Devasmita Choudhury

Intensity of renal support in critically ill patients with acute kidney injury.

BACKGROUND The optimal intensity of renal-replacement therapy in critically ill patients with acute kidney injury is controversial. METHODS We randomly assigned critically ill patients with acute kidney injury and failure of at least one nonrenal organ or sepsis to receive intensive or less intensive renal-replacement therapy. The primary end point was death from any cause by day 60. In both study groups, hemodynamically stable patients underwent intermittent hemodialysis, and hemodynamically unstable patients underwent continuous venovenous hemodiafiltration or sustained low-efficiency dialysis. Patients receiving the intensive treatment strategy underwent intermittent hemodialysis and sustained low-efficiency dialysis six times per week and continuous venovenous hemodiafiltration at 35 ml per kilogram of body weight per hour; for patients receiving the less-intensive treatment strategy, the corresponding treatments were provided thrice weekly and at 20 ml per kilogram per hour. RESULTS Baseline characteristics of the 1124 patients in the two groups were similar. The rate of death from any cause by day 60 was 53.6% with intensive therapy and 51.5% with less-intensive therapy (odds ratio, 1.09; 95% confidence interval, 0.86 to 1.40; P=0.47). There was no significant difference between the two groups in the duration of renal-replacement therapy or the rate of recovery of kidney function or nonrenal organ failure. Hypotension during intermittent dialysis occurred in more patients randomly assigned to receive intensive therapy, although the frequency of hemodialysis sessions complicated by hypotension was similar in the two groups. CONCLUSIONS Intensive renal support in critically ill patients with acute kidney injury did not decrease mortality, improve recovery of kidney function, or reduce the rate of nonrenal organ failure as compared with less-intensive therapy involving a defined dose of intermittent hemodialysis three times per week and continuous renal-replacement therapy at 20 ml per kilogram per hour. (ClinicalTrials.gov number, NCT00076219.)

Advanced glycation end products: a Nephrologist's perspective.

Advanced glycation end products (AGEs) are a heterogeneous group of molecules that accumulate in plasma and tissues with advancing age, diabetes, and renal failure. There is emerging evidence that AGEs are potential uremic toxins and may have a role in the pathogenesis of vascular and renal complications associated with diabetes and aging. AGEs are formed when a carbonyl of a reducing sugar condenses with a reactive amino group in target protein. These toxic molecules interact with specific receptors and elicit pleiotropic responses. AGEs accelerate atherosclerosis through cross-linking of proteins, modification of matrix components, platelet aggregation, defective vascular relaxation, and abnormal lipoprotein metabolism. In vivo and in vitro studies indicate that AGEs have a vital role in the pathogenesis of diabetic nephropathy and the progression of renal failure. The complications of normal aging, such as loss of renal function, Alzheimers disease, skin changes, and cataracts, may also be mediated by progressive glycation of long-lived proteins. AGEs accumulate in renal failure as a result of decreased excretion and increased generation resulting from oxidative and carbonyl stress of uremia. AGE-modified beta(2)-microglobulin is the principal pathogenic component of dialysis-related amyloidosis in patients undergoing dialysis. Available dialytic modalities are not capable of normalizing AGE levels in patients with end-stage renal disease. A number of reports indicated that restoration of euglycemia with islet-cell transplantation normalized and prevented further glycosylation of proteins. Aminoguanidine (AGN), a nucleophilic compound, not only decreases the formation of AGEs but also inhibits their action. A number of studies have shown that treatment with AGN improves neuropathy and delays the onset of retinopathy and nephropathy. N-Phenacylthiazolium bromide is a prototype AGE cross-link breaker that reacts with and can cleave covalent AGE-derived protein cross-links. Thus, there is an exciting possibility that the complications of diabetes, uremia, and aging may be prevented with these novel agents.

Drug-associated renal dysfunction and injury

Renal dysfunction and injury secondary to medications are common, and can present as subtle injury and/or overt renal failure. Some drugs perturb renal perfusion and induce loss of filtration capacity. Others directly injure vascular, tubular, glomerular and interstitial cells, such that specific loss of renal function leads to clinical findings, including microangiopathy, Fanconi syndrome, acute tubular necrosis, acute interstitial nephritis, nephrotic syndrome, obstruction, nephrogenic diabetes insipidus, electrolyte abnormalities and chronic renal failure. Understanding the mechanisms involved, and recognizing the clinical presentations of renal dysfunction arising from use of commonly prescribed medications, are important if injury is to be detected early and prevented. This article reviews the clinical features and basic processes underlying renal injury related to the use of common drugs.

Chemotherapy-associated renal dysfunction.

The presence of renal dysfunction in a patient receiving chemotherapy can be devastating. Although many patients with cancer have underlying compromised renal function, some chemotherapeutic agents can actually induce renal abnormalities. An understanding of which traditional and newer chemotherapy agents can affect renal function is useful for physicians so that they can monitor patients for renal abnormalities and initiate preventive strategies to minimize renal complications. This Review highlights renal abnormalities associated with current chemotherapy agents and provides suggestions for preventive measures.

Kidney aging--inevitable or preventable?

The aging process affects all organs, including the kidneys. As part of this process, progressive scarring and a measurable decline in renal function occur in most people over time. The improved understanding of the processes that can lead to and/or hasten scarring and loss of renal function over time parallels advances in our understanding of the aging process. Clinical factors, including hypertension, diabetes mellitus, obesity, abnormal lipid levels and vitamin D deficiency, have been associated with increasing renal sclerosis with age. In addition, tissue factors such as angiotensin II, advanced glycation end products, oxidative stress and Klotho are associated with renal aging. These associations and possible interventions, including the control of blood pressure, blood sugar, weight, diet and calorie restriction might make renal aging more preventable than inevitable.

Drug-induced nephrotoxicity.

Drug-induced renal dysfunction is not an uncommon event, which can cause significant morbidity and can be easily overlooked. Many medications can lead to renal dysfunction through various mechanisms. The most common medications or classes of medications along with their clinical presentations are discussed in this article. As can be noted, many drugs can cause nephropathy in more than one way. Because it is difficult to discuss nephrotoxicities of every reported medication, Tables 1, 2, and 3 are provided; although these tables are by no means comprehensive, they may serve as further reference. This article is intended to provide a broad overview of the spectrum of presentation associated with drug-induced nephrotoxicity to guide the clinician to familiarity with this entity.

Lessons for successful study enrollment from the Veterans Affairs/National Institutes of Health acute renal failure trial network study

BACKGROUND AND OBJECTIVES Design elements of clinical trials can introduce recruitment bias and reduce study efficiency. Trials involving the critically ill may be particularly prone to design-related inefficiencies. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS Enrollment into the Veterans Affairs/National Institutes of Health Acute Renal Failure Trial Network Study was systematically monitored. Reasons for nonenrollment into this study comparing strategies of renal replacement therapy in critically ill patients with acute kidney injury were categorized as modifiable or nonmodifiable. RESULTS 4339 patients were screened; 2744 fulfilled inclusion criteria. Of these, 1034 were ineligible by exclusion criteria. Of the remaining 1710 patients, 1124 (65.7%) enrolled. Impediments to informed consent excluded 21.4% of potentially eligible patients. Delayed identification of potential patients, physician refusal, and involvement in competing trials accounted for 4.4, 2.7, and 2.3% of exclusions. Comfort measures only status, chronic illness, chronic kidney disease, and obesity excluded 11.8, 7.8, 7.6, and 5.9% of potential patients. Modification of an enrollment window reduced the loss of patients from 6.6 to 2.3%. CONCLUSIONS The Acute Renal Failure Trial Network Studys enrollment efficiency compared favorably with previous intensive care unit intervention trials and supports the representativeness of its enrolled population. Impediments to informed consent highlight the need for nontraditional acquisition methods. Restrictive enrollment windows may hamper recruitment but can be effectively modified. The low rate of physician refusal acknowledges clinical equipoise in the study design. Underlying comorbidities are important design considerations for future trials that involve the critically ill with acute kidney injury.

Nuclear hormone receptors as therapeutic targets.

In spite of excellent glucose and blood pressure control, including administration of angiotensin-converting enzyme inhibitors and/or angiotensin II receptor blockers, diabetic nephropathy (DN) still develops and progresses. The development of additional protective therapeutic interventions is, therefore, a major priority. Nuclear hormone receptors regulate carbohydrate metabolism, lipid metabolism, the immune response, inflammation and development of fibrosis. The increasing prevalence of DN has led to intense investigation of the role that nuclear hormone receptors may have in slowing or preventing the progression of renal disease. Several nuclear receptor-activating ligands (agonists) have been shown to have a renal protective effect in the context of DN. This review will discuss the evidence regarding the beneficial effects of the activation of the vitamin D receptor (VDR) and the farnesoid X receptor (FXR) in preventing the progression of DN, and will describe how the discovery and development of compounds that modulate the activity of VDR and FXR may provide potential additional therapeutic approaches in the management of DN.

Preventive health care in chronic kidney disease and end-stage renal disease.

The complex care that must be provided for patients with renal disease might interfere with provision of basic preventive measures in this population. Preventive health care, including infection screening and prophylaxis, vaccinations, management of blood glucose and lipid levels, and cancer screening, is important, as it might decrease acute morbidity and mortality. This Review highlights useful preventive and health maintenance strategies for patients with chronic kidney disease and those with end-stage renal disease.

Acute kidney injury: current perspectives.

Abstract Acute kidney injury (AKI) increases morbidity and mortality, particularly for the critically ill. Recent definitions standardizing AKI to reflect graded changes in serum creatinine and urine output (per the Risk, Injury, Failure, Loss, and End-stage renal failure [RIFLE] and Acute Kidney Injury Network [AKIN] criteria) with severity of renal injury and developments in AKI pathobiology are being utilized to identify biomarkers of early kidney injury. These developments may be useful in the early intervention of preventing AKI. Although there has been progress in the management of AKI, therapeutic challenges include appropriate prophylaxis prior to contrast administration, use of diuretics, vasopressors, and the type and dose of renal replacement therapy. Future use of bioartificial dialyzers, plasma therapies, and the possibility of stem cell regeneration of injured kidney tissue are being actively investigated to provide alternative treatment options for AKI. This review aims to provide an overview of current practices, available therapies, and continued research in AKI therapy.