Solid Organ Failure Research Articles

Mammalian organ regeneration in spiny mice.

Fibrosis-driven solid organ failure is a major world-wide health burden with few therapeutic options. Spiny mice (genus: Acomys) are terrestrial mammals that regenerate severe skin wounds without fibrotic scars to evade predators. Recent studies have shown that spiny mice also regenerate acute ischemic and traumatic injuries to kidney, heart, spinal cord, and skeletal muscle. A common feature of this evolved wound healing response is a lack of formation of fibrotic scar tissue that degrades organ function, inhibits regeneration, and leads to organ failure. Complex tissue regeneration is an extremely rare property among mammalian species. In this article, we discuss the evidence that Acomys represents an emerging model organism that offers a unique opportunity for the biomedical community to investigate and clinically translate molecular mechanisms of scarless wound healing and regeneration of organ function in a mammalian species.

Spiny mice activate unique transcriptional programs after severe kidney injury regenerating organ function without fibrosis

SummaryFibrosis-driven solid organ failure is an enormous burden on global health. Spiny mice (Acomys) are terrestrial mammals that can regenerate severe skin wounds without scars to avoid predation. Whether spiny mice also regenerate internal organ injuries is unknown. Here, we show that despite equivalent acute obstructive or ischemic kidney injury, spiny mice fully regenerate nephron structure and organ function without fibrosis, whereas C57Bl/6 or CD1 mice progress to complete organ failure with extensive renal fibrosis. Two mechanisms for vertebrate regeneration have been proposed that emphasize either extrinsic (pro-regenerative macrophages) or intrinsic (surviving cells of the organ itself) controls. Comparative transcriptome analysis revealed that the Acomys genome appears poised at the time of injury to initiate regeneration by surviving kidney cells, whereas macrophage accumulation was not detected until about day 7. Thus, we provide evidence for rapid activation of a gene expression signature for regenerative wound healing in the spiny mouse kidney.

Promoting cardiovascular health post-transplant through early diagnosis and adequate management of hypertension and dyslipidemia.

Despite correction of underlying solid organ failure by transplantation, pediatric transplant recipients still have increased mortality rates compared to the general pediatric population, in part due to increased cardiovascular risk. In particular, pediatric kidney and non-kidney transplant recipients with chronic kidney disease have significant cardiovascular risk that worsens with declining kidney function. Biomarkers associated with future cardiovascular risk such as casual and ambulatory hypertension, dyslipidemia, vascular stiffness and calcification, and left ventricular hypertrophy can be detected throughout the post-transplant period and in patients with stable kidney function. Among these, hypertension and dyslipidemia are two potentially modifiable cardiovascular risk factors that are highly prevalent in kidney and non-kidney pediatric transplant recipients. Standardized approaches to appropriate BP measurement and lipid monitoring are needed to detect and address these risk factors in a timely fashion. To achieve sustained improvement in cardiovascular health, clinicians should partner with patients and their caregivers to address these and other risk factors with a combined approach that integrates pharmacologic with non-pharmacologic approaches. This review outlines the scope and impact of hypertension and dyslipidemia in pediatric transplant recipients, with a particular focus on pediatric kidney transplantation given the high burden of chronic kidney disease-associated cardiovascular risk. We also review the current published guidelines for monitoring and managing abnormalities in blood pressure and lipids, highlighting the important role of therapeutic lifestyle changes in concert with antihypertensive and lipid-lowering medications.

6. Organ & tissue preservation as a transformative platform technology

The ability to preserve organs and tissues outside of the body for periods exceeding even a few hours is a longstanding medical goal that if achieved could eliminate death resulting from solid organ failure and disability from trauma, burns, and amputation. In the last 50 years only incremental progress has been made in this area, largely due to public and private underinvestment and a fragmented scientific effort with few interdisciplinary synergies or collaborative efforts. However, there is growing evidence of rapid technological convergence that hints at a revolution in this field. Previously inaccessible approaches to slow down or stop biological time are now being enabled by this rapid convergence. Concrete examples of this can be found in the enabling work of fields not normally associated with cryobiology. High performance computing, thermo-mechanical modeling of biological systems, high-throughput cryo-protectant screening, and micro-physiological platforms (organ-on-a-chip systems), are all starting play a role in answering key questions about how to protect biological systems in sub-normo-thermic regimes, and indeed even at the sub-zero temperatures that would permit longer preservation on the order of days to years. A true organ and tissue banking capability would transform medicine as we know it. Even if this were as modest as extending the time that an organ or tissue could be preserved to 48 h instead of the current 2–8 h as it is for some solid organs, it would enable a whole host of curative therapies that are currently off limits. One can envision the impact this would have: organ waiting lists could disappear; HLA matching/could be ideal the majority of the time instead of just a fraction of the time, thus doubling 5-year survival rates; survival rates for non-metastatic cancers of a vital organ (such as liver or lung) would immediately spike to above 90% due to routine organ replacement; the entire field of tissue engineering would be able to give their products a shelf-life thus unleashing the true potential of engineered tissues and creating new markets. The impact would be immediate and transformational. Induction of immune tolerance for allogeneic tissues is an emerging area of transplant medicine that seeks to overcome immune rejection. Tolerance induction is a factor in all donated tissues and will become an important consideration for any engineered tissues. The key factor for inducing immune tolerance is time. Whether through hematopoietic chimerism, or intrathymic transplant, the body requires 2–3 weeks to adapt to the allogeneic environment, during which time the donor organ must be preserved in waiting until tolerance is fully induced and the transplant can proceed. In cases of trauma, the ability to preserve tissue and severed limbs until advanced surgery is possible would mean far fewer amputations and vastly superior outcomes following reconstruction. This has tremendous implications for military trauma treatment. In practice many traumatic injuries that result in limb severance could be corrected surgically with good outcomes; however, the expertise to perform these procedures is usually more than 48 h away from the point of injury on the battlefield. The DoD’s Tissue Injury and Regenerative Medicine Program Office which oversees the Armed Forces Institute of Regenerative Medicine (AFIRM) also oversees the DoD’s arm and face transplant programs. Together these constitute close to $1B in federal investment. The entirety of this portfolio would benefit from the emergence of an organ and tissue banking capability.

Regulated cell death and inflammation: an auto-amplification loop causes organ failure.

Regulated cell death (RCD) is either immunologically silent or immunogenic. RCD in parenchymal cells may lead to the release of damage- associated molecular patterns that drive both tissue inflammation and the activation of further pathways of RCD. Following an initial event of regulated necrosis, RCD and inflammation can induce each other and drive a local auto-amplification loop that leads to exaggerated cell death and inflammation. In this Opinion article, we propose that such crosstalk between pro-inflammatory and RCD pathways has pathophysiological relevance in solid organ failure, transplantation and cancer. In our opinion, clinicians should not only prescribe immunosuppressive treatments to disrupt this circuit, but also implement the neglected therapeutic option of adding compounds that interfere with RCD.

Allogeneic Hematopoietic Stem Cell Transplantation Is Feasible After Solid Organ Transplantation: A Retrospective Analysis By The Early Complications Subcommittee Of The Complications and Quality Of Life Working Party, EBMT

The recipients of solid organ transplants are infrequent candidates for allogeneic hematopoietic stem cell transplantation (alloHSCT). However, such situations occur more frequently with increasing number of solid organ transplantation (SOT) survivors who may suffer from hematopoietic disorders. AlloHSCT may cause immune reactions towards transplanted organ leading to its failure. Since the reported clinical experiences have been anecdotal, outcomes of alloHSCT after SOT are not well known. In order to document the feasibility of alloHSCT after SOT, we decided to perform a retrospective analysis of patients reported to the EBMT registry.The only inclusion criterion was alloHSCT performed after SOT. An invitation to participate was sent to all EBMT transplant centers (N=565). In 18/101 centers which responded to the survey, we identified 28 patients who fulfilled the criterion. This group included 12 patients with kidney (1 case with subsequent pancreatic transplantation), 13 with liver and 3 with heart transplant. The reason for heart transplantation was insufficiency due to multiple myocardial infarctions, anthracyclin-associated myocarditis or dilated cardiomyopathy. Liver transplantations were performed for hepatocellular cancer (N=4), cirrhosis without cancer (N=4), sclerosing cholangitis (N=1), acute liver failure after chemotherapy (N=1) or idiopathic liver failure (N=3). The cause of kidney transplantation was pyelonephritis (N=3), glomerulonephritis (N=2), polycystic disease (N=1), tubulointerstitial nephropathy (N=1), diabetic nephropathy (N=1) or idiopathic kidney failure (N=4). The indications for alloSCT were: acute leukemia (N=10), chronic leukemia (N=4), lymphoma (N=3), myelodysplastic/myeloproliferative disease (N=4), bone marrow failure (N=4) and inherited disorders (N=2). The median time from SOT to hematologic diagnosis was 23 months (range, -206 to 294), in 8 patients the diagnosis was known before SOT. Twenty eight SOT recipients underwent 31 alloHSCT (3 patients underwent double alloHSCT after SOT), while in 2/28 alloHSCT was preceded by autoSCT. The median year of alloSCT was 2006 (range, 1990-2012) and the median time between SOT and alloHSCT was 35 months (range, 1-315). The conditioning was standard (N=16) or reduced (N=14) and included TBI in 12 cases, but the regimens were heterogeneous. The HSCT was performed with either peripheral blood stem cells (N=20), bone marrow (N=9) or both (N=1) obtained from HLA-identical sibling (N=12), matched (N=11) and mismatched (N=3) unrelated or haploidentical (N=5) donors. T cell depletion was performed in 20/29 cases (in vivo N=15, ex vivo N=2, in vivo and ex vivo N=3). The most common GvHD /SOT rejection prophylaxis was cyclosporine A and methotrexate (N=12) followed by cyclosporine A and mycophenolate (N=5), tacrolimus and mycophenolate (N=5) and tacrolimus with methotrexate (N=1), but frequently included also other immunosuppressive drugs, especially steroids.Hematopoietic engraftment was achieved after 25/30 transplantations including 2 cases where the graft was lost. In evaluable patients, time to neutrophil recovery (>0.5 G/L) was 13.5 days (9-37, N=22), in 3 patients the platelet count never fell below 20 G/L and the rest recovered after median of 17 days (range, 10-103). Acute GvHD was observed in 17/31 cases including 10 with grade II-IV disease. Terminal solid organ transplant failure was observed in 10 of 30 alloHSCTs (1/3 heart, 3/13 liver and 6/11 kidney transplants) after median of 6 weeks (range, 0-569) after HSCT (8/10 in early post-HSCT period). Six of 10 failure cases have been described as SOT rejections (4 kidneys, 1 liver, 1 heart). After median of 14 months from alloHSCT (range, 0,3-244) 13/28 patients were alive (46%, 8/13 patients after liver, 5/12 after kidney and none after heart transplantation). The estimated probability of survival after HSCT was 75% at 3 months, 60% at 12, 45% at 36, and 40% at 60 months. In one third of patients (5/15), death was directly related to transplanted solid organ failure.In summary, a significant proportion of patients enjoy long term survival without graft loss, especially after liver transplantation. Therefore our results suggest that alloHSCT is a feasible treatment option for patients after SOT. However, the risk of transplanted solid organ failure is high, including the possibility of solid organ rejection.▪ Disclosures:No relevant conflicts of interest to declare.

Human immunodeficiency virus infection and kidney disease

Since the introduction of highly active antiretroviral therapy (HAART) in 1996, mortality in patients with human immunodeficiency virus (HIV) infection has decreased markedly. As a result, morbidity from other chronic conditions such as kidney, liver and heart disease is increasing. This is in part as a natural consequence of ageing, and in part due to the higher risk of solid organ failure in these individuals. This higher risk is related to the co-morbidities associated with HIV infection and to the metabolic consequences of drug therapy. Kidney disease is an important cause of morbidity and mortality in patients with HIV infection and encompasses a range of clinical presentations including acute kidney injury, chronic kidney disease (CKD), and end-stage kidney disease. Black race is the most important predictor of kidney disease in HIV-infected persons due to both genetic and modifiable causes. HIVassociated nephropathy (HIVAN) is caused by viral infection of the renal epithelium and, although decreasing in incidence, remains the most common cause of CKD in HIV-infected persons. In addition to HIVAN, a wide spectrum of other histopathological presentations, many of which are immune complex-mediated, is increasingly recognised. Clinicians who treat these patients should be aware of the nephrotoxic potential of several commonly used medications, particularly antiviral agents, and also the need to dose-adjust medication in renal impairment. The increased life expectancy of patients with HIV and end-stage kidney disease has meant that kidney transplantation is increasingly an option. Results from carefully conducted prospective studies are promising, at least in the short term.

Solid-Organ Transplantation in Childhood: Transitioning to Adult Health Care

Pediatric solid-organ transplantation is an increasingly successful treatment for solid-organ failure. With dramatic improvements in patient survival rates over the last several decades, there has been a corresponding emergence of complications attributable to pretransplant factors, transplantation itself, and the management of transplantation with effective immunosuppression. The predominant solid-organ transplantation sequelae are medical and psychosocial. These sequelae have a substantial effect on transition to adult care; as such, hurdles to successful transition of care arise from the patients, their families, and pediatric and adult health care providers. Crucial to successful transitioning is the ongoing development of a sense of autonomy and responsibility for one's own care. In this article we address the barriers to transitioning that occur with long-term survival in pediatric solid-organ transplantation. Although a particular transitioning model is not promoted, practical tools and strategies that contribute to successful transitioning of pediatric patients who have received a transplant are suggested.

Osteoporosis is a prevalent finding in patients with solid organ failure awaiting transplantation – a population based study

Post-transplant bone disease is common in solid organ recipients; however, there is limited information on their pre-transplant bone status. We aimed to compare bone mineral density (BMD) in different categories of patients with end-stage organ failure awaiting transplantation (Tx) in Norway. Overall 291 adult patients were enrolled, including 60, 84, 81 and 66 patients with end-stage lung, liver, kidney and heart failure, respectively. Mean age was 51 ± 12 yr with no significant differences between the groups. We measured BMD in lumbar spine, femur, proximal one third and ultra-distal radius by dual energy X-ray absorptiometry. Differences in T- and Z-scores between the groups were compared by ANOVA. Low bone mass was found in all four groups of patients. Both T- and Z-scores differed (p < 0.05) at all measured sites between the groups. Patients with lung failure had the highest prevalence of osteoporosis (67%) and lowest Z-scores, followed by patients with liver (31%), kidney (24%), and heart (23%) failure. Osteoporosis is prevalent in all groups of organ transplant candidates, and poor bone health is remarkably pronounced in patients with chronic lung disease. General practitioners and specialists who care for these patients before they are referred for transplantation should consider measures to prevent osteoporosis at an earlier stage.