Institutional Affiliations Chair Costanzo MR: Midwest Heart Foundation, Lombard Illinois, USA Task Force 1 Dipchand A: Hospital for Sick Children, Toronto Ontario, Canada; Starling R: Cleveland Clinic Foundation, Cleveland, Ohio, USA; Anderson A: University of Chicago, Chicago, Illinois, USA; Chan M: University of Alberta, Edmonton, Alberta, Canada; Desai S: Inova Fairfax Hospital, Fairfax, Virginia, USA; Fedson S: University of Chicago, Chicago, Illinois, USA; Fisher P: Ochsner Clinic, New Orleans, Louisiana, USA; Gonzales-Stawinski G: Cleveland Clinic Foundation, Cleveland, Ohio, USA; Martinelli L: Ospedale Niguarda, Milano, Italy; McGiffin D: University of Alabama, Birmingham, Alabama, USA; Parisi F: Ospedale Pediatrico Bambino Gesu, Rome, Italy; Smith J: Freeman Hospital, Newcastle upon Tyne, UK Task Force 2 Taylor D: Cleveland Clinic Foundation, Cleveland, Ohio, USA; Meiser B: University of Munich/Grosshaden, Munich, Germany; Baran D: Newark Beth Israel Medical Center, Newark, New Jersey, USA; Carboni M: Duke University Medical Center, Durham, North Carolina, USA; Dengler T: University of Hidelberg, Heidelberg, Germany; Feldman D: Minneapolis Heart Institute, Minneapolis, Minnesota, USA; Frigerio M: Ospedale Niguarda, Milano, Italy; Kfoury A: Intermountain Medical Center, Murray, Utah, USA; Kim D: University of Alberta, Edmonton, Alberta, Canada; Kobashigawa J: Cedar-Sinai Heart Institute, Los Angeles, California, USA; Shullo M: University of Pittsburgh, Pittsburgh, Pennsylvania, USA; Stehlik J: University of Utah, Salt Lake City, Utah, USA; Teuteberg J: University of Pittsburgh, Pittsburgh, Pennsylvania, USA; Uber P: University of Maryland, Baltimore, Maryland, USA; Zuckermann A: University of Vienna, Vienna, Austria. Task Force 3 Hunt S: Stanford University, Palo Alto, California, USA; Burch M: Great Ormond Street Hospital, London, UK; Bhat G: Advocate Christ Medical Center, Oak Lawn, Illinois, USA; Canter C: St. Louis Children Hospital, St. Louis, Missouri, USA; Chinnock R: Loma Linda University Children's Hospital, Loma Linda, California, USA; Crespo-Leiro M: Hospital Universitario A Coruna, La Coruna, Spain; Delgado R: Texas Heart Institute, Houston, Texas, USA; Dobbels F: Katholieke Universiteit Leuven, Leuven, Belgium; Grady K: Northwestern University, Chicago, Illlinois, USA; Kao W: University of Wisconsin, Madison Wisconsin, USA; Lamour J: Montefiore Medical Center, New York, New York, USA; Parry G: Freeman Hospital, Newcastle upon Tyne, UK; Patel J: Cedar-Sinai Heart Institute, Los Angeles, California, USA; Pini D: Istituto Clinico Humanitas, Rozzano, Italy; Pinney S: Mount Sinai Medical Center, New York, New York, USA; Towbin J: Cincinnati Children's Hospital, Cincinnati, Ohio, USA; Wolfel G: University of Colorado, Denver, Colorado, USA Independent Reviewers Delgado D: University of Toronto, Toronto, Ontario, Canada; Eisen H: Drexler University College of Medicine, Philadelphia, Pennsylvania, USA; Goldberg L: University of Pennsylvania, Philadelphia, Pennsylvania, USA; Hosenpud J: Mayo Clinic, Jacksonville, Florida, USA; Johnson M: University of Wisconsin, Madison, Wisconsin, USA; Keogh A: St Vincent Hospital, Sidney, New South Wales, Australia; Lewis C: Papworth Hospital Cambridge, UK; O'Connell J: St. Joseph Hospital, Atlanta, Georgia, USA; Rogers J: Duke University Medical Center, Durham, North Carolina, USA; Ross H: University of Toronto, Toronto, Ontario, Canada; Russell S: Johns Hopkins Hospital, Baltimore, Maryland, USA; Vanhaecke J: University Hospital Gasthuisberg, Leuven, Belgium.

http://www.jsht.jp/uploads/ISHLT_GL_TaskForce2_110810.pdf

The International Society of Heart and Lung Transplantation Guidelines for the care of heart transplant recipients

The use of the calcineurin inhibitors cyclosporine and tacrolimus led to major advances in the field of transplantation, with excellent short-term outcome. However, the chronic nephrotoxicity of these drugs is the Achilles' heel of current immunosuppressive regimens. In this review, the authors summarize the clinical features and histologic appearance of both acute and chronic calcineurin inhibitor nephrotoxicity in renal and nonrenal transplantation, together with the pitfalls in its diagnosis. The authors also review the available literature on the physiologic and molecular mechanisms underlying acute and chronic calcineurin inhibitor nephrotoxicity, and demonstrate that its development is related to both reversible alterations and irreversible damage to all compartments of the kidneys, including glomeruli, arterioles, and tubulo-interstitium. The main question--whether nephrotoxicity is secondary to the actions of cyclosporine and tacrolimus on the calcineurin-NFAT pathway--remains largely unanswered. The authors critically review the current evidence relating systemic blood levels of cyclosporine and tacrolimus to calcineurin inhibitor nephrotoxicity, and summarize the data suggesting that local exposure to cyclosporine or tacrolimus could be more important than systemic exposure. Finally, other local susceptibility factors for calcineurin inhibitor nephrotoxicity are reviewed, including variability in P-glycoprotein and CYP3A4/5 expression or activity, older kidney age, salt depletion, the use of nonsteroidal anti-inflammatory drugs, and genetic polymorphisms in genes like TGF-beta and ACE. Better insight into the mechanisms underlying calcineurin inhibitor nephrotoxicity might pave the way toward more targeted therapy or prevention of calcineurin inhibitor nephrotoxicity.

Calcineurin Inhibitor Nephrotoxicity

Renal transplant recipients have increased mortality rates when compared with the general population. The new immunosuppressive drugs have improved short-term patient survival up to 95% at 1–2 years, but these data have to be confirmed in long-term follow-up. Furthermore, no particular regimen has proved to be superior over others with regard to patient survival.

Immunosuppressive drugs in kidney transplantation: impact on patient survival, and incidence of cardiovascular disease, malignancy and infection.

EASL Clinical Practice Guidelines: Liver transplantation

Cardiorenal syndrome encompasses a spectrum of disorders involving both the heart and kidneys in which acute or chronic dysfunction in 1 organ may induce acute or chronic dysfunction in the other organ. It represents the confluence of heart-kidney interactions across several interfaces. These include the hemodynamic cross-talk between the failing heart and the response of the kidneys and vice versa, as well as alterations in neurohormonal markers and inflammatory molecular signatures characteristic of its clinical phenotypes. The mission of this scientific statement is to describe the epidemiology and pathogenesis of cardiorenal syndrome in the context of the continuously evolving nature of its clinicopathological description over the past decade. It also describes diagnostic and therapeutic strategies applicable to cardiorenal syndrome, summarizes cardiac-kidney interactions in special populations such as patients with diabetes mellitus and kidney transplant recipients, and emphasizes the role of palliative care in patients with cardiorenal syndrome. Finally, it outlines the need for a cardiorenal education track that will guide future cardiorenal trials and integrate the clinical and research needs of this important field in the future.

https://www.ahajournals.org/doi/pdf/10.1161/CIR.0000000000000664

Cardiorenal Syndrome: Classification, Pathophysiology, Diagnosis, and Treatment Strategies: A Scientific Statement From the American Heart Association.

With the increasing use of mycophenolic acid (MPA) in solid organ transplantation, the need for more accurate drug dosing has become evident. Personalized immunosuppressive therapy requires better strategies for avoidance of drug-related toxicity while maintaining efficacy. Few studies have assessed the clinical usefulness of therapeutic drug monitoring (TDM) of MPA in solid organ transplantation in a prospective way, and they have produced opposing results. To provide clinicians with an objective and balanced clinical interpretation of the current scientific evidence on TDM of MPA, a consensus meeting involving 47 experts from around the world was commissioned by The Transplantation Society and held in Rome on November 20 to 21, 2008. The goal of this consensus meeting was to offer information to transplant practitioners on clinically relevant pharmacokinetic characteristics of MPA, to rationalize the basis for currently advised target exposure ranges for MPA in various types of organ transplantation, and to summarize available methods for application of MPA TDM in clinical practice. Although this consensus report does not evaluate the final role of MPA TDM in transplantation, it seeks to examine the current scientific evidence for concentration-controlled dosing of MPA.

Consensus report on therapeutic drug monitoring of mycophenolic acid in solid organ transplantation.

The calcineurin inhibitors (CNI) cyclosporine and tacrolimus remain the backbone of immunosuppression for most kidney transplant recipients. Despite many years of experience, protocols that optimize efficacy with minimal toxicity remain a subject of debate. Nevertheless, studies of the pharmacokinetic properties of the CNI, particularly cyclosporine, have led to improved dosing strategies. The purpose of this article is to review the current understanding of CNI pharmacokinetics and its relevance to proper dosing and monitoring of these medications. This article also reviews the trials that have helped to define the optimal dosages and discusses the effect of adjunctive immunosuppressive agents on CNI pharmacokinetics and dosing.

/pdf/therapeutic-monitoring-of-calcineurin-inhibitors-for-the-1svvyc4s3l.pdf

Therapeutic Monitoring of Calcineurin Inhibitors for the Nephrologist

To assess the safety profile of Neoral dose adjustment using cyclosporine (CsA) trough levels (C0) compared with levels obtained 2 h after the morning dose (C2), 30 stable adult heart transplant patients 1 yr or more after surgery were converted from Sandimmune to Neoral. After a baseline visit (before conversion), initial follow-up included two visits (2 and 4-6 wk after conversion). After the first visit, patients were randomized to Group I (C0: 100-200 ng/ml) or Group II (C2: 200-400 ng/ml). Abbreviated pharmacokinetics were obtained for the estimation of the AUC0-4 h. Renal function was assessed by serum creatinine and the cimetidine-modified creatinine clearance. C2 correlated better than C0 with the AUC0-4 h (r = 0.91 vs. 0.63). Initial Neoral dose (mg/kg/d) was similar in both groups (2.8 +/- 0.5 and 2.8 +/- 0.8), and was lower in Group II at the second visit (2.0 +/- 0.7 vs. 3.0 +/- 0.6, p = 0.0001). C2 levels decreased in Group II from 912 +/- 438 to 555 +/- 271 ng/ml (p = 0.01), without evidence of acute rejection on endomyocardial biopsies. After the second visit,-both groups were monitored with C2, and the range was increased to 300-600 ng/ml. At the last visit (additional follow-up of 5 +/- 1 months), Neoral dose (mg/kg/d) was reduced to 2.0 +/- 0.3 in Group I (p < 0.001) and 1.8 +/- 0.4 in Group II. Serum creatinine was lower in Group II at the second visit (138 +/- 59 vs. 168 +/- 37 mumol/L, p = 0.01) and was similar in both groups at the last visit. Neoral dose reduction based on C2 levels was not associated with acute rejection. The better correlation with the AUC0-4 h suggests that C2 may be more reliable than C0 for Neoral dose adjustment.

Two-hour cyclosporine level determination is the appropriate tool to monitor Neoral therapy.

To assess the safety profile of Neoral dose adjustment using cyclosporine (CsA) trough levels (C 0 ) compared with levels obtained 2 h after the morning dose (C 2 ), 30 stable adult heart transplant patients 1 yr or more after surgery were converted from Sandimmune to Neoral. After a baseline visit (before conversion), initial follow-up included two visits (2 and 4-6 wk after conversion). After the first visit, patients were randomized to Group I (C 0 : 100-200 ng/ml) or Group II (C 2 : 200-400 ng/ml). Abbreviated pharmacokinetics were obtained for the estimation of the AUC 0-4 h . Renal function was assessed by serum creatinine and the cimetidine-modified creatinine clearance. C 2 correlated better than C 0 with the AUC 0-4 h (r = 0.91 vs. 0.63). Initial Neoral dose (mg/kg/d) was similar in both groups (2.8 ± 0.5 and 2.8 ± 0.8), and was lower in Group II at the second visit (2.0 ± 0.7 vs. 3.0 ± 0.6, p = 0.0001). C 2 levels decreased in Group II from 912 ± 438 to 555 ± 271 ng/ml (p = 0.01), without evidence of acute rejection on endomyocardial biopsies. After the second visit, both groups were monitored with C 2 , and the range was increased to 300-600 ng/ml. At the last visit (additional follow-up of 5 ± 1 months), Neoral dose (mg/ kg/d) was reduced to 2.0 ± 0.3 in Group I (p < 0.001) and 1.8 ± 0.4 in Group II. Serum creatinine was lower in Group II at the second visit (138 ± 59 vs. 168 ± 37 μmol/L, p = 0.001) and was similar in both groups at the last visit. Neoral dose reduction based on C 2 levels was not associated with acute rejection. The better correlation with the AUC( 0-4 h suggests that C 2 may be more reliable than C 0 for Neoral dose adjustment.

Two-hour cyclosporine level determination is the appropriate tool to monitor Neoral therapy

Background. Based on the excellent correlation between cyclosporine A 2-hr postdose blood levels (C 2 ) and the area under the concentration versus time curve, we evaluated the clinical benefit of Neoral dose monitoring with C 2 compared trough levels (C 0 ) in stable heart transplant patients. Methods. We studied 114 stable adult patients followed at the heart transplant clinic, who were >1 year after surgery. In May 1996 (period 1, follow-up 10±4 months), Neoral dose monitoring was based on C 2 (300-600 ng/ml); while in May 1997 (period 2, follow-up 10±2 months), it was based on C 0 (100-200 ng/ml). Cyclosporine A levels were measured by an enzyme multiplied immunologic technique. Clinical benefit was defined by the absence of acute rejection, no mortality, no fall in left ventricular ejection fraction >10%, and no increase in serum creatinine >10% (compared with baseline). Results. During period 1, Neoral dose, cyclosporine A, C 0 and C 2 , and serum creatinine, decreased by 26, 56, 45, and 2.3%, respectively. At the end of period 2, the same variables increased by 24, 56, 38, and 10%, respectively (P<0.0001). The incidence of acute rejection was similar (period 1: 0.87%, period 2: 0.96%). The left ventricular ejection fraction (initial/final) remained stable (period 1: 57±9%/58±13%, period 2: 59±11%/58±10%). Mortality did not differ (period 1: 7.9%, period 2: 9.6%). A clinical benefit was observed in 69.3% of the patients during period 1 vs. 43.3% of the patients during period 2 (P<0.00001). Conclusions. In stable heart transplant patients, a greater clinical benefit was observed when Neoral dose monitoring was performed according to C 2 , compared with C 0 .

Marcelo Cantarovich

Papers

Consensus report on therapeutic drug monitoring of mycophenolic acid in solid organ transplantation.

Therapeutic Monitoring of Calcineurin Inhibitors for the Nephrologist

Two-hour cyclosporine level determination is the appropriate tool to monitor Neoral therapy.

Two-hour cyclosporine level determination is the appropriate tool to monitor Neoral therapy

Clinical benefit of neoral dose monitoring with cyclosporine 2-hr post-dose levels compared with trough levels in stable heart transplant patients.