/dl. Expression of NOS1 splice variants was measured with real-time PCR and Western blot. GFR was measured by plasma FITC-inulin clearance following a single bolus intravenous injection in conscious mice. GFR increased by 24.7% in diabetic WT mice (from 241.60±19.73 to 301.35±21.76 μl/min) and only by 16.5% in diabetic MD-NOS1KO mice (from 236.61±16.12 to 275.61±11.73 μl/min) (n=6/group, p

Renal infarction is an under-diagnosed and under-reported phenomenon. The U.S. incidence of renal infarction is estimated at 1.4%. Systemically thromboembolic originate from thrombus in the heart or aorta while renal infarction in situ typically involves the main renal artery or its branches. Acute or aggravated hypertension is commonly observed in previously normotensive or hypertensive patients with renal infarction. However, these pathophysiological mechanisms have not been elucidated. The goal of this study was to develop a hypertensive mouse model of renal infarction. Partial renal infarction was performed in C57BL/6 mice by ligating either the upper (LU) or lower (LL) branch of the renal artery in the left kidney while the right kidney remained intact. The mean arterial pressure (MAP) was continuously measured with a telemetry system in conscious mice fed 4 weeks of normal salt diet (NS) (0.4% NaCl) followed by 4 weeks of high salt diet (HS) (4% NaCl). Plasma renin concentration (PRC), renin mRNA in the kidney and TNF-α were measured. Body weight, salt and fluid intakes were similar in mice with LU and LL ligation compared with sham operated mice. The weight of the left kidney decreased by 16.3% in LU (118.1±8.9 mg) and 14.2% in LL (121.5±7.8 mg) compared with sham operated mice (141.0±9.5 mg) (n=6; p

Current animal models of hemorrhagic shock-induced acute kidney injury (HS-induced AKI) require extensive surgical procedures and constant monitoring of hemodynamic parameters. Application of these HS-induced AKI models in mice to produce consistent kidney injury is challenging. In the present study, we developed a simple and highly reproducible mouse model of HS-induced AKI by combining moderate bleeding and renal pedicle clamping, which was abbreviated as HS-AKI. HS was induced by retroorbital bleeding of 0.4 ml blood in C57BL/6 mice. Mice were left in HS stage for 30 min, followed by renal pedicle clamping for 18 min at 36.8–37.0°C. Mean arterial pressure (MAP) and heart rate were monitored with preimplanted radio transmitters throughout the experiment. The acute response in renal blood flow (RBF) triggered by HS was measured with transonic flow probe. Mice received sham operation; bleeding alone and renal pedicle clamping alone served as respective controls. MAP was reduced from 77 ± 4 to 35 ± 3 mmHg after bleeding. RBF was reduced by 65% in the HS period. Plasma creatinine and kidney injury molecule-1 levels were increased by more than 22-fold 24 h after reperfusion. GFR was declined by 78% of baseline 3 days after reperfusion. Histological examination revealed a moderate-to-severe acute tubular damage, mostly at the cortex-medulla junction area, followed by the medullar and cortex regions. HS alone did not induce significant kidney injury, but synergistically enhanced pedicle clamping-induced AKI. This is a well-controlled, simple, and reliable mouse model of HS-AKI.

Introduction: A fundamental gap in correlation appears to exist between bystander Cardiopulmonary Resuscitation (CPR) and preservation of the gift of life for people who die each day awaiting organ transplantation. As a result, the incidence of bystander CPR as a bridge to organ donation has not been articulated. Hypothesis: We assessed the hypothesis that kidneys recovered with bystander CPR demonstrate equivalent survival rates with first responder CPR and or no CPR. Methods: We retrospectively analyzed our transplant database from 2008-2013. We also evaluated the nationwide, population-based database from the United Network for Organ Sharing. Results: A total of 643 deceased donors were utilized to sustain life in a sample size of 882 kidney transplant recipients at our center. There were 77 bystander CPR - mean age 49.8 (SEM 1.75), 192 first responder CPR - mean age 52.45 (SEM 1.05), and 613 no CPR - mean age 52.58 (SEM 0.63). The mean length of stay days were 9.42 (SEM 0.64) bystander CPR, 9.03 (SEM 0.51) first responder CPR, and 10.73 (SEM 0.49) no CPR. The mean one year graft survival rate was 97.4% (SEM 0.01, CI 94.85-99.94) bystander CPR, 93.8% (SEM 0.02, CI 90.46-97.03) first responder CPR and 94.1% (SEM 0.01, CI 92.33-95.86). The mean death-censored graft survival days were 2230 (SEM 67.98) bystander CPR, 2351.22 (SEM 38.02) first responder CPR, and 2292.41 (SEM 26.32) no CPR; with a Log rank p-value=0.338. The United States’ data demonstrated 133,369 deceased donors with 44,469 receiving CPR (33.34%). The mean graft survival rate at one year was 92.62% (CI 92.18-93.06) with CPR and 91.54 % (CI 91.21-91.88) no CPR. No distinctions were made regarding the type of CPR in the national database. Conclusions: Bystander CPR saves lives both with the primary return to baseline function and the secondary gain of the gift of life. Intentional effort should be devoted to tracking the results of bystander CPR and the parallel consequence of organ donation.

Cryopreserved cadaveric venous or arterial allografts are used in ESRD patients as an alternative to synthetic grafts for hemodialysis access. We evaluated the effect of these allografts on the PRA against HLA class I and II antigens in 11 ESRD patients awaiting a kidney transplant.Flow Cytometry using purified antigen coated beads (Flow PRA Beads) was used to determine PRA against HLA class I and II antigens.Patients with no antibody prior to allograft implantation were all positive for HLA class I and II antibodies after implantation. Patients with anti-HLA class I and II antibodies prior to allografting, developed higher antibody titers. Of the 11 patients that received cryopreserved cadaveric allografts no deaths were reported. Two grafts were removed due to thrombosis consistent with rejection.Recipients of cadaveric venous or arterial allografts elicit an HLA antibody response attesting to the antigenicity of cryopreserved cadaveric allografts.