The COVID-19 pandemic has significantly impacted on the delivery of clinical trials in the UK, posing complicated organisational challenges and requiring adaptations, especially to exercise intervention studies based in the community. We aim to identify the challenges of public involvement, recruitment, consent, follow-up, intervention and the healthcare professional delivery aspects of a feasibility study of exercise in hypertensive primary care patients during the COVID-19 pandemic. While these challenges elicited many reactive changes which were specific to, and only relevant in the context of 'lockdown' requirements, some of the protocol developments that came about during this unprecedented period have great potential to inform more permanent practices for carrying out this type of research. To this end, we detail the necessary adaptations to many elements of the feasibility study and critically reflect on our approach to redesigning and amending this ongoing project in order to maintain its viability to date. Some of the more major protocol adaptations, such as moving the study to remote means wherever possible, had further unforeseen and undesirable outcomes (eg, additional appointments) with regards to extra resources required to deliver the study. However, other changes improved the efficiency of the study, such as the remote informed consent and the direct advertising with prescreening survey. The adaptations to the study have clear links to the UK Plan for the future of research delivery. It is intended that this specific documentation and critical evaluation will help those planning or delivering similar studies to do so in a more resource efficient and effective way. In conclusion, it is essential to reflect and respond with protocol changes in the current climate in order to deliver clinical research successfully, as in the case of this particular study.

Hypertension (HTN) affects approximately 25% of the UK population and is a leading cause of mortality. Associated annual health care costs run into billions. National treatment guidance includes initial lifestyle advice, followed by anti-hypertensive medication if blood pressure (BP) remains high. However, adoption and adherence to recommended exercise guidelines, dietary advice and anti-hypertensive medication is poor. Four short bouts of isometric exercise (IE) performed 3 days per week (d/wk) at home elicits clinically significant reductions in BP in those with normal to high-normal BP. This study will determine the feasibility of delivering personalised IE to patients with stage 1 hypertension for whom lifestyle changes would be recommended before medication within NHS primary care.

Background: Improving recognition of patients at increased risk of acute kidney injury (AKI) in the community may facilitate earlier detection and implementation of proactive prevention measures that mitigate the impact of AKI. The aim of this study was to develop and externally validate a practical risk score to predict the risk of AKI in either hospital or community settings using routinely collected data. Methods: Routinely collected linked datasets from Tayside, Scotland, were used to develop the risk score and datasets from Kent in the UK and Alberta in Canada were used to externally validate it. AKI was defined using the Kidney Disease: Improving Global Outcomes serum creatinine–based criteria. Multivariable logistic regression analysis was performed with occurrence of AKI within 1 year as the dependent variable. Model performance was determined by assessing discrimination (C-statistic) and calibration. Results: The risk score was developed in 273 450 patients from the Tayside region of Scotland and externally validated into two populations: 218 091 individuals from Kent, UK and 1 173 607 individuals from Alberta, Canada. Four variables were independent predictors for AKI by logistic regression: older age, lower baseline estimated glomerular filtration rate, diabetes and heart failure. A risk score including these four variables had good predictive performance, with a C-statistic of 0.80 [95% confidence interval (CI) 0.80–0.81] in the development cohort and 0.71 (95% CI 0.70–0.72) in the Kent, UK external validation cohort and 0.76 (95% CI 0.75–0.76) in the Canadian validation cohort. Conclusion We have devised and externally validated a simple risk score from routinely collected data that can aid both primary and secondary care physicians in identifying patients at high risk of AKI.

Background Circulating asymmetric (ADMA) and symmetric dimethylarginine (SDMA) are increased in patients with kidney disease. SDMA is considered a good marker of glomerular filtration rate (GFR) whilst ADMA is a marker of cardiovascular risk. However, a link between SDMA and all-cause mortality has been reported. In the present study we evaluated both dimethylarginines as risk and GFR markers in a cohort of elderly white individuals, both with and without CKD. Methods GFR was measured in 394 individuals aged >74 years using an iohexol clearance method. Plasma ADMA, SDMA and iohexol were measured simultaneously using isotope dilution tandem mass spectrometry. Results Plasma ADMA concentrations were increased (P<0.01) in people with GFR <60 mL/min/1.73 m² compared to those with GFR >60 mL/min/1.73 m², but did not differ (P>0.05) between those with GFR 30-59 mL/min/1.73 m² and <30 mL/min/1.73 m². Plasma SDMA increased consistently across declining GFR categories (P<0.0001). GFR had an independent effect on plasma ADMA concentration whilst GFR, gender, body mass index and haemoglobin had independent effects on plasma SDMA concentration. Participants were followed for a median of 33 months. There were 65 deaths. High plasma ADMA (P=0.0412) and SDMA (P<0.0001) concentrations were independently associated with reduced survival. Conclusions Amongst elderly white individuals with a range of kidney function, SDMA was a better marker of GFR and a stronger predictor of outcome than ADMA. Future studies should further evaluate the role of SDMA as a marker of outcome and assess its potential value as a marker of GFR.

Background: Acute T-cell mediated rejection (TCMR) is usually indicated by alteration in serum-creatinine measurements when considerable transplant damage has already occurred. There is, therefore, a need for non-invasive early detection of immune signals that would precede the onset of rejection, prior to transplant damage. Methods: We examined the RT-qPCR expression of 22 literature-based genes in peripheral blood samples from 248 patients in the Kidney Allograft Immune Biomarkers of Rejection Episodes (KALIBRE) study. To account for post-transplantation changes unrelated to rejection, we generated time-adjusted gene-expression residuals from linear mixed-effects models in stable patients. To select genes, we used penalised logistic regression based on 27 stable patients and 27 rejectors with biopsy-proven T-cell-mediated rejection, fulfilling strict inclusion/exclusion criteria. We validated this signature in i) an independent group of stable patients and patients with concomitant T-cell and antibody-mediated-rejection, ii) patients from an independent study, iii) cross-sectional pre-biopsy samples from non-rejectors and iv) longitudinal follow-up samples covering the first posttransplant year from rejectors, non-rejectors and stable patients. Findings: A parsimonious TCMR-signature (IFNG, IP-10, ITGA4, MARCH8, RORc, SEMA7A, WDR40A) showed cross-validated area-under-ROC curve 0·84 (0·77-0·88) (median, 2·5th-97·5th centile of fifty cross-validation cycles), sensitivity 0·67 (0·59-0·74) and specificity 0·85 (0·75-0·89). The estimated probability of TCMR increased seven weeks prior to the diagnostic biopsy and decreased after treatment. Gene expression in all patients showed pronounced variability, with up to 24% of the longitudinal samples in stable patients being TCMR-signature positive. In patients with borderline changes, up to 40% of pre-biopsy samples were TCMR-signature positive. Interpretation Molecular marker alterations in blood emerge well ahead of the time of clinically overt TCMR. Monitoring a TCMR-signature in peripheral blood could unravel Tcell-related pro-inflammatory activity and hidden immunological processes. This additional information could support clinical management decisions in cases of patients with stable but poor kidney function or with inconclusive biopsy results.

Background Acute Kidney Injury (AKI) is associated with adverse outcomes; identifying patients who are at risk of developing AKI in hospital may lead to targeted prevention. This approach is advocated in national guidelines but is not well studied in acutely unwell medical patients. We therefore aimed to undertake a UK-wide study in acute medical units (AMUs) with the following aims: to define the proportion of acutely unwell medical patients who develop hospital-acquired AKI (hAKI); to determine risk factors associated with the development of hAKI; and to assess the feasibility of using these risk factors to develop an AKI risk prediction score. Methods In September 2016, a prospective multicentre cohort study across 72 UK AMUs was undertaken. Data were collected from all patients who presented over a 24-hour period. Chronic dialysis, community-acquired AKI (cAKI) and those with fewer than two creatinine measurements were subsequently excluded. The primary outcome was the development of h-AKI. Results 2,446 individuals were admitted to the AMUs of the 72 participating centres. 384 patients (16%) sustained AKI of whom 287 (75%) were cAKI and 97 (25%) were hAKI. After exclusions, 1,235 participants remained in whom chronic kidney disease (OR 3.08, 95% CI 1.96-4.83), diuretic prescription (OR 2.33, 95% CI 1.5-3.65), a lower haemoglobin concentration and an elevated serum bilirubin were independently associated with development of hAKI. Multivariable model discrimination was moderate (c-statistic 0.75), and this did not support the development of a robust clinical risk prediction score. Mortality was higher in those with hAKI (adjusted OR 5.22; 95% CI 2.23-12.20). Conclusion AKI in AMUs is common and associated with worse outcomes, with the majority of cases community acquired. The smaller proportion of hAKI cases, only moderate discrimination of prognostic risk factor modelling and the resource implications of widespread application of an AKI clinical risk score across all AMU admissions suggests that this approach is not currently justified. More targeted risk assessment or automated methods of calculating individual risk may be more appropriate alternatives.

Until the law in the United Kingdom changed in May 2016 so called "legal highs" or "new psychoactive substances" were freely available in high street shops across the United Kingdom (UK). Following prohibition these drugs are still easily purchased illegally via the internet. We report a case of a patient who self-administered 3-Fluorophenmetrazine intravenously with catastrophic consequences. Adverse effects were almost immediate with symptoms of malaise and tachycardia. Two days post administration he was transferred to the intensive therapy unit with acute kidney injury and irreversible four limb ischaemia. He required a period of renal replacement therapy and bilateral lower limb amputation. This case highlights the fact that new psychoactive substances have many unintended adverse effect which have not been previously described. Multiple routes of administration are used by people taking these agents including intravenously. Medical practitioners should always consider ingestion of new psychoactive substances in the differential diagnosis of acutely ill patients.

Background: the use of antihypertensive medication in older people in order to prevent cardiovascular events is well established. The use of such agents has been encouraged by incentive schemes in the United Kingdom including the Quality and Outcomes Framework. In addition, many guidelines recommend good blood pressure (BP) control in the elderly. However, in older people antihypertensives can cause adverse effects related to hypotension. Aim: the aim of this study was to assess the prevalence of low BP and impact on outcomes, particularly in the presence of antihypertensive treatment, in a primary care population of older people. Design: a retrospective observational cohort study in people over the age of 70 years registered with primary care providers in Kent. Results: a total of 11,167 patients over 70 years old were analysed, 6,373 female (57%). Systolic blood pressure (SBP) was below 120 mmHg in 1,297 people (844 on antihypertensives), below 110 mmHg in 474 (313 on antihypertensives) and below 100 mmHg in 128 (89 on antihypertensives). Hypotension was independently associated with mortality, acute kidney injury and hospital admission. Conclusions: the results demonstrate that low SBP is associated with adverse events, it is possible that the pursuit of BP control at a population level may lead to over-treatment in certain groups of patients. This may result in an increased incidence of adverse events particularly in older people.

Acute kidney injury (AKI) is a medical emergency that commonly occurs in primary and secondary care. The National Confidential Enquiry into Perioperative Deaths report found that AKI was avoidable in 30% of patients who died from AKI in hospitals. The cost of caring for patients with AKI has been estimated to be £1.02 billion in England. NHS England has prioritised AKI as an area for quality improvement and has positioned AKI in the Patient Safety workstream, establishing the Think Kidneys AKI Programme.

BACKGROUND: Identification of acute kidney injury (AKI) is predominantly based on changes in plasma creatinine concentration, an insensitive marker. Alternative biomarkers have been proposed. The reference change value (RCV), the point at which biomarker change can be inferred to have occurred with statistical certainty, provides an objective assessment of change in serial tests results in an individual. METHODS: In 80 patients with chronic kidney disease, weekly measurements of blood and urinary biomarker concentrations were undertaken over 6 weeks. Variability was determined and compared before and after adjustment for urinary creatinine and across subgroups stratified by level of kidney function, proteinuria, and presence or absence of diabetes. RESULTS: RCVs were determined for whole blood, plasma, and urinary neutrophil gelatinase-associated lipocalin (111%, 59%, and 693%, respectively), plasma cystatin C (14%), creatinine (17%), and urinary kidney injury molecule 1 (497%), tissue inhibitor of metalloproteinases 2 (454%), N-acetyl-?-d-glucosaminidase (361%), interleukin-18 (819%), albumin (430%), and ?1-microglobulin (216%). Blood biomarkers exhibited lower variability than urinary biomarkers. Generally, adjusting urinary biomarker concentrations for creatinine reduced (P < 0.05) within-individual biological variability (CVI). For some markers, variation differed (P < 0.05) between subgroups. CONCLUSIONS: These data can form a basis for application of these tests in clinical practice and research studies and are applicable across different levels of kidney function and proteinuria and in the presence or absence of diabetes. Most of the studied biomarkers have relatively high CVI (noise) but also have reported large concentration changes in response to renal insult (signal); thus progressive change should be detectable (high signal-to-noise ratio) when baseline data are available.

This study provides valuable evidence of relationships between key variables and AKI. We have developed a clinical algorithm and risk models for risk assessment within the first 24 hours of hospital admission. However, the study has its limitations, and further analysis and testing, including continuous modelling, non-linear modelling and interaction exploration, may further refine the models. The qualitative study has highlighted the complexity regarding the implementation and delivery of alerting systems in clinical practice.

Background: Acute kidney injury (AKI) is a common clinical problem with significant morbidity and mortality. All hospitalised patients are at risk. AKI is often preventable and reversible; however, the 2009 National Confidential Enquiry into Patient Outcome and Death highlighted systematic failings of identification and management, and recommended risk assessment of all emergency admissions. Objectives: To develop three predictive models to stratify the risk of (1) AKI on arrival in hospital; (2) developing AKI during admission; and (3) worsening AKI if already present; and also to (4) develop a clinical algorithm for patients admitted to hospital and explore effective methods of delivery of this information at the point of care. Study design: Quantitative methodology (1) to formulate predictive risk models and (2) to validate the models in both our population and a second population. Qualitative methodology to plan clinical decision support system (CDSS) development and effective integration into clinical care. Settings and participants Quantitative analysis – the study population comprised hospital admissions to three acute hospitals of East Kent Hospitals University NHS Foundation Trust in 2011, excluding maternity and elective admissions. For validation in a second population the study included hospital admissions to Medway NHS Foundation Trust. Qualitative analysis – the sample consisted of six renal consultants (interviews) and six outreach nurses (focus group), with representation from all sites. Data collection: Data (comprising age, sex, comorbidities, hospital admission and outpatient history, relevant pathology tests, drug history, baseline creatinine and chronic kidney disease stage, proteinuria, operative procedures and microbiology) were collected from the hospital data warehouse and the pathology and surgical procedure databases. Data analysis: Quantitative – both traditional and Bayesian regression methods were used. Traditional methods were performed using ordinal logistic regression with univariable analyses to inform the development of multivariable analyses. Backwards selection was used to retain only statistically significant variables in the final models. The models were validated using actual and predicted probabilities, an area under the receiver operating characteristic (AUROC) curve analysis and the Hosmer–Lemeshow test. Qualitative – content analysis was employed. Main outcome measures: (1) A clinical pratice algorithm to guide clinical alerting and risk modeling for AKI in emergency hospital admissions; (2) identification of the key variables that are associated with the risk of AKI; (3) validated risk models for AKI in acute hospital admissions; and (4) a qualitative analysis providing guidance as to the best approach to the implementation of clinical alerting to highlight patients at risk of AKI in hospitals. Findings: Quantitative – we have defined a clinical practice algorithm for risk assessment within the first 24 hours of hospital admission. Bayesian methodology enabled prediction of low risk but could not reliably identify high-risk patients. Traditional methods identified key variables, which predict AKI both on admission and at 72 hours post admission. Validation demonstrated an AUROC curve of 0.75 and 0.68, respectively. Predicting worsening AKI during admission was unsuccessful. Qualitative – analysis of AKI alerting gave valuable insights in terms of user friendliness, information availability, clinical communication and clinical responsibility, and has informed CDSS development. Conclusions: This study provides valuable evidence of relationships between key variables and AKI. We have developed a clinical algorithm and risk models for risk assessment within the first 24 hours of hospital admission. However, the study has its limitations, and further analysis and testing, including continuous modelling, non-linear modelling and interaction exploration, may further refine the models. The qualitative study has highlighted the complexity regarding the implementation and delivery of alerting systems in clinical practice.

Background: Use of renin-angiotensin system (RAS) blockade has become increasingly widespread driven by evidence-based guidance. There is concern about the role of these agents in the genesis of avoidable acute kidney injury (AKI). Objectives: To investigate the association between AKI and use of RAS blockade. Design: Multilevel hierarchical analysis of a large cohort of patients registered with UK general practitioners. Setting: Primary care practices in East and West Kent, United Kingdom. Patients: 244,715 patients from 27 practices. Measurements: Demographic, clinical, biochemical and prescription data. Methods: Analyses of data acquired between 02/3/2004 and 17/04/2012 using multilevel logistic regression to determine the relationship between AKI and use of RAS blockade; further analysed by indication for treatment with RAS blockade. Results: Sufficient serum creatinine data were available to define AKI in 63,735 patients with 208,275 blood test instances. In 95,569 instances the patient was prescribed a RAS antagonist of which 5.4% fulfilled criteria for AKI. The unadjusted odds ratio (OR) for AKI in those prescribed RAS blockade was 1.93 (1.81-2.06, 95%CI) falling to 1.11 (1.02-1.20, 95%CI) when adjusted for age, gender, co-morbidity, GFR category, proteinuria, systolic blood pressure and diuretic therapy. In patients with an evidence-based indication there was no difference in absolute risk of AKI. However, prescription of RAS blockade in the absence of indication appeared to be associated with greater risk of AKI. When analysis was repeated with AKIN2/AKIN3 as the outcome, although risk of AKI remained significant when unadjusted (OR 1.73, 95%CI 1.42-2.11, p<0.001), after full adjustment there was no increased risk (OR 0.83, 95%CI 0.63-1.09) in those taking RAS antagonists. However, when analysed by indication AKIN2/AKIN3 was significantly more likely in those prescribed RAS antagonists without indication (OR 2.04, 95%CI 1.41-2.94, p<0.001). Limitations: Observational database study. No information concerning hospitalisation. Prescribing assumptions and potential inaccurate coding. Potential survival bias; patients surviving longer will contribute more data. Conclusions: Use of RAS antagonists increased the risk of AKI, independent of common confounding variables. After correction for confounders the risk fell away and became non-significant for moderate and severe AKI. However, where there was no evidence-based indication for RAS antagonists the risk of AKI, whether mild, moderate or severe, remained greater.

Unscheduled care is complex, particularly because many patients have multiple long term medical conditions. It is difficult to ensure the appropriate care is delivered by specialist services to patients in a timely manner. Lack of specialist input may impact on patient safety and adversely affect outcomes. We describe an automated email alerting system which was developed as result of a clinical incident. Using free software and minimal computing resources an automated email alerting system was developed. The system identified patient admissions, compared them against patient cohorts and created alerts. It used only around 1,000 lines of Java7 code combined with free software and secure NHS mail accounts. The system currently sends alerts to many different teams at our hospital. The patient population includes 6,047 patients on one of our 10 monitored lists or special registers. From May to June 2013 the system alerted to 863 monitored patient admissions in 2,158 separate messages. This system has been adopted across multiple specialties, has been well received and has had a direct impact on patient care. Not only is this system efficient and effective, but importantly can be implemented with low cost and complexity and is hence easily reproducible across the NHS.

Background 5-Amino salicylate (5-ASA) medications may rarely be associated with a significant decline in renal function and interstitial nephritis. British Society of Gastroenterology guidelines advise regular renal function monitoring for patients taking these drugs. Aim To assess whether gastroenterologists in Kent were following best practice guidelines regarding the monitoring of their patients on 5-ASA therapy. Methods Using longitudinal community and regional pathology databases for the Kent population, our renal unit regularly screens a total population of 300?000 for evidence of renal disease. The data extracted are analysed using an automated computerised system to identify patients requiring intervention for kidney disease. All patients taking 5-ASA medication were identified from a population of 300?000. The pathology database was studied to identify the patients on 5-ASA treatment and whether they had had renal function tests. Results 800 adult patients were identified taking 5-ASA therapy. 612 patients received 5-ASAs for 3?months or more, and these were included in the final analysis. 293 patients had no renal function checks while on treatment. 79 patients had renal function tests less than once every 4?years and 36 patients once every 2–4 years. 204 patients had renal function measurements in 50% or more of years of treatment, of whom 116 were checked every year. Some patients were started on treatment with abnormal results at baseline and some with identified kidney disease continued on their 5-ASAs. Conclusions The majority of patients receiving 5-ASA compounds do not have regular renal function monitoring. Clinicians are failing to follow best practice guidelines.

Background: Acute kidney injury (AKI) is a common clinical problem. Studies have documented the incidence of AKI in a variety of populations but to date we do not believe the real incidence of AKI has been accurately documented in a district general hospital setting. The aim here was to describe the detected incidence of AKI in a typical general hospital setting in an unselected population, and describe associated short and long-term outcomes. Methods: A retrospective observational database study from secondary care in East Kent (adult catchment population of 582,300). All adult patients (18 years or over) admitted between 1st February 2009 and 31st July 2009, were included. Patients receiving chronic renal replacement therapy (RRT), maternity and day case admissions were excluded. AKI was defined by the acute kidney injury network (AKIN) criteria. A time dependent risk analysis with logistic regression and Cox regression was used for the analysis of in-hospital mortality and survival. Results: The incidence of AKI in the 6 month period was 15,325 pmp/yr (adults) (69% AKIN1, 18% AKIN2 and 13% AKIN3). In-hospital mortality, length of stay and ITU utilisation all increased with severity of AKI. Patients with AKI had an increase in care on discharge and an increase in hospital readmission within 30 days. Conclusions: This data comes closer to the real incidence and outcomes of AKI managed in-hospital than any study published in the literature to date. Fifteen percent of all admissions sustained an episode of AKI with increased subsequent short and long term morbidity and mortality, even in those with AKIN1. This confers an increased burden and cost to the healthcare economy, which can now be quantified. These results will furnish a baseline for quality improvement projects aimed at early identification, improved management, and where possible prevention, of AKI.

Chronic kidney disease prevalence increases markedly with age1 and accurate estimation of GFR is an important issue in older people. The Chronic Kidney Disease Epidemiology Collaboration creatinine equation (CKD-EPIcr)2 and variations including cystatin C (CKD-EPIcys) or both creatinine and cystatin C (CKD-EPIcr-cys)3 have been recommended for estimating GFR.4 Recently, the Berlin Initiative Study (BIS) reported 2 GFR equations specifically developed in older people: BIS1, which uses creatinine, and BIS2, which uses both creatinine and cystatin C.5 Here, we compare how the BIS and CKD-EPI equations perform in a large cohort of older people.

Background: The significant impact Acute Kidney Injury (AKI) has on patient morbidity and mortality emphasizes the need for early recognition and effective treatment. AKI presenting to or occurring during hospitalisation has been widely studied but little is known about the incidence and outcomes of patients experiencing acute elevations in serum creatinine in the primary care setting where people are not subsequently admitted to hospital. The aim of this study was to define this incidence and explore its impact on mortality. Methods: The study cohort was identified by using hospital data bases over a six month period. Inclusion criteria: People with a serum creatinine request during the study period, 18 or over and not on renal replacement therapy. The patients were stratified by a rise in serum creatinine corresponding to the Acute Kidney Injury Network (AKIN) criteria for comparison purposes. Descriptive and survival data were then analysed. Ethical approval was granted from National Research Ethics Service (NRES) Committee South East Coast and from the National Information Governance Board. Results: The total study population was 61,432. 57,300 subjects with 'no AKI', mean age 64.The number (mean age) of acute serum creatinine rises overall were, 'AKI 1' 3,798 (72), 'AKI 2' 232 (73), and 'AKI 3' 102 (68) which equates to an overall incidence of 14,192 pmp/year (adult). Unadjusted 30 day survival was 99.9% in subjects with 'no AKI', compared to 98.6%, 90.1% and 82.3% in those with 'AKI 1', 'AKI 2' and 'AKI 3' respectively. After multivariable analysis adjusting for age, gender, baseline kidney function and co-morbidity the odds ratio of 30 day mortality was 5.3 (95% CI 3.6, 7.7), 36.8 (95% CI 21.6, 62.7) and 123 (95% CI 64.8, 235) respectively, compared to those without acute serum creatinine rises as defined. Conclusions: People who develop acute elevations of serum creatinine in primary care without being admitted to hospital have significantly worse outcomes than those with stable kidney function.

Cyclosporin A (CsA) and Tacrolimus (FK-506) are potent immunosuppressant drugs widely used to prevent allograft rejection in organ transplantation. They are calcineurin inhibitors (CNIs) and have limiting side effects including nephrotoxicity that impact upon long-term renal allograft and patient survival in other organ transplantation. The precise mechanisms of CNI-induced toxicity are unknown, although ischemic injury resulting from impairment of endothelial cell function, reduced production of endogenous renal vasodilators and concomitant release of vasoconstrictors resulting in net vasoconstriction have been described. We have utilized the live kidney slice model, developed by our group [1], to investigate the mechanisms of CNI-induced nephrotoxicity in the renal medulla, a region of the kidney that is particularly sensitive to ischemia Data presented here demonstrates both CsA (600 ng/ml) and FK-506 (800 ng/ml) cause vasoconstriction (9.9% ± 0.88% and 9.2% ± 0.63%, respectively) of vasa recta via their specific action at contractile pericytes. Tubule diameter was unaffected by bath application of both CsA and FK-506. Data suggest that CNI-induced constriction of vasa recta by pericytes may exacerbate renal medullary ischemia contributing to observed nephrotoxicity in solid organ transplantation.