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Heart and kidney diseases cause high morbidity and mortality. Heart and kidneys have vital functions in the human body and, interestingly, reciprocally influence each other’s behavior: pathological changes in one organ can damage the other. Cardiorenal syndrome (CRS) is a group of disorders in which there is combined dysfunction of both heart and kidney, but its underlying biological mechanisms are not fully understood. This is because complex, multifactorial, and dynamic mechanisms are likely involved. Effective treatments are currently unavailable, but this may be resolved if more was known about how the disease develops and progresses. To date, CRS has actually only been modeled in mice and rats in vivo. Even though these models can capture cardiorenal interaction, they are difficult to manipulate and control. Moreover, interspecies differences may limit extrapolation to patients. The questions we address here are what would it take to model CRS in vitro and how far are we? There are already multiple independent in vitro (human) models of heart and kidney, but none have so far captured their dynamic organ-organ crosstalk. Advanced in vitro human models can provide an insight in disease mechanisms and offer a platform for therapy development. CRS represents an exemplary disease illustrating the need to develop more complex models to study organ-organ interaction in-a-dish. Human induced pluripotent stem cells in combination with microfluidic chips are one powerful tool with potential to recapitulate the characteristics of CRS in vitro. In this review, we provide an overview of the existing in vivo and in vitro models to study CRS, their limitations and new perspectives on how heart-kidney physiological and pathological interaction could be investigated in vitro for future applications.

Cardiotoxicity is an unexpected side effect of drugs and a major cause of drug failure in preclinical and clinical phases of drug discovery. Some drugs bind to the cardiac hERG ion channel and cause a prolongation of the heart QT interval, inducing arrhythmias that can eventually lead to sudden cardiac death. Notably, individuals with inherited long QT syndrome (LQTS) are more prone to develop drug-induced arrhythmia. We previously showed that the LUF7346 allosteric modulator can shorten the QT interval in vitro in LQTS human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CM). Our aim is to establish a drug-screening platform based on healthy and diseased hiPSC-CM to i) identify molecules with hERG allosteric modulator activity and ii) assess drug pro- and anti- arrhythmic effects. We used two isogenic hiPSC lines: one representing a severe form of LQTS, called Jervell and Lange-Nielsen syndrome (JLNS), carrying a homozygous mutation in the cardiac ion channel KCNQ1 gene, and its isogenic wild-type line, that we generated with CRISPR/Cas9 technology. Both lines were differentiated into cardiomyocytes and their electrophysiological properties were evaluated by multi-electrode array (MEA) recording of spontaneous beating activity and by patch clamp. JLNS hiPSC- CM action potential (AP) duration was prolonged compared to the isogenic wild type line. We then optimized seeding and recording conditions in 96-well MEA plates. Finally, we used a novel integrated system based on fluorescent dyes to simultaneously measure AP, calcium transient, and contraction upon application of the reference compound LUF7346. This platform can identify active molecules able to shorten AP. Our approach will provide evidence for the value of using hiPSC-CM in preclinical drug testing.

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BACKGROUND The number of elderly patients undergoing major surgical interventions and then needing admission to intensive care unit (ICU) grows steadily. We investigated this issue in a cohort of 232,278 patients admitted in five years (2011-2015) to 163 Italian general ICUs. METHODS Surgical patients older than 75 registered in the GiViTI MargheritaPROSAFE project were analyzed. The impact on hospital mortality of important chronic conditions (severe COPD, NYHA class IV, dementia, end-stage renal disease, cirrhosis with portal hypertension) was investigated with two prognostic models developed yearly on patients staying in the ICU less or more than 24 hours. RESULTS 44,551 elderly patients (19.2%) underwent emergency (47.3%) or elective surgery (52.7%). At least one severe comorbidity was present in 14.6% of them, yielding a higher hospital mortality (32.4%, vs. 21.1% without severe comorbidity). In the models for patients staying in the ICU 24 hours or more, cirrhosis, NYHA class IV, and severe COPD were constant independent predictors of death (adjusted odds ratios [ORs] range 1.67-1.97, 1.54-1.91, and 1.34-1.50, respectively), while dementia was statistically significant in four out of five models (adjusted ORs 1.23-1.28). End-stage renal disease, instead, never resulted to be an independent prognostic factor. For patients staying in the ICU less than 24 hours, chronic comorbidities were only occasionally independent predictors of death. CONCLUSIONS Our study confirms that elderly surgical patients represent a relevant part of all ICUs admissions. About one of seven bear at least one severe chronic comorbidity, that, excluding end-stage renal disease, are all strong independent predictors of hospital death.

OBJECTIVEdTo describe trends of primary efficacy and safety outcomes of islet transplantationin type 1 diabetes recipients with severe hypoglycemia from the Collaborative Islet TransplantRegistry (CITR) from 1999 to 2010.RESEARCH DESIGN AND METHODSdA total of 677 islet transplant-alone or isletafter-kidney recipients with type 1 diabetes in the CITR were analyzed for five primary efficacyoutcomes and overall safety to identify any differences by early (1999–2002), mid (2003–2006),or recent (2007–2010) transplant era based on annual follow-up to 5 years.RESULTSdInsulin independence at 3 years after transplant improved from 27% in the early era(1999–2002, n = 214) to 37% in the mid (2003–2006, n = 255) and to 44% in the most recent era(2007–2010, n = 208; P = 0.006 for years-by-era; P = 0.01 for era alone). C-peptide $0.3 ng/mL,indicative of islet graft function,was retained longer in themost recent era (P,0.001). Reduction ofHbA1c and resolution of severe hypoglycemia exhibited enduring long-term effects. Fasting bloodglucose stabilization also showed improvements in the most recent era. There were also modestreductions in the occurrence of adverse events. The islet reinfusion rate was lower: 48% by 1 yearin 2007–2010 vs. 60–65% in 1999–2006 (P , 0.01). Recipients that ever achieved insulinindependenceexperienced longer duration of islet graft function (P , 0.001).CONCLUSIONSdThe CITR shows improvement in primary efficacy and safety outcomes ofislet transplantation in recipients who received transplants in 2007–2010 compared with thosein 1999–2006, with fewer islet infusions and adverse events per recipient.

Patient-specific induced pluripotent stem cells (iPSCs) will assist research on genetic cardiac maladies if the disease phenotype is recapitulated in vitro. However, genetic background variations may confound disease traits, especially for disorders with incomplete penetrance, such as long-QT syndromes (LQTS). To study the LQT2-associated c.A2987T (N996I) KCNH2 mutation under genetically defined conditions, we derived iPSCs from a patient carrying this mutation and corrected it. Furthermore, we introduced the same point mutation in human embryonic stem cells (hESCs), generating two genetically distinct isogenic pairs of LQTS and control lines. Correction of the mutation normalized the current (IKr) conducted by the HERG channel and the action potential (AP) duration in iPSC-derived cardiomyocytes (CMs). Introduction of the same mutation reduced IKr and prolonged the AP duration in hESC-derived CMs. Further characterization of N996I-HERG pathogenesis revealed a trafficking defect. Our results demonstrated that the c.A2987T KCNH2 mutation is the primary cause of the LQTS phenotype. Precise genetic modification of pluripotent stem cells provided a physiologically and functionally relevant human cellular context to reveal the pathogenic mechanism underlying this specific disease phenotype., Isogenic human pluripotent stem cell pairs reveal the role of a KCNH2 mutation in long-QT syndrome Isogenic pairs of patient-derived iPS- and ES-cell lines reveal the molecular problems contributing to cardiac arrest in long-QT syndrome.

Myocardial infarction (MI) is the single most critical event in coronary disease. Whole blood transcription profiles from patients affected by their very first acute MI (FAMI) revealed quantitative differences from normal controls, showing inflammation signals. Platelets from the same patients were also profiled, showing a massive transcripts down-regulation. Conversely, platelet proteome showed a great up-regulation; of note, we identified four over-expressed proteins, whose matched mRNAs were instead down-regulated. The considerable down-regulation observed in platelets may suggest pre-activation of megakarycytes and/or platelets in FAMI patients before the acute event.