When Medications Backfire: A Case Report of Rifaximin-Induced Rhabdomyolysis in a Kidney Transplant Patient.

Rhabdomyolysis involves significant skeletal muscle injury and destruction, which can be triggered by trauma, intense physical activity, heat, prolonged immobility, certain medications, and endocrine disorders. Rhabdomyolysis in renal transplants can be more complicated, and the prognosis is not well known, especially in the context of coexisting rejection. We present a case of rifampicin-induced rhabdomyolysis with superimposed acute cellular rejection in a kidney transplant patient.

Evolving trends in immunosuppression use and cytomegalovirus infection risk over the past decade in kidney transplantation.

BACKGROUND: The goal was to determine trends in immunosuppression use and its impact on cytomegalovirus (CMV) outcomes over the past 10 years. METHODS: This was a single-center longitudinal cohort study of adult kidney recipients transplanted between Jan 2012 and June 2021. Baseline and follow-up data were gathered via chart abstraction and analyzed using univariate and multivariate analyses. RESULTS: Of 2392 kidney transplants conducted, 131 patients did not meet inclusion criteria. The mean age was 52 years, 41% were female, 57% were black, and 19% were CMV high-risk. The use of rabbit anti-thymocyte globulin (RATG) induction (odds ratio [OR] 1.6, 1.3-2.1), tacrolimus (FK) level >8 ng/mL (OR 1.1, 1.09-1.11), CMV D+/R- rates (OR 1.06, 1.02-1.10), white blood cell count <3000 (OR 1.22, 1.18-1.26) and valganciclovir prophylaxis (OR 1.7, 1.6-1.9) have significantly increased over the past 10 years.  Rejection rates (OR 0.86, 0.82-0.91) and BK viremia >2000 (OR 0.91, 0.91-0.98) have decreased. RATG induction (adjusted hazard ratio [aHR] 1.35, 1.2-1.5), FK >8 ng/mL (aHR 3.5, 3.2-3.9), Belatacept conversion (aHR 2.5, 2.1-3.1), and rejection (aHR 1.8, 1.6-2.0) were significant risk factors for developing CMV infection, while mycophenolate mofetil <1500 mg (aHR 0.52, 0.47-0.59), mammalian target of rapamycin inhibitor (mTORi) conversion (0.77, 0.56-0.89), cyclosporine-A conversion (aHR 0.68, 0.56-0.84) were associated with lower risk of CMV infection. CONCLUSION: Increasing use of potent immunosuppression coupled with higher CMV D+/R- F rates may be driving higher rates of CMV infection. Cyclosporine and mTORi conversion appears to be protective against CMV.  A more individualized immunosuppression regimen based on infection risk merits consideration.

Methylene Blue in Septic Shock: A Systematic Review and Meta-Analysis.

OBJECTIVES: Although clinicians may use methylene blue (MB) in refractory septic shock, the effect of MB on patient-important outcomes remains uncertain. We conducted a systematic review and meta-analysis to investigate the benefits and harms of MB administration in patients with septic shock. DATA SOURCES: We searched six databases (including PubMed, Embase, and Medline) from inception to January 10, 2024. STUDY SELECTION: We included randomized clinical trials (RCTs) of critically ill adults comparing MB with placebo or usual care without MB administration. DATA EXTRACTION: Two reviewers performed screening, full-text review, and data extraction. We pooled data using a random-effects model, assessed the risk of bias using the modified Cochrane tool, and used Grading of Recommendations Assessment, Development, and Evaluation to rate certainty of effect estimates. DATA SYNTHESIS: We included six RCTs (302 patients). Compared with placebo or no MB administration, MB may reduce short-term mortality (RR [risk ratio] 0.66 [95% CI, 0.47-0.94], low certainty) and hospital length of stay (mean difference [MD] -2.1 d [95% CI, -1.4 to -2.8], low certainty). MB may also reduce duration of vasopressors (MD -31.1 hr [95% CI, -16.5 to -45.6], low certainty), and increase mean arterial pressure at 6 hours (MD 10.2 mm Hg [95% CI, 6.1-14.2], low certainty) compared with no MB administration. The effect of MB on serum methemoglobin concentration was uncertain (MD 0.9% [95% CI, -0.2% to 2.0%], very low certainty). We did not find any differences in adverse events. CONCLUSIONS: Among critically ill adults with septic shock, based on low-certainty evidence, MB may reduce short-term mortality, duration of vasopressors, and hospital length of stay, with no evidence of increased adverse events. Rigorous randomized trials evaluating the efficacy of MB in septic shock are needed. REGISTRATION: Center for Open Science (https://osf.io/hpy4j).

COVID-19 and renal allograft rejection: insight from controlled and non-controlled studies.

AIM: Kidney transplant recipients (KTRs), due to their immunosuppressed status, are potentially more susceptible to both the severe effects of COVID-19 and complications in their transplanted organ. The aim of this study is to investigate whether COVID-19 infection increases the risk of rejection in kidney transplant recipients (KTRs). METHODS: This study involved a detailed literature review, conducted using PubMed, with the search being completed by September 7th, 2023. The search strategy incorporated a combination of relevant keywords: 'COVID', 'Renal', 'Kidney', 'Transplant', and 'Rejection'. The results from controlled and uncontrolled studies were separately collated and analyzed. RESULTS: A total of 11 studies were identified, encompassing 1,179 patients. Among these, two controlled studies reported the incidence of rejection in KTRs infected with COVID-19. Pooling data from these studies revealed no significant statistical correlation between COVID-19 infection and biopsy-proven rejection (p = 0.26). In addition, nine non-controlled studies were found, with rejection incidences ranging from 0% to 66.7%. The majority of these studies (eight out of nine) had small sample sizes, ranging from 3 to 75 KTRs, while the largest included 372 KTRs. The combined rejection rate across these studies was calculated to be 11.8%. CONCLUSION: In conclusion, the limited number of published controlled studies revealed no statistically significant association between COVID-19 infection and biopsy-proven rejection among KTRs. However, the broader analysis of non-controlled studies showed a variable rejection incidence with a pooled rejection rate of 11.8%. There is insufficient high-quality data to explore the association of COVID-19 infection and rejection.

Should Transplant Nephrology Pursue Recognition from the Accreditation Council for Graduate Medical Education (ACGME)?

Kidney transplant is not only the best treatment for patients with advanced kidney disease but it also reduces health care expenditure. The management of transplant patients is complex as they require special care by transplant nephrologists who have expertise in assessing transplant candidates, understand immunology and organ rejection, have familiarity with perioperative complications, and have the ability to manage the long-term effects of chronic immunosuppression. This skill set at the intersection of multiple disciplines necessitates additional training in Transplant Nephrology. Currently, there are more than 250,000 patients with a functioning kidney allograft and over 100,000 waitlisted patients awaiting kidney transplant, with a burgeoning number added to the kidney transplant wait list every year. In 2022, more than 40,000 patients were added to the kidney wait list and more than 25,000 received a kidney transplant. The Advancing American Kidney Health Initiative, passed in 2019, is aiming to double the number of kidney transplants by 2030 creating a need for additional transplant nephrologists to help care for them. Over the past decade, there has been a decline in the Nephrology-as well Transplant Nephrology-workforce due to a multitude of reasons. The American Society of Transplantation Kidney Pancreas Community of Practice created a workgroup to discuss the Transplant Nephrology workforce shortage. In this article, we discuss the scope of the problem and how the Accreditation Council for Graduate Medical Education recognition of Transplant Nephrology Fellowship could at least partly mitigate the Transplant Nephrology work force crisis.

Artificial intelligence and machine learning trends in kidney care.

BACKGROUND: The integration of artificial intelligence (AI) and machine learning (ML) in kidney care has seen a significant rise in recent years. This study specifically analyzed AI and ML research publications related to kidney care to identify leading authors, institutions, and countries in this area. It aimed to examine publication trends and patterns, and to explore the impact of collaborative efforts on citation metrics. METHODS: The study used the Science Citation Index Expanded (SCI-EXPANDED) of Clarivate Analytics Web of Science Core Collection to search for AI and machine learning publications related to nephrology from 1992 to 2021. The authors used quotation marks and Boolean operator "or" to search for keywords in the title, abstract, author keywords, and Keywords Plus. In addition, the 'front page' filter was applied. A total of 5425 documents were identified and analyzed. RESULTS: The results showed that articles represent 75% of the analyzed documents, with an average author to publications ratio of 7.4 and an average number of citations per publication in 2021 of 18. English articles had a higher citation rate than non-English articles. The USA dominated in all publication indicators, followed by China. Notably, the research also showed that collaborative efforts tend to result in higher citation rates. A significant portion of the publications were found in urology journals, emphasizing the broader scope of kidney care beyond traditional nephrology. CONCLUSIONS: The findings underscore the importance of AI and ML in enhancing kidney care, offering a roadmap for future research and implementation in this expanding field.

Peer-reviewed visuals and auditory - isn't it time to incorporate?

A remarkable opportunity emerges amidst the dynamic evolution of medical education, one that could fundamentally alter how healthcare professionals gain and share knowledge. The concept of incorporating a structured, peer-reviewed video and audio section, as well as a dedicated submission portal, into the medical journals symbolizes a revolutionary advance. This addition has the potential to not only improve the educational experiences of the journal's audience, but also to create a more accessible forum for the exchange of knowledge and citation. In this article, we explore the compelling potential of introducing structured videos and podcasts into the domain of medical literature, as well as the promising implications for revamping medical practitioners' learning strategies.

Renal arterial embolization: Indications, angiographic findings, and outcomes in a series of 170 patients.

Background: The lack of overall experience and reporting on angiographic findings in previously published studies of renal arterial embolization (RAE) compelled us to report our overall experience on a series of patients. Materials and methods: A retrospective study was performed analyzing data of patients enrolled for RAE between 2010 and 2019. History, physical examination, and laboratory data were reviewed for all patients. Abdominal ultrasound was the initial imaging study, and all patients underwent subsequent computed tomography or magnetic resonance imaging. The outcome of RAE was determined based on radiographic and clinical findings. Results: Data from 202 patients were analyzed, with a mean age of 45 ± 15 years, and 71.3% of patients were male. Iatrogenic injury was the most common indication for RAE (54%), followed by renal tumors, trauma, and spontaneous, in 27.7%, 10.4%, and 8.4% of patients, respectively. Renal angiography revealing pseudoaneurysm alone or with other pathology in the lower pole of the kidney was the most common finding (40.6%), whereas no lesions were identified on angiography in 32 patients (15.8%), after which RAE was subsequently aborted. Renal arterial embolization was successful in 158 of 170 patients (92.9%) after 1 or more trials (maximum of 4). Microcoil alone or with other embolic materials was the most commonly used material for embolization (85%). Conclusions: Iatrogenic injury was the most common indication for RAE. Pseudoaneurysm alone or with other lesions was the most common lesion on renal angiography; however, angiography showed a negative result in 16% of patients, even those with symptoms. When lesions are present on angiography, the overall success of repeated trials of RAE reached 92.9%.

A brain-based definition of death and criteria for its determination after arrest of circulation or neurologic function in Canada: a 2023 clinical practice guideline.

This 2023 Clinical Practice Guideline provides the biomedical definition of death based on permanent cessation of brain function that applies to all persons, as well as recommendations for death determination by circulatory criteria for potential organ donors and death determination by neurologic criteria for all mechanically ventilated patients regardless of organ donation potential. This Guideline is endorsed by the Canadian Critical Care Society, the Canadian Medical Association, the Canadian Association of Critical Care Nurses, Canadian Anesthesiologists' Society, the Canadian Neurological Sciences Federation (representing the Canadian Neurological Society, Canadian Neurosurgical Society, Canadian Society of Clinical Neurophysiologists, Canadian Association of Child Neurology, Canadian Society of Neuroradiology, and Canadian Stroke Consortium), Canadian Blood Services, the Canadian Donation and Transplantation Research Program, the Canadian Association of Emergency Physicians, the Nurse Practitioners Association of Canada, and the Canadian Cardiovascular Critical Care Society.

RéSUMé: Ces Lignes directrices de pratique clinique 2023 Lignes directrices de pratique clinique dicale du décès basée sur l'arrêt permanent de la fonction cérébrale qui s'applique à toute personne, ainsi que des recommandations pour la détermination du décès par des critères circulatoires pour des donneurs d'organes potentiels et des recommandations pour la détermination du décès par des critères neurologiques pour tous les patients sous ventilation mécanique, indépendamment de leur potentiel de donneur d'organes. Les présentes Lignes directrices sont approuvées par la Société canadienne de soins intensifs, l'Association médicale canadienne, l'Association canadienne des infirmiers/infirmières en soins intensifs, la Société canadienne des anesthésiologistes, la Fédération des sciences neurologiques du Canada (représentant la Société canadienne de neurologie, la Société canadienne de neurochirurgie, la Société canadienne de neurophysiologie clinique, l'Association canadienne de neurologie pédiatrique, la Société canadienne de neuroradiologie et le Consortium neurovasculaire canadien), la Société canadienne du sang, le Programme de recherche en don et transplantation du Canada, l'Association canadienne des médecins d'urgence, l'Association des infirmières et infirmiers praticiens du Canada, et la Société canadienne de soins intensifs cardiovasculaires (CANCARE) et la Société canadienne de pédiatrie.

Is the combination of linagliptin and allopurinol better prophylaxis against post-contrast acute kidney injury? A multicenter prospective randomized controlled study.

BACKGROUND: Patients with diabetic kidney disease (DKD) are at increased risk to develop post-contrast acute kidney injury (AKI). Diabetic patients under dipeptidyl peptidase 4 inhibitors (DPP4Is) experience a lower propensity to develop AKI. We speculated that linagliptin as a single agent or in combination with allopurinol may reduce the incidence of post-contrast AKI in stage 3-5 chronic kidney disease (CKD) patients with underlying DKD. METHODS: Out of 951 DKD patients eligible for this study, 800 accepted to sign informed consent. They were randomly allocated to 4 equal groups that received their prophylaxis for 2 days before and after radiocontrast. The first control group received N-acetyl cysteine and saline, the 2nd received allopurinol, the 3rd group received linagliptin, and the 4th received both allopurinol and linagliptin. Post-procedure follow-up for kidney functions was conducted for 2 weeks in all patients. RESULTS: 20, 19, 14, and 8 patients developed post-contrast AKI in groups 1 through 4, respectively. Neither linagliptin nor allopurinol was superior to N-acetyl cysteine and saline alone. However, the combination of the two agents provided statistically significant renal protection: post-contrast AKI in group 4 was significantly lower than in groups 1 and 2 (p < 0.02 and <0.03, respectively). None of the post-contrast AKI cases required dialysis. CONCLUSION: Linagliptin and allopurinol in combination may offer protection against post-contrast AKI in DKD exposed to radiocontrast. Further studies are needed to support this view. TRIAL REGISTRATION CLINICALTRIALS.GOV: NCT03470454.

Pneumoperitoneum and Acute Kidney Injury-An Integrative Clinical Concept Review.

An increased intraabdominal pressure, particularly when occurring during periods of hemodynamic instability or fluid overload, is regarded as a major contributor to acute kidney injury (AKI) in intensive care units. During abdominal laparoscopic procedures, intraoperative insufflation pressures up to 15 mmHg are applied, to enable visualization and surgical manipulation but with the potential to compromise net renal perfusion. Despite the widely acknowledged renal arterial autoregulation, net arterial perfusion pressure is known to be narrow, and the effective renal medullary perfusion is disproportionately impacted by venous and lymphatic congestion. At present, the potential risk factors, mitigators and risk-stratification of AKI during surgical pneumoperitoneum formation received relatively limited attention among nephrologists and represent an opportunity to look beyond mere blood pressure and intake-output balances. Careful charting and reporting duration and extent of surgical pneumoperitoneum represents an opportunity for anesthesia teams to better communicate intraoperative factors affecting renal outcomes for the postoperative clinical teams. In this current article, the authors are integrating preclinical data and clinical experience to provide a better understanding to optimize renal perfusion during surgeries. Future studies should carefully consider intrabdominal insufflation pressure as a key variable when assessing outcomes and blood pressure goals in these settings.

Mortality rate of COVID-19 infection in end stage kidney disease patients on maintenance hemodialysis: A systematic review and meta-analysis.

BACKGROUND: Coronavirus disease 2019 (COVID-19) has been the most talked-about disease of the past few years. Patients with significant comorbidities have been at particular risk of adverse outcomes. This study looked at the outcomes and risk factors for adverse outcomes among patients on chronic hemodialysis for end-stage renal disease, a group of patients known to be particularly susceptible to infectious complications. AIM: To assess outcomes and risk factors for adverse outcomes of COVID-19 infection among patients on chronic hemodialysis. METHODS: We searched PubMed/MEDLINE, EMBASE, Reference Citation Analysis (https://www.referencecitationanalysis.com/) and Web of Science databases for relevant terms and imported the results into the Covidence platform. From there, studies were assessed in two stages for relevance and quality, and data from studies that satisfied all the requirements were extracted into a spreadsheet. The data was then analyzed descriptively and statistically. RESULTS: Of the 920 studies identified through the initial database search, only 17 were included in the final analysis. The studies included in the analysis were mostly carried out during the first wave. We found that COVID-19 incidence among patients on hemodialysis was significant, over 10% in some studies. Those who developed COVID-19 infection were most likely going to be hospitalized, and over 1 in 5 died from the infection. Intensive care unit admission rate was lower than the infection lethality rate. Biochemical abnormalities and dyspnea were generally reported to be associated with adverse outcomes. CONCLUSION: This systematic review confirms that patients on chronic hemodialysis are very high-risk individuals for COVID-19 infections, and a significant proportion was infected during the first wave. Their prognosis is overall much worse than in the general population, and every effort needs to be made to decrease their exposure.

Predictors of renal angioembolization outcome: A retrospective analysis with 148 patients at a tertiary urology institute.

Objective: The aim of this study was to evaluate the predictor of unsuccessful outcome of renal angioembolization (RAE). Knowing those predictors may help in avoiding unnecessary RAE procedures and their associated side effects, while helping to prepare for an alternate procedure and improving patient's overall satisfaction. Methods: A retrospective analysis between January 2006 and December 2018 was performed, and the indications for RAE were classified into post-traumatic, iatrogenic, renal tumors, and spontaneous. Patients who underwent RAE prior to nephrectomy were eliminated. Computed tomography angiography was performed in patients with normal renal function and those who had no contrast allergy, otherwise magnetic resonance angiography was performed. For the purpose of statistical analysis, we stratified patients into two main categories based on the final outcome-successful or failed. Results: Of 180 patients, 32 with negative angiography were eliminated, leaving 148 patients; 136 (91%) had successful outcomes after one or more trials and 12 had unsuccessful outcomes. The mean age was 45±15 years, and 105 (71%) were male. Neither gender, side of the lesion, presence of hematuria, indication for RAE, nor the type of lesion affected the outcome. On the other hand, renal anatomy with presence of accessory artery was the only predictor to failed RAE (p=0.001). Failed RAE trial was a predictor for nephrectomy as a secondary procedure (p=0.03). Conclusion: No pre-procedural predictors could anticipate the RAE outcome, and different indications can be scheduled to RAE, which is equally effective. The presence of accessory renal artery on diagnostic angiography is the only factor that may predict the failure of the procedure.

Mediators of Regional Kidney Perfusion during Surgical Pneumo-Peritoneum Creation and the Risk of Acute Kidney Injury-A Review of Basic Physiology.

Acute kidney injury (AKI), especially if recurring, represents a risk factor for future chronic kidney disease. In intensive care units, increased intra-abdominal pressure is well-recognized as a significant contributor to AKI. However, the importance of transiently increased intra-abdominal pressures procedures is less commonly appreciated during laparoscopic surgery, the use of which has rapidly increased over the last few decades. Unlike the well-known autoregulation of the renal cortical circulation, medulla perfusion is modulated via partially independent regulatory mechanisms and strongly impacted by changes in venous and lymphatic pressures. In our review paper, we will provide a comprehensive overview of this evolving topic, covering a broad range from basic pathophysiology up to and including current clinical relevance and examples. Key regulators of oxidative stress such as ischemia-reperfusion injury, the activation of inflammatory response and humoral changes interacting with procedural pneumo-peritoneum formation and AKI risk will be recounted. Moreover, we present an in-depth review of the interaction of pneumo-peritoneum formation with general anesthetic agents and animal models of congestive heart failure. A better understanding of the relationship between pneumo-peritoneum formation and renal perfusion will support basic and clinical research, leading to improved clinical care and collaboration among specialists.

New onset hypertension after transplantation.

It has been reported that up to 90% of organ transplant recipients have suboptimal blood pressure control. Uncontrolled hypertension is a well-known culprit of cardiovascular and overall morbidity and mortality. In addition, rigorous control of hypertension after organ transplantation is a crucial factor in prolonging graft survival. Nevertheless, hypertension after organ transplantation encompasses a broader range of causes than those identified in non-organ transplant patients. Hence, specific management awareness of those factors is mandated. An in-depth understanding of hypertension after organ transplantation remains a debatable issue that necessitates further clarification. This article provides a comprehensive review of the prevalence, risk factors, etiology, complications, prevention, and management of hypertension after organ transplantation.

Hyperkalemia in chronic peritoneal dialysis patients.

Background. Chronic peritoneal dialysis (PD) patients often develop hypokalemia but less commonly hyperkalemia.Methods. We explored incidence and mechanisms of hyperkalemia in 779 serum samples from 33 patients on PD for 1 - 59 months. Normal serum potassium concentration was defined as 3.5 - 5.1 meq/l.Results. Mean monthly serum potassium concentrations were normal (except for 1 month), but we observed hypokalemia (<3.5 meq/l) in 5% and hyperkalemia (>5.1 meq/l) in 14% of 779 serum samples. Incidence of hyperkalemia did not change over time on PD: Year 1 (15%), Year 2 (11%), Year 3 (19%), Years 4-5 (22%). Hyperkalemia was mostly modest but occasionally extreme [5.2-5.4 meq/l (55%), 5.5-5.7 meq/l (21%), 5.8-6.0 meq/l (10%), >6.0 meq/l (14%)]. Of 31 patients (2 excluded due to brief PD time), 39% displayed hyperkalemia only, 23% displayed hypokalemia only, and the remainder (38%) displayed both or neither. Comparing hypokalemia-only with hyperkalemia-only patients, we found no difference in potassium chloride therapy, medications interrupting the renin-angiotensin system, small-molecule transport status, and renal urea clearance. We compared biochemical parameters from the hypokalemic and hyperkalemic serum samples and observed lower bicarbonate concentrations, higher creatinine concentrations, and higher urea nitrogen concentrations in the hyperkalemic samples (p < 0.001 for each), without difference in glucose concentrations.Conclusion. We observed hyperkalemia 3 times as frequently as hypokalemia in our PD population. High-potassium diet, PD noncompliance, increased muscle mass, potassium shifts, and/or the daytime period without PD might contribute to hyperkalemia.

Facteurs qui influent sur le consentement au don d'organes : étude rétrospective basée dans la population.

CONTEXTE: Améliorer l'approche des donneurs d'organes potentiels et obtenir leur consentement pourrait favoriser l'autonomie des patients et donner accès à un plus grand nombre d'organes à transplanter. Nous avons voulu identifier les facteurs modifiables qui influent sur le consentement au don d'organes. MÉTHODES: Nous avons procédé à une étude de cohorte rétrospective regroupant les adultes (≥ 18 ans) consécutivement orientés vers le système de don d'organes en Ontario entre avril 2013 et juin 2019. Nous avons analysé les données cliniques et démographiques des patients, les données relatives à leurs mandataires et les particularités des approches pour le consentement au don. Les paramètres de l'étude étaient le consentement au don d'organes et le taux d'approches. Nous avons analysé les liens indépendants entre le consentement et les facteurs propres aux approches et au système. RÉSULTATS: Nous avons identifié 34 837 signalements de donneurs d'organes potentiels, dont 6548 (18,8 %) ont fait l'objet d'approches auprès de leurs mandataires en vue d'un consentement. Parmi ces derniers, 3927 (60,0 % des approches) ont mené à un consentement au don d'organes et 1883 patients (48,0 % des consentements) ont effectivement été donneurs. La raison la plus courante pour laquelle des mandataires n'ont pas été approchés en vue du consentement à un don potentiel était un retard de signalement de la part de l'équipe soignante (45,2 %). Les facteurs modifiables indépendants associés au consentement incluaient : approche téléphonique (rapport des cotes [RC] ajusté 0,46, intervalle de confiance IC à 95 % 0,35­0,58) et approche en collaboration avec le médecin et la coordination des dons (RC ajusté 1,26, IC à 95 % 1,01­1,59). INTERPRÉTATION: Le consentement au don d'organes a été associé à plusieurs facteurs modifiables. Les organisations devraient cibler des interventions visant à assurer un signalement rapide aux organisations de don d'organes, favoriser les approches en personne et promouvoir la participation des médecins au processus d'approche.