Use of Renin-Angiotensin System Blockade in Advanced CKD: An NKF-KDOQI Controversies Report.

Multiple clinical trials have demonstrated that renin-angiotensin system (RAS) blockade with either angiotensin-converting enzyme inhibitors or angiotensin receptor blockers effectively reduces chronic kidney disease (CKD) progression. However, most clinical trials excluded participants with advanced CKD (ie, estimated glomerular filtration rate [eGFR]<30mL/min/1.73m2). It is acknowledged that initiation of RAS blockade is often associated with an acute reduction in eGFR, which is thought to be functional, but may result in long-term preservation of kidney function through the reductions in glomerular intracapillary pressure conferred by these agents. In this National Kidney Foundation-Kidney Disease Outcomes Quality Initiative (NKF-KDOQI) report, we discuss the controversies regarding use of RAS blockade in patients with advanced kidney disease. We review available published data on this topic and provide perspective on the impact of RAS blockade on changes in eGFRs and potassium levels. We conclude that more research is needed to evaluate the therapeutic index of RAS blockade in patients with advanced CKD.

Obesity and Kidney Disease.

Obesity is a systemic disease of the white adipose tissue, which has evolved into a global epidemic. It is associated with a plethora of adipocyte hormonal (adipokine) imbalances, dysregulation of the energy-balance system, imbalances in metabolic homeostasis, a pro-inflammatory state and multiple target organ damages. Clinically, the obesity phenotype is not homogenous and is more likely to represent a spectrum with varying degrees of metabolic un-health; metabolically-unhealthy obesity is often a part of the metabolic syndrome. The links between obesity and chronic kidney disease are numerous, bidirectional, multi-layered and complex; this complexity may be explained by shared pathophysiological pathways (e.g. chronic inflammation, increased oxidative stress, and hyper-insulinemia), shared clusters of risk factors as well as associated diseases (e.g. insulin resistance, hypertension and dyslipidemia). We will review these links and their clinical manifestations, and offer a summary of available non-pharmacological as well as pharmacological therapeutic strategies.

Hyperkalemia in the Hypertensive Patient.

PURPOSE OF REVIEW: Hyperkalemia develops in a patient with systemic arterial hypertension (HTN) if one or more risk factors are present, namely chronic kidney disease (CKD) (especially severe stage 4-5 CKD), diabetes mellitus (DM), heart failure (HF), or pharmacological therapies that interfere with potassium homeostasis, mainly through renin-angiotensin-aldosterone inhibition (RAASi). Hyperkalemia is a considerable reason of morbidity (emergency department (ED) visits and hospitalizations) and portends a higher mortality risk in patients at risk; for instance, hyperkalemia increases the risk of mortality within 1 day of a hyperkalemic event. This review aims to identify the risk factors for high-serum potassium, highlight the risk versus benefit of RAASi in certain patient populations, and outline preventive as well as therapeutic strategies for hyperkalemia. RECENT FINDINGS: A growing body of evidence supports the safety and efficacy of cation-exchange resins, patiromer, or sodium zirconium cyclosilicate, in patients with a compelling indication for RAASi, yet in whom such therapy was complicated by hyperkalemia, allowing these patients to benefit from continued RAASi therapy. In summary, novel cation exchange polymers present the clinician with a new and safe strategy to address hyperkalemia in patients with a compelling indication for ongoing RAASi therapy instead of withdrawal of such therapy.

Treatment-resistant hypertension in the transplant recipient.

Treatment-resistant hypertension (TRH) is defined as follows: (1) the failure to achieve optimal blood pressure control to levels less than 140/90 mm Hg despite the concomitant use of 3 or more different classes of antihypertensive agents, one of which is a diuretic, or (2) the simultaneous use of 4 or more different classes of antihypertensive agents in a patient irrespective of blood pressure control and the exclusion of pseudoresistance. Patients with TRH constitute only a subset of patients with poorly controlled hypertension, which also includes other subsets of patients who are treated inadequately or who are noncompliant with prescribed pharmacologic and nonpharmacologic therapy. TRH does occur in kidney-transplant recipients. This may be related to a variety of factors including reduced renal function, renal artery stenosis, concurrent use of medications that increase blood pressure, lack of use or insufficient use of diuretics, noncompliance related to complex medication regimens, or activated neurohormonal pathways, especially aldosterone or the sympathetic nervous system. After kidney transplantation, normalization of blood pressure occurs only in a minority of patients, and it is estimated that 67% to 90% of kidney transplant patients have arterial hypertension and the improvement in glomerular filtration rate and fluid management offered by the kidney transplant may be offset by a wide array of factors. Epidemiologic studies that describe the prevalence of TRH in kidney transplant recipients are lacking.

Pharmacological strategies for kidney function preservation: are there differences by ethnicity?

The prevalence of chronic kidney disease (CKD) is on the rise in all ethnic groups. This is because of the increased prevalence of obesity, diabetes mellitus, the metabolic syndrome, and the inadequate control of elevated blood pressure and other cardiovascular-renal risk factors, especially in ethnic minority populations. The implications of the aforementioned trends in risk factor prevalence and control are profound. Moreover, these trends negatively impact patient quality of life and place an enormous financial burden on the health care system for the provision of care to patients with CKD, end-stage renal disease (ESRD), and/or cardiovascular disease (CVD). Thus, it is of utmost importance to devise strategies that prevent kidney disease and delay progressive loss of kidney function in persons with CKD. Proven strategies include pharmacological interventions that lower blood pressure to less than target levels (<130/80 mm Hg), attainment of optimal glycemic control (Hb A1c <7%), and reducing urinary protein excretion. It is also possible, although yet unproven, that correction of anemia and aggressive treatment of dyslipidemia may forestall the loss of kidney function. In general, ethnic minorities are underrepresented in most large trials. Recently, a few outcome clinical trials in blacks have reinforced the lessons of kidney function preservation already learned in nonblack populations. That is, the reversible risk factors for CKD appear to be virtually identical and, at least in nondiabetic CKD, pharmacological targeting of the renin-angiotensin-aldosterone system (RAAS) with angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers preserves kidney function better than non-RAAS blood pressure-lowering regimens, especially when significant proteinuria exists. Although more CKD studies in ethnic minorities are needed, until they become available, the best available evidence from the existing clinical trial database should be applied to minorities with CKD-even when specific data are not available for a specific racial or ethnic group. Why this approach? First, there are no known unique risk factors for kidney disease in any ethnic group. Second, poor control of reversible risk factors for CKD is universal, particularly in blacks and other ethnic minorities. Thus, it is logical to predict that more efficient use of strategies proven to forestall loss of kidney function will reduce the excess of CKD and ESRD in ethnic minorities relative to non-minority populations. However, medical-based strategies alone are probably not enough. The global epidemic of obesity will fuel the growing population of persons, especially among ethnic minorities, with diabetes, the main cause of CKD, ESRD, and CVD. The obesity and diabetes epidemics are unlikely to abate without innovative and ultimately effective public health approaches.

RAAS escape: a real clinical entity that may be important in the progression of cardiovascular and renal disease.

Interruption of the renin-angiotensin-aldosterone system (RAAS) at different levels is target-organ protective in several disease states; however, complete blockade is unlikely to be achieved due to escape mechanisms whenever blockade is attempted, incomplete knowledge of the role of all elements of the RAAS, and lack of pharmacotherapy against some elements that have been shown to contribute to disease states. Aldosterone has been overlooked as a mediator of RAAS escape and a key factor in target-organ injury despite the use of available RAAS blockers. Aldosterone is thought to play a role in the development of hypertension, alteration in vascular structure, vascular smooth muscle hypertrophy, endothelial dysfunction, structural renal injury, proteinuria, left ventricular remodeling, collagen synthesis, and myocardial fibrosis. Aldosterone receptor antagonists have been shown to antagonize all these effects in experimental models. Clinical trials with aldosterone antagonists showed an improvement in survival and left ventricular mass index in patients with congestive heart failure, and a reduction in urinary protein excretion and left ventricular mass index in patients with type 2 diabetes and early nephropathy who developed aldosterone synthesis escape. Consequently, aldosterone receptor antagonists may have specific benefits for reducing target-organ injury, particularly if there is evidence of RAAS escape.

Optimizing target-organ protection in patients with diabetes mellitus: angiotensin-converting enzyme inhibitors or angiotensin receptor blockers?

High blood pressure in the setting of type 1 and type 2 diabetes is commonly associated with the earlier development of target-organ damage, including cardiovascular and cerebrovascular disease and progressive renal insufficiency. The major goal of treating high blood pressure in this population is to prevent or reduce the likelihood of target-organ damage. The treatment goal for high blood pressure, therefore, has to be defined based on optimal means of preventing cardiovascular and renal events. The reduction of high blood pressure with pharmacologic therapy is associated with reduction of cardiovascular events, renal disease, and associated mortality. However, many questions remain. Some of the basic and important questions include the following: What should be the goal of treated blood pressure in the diabetic, and are there preferred agents that should be used in the hypertensive diabetic population? How do angiotensin-converting enzyme inhibitors and angiotensin receptor blockers fit in? Are there advantages of one class over the other? The goal of this review is to summarize the recent clinical trial findings and try to provide recommendations based on the evidence of these trials to help the clinician better choose blood pressure goals and treatment strategies in the diabetic population.

Expression of NHERF-1, NHERF-2, PDGFR-alpha, and PDGFR-beta in normal human kidneys and in renal transplant rejection.

Sodium-hydrogen exchanger regulatory factor-1 and -2 (NHERF-1 and NHERF-2) are adaptor proteins that regulate renal electrolyte transport and interact with the platelet-derived growth factor receptors (PDGFR). The distribution of the NHERF proteins and PDGFR was studied in normal human kidneys and in renal transplant rejection using immunocytochemistry. In normal kidneys, NHERF-1 was detected in proximal tubules. NHERF-2 was detected in glomeruli, peritubular capillaries, and collecting duct principal cells. NHERF-2 was also weakly detected in the proximal tubule. PDGFR-beta was detected in glomeruli but not in tubules while PDGFR-alpha was detected in renal tubules and minimally in glomeruli. Acute and chronic transplant rejection was associated with increased expression of PDGFR-alpha in tubules and expression in the glomeruli. PDGFR-beta expression in the glomeruli was increased in transplant rejection and became detectable in tubules. Expression of NHERF-1 and NHERF-2 was not different in the patient groups. These results indicate that in contrast to the rat, both NHERF isoforms are detected in the human proximal tubule. In renal transplant rejection, there is increased expression of both PDGFR subtypes consistent with a role for PDGF in injury or repair.