Elaine Ku

Association between strict blood pressure control during chronic kidney disease and lower mortality after onset of end-stage renal disease

There is controversy regarding whether strict blood pressure control is indicated in chronic kidney disease (CKD) since the primary results of randomized controlled trials failed to show any impact on progression of kidney disease with this strategy. However, strict blood pressure control may have other beneficial effects beyond reducing risk of end-stage renal disease (ESRD), such as lowering mortality after ESRD onset. The Modification of Diet in Renal Disease (MDRD) trial randomized 840 patients with CKD to strict (mean arterial pressure under 92 mm Hg) versus usual (mean arterial pressure under 107 mm Hg) blood pressure control between 1989–1993. Here we extended follow-up of study enrollees by linkage with United States Renal Data System and National Death Index to ascertain ESRD and vital status through 2010. Overall, 627 patients developed ESRD through 2010 with median follow-up of 19.3 years. After ESRD onset, there were 142 deaths in the strict blood pressure arm and 182 deaths in the usual blood pressure arm (significant unadjusted hazard ratio for death 0.72 (95% CI 0.58–0.89)). Overall, there were 212 deaths in the strict blood pressure control arm and 233 deaths in the usual arm (significant unadjusted hazard ratio for death 0.82 (95% CI 0.68–0.98)). Thus, although strict blood pressure control did not delay progression of CKD to ESRD, this strategy was associated with a lower risk of death after ESRD. Hence, long-term post-ESRD outcomes should be considered when formulating blood pressure targets for CKD.

Sympathetic Renal Innervation and Resistant Hypertension

Hypertension in chronic renal disease and renovascular disease is often resistant to therapy. Understanding the pathogenic mechanisms responsible for hypertension in these conditions may lead to improved and more targeted therapeutic interventions. Several factors have been implicated in the pathogenesis of hypertension associated with renal disease and/or renal failure. Although the role of sodium retention, total body volume expansion, and hyperactivity of the renin-angiotensin-aldosterone system (RAAS) are well recognized, increasing evidence suggests that afferent impulses from the injured kidney may increase sympathetic nervous system activity in areas of the brain involved in noradrenergic regulation of blood pressure and contribute to the development and maintenance of hypertension associated with kidney disease. Recognition of this important pathogenic factor suggests that antiadrenergic drugs should be an essential component to the management of hypertension in patients with kidney disease, particularly those who are resistant to other modalities of therapy.

Regional variation in the incidence of dialysis-requiring AKI in the United States

BACKGROUND AND OBJECTIVES Little is known about geographic differences in the incidence of AKI. The objective of this study was to determine if regional variation exists in the population incidence of dialysis-requiring AKI in the United States. DESIGN, SETTING, PARTICIPANTS, & METHODS Data from the Nationwide Inpatient Sample, a US nationally representative sample of hospitalizations, were used to determine the incidence rates of dialysis-requiring AKI between 2007 and 2009 among the four US Census-designated regions. Cases were identified using validated discharge codes. Poisson regression models were used to estimate overall regional rates, accounting for the datas sampling scheme. RESULTS In 2007-2009, the population incidence rates of dialysis-requiring AKI differed across the four Census-designated regions (P=0.04). Incidence was highest in the Midwest (523 cases/million person-yr, 95% confidence interval=483 to 568) and lowest in the Northeast (457 cases/million person-yr, 95% confidence interval=426 to 492). The pattern of regional variation in the incidence of dialysis-requiring AKI was not the same as the pattern of regional variation in the incidence of renal replacement therapy-requiring ESRD (obtained from the US Renal Data System). In-hospital mortality associated with dialysis-requiring AKI differed across the four regions, with the highest case fatality in the Northeast (25.9%) and the lowest case fatality in the Midwest (19.4%). CONCLUSIONS Significant regional variation exists in the population incidence of dialysis-requiring AKI in the United States, and additional investigation is warranted to uncover potential causes behind these geographic differences.

Aldosterone in the Pathogenesis of Chronic Kidney Disease and Proteinuria

There has been much recent interest in the role of aldosterone as an independent contributor to the progression of chronic kidney disease. Despite treatment with agents such as angiotensin-converting enzyme inhibitors and angiotensin receptor blockers, many studies have shown that there is incomplete blockade of the renin-angiotensin cascade evidenced by persistent or rising plasma aldosterone levels despite therapeutic renin-angiotensin blockade. This phenomenon is commonly referred to as “aldosterone escape” and is thought to be one of the main contributors to chronic kidney disease progression despite conventional therapeutics. Animal models of the effects of exposure to exogenous aldosterone demonstrate the development of inflammation and fibrosis in both the myocardium and renal parenchyma. In limited human studies, aldosterone receptor antagonism is associated with decreased proteinuria and improved glomerular filtration rate. Although data support the addition of an aldosterone antagonist to conventional therapy when treating patients with chronic kidney disease, more studies are needed to determine the precise clinical indications and the appropriate safety monitoring.

BP Control and Long-Term Risk of ESRD and Mortality

We recently showed an association between strict BP control and lower mortality risk during two decades of follow-up of prior participants in the Modification of Diet in Renal Disease (MDRD) trial. Here, we determined the risk of ESRD and mortality during extended follow-up of the African American Study of Kidney Disease and Hypertension (AASK) trial. We linked 1067 former AASK participants with CKD previously randomized to strict or usual BP control (mean arterial pressure ≤92 mmHg or 102-107 mmHg, respectively) to the US Renal Data System and Social Security Death Index; 397 patients had ESRD and 475 deaths occurred during a median follow-up of 14.4 years from 1995 to 2012. Compared with the usual BP arm, the strict BP arm had unadjusted and adjusted relative risks of ESRD of 0.92 (95% confidence interval [95% CI], 0.75 to 1.12) and 0.95 (95% CI, 0.78 to 1.16; P=0.64), respectively, and unadjusted and adjusted relative risks of death of 0.92 (95% CI, 0.77 to 1.10) and 0.81 (95% CI, 0.68 to 0.98; P=0.03), respectively. In meta-analyses of individual-level data from the MDRD and the AASK trials, unadjusted relative risk of ESRD was 0.88 (95% CI, 0.78 to 1.00) and unadjusted relative risk of death was 0.87 (95% CI, 0.76 to 0.99) for strict versus usual BP arms. Our findings suggest that, during long-term follow-up, strict BP control does not delay the onset of ESRD but may reduce the relative risk of death in CKD.

Association of Body Mass Index with Patient-Centered Outcomes in Children with ESRD

Obesity is associated with less access to transplantation among adults with ESRD. To examine the association between body mass index at ESRD onset and survival and transplantation in children, we performed a retrospective analysis of children ages 2-19 years old beginning RRT from 1995 to 2011 using the US Renal Data System. Among 13,172 children, prevalence of obesity increased from 14% to 18%, whereas prevalence of underweight decreased from 12% to 9% during this period. Over a median follow-up of 7.0 years, 10,004 children had at least one kidney transplant, and 1675 deaths occurred. Risk of death was higher in obese (hazard ratio [HR], 1.17; 95% confidence interval [95% CI], 1.03 to 1.32) and underweight (HR, 1.26; 95% CI, 1.09 to 1.47) children than children with normal body mass indices. Obese and underweight children were less likely to receive a kidney transplant (HR, 0.92; 95% CI, 0.87 to 0.97; HR, 0.83; 95% CI, 0.78 to 0.89, respectively). Obese children had lower odds of receiving a living donor transplant (odds ratio, 0.85; 95% CI, 0.74 to 0.98) if the transplant occurred within 18 months of ESRD onset. Adjustment for transplant in a time-dependent Cox model attenuated the higher risk of death in obese but not underweight children (HR, 1.09; 95% CI, 0.96 to 1.24). Lower rates of kidney transplantation may, therefore, mediate the higher risk of death in obese children with ESRD. The increasing prevalence of obesity among children starting RRT may impede kidney transplantation, especially from living donors.

Lixivaptan: a novel vasopressin receptor antagonist

Arginine vasopressin, also known as antidiuretic hormone, is a neuropeptide that functions in the maintenance of body water homeostasis. Inappropriate secretion of vasopressin has been implicated in the pathophysiology of multiple diseases, including polycystic kidney disease, syndrome of inappropriate antidiuretic hormone (SIADH) secretion, and the hyponatremia commonly associated with cirrhosis and congestive heart failure. Vasopressin receptor antagonists are novel agents that block the physiologic actions of vasopressin. Lixivaptan is a vasopressin receptor antagonist with high V2 receptor affinity and is now undergoing Phase III clinical trials. Studies so far have demonstrated that lixivaptan is efficacious in the correction of hyponatremia in SIADH, heart failure and liver cirrhosis with ascites, and few adverse effects have been noted. Thus, lixivaptan remains a promising therapeutic modality for the treatment of multiple diseases and prevention of the associated morbidity and mortality associated with hyponatremia.

The Hazards of Dual Renin-Angiotensin Blockade in Chronic Kidney Disease

C HRONIC KIDNEY DISease (CKD) is increasing in prevalence in the United States. Therapies that can retard the progression of CKD are needed to prevent the morbidity and mortality associated with reduced renal function. Although multiple studies published in the past 10 years have supported the combination use of angiotensinconverting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) to decrease proteinuria and delay disease progression, it is our position that combinations of ACE inhibitors and ARBs should be used with great caution in patients with CKD. We do not dispute that ACE inhibitors or ARBs used as monotherapy can decrease proteinuria and retard progression of renal disease. However, in combination, the risks of adverse effects, including hyperkalemia, hypotension, and worsening renal failure, could outweigh the purported benefits of dual blockade. Until more studies are conducted on the safety of dual renin-angiotensin blockade on the average patient in the community who has CKD, the simultaneous use of ACE inhibitors and ARBs should be discouraged in primary care.

Do HMG-CoA reductase inhibitors improve kidney function? The saga continues

Several reviews have addressed the role of dyslipidemia in renal injury and the potential renal protective effects of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins). Experimental evidence in animals strongly supports the concept that statins may be renal protective. However, data in humans are scanty and contradictory. A recent controlled study using rosuvastatin has cast some doubts on the renal protective effect of this drug. This article reviews the available evidence pro and con the renal protective effects of statins in human subjects.

Acute Declines in Renal Function during Intensive BP Lowering: Implications for Future ESRD Risk

The magnitude of decline in renal function that should be tolerated during intensive BP lowering and its association with risk of ESRD are unclear. To determine whether the acute declines in kidney function in the intensive BP lowering arm of two trials in CKD associated with higher risk of ESRD, we performed a retrospective study of 899 African American Study of Kidney Disease and Hypertension (AASK) and 761 Modification of Diet in Renal Disease (MDRD) Trial participants previously randomized to strict versus usual BP control. The predictor was the percentage decline in eGFR (<5%, 5% to <20%, or ≥20%) between randomization and months 3 and 4 of the trial (time to achieve BP goals). ESRD was the outcome of interest. Compared with a <5% eGFR decline in the usual BP arm, a 5% to <20% eGFR decline during intensive BP lowering did not associate with a higher risk of ESRD in the AASK (adjusted hazard ratio [aHR], 1.19; 95% confidence interval [95% CI], 0.84 to 1.68) or the MDRD Trial (aHR, 1.08; 95% CI, 0.84 to 1.40). However, a 5% to <20% eGFR decline in the usual BP arm associated with higher risk of ESRD in AASK (aHR, 1.83; 95% CI, 1.30 to 2.57) and MDRD Trial (aHR, 1.62; 95% CI, 1.25 to 2.11). A ≥20% eGFR decline associated with higher risk of ESRD in both strict and usual BP arms. Thus, acute eGFR declines ≥20% during intensive BP lowering identified a subset of patients at higher risk for adverse outcomes.