Dialysis disequilibrium on CKRT: avoiding the steep slippery slope.

BACKGROUND: Current guidelines for initiation of kidney replacement do not include specific recommendations for prescription parameters and monitoring. CASE OUTLINE: A 16-year-old girl presented with kidney failure with creatinine of 19.8 mg/dL and BUN of 211 mg/dL. She initiated continuous kidney replacement therapy (CKRT) with clearance of 1,300 mL/min/1.73 m2 which was increased to 1,950 mL/min/1.73 m2 at 17 h of stable therapy. COMPLICATIONS: At 31 h of therapy, she developed generalized seizure activity. CT imaging was negative for acute intracranial process, and EEG demonstrated diffuse encephalopathy. CKRT was discontinued, and BUN was noted to be 47 mg/dL at that time (a 79% reduction from presenting BUN). KEY MANAGEMENT POINTS: • The potential for development of DDS is not isolated to intermittent hemodialysis and may occur later in presentation. • A decreased clearance rate should be considered in those with risk factors for development of dialysis disequilibrium syndrome (DDS). • Frequent monitoring of BUN/serum osmolality is important to allow for adjustment of the KRT prescription following initiation of therapy. • Additional research is needed to guide risk assessment for DDS and therapeutic timing and goals in the early stages of KRT initiation. • Inclusion of more specific guidelines surrounding DDS would assist in providing important support for nephrologists. LIST OF RELEVANT GUIDELINES: KDIGO clinical practice guideline for acute kidney injury [1] Clinical Practice Guideline for the Evaluation and Management of Chronic Kidney Disease [2] The Renal Association Clinical Practice Guideline Acute Kidney Injury (AKI) [3] The Japanese Clinical Practice Guideline for Acute Kidney Injury [4].

Mechanisms of cell death in heart disease.

The major cardiac syndromes, myocardial infarction and heart failure, are responsible for a large portion of deaths worldwide. Genetic and pharmacological manipulations indicate that cell death is an important component in the pathogenesis of both diseases. Cells die primarily by apoptosis or necrosis, and autophagy has been associated with cell death. Apoptosis has long been recognized as a highly regulated process. Recent data indicate that a significant subset of necrotic deaths is also programmed. In the review, we discuss the molecular mechanisms that underlie these forms of cell death and their interconnections. The possibility is raised that small molecules aimed at inhibiting cell death may provide novel therapies for these common and lethal heart syndromes.

Bax regulates primary necrosis through mitochondrial dynamics.

The defining event in apoptosis is mitochondrial outer membrane permeabilization (MOMP), allowing apoptogen release. In contrast, the triggering event in primary necrosis is early opening of the inner membrane mitochondrial permeability transition pore (mPTP), precipitating mitochondrial dysfunction and cessation of ATP synthesis. Bcl-2 proteins Bax and Bak are the principal activators of MOMP and apoptosis. Unexpectedly, we find that deletion of Bax and Bak dramatically reduces necrotic injury during myocardial infarction in vivo. Triple knockout mice lacking Bax/Bak and cyclophilin D, a key regulator of necrosis, fail to show further reduction in infarct size over those deficient in Bax/Bak. Absence of Bax/Bak renders cells resistant to mPTP opening and necrosis, effects confirmed in isolated mitochondria. Reconstitution of these cells or mitochondria with wild-type Bax, or an oligomerization-deficient mutant that cannot support MOMP and apoptosis, restores mPTP opening and necrosis, implicating distinct mechanisms for Bax-regulated necrosis and apoptosis. Both forms of Bax restore mitochondrial fusion in Bax/Bak-null cells, which otherwise exhibit fragmented mitochondria. Cells lacking mitofusin 2 (Mfn2), which exhibit similar fusion defects, are protected to the same extent as Bax/Bak-null cells. Conversely, restoration of fused mitochondria through inhibition of fission potentiates mPTP opening in the absence of Bax/Bak or Mfn2, indicating that the fused state itself is critical. These data demonstrate that Bax-driven fusion lowers the threshold for mPTP opening and necrosis. Thus, Bax and Bak play wider roles in cell death than previously appreciated and may be optimal therapeutic targets for diseases that involve both forms of cell death.

Cell death in the pathogenesis of heart disease: mechanisms and significance.

Cell death was once viewed as unregulated. It is now clear that at least a portion of cell death is a regulated cell suicide process. This type of death can exhibit multiple morphologies. One of these, apoptosis, has long been recognized to be actively mediated, and many of its underlying mechanisms have been elucidated. Moreover, necrosis, the traditional example of unregulated cell death, is also regulated in some instances. Autophagy is usually a survival mechanism but can occur in association with cell death. Little is known, however, about how autophagic cells die. Apoptosis, necrosis, and autophagy occur in cardiac myocytes during myocardial infarction, ischemia/reperfusion, and heart failure. Pharmacological and genetic inhibition of apoptosis and necrosis lessens infarct size and improves cardiac function in these disorders. The roles of autophagy in ischemia/reperfusion and heart failure are unresolved. A better understanding of these processes and their interrelationships may allow for the development of novel therapies for the major heart syndromes.

Regulation of p53 tetramerization and nuclear export by ARC.

Inactivation of the transcription factor p53 is central to carcinogenesis. Yet only approximately one-half of cancers have p53 loss-of-function mutations. Here, we demonstrate a mechanism for p53 inactivation by apoptosis repressor with caspase recruitment domain (ARC), a protein induced in multiple cancer cells. The direct binding in the nucleus of ARC to the p53 tetramerization domain inhibits p53 tetramerization. This exposes a nuclear export signal in p53, triggering Crm1-dependent relocation of p53 to the cytoplasm. Knockdown of endogenous ARC in breast cancer cells results in spontaneous tetramerization of endogenous p53, accumulation of p53 in the nucleus, and activation of endogenous p53 target genes. In primary human breast cancers with nuclear ARC, p53 is almost always WT. Conversely, nearly all breast cancers with mutant p53 lack nuclear ARC. We conclude that nuclear ARC is induced in cancer cells and negatively regulates p53.

Nipping at cardiac remodeling.

Much of the mortality following myocardial infarction results from remodeling of the heart after the acute ischemic event. Cardiomyocyte apoptosis has been thought to play a key role in this remodeling process. In this issue of the JCI, Diwan and colleagues present evidence that Bnip3, a proapoptotic Bcl2 family protein, mediates cardiac enlargement, reshaping, and dysfunction in mice without influencing infarct size.