Size Matching Deceased Donor Livers: The Tampa General Measurement System.

BACKGROUND: No reliable or standardized system exists for measuring the size of deceased donor livers to determine whether they will fit appropriately into intended recipients. METHODS: This retrospective, single-center study evaluated the efficacy of Tampa General Hospital's size-matching protocol for consecutive, deceased donor liver transplantations between October 2021 and November 2022. Our protocol uses cross-sectional imaging at the time of organ offer to compare the donor's right hepatic lobe size with the recipient's right hepatic fossa. Outcomes were analyzed, including large-for-size syndrome, small-for-size syndrome, early allograft dysfunction, primary nonfunction, graft survival, and patient survival. RESULTS: We included 171 patients in the study. The donor liver physically fit in all the patients except one whose pretransplant imaging was outdated. One patient (0.6%) had large-for-size syndrome, none had small-for-size syndrome, 15 (10%) had early allograft dysfunction, and none had primary nonfunction. There were 11 (7%) patient deaths and 11 (7%) graft failures. CONCLUSION: Our measurement system is fast and effective. It reliably predicts whether the donor liver will fit in the intended recipient and is associated with low rates of early allograft dysfunction.

Reducing ischemic kidney injury through application of a synchronization modulation electric field to maintain Na+/K+-ATPase functions.

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.

Role of the macula densa sodium glucose cotransporter type 1-neuronal nitric oxide synthase-tubuloglomerular feedback pathway in diabetic hyperfiltration.

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.

Knockout of Macula Densa Neuronal Nitric Oxide Synthase Increases Blood Pressure in db/db Mice.

[Figure: see text].

Macula Densa NOS1ß Modulates Renal Hemodynamics and Blood Pressure during Pregnancy: Role in Gestational Hypertension.

BACKGROUND: Regulation of renal hemodynamics and BP via tubuloglomerular feedback (TGF) may be an important adaptive mechanism during pregnancy. Because the ß-splice variant of nitric oxide synthase 1 (NOS1ß) 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 NOS1ß in the macula densa, thus blunting TGF, allowing the GFR to increase and BP to decrease. METHODS: We used sophisticated techniques, including microperfusion of juxtaglomerular apparatus in vitro, micropuncture of renal tubules in vivo, clearance kinetics of plasma FITC-sinistrin, and radiotelemetry BP monitoring, to determine the effects of normal pregnancy or reduced uterine perfusion pressure (RUPP) on macula densa NOS1ß/NO levels, TGF responsiveness, GFR, and BP in wild-type and macula densa-specific NOS1 knockout (MD-NOS1KO) mice. RESULTS: Macula densa NOS1ß 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 NOS1ß, 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 NOS1ß expression increased in normotensive pregnancies, but decreased in spontaneous gestational hypertensive pregnancies. CONCLUSIONS: Macula densa NOS1ß plays a critical role in the control of renal hemodynamics and BP during pregnancy.

The Impact of Virtual Crossmatch on Cold Ischemic Times and Outcomes Following Kidney Transplantation.

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.

The Association Between Alcoholic Liver Disease and Alcohol Tax.

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.

Recurrent Postoperative Toxic Shock Syndrome in a Living Kidney Transplant Recipient.

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.

A new mechanism for the sex differences in angiotensin II-induced hypertension: the role of macula densa NOS1ß-mediated tubuloglomerular feedback.

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 1ß (NOS1ß)-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 NOS1ß 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 NOS1ß, 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 NOS1ß expression in females than in males. In conclusion, macula densa NOS1ß-mediated TGF is a novel and important mechanism for the sex differences in ANG II-induced hypertension.

Outcomes in Renal Cell Carcinoma With IVC Thrombectomy: A Multiteam Analysis Between an NCI-Designated Cancer Center and a Quaternary Care Teaching Hospital.

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.

HCC Liver Transplantation Wait List Dropout Rates Before and After the Mandated 6-Month Wait Time.

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.

Cost Utilization and the Use of Pulmonary Function Tests in Preoperative Liver Transplant Patients.

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) <80% or obstructive disease of ratio of forced expiratory volume in the first 1 second to the first vital capacity of the lungs (FEV1/FVC) <70%. 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.

Pre-Liver Transplant Coronary Artery Disease Workup for Low-Risk Patients.

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.

Hepatitis C and Racial Disparity in Liver Transplant Waitlist Additions : Separate Not Equal.

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.

Operative Versus Nonoperative Management of Hemorrhage in the Postoperative Kidney Transplant Patient.

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.

Outcomes With Age Combinations in Living Donor Kidney Transplantation.

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.

A two-stage bilateral ischemia-reperfusion injury-induced AKI to CKD transition model in mice.

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.

New Mechanism for the Sex Differences in Salt-Sensitive Hypertension: The Role of Macula Densa NOS1ß-Mediated Tubuloglomerular Feedback.

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 NOS1ß (nitric oxide synthase ß)-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 NOS1ß-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 NOS1ß 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 NOS1ß 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 NOS1ß-mediated TGF is a novel and important mechanism for the sex differences in salt-sensitive hypertension.

Aging Impairs Renal Autoregulation in Mice.

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.