Radica Z. Alicic

Risks of Subsequent Hospitalization and Death in Patients with Kidney Disease

BACKGROUND AND OBJECTIVES Rates of hospitalization are known to be high in patients with kidney disease. However, ongoing risks of subsequent hospitalization and mortality are uncertain. The primary objective was to evaluate patients with kidney disease for long-term risks of subsequent hospitalization, including admissions resulting in death. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS Patients hospitalized in Washington State between April of 2006 and December of 2008 who survived to discharge (n=676,343) were classified by International Classification of Disease codes into CKD (n=27,870), dialysis (n=6131), kidney transplant (n=1100), and reference (n=641,242) cohorts. Cox proportional hazard models controlling for age, sex, payer, comorbidity, previous hospitalization, primary diagnosis category, and length of stay were conducted for time to event analyses. RESULTS Compared with the reference cohort, risks for subsequent hospitalization were increased in the CKD (hazard ratio=1.20, 99% confidence interval=1.18-1.23, P<0.001), dialysis (hazard ratio=1.76, 99% confidence interval=1.69-1.83, P<0.001), and kidney transplant (hazard ratio=1.85, 99% confidence interval=1.68-2.03, P<0.001) cohorts, with a mean follow-up time of 29 months. Similarly, risks for fatal hospitalization were increased for patients in the CKD (hazard ratio=1.41, 99% confidence interval=1.34-1.49, P<0.001), dialysis (hazard ratio=3.04, 99% confidence interval=2.78-3.31, P<0.001), and kidney transplant (hazard ratio=2.25, 99% confidence interval=1.67-3.03, P<0.001) cohorts. Risks for hospitalization and fatal hospitalization increased in a graded manner by CKD stage. CONCLUSIONS Risks of subsequent hospitalization, including admission resulting in death, among patients with kidney disease were substantially increased in a large statewide population. Patients with kidney disease should be a focus of efforts to reduce hospitalizations and mortality.

Diabetic Kidney Disease: Challenges, Progress, and Possibilities

Diabetic kidney disease develops in approximately 40% of patients who are diabetic and is the leading cause of CKD worldwide. Although ESRD may be the most recognizable consequence of diabetic kidney disease, the majority of patients actually die from cardiovascular diseases and infections before needing kidney replacement therapy. The natural history of diabetic kidney disease includes glomerular hyperfiltration, progressive albuminuria, declining GFR, and ultimately, ESRD. Metabolic changes associated with diabetes lead to glomerular hypertrophy, glomerulosclerosis, and tubulointerstitial inflammation and fibrosis. Despite current therapies, there is large residual risk of diabetic kidney disease onset and progression. Therefore, widespread innovation is urgently needed to improve health outcomes for patients with diabetic kidney disease. Achieving this goal will require characterization of new biomarkers, designing clinical trials that evaluate clinically pertinent end points, and development of therapeutic agents targeting kidney-specific disease mechanisms (e.g., glomerular hyperfiltration, inflammation, and fibrosis). Additionally, greater attention to dissemination and implementation of best practices is needed in both clinical and community settings. INTRODUCTION

Novel therapies for diabetic kidney disease.

The number of people diagnosed with diabetes is rising throughout the world, which in turn drives upward the global frequency of diabetic kidney disease (DKD). Individuals with DKD are at an increased risk for premature death, cardiovascular disease, and other severe illnesses that result in frequent hospitalizations and increased health-care utilization. Current treatments concentrate on controlling hyperglycemia and hypertension with the specific use of renin-angiotensin system inhibitors. Although such measures reduce the risk of progressive kidney disease, DKD remains the leading cause of ESRD and the major risk amplifier for death in this population. Therefore, novel therapeutic approaches are urgently needed. Ideas for novel targets for therapy are founded on recent advances in understanding DKD mechanisms that are based on experimental models and human observations. The purpose of this review is to describe the epidemiology and present knowledge of DKD pathophysiology as the basis for novel therapies including inhibitors of Janus kinases (JAK), protein kinase C, fibrosis, advanced glycation end products treatments, and endothelin.

Direct and Indirect Effects of Obesity on the Kidney

Over the last few decades, much of the world has experienced an epidemic of obesity. In the year 2008, 1.4 billion people worldwide were overweight, and 500 million were obese. Even more alarming is a fact that in the year 2010, 40 million children under the age of 5 years were overweight or obese. In the same time period, the incidence of CKD has also increased worldwide. Obesity has been recognized as a driving force of another global epidemic-diabetes, the leading cause of ESRD. Recent studies are confirming that in addition to risk associated with diabetes per se, increased body mass index is independently linked to increased risk for various kidney disorders, prominently CKD, but also renal cell carcinoma and nephrolithiasis. The purpose of this article is to review current knowledge regarding adverse effects of obesity on the kidney.

Management of the Diabetic Patient with Advanced Chronic Kidney Disease

Diabetic kidney disease (DKD) is the leading cause of end‐stage renal disease (ESRD), and one of the most prevalent microvascular complications of both type 1 and type 2 diabetes. Additionally, risk of death is increased at all stages of DKD. As early as the microalbuminuric stage, the death rate approaches 20% per year. Therefore, management strategies should address reducing risk of mortality as well as progression to ESRD. DKD is associated with multiple co‐morbidities including hypertension, dyslipidemia, cardiovascular disease, anemia, and bone and mineral metabolism disorders (BMD). Anemia and BMD often occur earlier in the course of DKD than with other forms of chronic kidney disease. Pharmacological and dietary management of hyperglycemia, hypertension, dyslipidemia, anemia, and BMD pose specific challenges in DKD. However, with heightened awareness of risks and a multifactorial management approach, the impact of DKD on micro‐ and macrovascular complications and death can be reduced.

Therapeutic Considerations for Antihyperglycemic Agents in Diabetic Kidney Disease

Diabetic kidney disease is among the most frequent complications of diabetes, with approximately 50% of patients with ESRD attributed to diabetes in developed countries. Although intensive glycemic management has been shown to delay the onset and progression of increased urinary albumin excretion and reduced GFR in patients with diabetes, conservative dose selection and adjustment of antihyperglycemic medications are necessary to balance glycemic control with safety. A growing body of literature is providing valuable insight into the cardiovascular and renal safety and efficacy of newer antihyperglycemic medications in the dipeptidyl peptidase-4 inhibitor, glucagon-like peptide-1 receptor agonist, and sodium-glucose cotransporter 2 inhibitor classes of medications. Ongoing studies will continue to inform future use of these agents in patients with diabetic kidney disease.

Novel Therapies for Diabetic Kidney Disease: Storied Past and Forward Paths

IN BRIEF Current therapeutic approaches are only moderately efficacious at preventing the progression of diabetic kidney disease (DKD). As the number of people with DKD continues to rise worldwide, there is an urgent need for novel therapies. A better understanding of the root causes and molecular mechanisms of DKD pathogenesis has enabled the identification of numerous new therapeutic targets, including advanced glycation end products, reactive oxygen species, protein kinase C, and serum amyloid A. Although experimental studies have illustrated the potential of such approaches, challenges in clinical translation remain a barrier in therapeutic development. Advances in preclinical safety and efficacy evaluations and improved delivery systems may aid in clinical translation of novel DKD therapies.

Serum amyloid a and risk of death and end-stage renal disease in diabetic kidney disease.

AIMS To determine if serum levels of serum amyloid A (SAA) predict death and end-stage renal disease in a cohort of people with diabetic kidney disease. METHODS In a longitudinal cohort study of 135 participants with type 2 diabetes and diabetic kidney disease, serum samples were assayed for SAA. Censored time-to-event analyses in Cox-proportional hazard models were utilized to assess SAA as a predictor of the primary outcome of death and end-stage renal disease. RESULTS Participants were 73% Mexican-American (99/135) and 55% men (75/135), with a mean±SD age of 57±7.5years. At baseline, participants had hemoglobin A1c of 8.6±2.3%, systolic blood pressure of 153±27mm Hg, body mass index of 31±9kg/m2, median urine-albumin-to-creatinine ratio of 1861mg/g (interquartile range 720-3912mg/g), and estimated glomerular filtration rate of 55.7±22.3ml/min/1.73m2. Over a median duration of follow-up of 3.5years, 44% (60/135) of participants experienced a primary outcome event. The hazards ratio for the primary outcome was 3.03 (95% CI 1.43-6.40, p=0.003) in the highest (>1.0 μg/ml) compared to the lowest (<0.55 μg/ml) SAA tertile in a model adjusted for urine-albumin-to-creatinine ratio, estimated glomerular filtration rate, age, sex, and race/ethnicity. Addition of SAA as a covariate improved the model C-statistic (Δ c=0.017). CONCLUSIONS In a longitudinal cohort study of participants with type 2 diabetes and DKD, higher levels of serum SAA predicted higher risk of death and ESRD. SAA is a promising targetable biomarker for DKD.

Medication Intervention for Chronic Kidney Disease Patients Transitioning from Hospital to Home: Study Design and Baseline Characteristics.

Background: The hospital readmission rate in the population with chronic kidney disease (CKD) is high and strategies to reduce this risk are urgently needed. Methods: The CKD-Medication Intervention Trial (CKD-MIT; www.clinicaltrials.gov; NCTO1459770) is a single-blind (investigators), randomized, clinical trial conducted at Providence Health Care in Spokane, Washington. Study participants are hospitalized patients with CKD stages 3-5 (not treated with kidney replacement therapy) and acute illness. The study intervention is a pharmacist-led, home-based, medication management intervention delivered within 7 days after hospital discharge. The primary outcome is a composite of hospital readmissions and visits to emergency departments and urgent care centers for 90 days following hospital discharge. Secondary outcomes are achievements of guideline-based targets for CKD risk factors and complications. Results: Enrollment began in February 2012 and ended in May 2015. At baseline, the age of participants was 69 ± 11 years (mean ± SD), 50% (77 of 155) were women, 83% (117 of 141) had hypertension and 56% (79 of 141) had diabetes. At baseline, the estimated glomerular filtration rate was 41 ± 14 ml/min/1.73 m2 and urine albumin-to-creatinine ratio was 43 mg/g (interquartile range 8-528 mg/g). The most frequent diagnosis category for the index hospital admission was cardiovascular diseases at 34% (53 of 155), but the most common single diagnosis for admission was community-acquired acute kidney injury at 10% (16 of 155). Conclusion: Participants in CKD-MIT are typical of acutely ill hospitalized patients with CKD. A medication management intervention after hospital discharge is under study to reduce post-hospitalization acute care utilization and to improve CKD management.

SGLT2 Inhibition for the Prevention and Treatment of Diabetic Kidney Disease: A Review

Diabetic kidney disease (DKD) is the leading cause of end-stage kidney disease in the United States and the world alike, and there is a great unmet need for treatments to reduce DKD development and progression. Inhibition of sodium/glucose co-transporter 2 (SGLT2) in the proximal tubule of the kidney has emerged as an effective antihyperglycemic treatment, leading to regulatory approval of several first-generation SGLT2 inhibitors for the treatment of type 2 diabetes. In follow-on clinical trials for the cardiovascular safety of the SGLT2 inhibitors, secondary effects to prevent or reduce albuminuria and decline in estimated glomerular filtration rate spurred further investigation into their potential application in DKD. This review summarizes the current understanding of mechanisms by which SGLT2 inhibitors block glucose reabsorption in the proximal tubule and improve systemic glucose homeostasis, the hypothesized mechanisms for kidney-protective effects of SGLT2 inhibition, and current recommendations for use of this class of antihyperglycemic agents in diabetic patients with low estimated glomerular filtration rates. Results of ongoing clinical trials in patients with DKD are eagerly awaited to expand knowledge of how SGLT2 inhibitors might be used for prevention and treatment.