Mitchell H. Rosner

Statement of the Second International Exercise-Associated Hyponatremia Consensus Development Conference, New Zealand, 2007.

Tamara Hew-Butler, DPM, PhD,* J. Carlos Ayus, MD,† Courtney Kipps, BMBS, MSc,‡ Ronald J. Maughan, PhD,§ Samuel Mettler, MSc,¶ Willem H. Meeuwisse, MD, PhD (chair),k Anthony J. Page, MBChB, MD,** Stephen A. Reid, MBBS, PhD,†† Nancy J. Rehrer, PhD,‡‡ William O. Roberts, MD, MSc,§§ Ian R. Rogers, MBBS,¶¶ Mitchell H. Rosner, MD,kk Arthur J. Siegel, MD,*** Dale B. Speedy, MBChB, MD,††† Kristin J. Stuempfle, PhD,‡‡‡ Joseph G. Verbalis, MD,§§§ Louise B. Weschler, MAT, PT,¶¶¶ and Paul Wharam, MMedSckkk

Pharmacologic Treatment of Acute Kidney Injury: Why Drugs Haven’t Worked and What Is on the Horizon

Current strategies to limit the extent of injury in acute renal failure are based on extensive studies that identified cellular and molecular mechanisms of acute kidney injury. Despite successes in various animal models, translation to human studies has failed or studies are inconclusive. This review describes past failures and barriers to successful clinical trials. It also focuses on promising preclinical studies using novel compounds that currently are in or close to human investigation. Implementation of previous or novel compounds in well-designed clinical trials provides hope for the successful treatment of this devastating disorder.

Analytic Reviews: Cardiac Surgery as a Cause of Acute Kidney Injury: Pathogenesis and Potential Therapies

Cardiopulmonary bypass surgery occurs in nearly 1 million patients per year. Acute kidney injury requiring dialysis can occur in up to 1% of these patients. The development of acute kidney injury is associated with substantial morbidity and mortality independent of all other factors, and many patients are left dependent on dialysis therapies. The pathogenesis of acute kidney injury involves multiple pathways. Hemodynamic, inflammatory, and nephrotoxic factors are involved and overlap each other in leading to kidney injury. Clinical studies have identified risk factors for acute kidney injury that can be used to effectively determine the risk of acute kidney injury in patients undergoing bypass surgery. These high-risk patients can then be targeted for renal protective strategies. Thus far, no single strategy has conclusively demonstrated its ability to prevent renal injury post-bypass surgery. Novel anti-inflammatory agents are in development and offer hope as potential therapies.

Osmotic Demyelination Syndrome

The osmotic demyelination syndrome (ODS) has been a recognized complication of the rapid correction of hyponatremia for decades. However, in recent years, a variety of other medical conditions have been associated with the development of ODS, independent of changes in serum sodium. This finding suggests that the pathogenesis of ODS may be more complex and involve the inability of brain cells to respond to rapid changes in osmolality of the interstitial (extracellular) compartment of the brain, leading to dehydration of energy-depleted cells with subsequent axonal damage that occurs in characteristic areas. Features of the syndrome include quadriparesis and neurocognitive changes in the presence of characteristic lesions found on magnetic resonance imaging of the brain. Although slow correction of hyponatremia seems to be the best way to prevent development of the syndrome, there are new data that suggest reintroduction of hyponatremia in those patients who have undergone inadvertent rapid correction of the serum sodium and corticosteroids may play a role in prevention of ODS.

AKI Associated with Cardiac Surgery

Approximately 18% of patients undergoing cardiac surgery experience AKI (on the basis of modern standardized definitions of AKI), and approximately 2%-6% will require hemodialysis. The development of AKI after cardiac surgery portends poor short- and long-term prognoses, with those developing RIFLE failure or AKI Network stage III having an almost 2-fold increase in the risk of death. AKI is caused by a variety of factors, including nephrotoxins, hypoxia, mechanical trauma, inflammation, cardiopulmonary bypass, and hemodynamic instability, and it may be affected by the clinicians choice of fluids and vasoactive agents as well as the transfusion strategy used. The risk of AKI may be ameliorated by avoidance of nephrotoxins, achievement of adequate glucose control preoperatively, and use of goal-directed therapy hemodynamic strategies. Remote ischemic preconditioning is an exciting future strategy, but more work is needed before widespread implementation. Unfortunately, there are no pharmacologic agents known to reduce the risk of AKI or treat established AKI.

Acute kidney disease and renal recovery: consensus report of the Acute Disease Quality Initiative (ADQI) 16 Workgroup

Consensus definitions have been reached for both acute kidney injury (AKI) and chronic kidney disease (CKD) and these definitions are now routinely used in research and clinical practice. The KDIGO guideline defines AKI as an abrupt decrease in kidney function occurring over 7 days or less, whereas CKD is defined by the persistence of kidney disease for a period of >90 days. AKI and CKD are increasingly recognized as related entities and in some instances probably represent a continuum of the disease process. For patients in whom pathophysiologic processes are ongoing, the term acute kidney disease (AKD) has been proposed to define the course of disease after AKI; however, definitions of AKD and strategies for the management of patients with AKD are not currently available. In this consensus statement, the Acute Disease Quality Initiative (ADQI) proposes definitions, staging criteria for AKD, and strategies for the management of affected patients. We also make recommendations for areas of future research, which aim to improve understanding of the underlying processes and improve outcomes for patients with AKD.

Pretransplant predictors of recovery of renal function after liver transplantation

The Model for End‐Stage Liver Disease system has given priority on the liver transplant waiting list to candidates with renal failure. This study determined the predictors of spontaneous recovery of renal function after transplantation in 1041 liver transplant recipients on renal replacement therapy (RRT) at the time of transplant (from February 2002 to January 2007). Data from these patients were obtained from the US Organ Procurement and Transplantation Network and US Renal Data System databases. Univariate and multivariate survival models were constructed along with multivariate logistic regression models to find independent predictors of spontaneous renal recovery. Seven hundred seven recipients (67.9%) had spontaneous recovery of renal function after liver transplantation. Those recovering spontaneously had a significantly shorter course of RRT in the pretransplant time period (15.6 versus 36.6 days, P < 0.001). Recovery of renal function was observed in 70.8% and 11.5% of recipients on RRT for less than 30 days and more than 90 days, respectively. Other statistically significant pretransplant variables independently associated with recovery of renal function included recipient age, recipient pretransplant diabetes, and donor age. In conclusion, the duration of pretransplant RRT is highly predictive of spontaneous renal recovery post‐transplant. Liver transplant candidates requiring less than 30 days of pretransplant RRT are likely to spontaneously recover renal function after liver transplantation, whereas those on RRT for more than 90 days are not. Liver Transpl, 2010.

Inflammation in AKI: Current Understanding, Key Questions, and Knowledge Gaps

Inflammation is a complex biologic response that is essential for eliminating microbial pathogens and repairing tissue after injury. AKI associates with intrarenal and systemic inflammation; thus, improved understanding of the cellular and molecular mechanisms underlying the inflammatory response has high potential for identifying effective therapies to prevent or ameliorate AKI. In the past decade, much knowledge has been generated about the fundamental mechanisms of inflammation. Experimental work in small animal models has revealed many details of the inflammatory response that occurs within the kidney after typical causes of AKI, including insights into the molecular signals released by dying cells, the role of pattern recognition receptors, the diverse subtypes of resident and recruited immune cells, and the phased transition from destructive to reparative inflammation. Although this expansion of the basic knowledge base has increased the number of mechanistically relevant targets of intervention, progress in developing therapies that improve AKI outcomes by modulation of inflammation remains slow. In this article, we summarize the most important recent developments in understanding the inflammatory mechanisms of AKI, highlight key limitations of the commonly used animal models and clinical trial designs that may prevent successful clinical application, and suggest priority approaches for research toward clinical translation in this area.

Epidemiology of acute kidney injury.

Different definitions for acute kidney injury (AKI) once posed an important impediment to research. The RIFLE consensus classification was the first universally accepted definition for AKI, and has facilitated a much better understanding of the epidemiology of this condition. The RIFLE classification was adapted by a broad platform of world societies, the Acute Kidney Injury Network group, as the preferred AKI diagnostic and staging system. RIFLE defines three increasing severity stages of AKI. One- to two-thirds of intensive care unit (ICU) patients develop AKI according to these criteria which is associated with worse outcomes such as increased length of ICU stay, costs, and mortality. Over the last decade the incidence of AKI has increased, probably as a consequence that baseline characteristics of ICU patients have changed. Another factor that may explain this is that more patients are treated in clinical settings that are associated with high risk for development of AKI. In addition, there may be genetically predetermined risk profiles for development of AKI such homozygotes for the low activity form of the COMT gene. Mortality of AKI patients has decreased over the last few decades, especially when underlying severity of illness is considered. An important consequence of this is the increasing number of surviving AKI patients who develop chronic kidney disease and end-stage kidney disease. In the specific setting of cardiac surgery, AKI occurs in 19-45% of patients. Renal replacement therapy is necessary in approximately 2% of this cohort. AKI that occurs within a 7-day period after cardiac surgery is related to perioperative risk factors, such as preexisting chronic kidney disease, acute ischemia, aorta cross-clamping, or use of cardiopulmonary bypass. AKI that occurs after the first week is mostly a consequence of sepsis or heart failure.

Onco-Nephrology: The Pathophysiology and Treatment of Malignancy-Associated Hypercalcemia

Hypercalcemia complicates the course of 10%-30% of all patients with malignancies and can be a sign of very poor prognosis and advanced malignancy. Prompt recognition of the nonspecific signs and symptoms of hypercalcemia and institution of therapy can be lifesaving, affording the opportunity to address the underlying etiology. The mechanisms of malignancy-associated hypercalcemia generally fall into three categories: humoral hypercalcemia due to secreted factors (such as parathyroid-related hormone), local osteolysis due to tumor invasion of bone, and absorptive hypercalcemia due to excess vitamin D produced by malignancies. The mainstays of therapy for hypercalcemia are aggressive intravenous volume expansion with saline, bisphosphonate therapy, and perhaps loop diuretics. Adjunctive therapy may include calcitonin and corticosteroids. In refractory cases, gallium nitrate and perhaps denosumab are alternatives. In patients presenting with severe AKI, hemodialysis with a low-calcium bath can be effective. In most cases, therapy normalizes calcium levels and allows for palliation or curative therapy of the malignancy.