Improvement in Lung Clearance Index and Chest Computed Tomography Scores with Elexacaftor/Tezacaftor/Ivacaftor Treatment in People with Cystic Fibrosis Aged 12 Years and Older - The RECOVER Trial.

Rationale: Clinical trials have shown that use of elexacaftor/tezacaftor/ivacaftor (ETI) is associated with improvements in sweat chloride, pulmonary function, nutrition, and quality of life in people with cystic fibrosis (CF). Little is known about the impact of ETI on ventilation inhomogeneity and lung structure. Objectives: RECOVER is a real-world study designed to measure the impact of ETI in people with CF. The primary endpoints were lung clearance (lung clearance index; LCI2.5) and FEV1. Secondary endpoints included spirometry-controlled chest computed tomography (CT) scores. Methods: The study was conducted in seven sites in Ireland and the United Kingdom. Participants ages 12 years and older who were homozygous for the F508del mutation (F508del/F508del) or heterozygous for F508del and a minimum-function mutation (F508del/MF) were recruited before starting ETI and were followed up over 12 months. LCI2.5 was measured using nitrogen multiple breath washout (MBW) at baseline and at 6 and 12 months. Spirometry was performed as per the criteria of the American Thoracic Society and the European Respiratory Society. Spirometry-controlled chest CT scans were performed at baseline and at 12 months. CT scans were scored using the Perth Rotterdam Annotated Grid Morphometric Analysis (PRAGMA) system. Other outcome measures include weight, height, Cystic Fibrosis Quality of Life Questionnaire-Revised (CFQ-R), and sweat chloride. Measurements and Main Results: One hundred seventeen people with CF ages 12 and older were recruited to the study. Significant improvements were seen in LCI scores (-2.5; 95% confidence interval [CI], -3.0, -2.0) and in the percents predicted for FEV1 (8.9; 95% CI, 7.0, 10.9), FVC (6.6; 95% CI, 4.9, 8.3), and forced expiratory flow between 25% and 75% of expired volume (12.4; 95% CI, 7.8, 17.0). Overall PRAGMA-CF scores reflecting airway disease improved significantly (-3.46; 95% CI, -5.23, -1.69). Scores for trapped air, mucus plugging, and bronchial wall thickening improved significantly, but bronchiectasis scores did not. Sweat chloride levels decreased in both F508del/F508del (-43.1; 95% CI, -47.4, -38.9) and F508del/MF (-42.8; 95% CI, -48.5, -37.2) groups. Scores on the Respiratory Domain of the CFQ-R improved by 14.2 points (95% CI, 11.3, 17.2). At 1 year, sweat chloride levels were significantly lower for the F508del/F508del group compared with scores for the F508del/MF group (33.93 vs. 53.36, P < 0.001). Conclusions: ETI is associated with substantial improvements in LCI2.5, spirometry, and PRAGMA-CF CT scores in people with CF ages 12 years and older. ETI led to improved nutrition and quality of life. People in the F508del/F508del group had significantly lower sweat chloride on ETI treatment compared with the F508del/MF group. Clinical trial registered with www.clinicaltrials.gov (NCT04602468).

Association of Geographic Distance and Hospital Characteristics With Use of Interhospital Transfer by Air: A Multicenter Retrospective Study.

OBJECTIVE: Interhospital transfer by air (IHTA) represents the majority of helicopter air ambulance transports in the United States, but the evaluation of what factors are associated with utilization has been limited. We aimed to assess the association of geographic distance and hospital characteristics (including patient volume) with the use of IHTA. METHODS: This was a multicenter, retrospective study of helicopter flight request data from 2018 provided by a convenience sample of 4 critical care transport medicine programs in 3 US census regions. Nonfederal referring hospitals located in the home state of the associated critical care transport medicine program and within 100 miles of the primary receiving facility in the region were included if complete data were available. We fit a Poisson principal component regression model incorporating geographic distance, the number of emergency department visits, the number of hospital discharges, case mix index, the number of intensive care unit beds, and the number of general beds and tested the association of the variables with helicopter emergency medical services utilization. RESULTS: A total of 106 referring hospitals were analyzed, 21 of which were hospitals identified as having a consistent request pattern. Using the hospitals with a consistent referral pattern, geographic distance had a significant positive association with flight request volume. Other variables, including emergency department visit volume, were not associated. Overall, the included variables offered poor explanatory power for the observed variation between referring facilities in the use of IHTA (r2 = 0.09). Predicted flights based on the principal component regression model for all referring hospitals suggested the majority of referring hospitals used multiple flight programs. CONCLUSION: Geographic distance is associated with the use of IHTA. Unexpectedly, most basic hospital characteristics are not associated with the use of IHTA, and the degree of variation between referring facilities that is explained by patient volume is limited. The evaluation of nonhospital factors, such as the density and availability of critical care or advanced life support ground emergency medical services resources, is needed.

Generalized lymphatic anomaly successfully treated with long-term, low-dose sirolimus.

Generalized lymphatic anomaly is a rare, complex, lymphatic anomaly generally involving soft tissues, spleen, and bones. It can lead to focal skeletal fragility and pathologic effusions. A recent prospective trial of sirolimus for complicated vascular anomalies showed partial response in seven patients with generalized lymphatic anomaly treated with sirolimus with a target trough level of 10-15 ng/mL for 1 year (Adams et al). We describe successful treatment of generalized lymphatic anomaly with a lower-dose, long-term course of sirolimus.

Maternal eating behaviour differs between ethnic groups: Considerations for research and practice.

Maternal eating behaviours such as cognitive restraint, uncontrolled, and emotional eating styles can have important implications for both maternal own weight, and the weight and eating behaviour of her children. Maternal eating style can affect her feeding interactions with her child, which in turn can influence their weight and eating behaviour. However, despite a body of research examining these relationships, research examining differences in maternal eating behaviour between ethnic groups is sparse with much of the research, particularly in the UK, conducted with White British samples. The aim of the current research was therefore to explore how maternal eating behaviour may differ between ethnic groups in the UK; 659 UK mothers with a child aged 5-11 years completed a self-report questionnaire. Items included ethnicity, demographic data, and the 3-factor eating questionnaire to measure maternal cognitive restraint, uncontrolled, and emotional eating. Mothers from Chinese backgrounds were significantly higher in cognitive restraint and lower in emotional and uncontrolled eating compared with all groups. Conversely, mothers from South Asian backgrounds were the highest in emotional and uncontrolled eating and lower in cognitive restraint than all other groups. Black mothers were also higher in uncontrolled eating compared with White British and Chinese mothers. Variations in maternal eating behaviours vary between ethnic groups. Understanding how cultural factors may influence these variations is important, as maternal eating behaviours can influence her own and her child's weight. Maternal eating behaviour may therefore be a contributor to higher levels of overweight among South Asian and Black children living in the UK.

Computed tomography and upper gastrointestinal series findings of esophageal bronchi in infants.

BACKGROUND: Esophageal bronchus is a rare form of communicating bronchopulmonary foregut malformation and a rare but important cause of an opaque hemithorax on chest radiography. A higher incidence of esophageal bronchus is associated with esophageal atresia, tracheo-esophageal fistula (TEF) and VACTERL (vertebral defects, anal atresia, cardiac defects, tracheo-esophageal fistula, renal anomalies, and limb abnormalities) association. In the presence of these conditions, the pediatric radiologist may be the first to consider the diagnosis of esophageal bronchus or esophageal lung. OBJECTIVE: To describe the imaging features in five children with esophageal bronchus. MATERIALS AND METHODS: We reviewed hospital records and teaching files at two large pediatric tertiary referral centers over the 24-year period from January 1992 to January 2016. We reviewed all imaging studies and tabulated findings on radiography, fluoroscopic upper gastrointestinal (GI) series and CT. We then described the imaging features of esophageal bronchi with emphasis on CT and upper GI findings in four infants and one toddler. RESULTS: Three cases were identified from one institution (cases 2, 3, 4) and two from another (cases 1, 5). All five cases occurred in association with other midline malformations: four of the five had VACTERL association and three of the five had esophageal atresia and TEF. CONCLUSION: Lung opacification, ipsilateral mediastinal shift, and an abnormal carina and anomalous vascular anatomy suggest an esophageal bronchus or an esophageal lung on CT. While esophageal bronchus is a rare cause of an opaque hemithorax, CT and upper GI imaging play key roles in its diagnosis. Associations with esophageal atresia with tracheo-esophageal fistula and VACTERL association are particularly pertinent. Early diagnosis of esophageal bronchus might prevent complications such as aspiration and infection, which can allow for parenchymal sparing surgery as opposed to pneumonectomy.

A pilot randomized controlled trial comparing bismuth iodine paraffin paste external ear pack and no ear pack after middle ear surgery.

To pilot a substantive randomized control trial comparing post-operative external ear canal pack with no ear pack after middle ear surgery, 32 adults undergoing primary posterior bony canal wall preserving middle ear surgery were randomized to have either a bismuth iodoform paraffin paste pack or no ear pack post-operatively. Outcome measures included clinician- and patient-recorded visual analogue scale scores for ear signs and symptoms at 3 weeks and 3 months and audiometric findings at 3 months post-operatively. There was no statistically significant inter-group difference in 3-week clinician and patient cumulative scores for ear signs and symptoms. There was also no significant difference in graft take rate, appearance of ear canals and audiometric results in either group at 3 months. No difference in ear symptoms, clinician findings or hearing was demonstrated between patients with a post-operative pack compared to those without a pack following middle ear surgery in this pilot study.

This infant is having a stroke: an illustrative case report.

BACKGROUND: Paediatric stroke is a rare event, and timely intervention is required to minimise long-term disability, reduced quality of life and financial implications. Although reperfusion strategies such as thrombolysis and thrombectomy are now well established in the adult population, and paediatric consensus guidelines allow for reperfusion therapies in children, access is currently limited due to diagnostic delays. This challenge is partly due to the rarity of presentation, infrastructure and public awareness to support early diagnosis as exists in the adult setting. We use an illustrative case and literature to describe an achieved case of paediatric stroke within an Irish setting. METHODS: We use the case of an 8-month-old male infant presenting with acute-onset left-sided hemiplegia to illustrate what can be achieved in an Irish setting. RESULTS: Stroke was identified quickly following presentation, timely neuroimaging and multidisciplinary involvement with disposition to paediatric intensive care unit where thrombolysis was administered. Although the patient has some speech delay, he is recovering well with normal gross motor function. CONCLUSIONS: Paediatric stroke care should be available to all children presenting with acute stroke symptoms; however, the rarity of the diagnosis would suggest a national strategy will be required to provide equitable care at a national level.

Prostate cancer knowledge in Irish men.

Men require prostate cancer (Pca) knowledge to practice health-seeking behaviours. Nine hundred seventy-nine men participated in a Pca screening programme comprising IPSS, bother score and health belief questionnaire. Men with private insurance had greater knowledge. Forty-nine percent (481) assessed their health status as average. Seventy-five percent (735) visited the GP at least once per year. The majority (576) felt well informed about health matters. Fifty-five percent (542) knew the prostate location but only 319 (33%) could identify it on a diagram. Forty-one percent (401) could not name a symptom. Few knew risk factors but 98% would attend a Pca screening clinic and sought more information. Men lack knowledge to pursue healthier behaviours and should be targeted possibly through a men's health initiative.

PHACE syndrome: MRI of intracerebral vascular anomalies and clinical findings in a series of 12 patients.

BACKGROUND: PHACE (posterior fossa defects, haemangioma, arterial anomalies, coarctation of the aorta and cardiac defects, eye abnormalities) syndrome describes a constellation of abnormalities that can occur in association with segmental craniofacial infantile haemangioma. OBJECTIVE: To report the spectrum of clinical and imaging abnormalities seen in a cohort of children. MATERIALS AND METHODS: A retrospective review of the clinical and imaging records of all patients diagnosed with PHACE syndrome between 1998 and 2009 was performed. Information sought included patient demographics, craniofacial segments involved, imaging findings and other extracutaneous abnormalities. RESULTS: Twelve patients were diagnosed with PHACE syndrome over 11 years. All patients had a segmental craniofacial haemangioma. Involved facial segments, in order of frequency, were frontotemporal (12), maxillary (8), mandibular (5) and frontonasal (1). The most common extracutaneous abnormalities were neurovascular anomalies (10), with many patients having multiple anomalies. The spectrum of arterial anomalies ranged from hypoplasia (9) to ectasia (3), anomalous origin/course (2) and persistent fetal anastomosis (2). Other anomalies found included cardiac anomalies (3), coarctation of the aorta (2), posterior fossa malformations (1) and sternal region anomalies (1). CONCLUSION: Intracranial anomalies are the most common extracutaneous feature of PHACE syndrome. The contribution of the radiologist in the recognition of such anomalies is important for the diagnosis of PHACE syndrome.

Clinical experience with the AKT1 inhibitor miransertib in two children with PIK3CA-related overgrowth syndrome.

BACKGROUND: PIK3CA-related overgrowth spectrum (PROS) refers to a group of rare disorders, caused by somatic activating mutations in PIK3CA, resulting in abnormal PI3K-AKT-mTOR pathway signalling. Significant associated morbidity is frequently observed, and approved treatments are lacking. Miransertib (ARQ 092) is a novel, orally available, selective pan-AKT inhibitor with proven in vitro efficacy. Following recent results of the use of AKT inhibitors in Proteus syndrome (PS) and AKT-mutant cancers, we investigated its therapeutic use in two patients with severe PROS who had exhausted conventional treatment methods. RESULTS: Two patients, one with CLOVES variant (P1) and one with facial infiltrating lipomatosis and hemimegalencephaly (P2), were commenced on miransertib treatment on a compassionate use basis. In patient one, intra-abdominal and paraspinal overgrowth had resulted in respiratory compromise, obstructive uropathy, dysfunctional seating and lying postures, and chronic pain. In patient two, hemifacial overgrowth and hemimegalencephaly had caused difficulties with articulation and oral function, and refractory epilepsy. Miransertib treatment was continued for a median duration of 22 months (range 22-28). In patient one, alleviation of respiratory compromise was observed and functionally, seating and lying postures improved. Serial volumetric MRI analysis revealed 15% reduction in calculated volumes of fatty overgrowth between treatment commencement and end. In patient two, reduction in seizure burden and improved parent-reported quality of life measures were reported. Treatment was discontinued in both patients due to lack of sustained response, and poor compliance in year two of treatment (P2). No significant toxicities were reported. CONCLUSION: We report the first paediatric case series of the use of miransertib in two children with PROS. Objective clinical response was observed in patient one, and improvement in key qualitative outcomes was reported in patient two. Treatment was well tolerated with no significant toxicities reported. This case series highlights the potential therapeutic utility of miransertib in selected paediatric patients with severe PROS, and further demonstrates the potential for re-purposing targeted therapies for the treatment of rare diseases. An open label, Phase 1/2 study of miransertib in children with PROS and PS is underway to more accurately assess the efficacy of miransertib in the treatment of PROS disorder (NCT03094832).

Transplantation for cholangiocarcinoma: when and for whom?

Liver transplantation for cholangiocarcinoma has historically been maligned. Because of a high recurrence rate and poor patient survival, the disease has been viewed as an absolute contraindication to transplantation. Based on good results using neoadjuvant and palliative radiation, a protocol for liver transplantation in selected patients with unresectable hilar cholangiocarcinoma was developed in 1993. Neoadjuvant radiation is followed by operative staging to rule out patients with lymph node metastases before liver transplantation. This approach has achieved results superior to standard surgical therapy, with 72% 5-year survival for patients with unresectable disease.

Symptomatic caval penetration by a Celect inferior vena cava filter.

We report a case of penetration of the inferior vena cava (IVC) by all four primary struts of a Celect caval filter in a 17-year-old girl with Klippel-Trénaunay syndrome. The girl presented with acute lower abdominal and right leg pain 17 days after filter insertion. An abdominal radiograph demonstrated that the filter had moved caudally and that the primary struts had splayed considerably since insertion. Contrast-enhanced CT confirmed that all four primary struts had penetrated the IVC wall. There was a small amount of retroperitoneal hemorrhage. The surrounding vessels and viscera were intact. The filter was subsequently retrieved without complication.

Descent of the human larynx: An unrecognized factor in airway distress in babies with cleft palate?

The intranarial epiglottis, a feature of all newborn mammals, allows suckling and breathing to continue almost simultaneously by separating an oral food stream from a nasal airstream. In contrast to other mammals, the human larynx descends in the neck between birth and six months, extending the distance between the caudal aspect of the soft palate and the cephalic tip of the epiglottis. The mechanism of airway protection changes from a pattern in which an upright epiglottis is grasped by an intact palatopharyngeal sphincter to one in which the epiglottis folds down over the laryngeal aditus and the adducted vocal folds. The comparative anatomy and anthropological literature describing laryngeal descent was reviewed. A series of MRI images were used to illustrate the normal descent of the human larynx, which take place in infants in the first six months of life. Based on this information, we hypothesize that a cleft palate, by interrupting the sphincter function of palatopharyngeus on a high neonatal epiglottis, precipitates a need for premature and rapid maturation of the neonate's airway protection pattern, particularly during feeding. This may explain why, even in the absence of Robin sequence, some babies with cleft palates suffer respiratory distress during feeding.

Raising suspicion of maltreatment from burns: Derivation and validation of the BuRN-Tool.

BACKGROUND: 10-25% of childhood burns arise from maltreatment. AIM: To derive and validate a clinical prediction tool to assist the recognition of suspected maltreatment. METHODS: Prospectively collected data from 1327 children with burns were analyzed using logistic regression. Regression coefficients for variables associated with 'referral for child maltreatment investigation' (112 cases) in multivariable analyses were converted to integers to derive the BuRN-Tool, scoring each child on a continuous scale. A cut-off score for referral was established from receiver operating curve analysis and optimal sensitivity and specificity values. We validated the BuRN-Tool on 787 prospectively collected novel cases. RESULTS: Variables associated with referral were: age <5years, known to social care, concerning explanation, full thickness burn, uncommon body location, bilateral pattern and supervision concern. We established 3 as cut-off score, resulting in a sensitivity and specificity for scalds of 87.5% (95% CI:61.7-98.4) and 81.5% (95% CI:77.1-85.4) respectively and for non-scalds sensitivity was 82.4% (95%CI:65.5-93.2) and specificity 78.7% (95% CI:73.9-82.9) when applied to validation data. Area under the curve was 0.87 (95% CI:0.83-0.90) for scalds and 0.85 (95% CI:0.81-0.88) for non-scalds. CONCLUSION: The BuRN-Tool is a potential adjunct to clinical decision-making, predicting which children warrant investigation for child maltreatment. The score is simple and easy to complete in an emergency department setting.

Impact of rural-urban status on survival after mastectomy without reconstruction versus mastectomy with reconstruction.

BACKGROUND: Disparities in access to care exist for breast cancer patients, including access to surgeons performing reconstruction. We hypothesized rural patients have delayed time to surgery after mastectomy with reconstruction with implications on survival. METHODS: An observational study was conducted using the National Cancer Database on patients with breast cancer from 2003 to 2007 who underwent mastectomy, with or without reconstruction from 2003 to 2007 (n = 90,319). RESULTS: Patients with, and without, reconstruction varied by demographics, facility type and stage. Time to surgery was longer for mastectomy with reconstruction. Unadjusted analysis demonstrated marginally decreased survival for rural patients undergoing mastectomy alone but not for mastectomy with reconstruction. Cox proportional hazards analysis revealed no significant differences by rural-urban status, but a survival advantage was seen after mastectomy with reconstruction, which persisted up to a delay of 180 days. CONCLUSION: Patients who underwent reconstruction had improved survival. Time to surgery is shorter for rural patients (for all types of mastectomy). We found no significant rural-urban disparity in survival.

Patient safety in primary care: incident reporting and significant event reviews in British general practice.

Over the past 20 years, healthcare has adapted to the 'quality revolution' by moving away from direct provision and hierarchical control mechanisms. In their place, new structures based on contractual relationships are being developed coupled with attempts to create an organisational culture that shares learning and that scrutinises existing practice so that it can be improved. The issue here is that contractual arrangements require surveillance, monitoring, regulation and governance systems that can be perceived as antipathetic to the examination of practice and subsequent learning. Historically, reporting levels from general practice have remained low; little information is shared and consequently lessons are not shared across the general practice community. Given large-scale under-engagement of general practitioners (GPs) in incident reporting systems, significant event analysis is advocated to encourage sharing of information about incidents to inform the patient safety agenda at a local and national level. Previous research has concentrated on the secondary care environment and little is known about the situation in primary care, where the majority of patient contacts with healthcare occur. To explore attitudes to incident reporting, the study adopted a qualitative approach to GPs working in a mixture of urban and rural practices reporting to a Welsh Local Health Board. The study found that GPs used significant event analysis methodology to report incidents within their practice, but acknowledged under-reporting. They were less enthusiastic about reporting externally. A number of barriers exist to reporting, including insufficient time to report, lack of feedback, fear of blame, and damage to reputations and patient confidence in a competitive environment. If incident reporting processes are perceived as supportive and formative, and where protected time is allocated to discuss incidents, then GPs are willing to participate. They also need to know how the information is used, and whether lessons are being learnt from errors.

Hepatic resection for noncolorectal, nonneuroendocrine metastases.

Resection of certain hepatic metastases of noncolorectal, nonneuroendocrine (NCNNE) origin provides actual long-term (>5 years) survival. We conducted a retrospective outcome study at a single tertiary referral institution. Between January 1988 and October 1998, 64 consecutive patients underwent resection of hepatic metastases from NCNNE primary tumors. Overall and disease-free survival rates were correlated to clinicopathologic factors and operative morbidity and mortality. Thirteen patients underwent a right hepatectomy, 6 underwent a left hepatectomy, 3 had extended right and 2 extended left hepatectomy, 2 patients had segmentectomy, 24 underwent wedge resections, and 14 underwent a combination of these forms of resection. R0 resection was achieved in 56 patients (87.5%). The operative mortality was 1.5% (1 of 64). Actual 1-, 3-, and 5-year survivals were 81%, 43%, and 30%, respectively. The factor adversely associated with overall and disease-free survival was uniformly related to the interval between primary tumor resection and the development of hepatic metastases. A 1.5% operative mortality and an actual 5-year survival of 30% justifies hepatic resection, including major hepatic resection, for certain NCNNE metastases. The factor affecting prognosis in this highly select group of patients was the biological behavior of the tumor, with tumors that metastasize earlier having poorer survival rates.

A congenital foregut malformation with a laryngeal bronchus.

We present the case of a 2-month-old boy who required intubation at birth for stridor, at which point a supraglottic cyst was noted. With recurrence of the cyst, a subsequent computed tomographic scan and magnetic resonance imaging demonstrated a mass encroaching on the larynx, descending into the mediastinum, and encasing the major vessels. A median sternotomy and transcervical incision enabled excision of a well-defined mass with a laryngeal attachment. This attachment was consistent with a bronchus on histopathologic investigation. To our knowledge, this is the first reported case of ectopic lung tissue arising from the larynx and descending into the mediastinum.

Native Nephrectomy in Renal Transplant Recipients with Autosomal Dominant Polycystic Kidney Disease.

BACKGROUND: Native nephrectomy (NNx) is often done in patients with autosomal dominant polycystic kidney disease (ADPKD). Controversy exists concerning the need and timing of nephrectomy in transplant candidates. We hypothesize that post-transplant NNx does not negatively impact patient and graft survival. METHODS: Among 470 ADPKD transplant recipients included in the study, 114 (24.3%) underwent pre- (30.7%) or post-transplant (69.3%) NNx. Clinical data was retrieved from electronic records. Follow up was until death, graft loss or June 2014. Perioperative complications were compared between the surgical techniques (open or laparoscopic) and between the pre- and post-transplant nephrectomy groups. The effect of nephrectomy on graft survival was analyzed as a time-dependent covariate when performed post-transplant. RESULTS: Mean age at transplant was 52.4 years, 53.8% were male, 93% white, 70% were from living donors and 56.8% were pre-emptive. Nephrectomy was done laparoscopically in 31% and 86% in the pre- and post- transplant nephrectomy groups, respectively. Complications were less common in those who underwent nephrectomy post-transplant (26.6% vs. 48%, p=0.03) but were similar regardless of surgical technique (open, 33.3% vs. laparoscopic 33%, p=0.66). Patient and graft survival were similar between those who underwent pre-transplant nephrectomy and the rest of the recipients. In the post-transplant nephrectomy group, nephrectomy did not affect patient (HR 0.77, CI 0.38-1.54, p=0.45) or graft survival (HR 1.0, CI 0.57-1.76, p=0.1). CONCLUSIONS: Nephrectomy does not adversely affect patient or graft survival. Post-transplant nephrectomy is feasible when indicated without compromising long term graft outcome and has fewer complications than pre-transplant nephrectomy.

Acute nephrotoxicity of tacrolimus and sirolimus in renal isografts: differential intragraft expression of transforming growth factor-beta1 and alpha-smooth muscle actin.

BACKGROUND: Renal dysfunction early after kidney transplantation has multiple causes including ischemia-reperfusion (I/R) injury and drug-induced nephrotoxicity. This study assesses the acute nephrotoxicity of tacrolimus (Tac) and sirolimus (Sir) in a rat renal isograft model. METHODS: Lewis renal isografts and uninephrectomized rats that did not undergo transplantation were treated with various doses of Tac (0.5-5.0 mg/kg/d) or Sir (0.5-6.5 mg/kg/d). Kidneys were examined on day 14 by routine histology and immunohistochemistry for transforming growth factor (TGF)-beta1 and alpha-smooth muscle actin (SMA). RESULTS: Both Tac and Sir demonstrated evidence of nephrotoxicity in the early posttransplant period including increased serum creatinine and morphologic changes in the graft including interstitial inflammation, fibrosis, and tubular vacuolization. Nephrotoxicity was most prominent in the high-dose treatment groups for both drugs and was more severe in transplanted kidneys than in uninephrectomized animals that did not undergo transplantation, suggesting an additive effect of I/R injury and drug nephrotoxicity. Both Tac and Sir increased intragraft TGF-beta1 and alpha-SMA, but there were distinct differences in the patterns of TGF-beta1 expression. Both demonstrated TGF-beta1 in tubular epithelial cells, but Sir was associated with proximal tubular TGF-beta1 localization in a bright granular pattern, whereas Tac was associated with diffuse distal tubular staining. CONCLUSIONS: Both Tac and Sir may be nephrotoxic in the early posttransplant period, especially at high doses and when combined with I/R injury. Immunohistochemical localization of TGF-beta1 in the tubular cells was distinctly different with each drug, suggesting possible differences in the mechanism(s) of nephrotoxicity requiring further study.