Paul L. Kimmel

Acute Kidney Injury and Chronic Kidney Disease as Interconnected Syndromes

For more than 40 years, nephrologists have classified diminished kidney function as two distinct syndromes — acute and chronic kidney failure. Whereas chronic kidney disease was recognized in the 19th century, acute renal dysfunction became evident during the London Blitz of World War II, with the realization that crush injuries could cause dramatic but often reversible cessation of renal function. The disease states and stages of both acute and chronic renal syndromes are delineated according to the serum creatinine concentration or the glomerular filtration rate (GFR), functional markers that were identified in the early 20th century. 1 Advanced renal impairment in both syndromes is treated with dialysis. During the past decade, separate conceptual models for chronic kidney disease 2 and acute kidney injury 3 were developed to facilitate organized approaches to clinical research and trials. However, recent epidemiologic and mechanistic studies suggest that the two syndromes are not distinct entities but rather are closely interconnected — chronic kidney disease is a risk factor for acute kidney injury, acute kidney injury is a risk factor for the development of chronic kidney disease, and both acute kidney injury and chronic kidney disease are risk factors for cardiovascular disease (Fig. 1). 4

Acute kidney injury and chronic kidney disease: an integrated clinical syndrome

The previous conventional wisdom that survivors of acute kidney injury (AKI) tend to do well and fully recover renal function appears to be flawed. AKI can cause end-stage renal disease (ESRD) directly, and increase the risk of developing incident chronic kidney disease (CKD) and worsening of underlying CKD. In addition, severity, duration, and frequency of AKI appear to be important predictors of poor patient outcomes. CKD is an important risk factor for the development and ascertainment of AKI. Experimental data support the clinical observations and the bidirectional nature of the relationships between AKI and CKD. Reductions in renal mass and nephron number, vascular insufficiency, cell cycle disruption, and maladaptive repair mechanisms appear to be important modulators of progression in patients with and without coexistent CKD. Distinction between AKI and CKD may be artificial. Consideration should be given to the integrated clinical syndrome of diminished GFR, with acute and chronic stages, where spectrum of disease state and outcome is determined by host factors, including the balance of adaptive and maladaptive repair mechanisms over time. Physicians must provide long-term follow-up to patients with first episodes of AKI, even if they presented with normal renal function.

Depression in patients with chronic renal disease What we know and what we need to know

Depression is a common, but underdiagnosed and understudied problem in patients with renal disease. The overlap between symptoms of chronic medical illness and those of depression make for a particularly challenging diagnosis in this illness. The prevalence of depression varies with the diagnostic tool employed. The gold standard for the psychiatric diagnosis is the interview, using DSM-IV TR criteria. Researchers in the field of renal disease have often not distinguished between the diagnosis of major depression and high levels of depressive affect in studies. There are almost no data regarding the magnitude of depression in patients with chronic renal insufficiency, patients treated with peritoneal dialysis, and children with renal disease, compared with adults with end-stage renal disease treated with hemodialysis. The relationships between age, ethnicity, marital status and satisfaction, and perception of quality of life and level of depressive affect and diagnosis of depression, and medical outcomes have not been determined in patients with renal disease. The mediators which may underlie the deleterious effects of depression in patients with renal disease, and their relationship with stage of renal dysfunction have not been delineated. More emphasis must be placed on well-designed treatment studies and survival analyses in these populations, using longitudinal techniques.

Outcomes following diagnosis of acute renal failure in U.S. veterans: focus on acute tubular necrosis

When patients develop acute kidney injury, a small fraction of them will develop end-stage renal disease later. The severity of renal impairment in the remaining patients is uncertain because studies have not carefully examined renal function over time or the precise timing of entry into a late stage of chronic kidney disease. To determine these factors, we used a United States Department of Veterans Affairs database to ascertain long-term renal function in 113,272 patients. Of these, 44,377 had established chronic kidney disease and were analyzed separately. A cohort of 63,491 patients was hospitalized for acute myocardial infarction or pneumonia and designated as controls. The remaining 5,404 patients had diagnostic codes indicating acute renal failure or acute tubular necrosis. Serum creatinine, estimated glomerular filtration rates, and dates of death over a 75-month period were followed. Renal function deteriorated over time in all groups, but with significantly greater severity in those who had acute renal failure and acute tubular necrosis compared to controls. Patients with acute kidney injury, especially those with acute tubular necrosis, were more likely than controls to enter stage 4 chronic kidney disease, but this entry time was similar to that of patients who initially had chronic kidney disease. The risk of death was elevated in those with acute kidney injury and chronic kidney disease compared to controls after accounting for covariates. We found that patients who had an episode of acute tubular necrosis were at high risk for the development of stage 4 disease and had a reduced survival time when compared to control patients.

Depression in end-stage renal disease patients treated with hemodialysis: tools, correlates, outcomes, and needs.

Depression has been thought to be the most common psychiatric abnormality in hemodialysis (HD) patients. There are few data using psychiatric diagnostic criteria and a lack of large, well‐designed epidemiologic research studies in patients with end‐stage renal disease (ESRD) that can render definitive results on this topic. The prevalence of major depression or a defined psychiatric illness in ESRD patients is unknown, but is probably between 5% and 10%. The prevalence of increased levels of depressive affect is greater. Estimates of the prevalence will vary according to the screening techniques used. Depression could affect medical outcomes in ESRD patients through several mechanisms. Correlational analyses suggest stressors and protective factors play roles in mediating the level of depressive affect and associated outcomes. Although early studies suggested a deleterious effect of depression on survival in ESRD patients, more recent studies had failed to confirm such findings. The use of longitudinal analyses and larger samples has confirmed an association of depressive affect and morbidity and mortality in more contemporary ESRD populations. The importance of depressive affect compared with the presence of a defined psychiatric syndrome in mediating clinically important outcomes in patients with chronic kidney disease has not been determined. Studies of interventions designed to reduce levels of depressive affect in ESRD patients are urgently needed.

Psychiatric illness in patients with end-stage renal disease.

PURPOSE We sought to determine the prevalence of psychiatric illness in hospitalized patients with end-stage renal disease. We also examined the association between end-stage renal disease treatment modality and risk of hospitalization with a diagnosis of a mental disorder, and compared rates of hospitalization with a diagnosis of psychiatric illness in renal failure patients to patients with other chronic medical illnesses. SUBJECTS AND METHODS We performed a cohort study of all Medicare-enrolled dialysis patients in 1993. Risk of hospitalization with a diagnosis of a mental disorder among renal failure patients was compared with Medicare patients with diabetes mellitus, ischemic heart disease, cerebrovascular disease, and peptic ulcer disease. RESULTS Almost 9% of all dialysis patients were hospitalized with a mental disorder. Men, African-Americans, and younger patients were more likely to be hospitalized with a mental disorder. The adjusted risk of hospitalization for peritoneal dialysis patients was lower compared with hemodialysis patients for any mental disorder, depression, and alcohol and drug use. Hospitalization with mental disorders was 1.5 to 3.0 times higher for renal failure patients compared with other chronically ill patients. CONCLUSIONS Hospitalization with a psychiatric illness is common among the US end-stage renal disease population. Depression, dementia and drug-related disorders were especially common. The coexistence of psychiatric illness in patients with renal failure who require specialized medical regimens represents a challenge to nephrologists in diagnosis and treatment. Disparities between hospitalization rates of psychiatric illnesses among end-stage renal disease patients compared with other chronically ill populations warrant further research.

Depression and anxiety in urban hemodialysis patients.

Depression is well established as a prevalent mental health problem for people with ESRD and is associated with morbidity and mortality. However, depression in this population remains difficult to assess and is undertreated. Current estimates suggest a 20 to 30% prevalence of depression that meets diagnostic criteria in this population. The extent of other psychopathology in patients with ESRD is largely unknown. The aim of this study was to expand the research on psychiatric complications of ESRD and examine the prevalence of a broad range of psychopathology in an urban hemodialysis center and their impact on quality of life. With the use of a clinician-administered semistructured interview in this randomly selected sample of 70 predominately black patients, >70% were found to have a psychiatric diagnosis. Twenty-nine percent had a current depressive disorder: 20% had major depression, and 9% had a diagnosis of dysthymia or depression not otherwise specified. Twenty-seven percent had a current major anxiety disorder. A current substance abuse diagnosis was found in 19%, and 10% had a psychotic disorder. The mean Beck Depression Inventory score was 12.1 +/- 9.8. Only 13% reported being in current treatment by a mental health provider, and only 5% reported being prescribed psychiatric medication by their physician. A total of 7.1% had compound depression or depression coexistent with another psychiatric disorder. The construct of depression was also disentangled from the somatic effects of poor medical health by demonstrating a unique relationship between depressive affect and depression diagnosis, independent of health status. This study also suggests the utility of cognitive variables as a meaningful way of understanding the differences between patients who have ESRD with clinical depression or other diagnoses and those who have no psychiatric comorbidity. The findings of both concurrent and isolated anxiety suggest that the prevalence of psychopathology in patients with ESRD might be higher than previously expected, and the disorders may need to be treated independently. In addition, the data suggest that cognitive behavioral therapeutic techniques may be especially advantageous in this population of patients who are treated with many medications.

Psychosocial factors in adult end-stage renal disease patients treated with hemodialysis: Correlates and outcomes

The first three decades of the ESRD program were devoted to extending patient survival. Few data have been generated regarding the factors associated with successful patient adjustment. Depression and perception of the effects of illness are important responses to the experience of ESRD and may be associated with differential survival. Perception and extent of social support can moderate these factors. The association of psychosocial factors and assessments of quality of life are incompletely understood and are topics of research interest. The role of variation in socioeconomic status in association with these factors has not been extensively studied. The challenges for the next 30 years include understanding the relationship of psychosocial factors to demographic and medical factors in large ESRD patient populations and the refinement of associations between psychosocial factors and patient outcomes, including adjustment, compliance, morbidity, and mortality.

Screening, Diagnosis, and Treatment of Depression in Patients with End-Stage Renal Disease

Depression is common in patients with end-stage renal disease and has been linked to increased mortality. Screening for depression in the general medical population remains controversial; however, given the high prevalence of depression and its significant impact on morbidity and mortality, a strong case for depression screening in patients with end-stage renal disease can be made. Several studies have been performed to validate the more common depression screening measures in patients with chronic kidney disease. The Beck Depression Inventory, the Hamilton Rating Scale for Depression, the Nine-Question Patient Health Questionnaire, and the Center for Epidemiologic Studies Depression Scale are some of the measures that have been used to screen for depression in patients with end-stage renal disease. Data suggest a higher Beck Depression Inventory cutoff score, of >14 to 16, will have increased positive predictive value at diagnosing depression in patients with end-stage renal disease. There are limited data on the treatment of depression in this patient population. Pharmacotherapy, including selective serotonin reuptake inhibitors, can be used if deemed clinically indicated, and no active contraindication exists. There are even fewer data to support the role of cognitive behavioral therapy, social support group interventions, and electroconvulsive therapy for treatment of depression in patients with chronic kidney disease. Larger randomized, controlled clinical trials aimed at the treatment of depression in patients with end-stage renal disease are desperately needed.

Depression in end-stage renal disease hemodialysis patients

Depression has been identified as a complicating comorbid diagnosis in a variety of medical conditions, including end-stage renal disease (ESRD). Despite this, the psychological health of hemodialysis patients is understudied. The purpose of this paper is to review the research and issues involved in the assessment of depression and its sequelae in ESRD. Accurate estimation of the prevalence of depression in the ESRD population has been difficult due to the use of different definitions of depression and varied assessment techniques, the overlap of depressive symptomatology with symptoms of uremia, and the confounding effects of medications. We suggest that depressive affect is a more important construct to study than diagnosis of depression syndromes per se in patients with chronic kidney disease. The Beck Depression Inventory is a reasonable measure of depressive affect in the ESRD population, if a higher than usual cutoff score is used or if its somatic components are omitted. Several pathways link depression and ESRD, and are probably bidirectional. As such, treatment of depressive affect could impact medical as well as psychological outcomes. The need for treatment intervention trials is great. Limited evidence regarding the safety and efficacy of treatment of hemodialysis patients with selective serotonin reuptake inhibitors is available, and cognitive behavioral therapy holds promise as an intervention for depression in this complex medical population.