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1.  KDOQI US Commentary on the 2012 KDIGO Clinical Practice Guideline for Management of Blood Pressure in CKD 
In response to the 2012 KDIGO (Kidney Disease: Improving Global Outcomes) guideline for blood pressure management in patients with chronic kidney disease not on dialysis, the National Kidney Foundation organized a group of US experts in hypertension and transplant nephrology to review the recommendations and comment on their relevancy in the context of current US clinical practice and concerns. The overriding message was the dearth of clinical trial evidence to provide strong evidence-based recommendations. For patients with CKD with normal to mildly increased albuminuria, goal blood pressure has been relaxed to ≤140/90 mm Hg for both diabetic and nondiabetic patients. In contrast, KDIGO continues to recommend goal blood pressure ≤130/80 mm Hg for patients with chronic kidney disease with moderately or severely increased albuminuria and for all renal transplant recipients regardless of the presence of proteinuria, without supporting data. The expert panel thought the KDIGO recommendations were generally reasonable but lacking in sufficient evidence support and that additional studies are greatly needed.
doi:10.1053/j.ajkd.2013.03.018
PMCID: PMC3929429  PMID: 23684145
Kidney Disease: Improving Global Outcomes (KDIGO); guideline; blood pressure
2.  Renin-Angiotensin Inhibition in Diastolic Heart Failure and Chronic Kidney Disease 
The American journal of medicine  2013;126(2):150-161.
BACKGROUND
The role of renin-angiotensin inhibition in older patients with diastolic heart failure and chronic kidney disease remains unclear.
METHODS
Of the 1340 patients (age ≥65 years), with diastolic heart failure (ejection fraction ≥45%) and chronic kidney disease (estimated glomerular filtration rate <60 ml/min/1.73 m2), 717 received angiotensin-converting enzyme inhibitors or angiotensin receptor blockers. Propensity scores for the use of these drugs, estimated for each of the 1340 patients, were used to assemble a cohort of 421 pairs of patients, receiving and not receiving these drugs, who were balanced on 56 baseline characteristics.
RESULTS
During more than 8 years of follow-up, all-cause mortality occurred in 63% and 69% of matched patients with chronic kidney disease receiving and not receiving angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, respectively (hazard ratio {HR}, 0.82; 95% confidence interval {CI}, 0.70–0.97; p=0.021). There was no association with heart failure hospitalization (HR, 0.98; 95% CI, 0.82–1.18; p=0.816). Similar mortality reduction (HR, 0.81; 95% CI, 0.66–0.995; p=0.045) occurred in a subgroup of matched patients with an estimated glomerular filtration rate <45 ml/min/1.73 m2. Among 207 pairs of propensity-matched patients without chronic kidney disease, the use of these drugs was not associated with mortality (HR, 1.03; 95% CI, 0.80–1.33; p=0.826) or heart failure hospitalization (HR, 0.99; 95% CI, 0.76–1.30; p=0.946).
CONCLUSIONS
A discharge prescription for angiotensin-converting enzyme inhibitors or angiotensin receptor blockers was associated with a significant reduction in all-cause mortality in older patients with diastolic heart failure and chronic kidney disease including those with more advanced chronic kidney disease.
doi:10.1016/j.amjmed.2012.06.031
PMCID: PMC3575519  PMID: 23331442
Angiotensin-converting enzyme inhibitors; Angiotensin receptor blockers; Chronic kidney disease; Diastolic heart failure
3.  Effect of Dietary Salt on Regulation of TGF-β in the Kidney 
Seminars in nephrology  2012;32(3):269-276.
Dietary sodium chloride (salt) has long been considered injurious to the kidney by promoting the development of glomerular and tubulointerstitial fibrosis. Endothelial cells throughout the vasculature and glomeruli respond to increased dietary salt intake with increased production of transforming growth factor beta (TGF-β) and nitric oxide (NO). High-salt intake activates large conductance, voltage- and calcium-activated potassium channels (BKCa) channels in endothelial cells. Activation of BKCa channels promotes signaling through proline-rich tyrosine kinase-2 (Pyk2), c-Src, Akt, and mitogen-activated protein kinase (MAPK) pathways that lead to endothelial production of TGF-β and NO. TGF-β signaling is broadly accepted as a strong stimulator of renal fibrosis. The classic description of TGF-β signaling pathology in renal disease involves signaling through Smad proteins resulting in extracellular matrix (ECM) deposition and fibrosis. Active TGF-β1 also causes fibrosis by inducing epithelial-mesenchymal transition (EMT) and apoptosis. By enhancing TGF-β signaling, increased dietary salt intake leads to progressive renal failure from nephron loss and glomerular and tubulointerstitial fibrosis.
doi:10.1016/j.semnephrol.2012.04.006
PMCID: PMC3407676  PMID: 22835458
sodium chloride; salt; transforming growth factor-beta; kidney; fibrosis
4.  Mechanism and prevention of acute kidney injury from cast nephropathy in a rodent model 
The Journal of Clinical Investigation  2012;122(5):1777-1785.
A common renal complication of multiple myeloma is “myeloma kidney,” a condition also known as cast nephropathy. The renal lesions (casts) are directly related to the production of monoclonal immunoglobulin free light chains (FLCs), which coprecipitate with Tamm-Horsfall glycoprotein (THP) in the lumen of the distal nephron, obstructing tubular fluid flow. Here, we report that analysis of the binding interaction between FLCs and THP demonstrates that the secondary structure and key amino acid residues on the complementarity-determining region 3 (CDR3) of FLCs are critically important determinants of the molecular interaction with THP. The findings permitted development of a cyclized competitor peptide that demonstrated strong inhibitory capability in the binding of FLCs to THP in vitro. When used in a rodent model of cast nephropathy, this cyclized peptide construct served as an effective inhibitor of intraluminal cast formation and prevented the functional manifestations of acute kidney injury in vivo. These experiments provide proof of concept that intraluminal cast formation is integrally involved in the pathogenesis of acute kidney injury from cast nephropathy. Further, the data support a clinically relevant approach to the management of renal failure in the setting of multiple myeloma.
doi:10.1172/JCI46490
PMCID: PMC3336971  PMID: 22484815
5.  A reproducible mouse model of chronic allograft nephropathy with vasculopathy 
Kidney international  2012;82(11):1231-1235.
While short-term outcomes in kidney transplantation have improved dramatically, long-term survival remains a major challenge. A key component of long-term, chronic allograft injury in solid organ transplants is arteriosclerosis characterized by vascular neointimal hyperplasia and inflammation. Establishing a model of this disorder would provide a unique tool, not only to identify mechanisms of disease, but also test potential therapeutics for late graft injury. To this end, we utilized a mouse orthotopic renal transplant model in which C57BL/6J (H-2b) recipients were given either a kidney allograft from a completely mismatched Balb/cJ mouse (H-2d), or an isograft from a littermate. A unilateral nephrectomy was performed at the time of transplant followed by a contralateral nephrectomy on post-transplant day seven. Recipients were treated with daily cyclosporine subcutaneously for 14 days and then studied 8 and 12 weeks post transplantation. Renal function was significantly worse in allograft compared to isograft recipients. Moreover, the allografts had significantly more advanced tubulointerstitial fibrosis and profound vascular disease characterized by perivascular leukocytic infiltration and neointimal hyperplasia affecting the intrarenal blood vessels. Thus, we describe a feasible and reproducible murine model of intrarenal transplant arteriosclerosis useful to study allograft vasculopathy.
doi:10.1038/ki.2012.277
PMCID: PMC3495090  PMID: 22874842
6.  Renin-angiotensin inhibition in systolic heart failure and chronic kidney disease 
The American Journal of Medicine  2012;125(4):399-410.
Background
The role of renin-angiotensin inhibition in older systolic heart failure patients with chronic kidney disease remains unclear.
Methods
Of the 1665 patients, age ≥65 years, with systolic heart failure (ejection fraction <45%) and chronic kidney disease (estimated glomerular filtration rate <60 ml/min/1.73 m2), 1046 received angiotensin-converting enzyme inhibitors or angiotensin receptor blockers. Propensity scores for the receipts of these drugs, estimated for each of the 1665 patients, were used to assemble a matched cohort of 444 pairs of patients receiving and not receiving these drugs who were balanced on 56 baseline characteristics.
Results
During over 8 years of follow-up, all-cause mortality occurred in 75% and 79% of matched patients with chronic kidney disease receiving and not receiving angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, respectively (hazard ratio {HR}, 0.86; 95% confidence interval {CI}, 0.74–0.996; p=0.045). There was no significant association with heart failure hospitalization (HR, 0.86; 95% CI, 0.72–1.03; p=0.094). Similar mortality reduction (HR, 0.83; 95% CI, 0.70–1.00; p=0.046) occurred in a subgroup of matched patients with estimated glomerular filtration rate <45 ml/min/1.73 m2. Among 171 pairs of propensity-matched patients without chronic kidney disease, the use of these drugs was associated with significant reduction in all-cause mortality (HR, 0.72; 95% CI, 0.55–0.94; p=0.015) and heart failure hospitalization (HR, 0.71; 95% CI, 0.52–0.95; p=0.023).
Conclusions
Discharge prescription of angiotensin-converting enzyme inhibitors or angiotensin receptor blockers was associated with a significant modest reduction in all-cause mortality in older systolic heart failure patients with chronic kidney disease including those with more advanced chronic kidney disease.
doi:10.1016/j.amjmed.2011.10.013
PMCID: PMC3324926  PMID: 22321760
systolic heart failure; chronic kidney disease; angiotensin-converting enzyme inhibitors; angiotensin receptor blockers
7.  Dietary Salt Intake, Salt Sensitivity and Cardiovascular Health 
Hypertension  2009;53(3):442-445.
doi:10.1161/HYPERTENSIONAHA.108.120303
PMCID: PMC2678240  PMID: 19153264
8.  Enabling innovative translational research in acute kidney injury 
Acute kidney injury (AKI) is a common, heterogeneous and detrimental clinical condition that has significant attributable morbidity and mortality. Despite major advances in understanding the epidemiology, pathogenesis and outcomes of AKI, preventive measures remain inadequate and therapeutic approaches (except for renal replacement therapy) have largely proven futile so far. Critical to the process of designing rational therapies is translational research, which involves the transition between the basic research discoveries and everyday clinical applications to prevent, diagnose and treat human diseases. Progress in innovative approaches has been hampered due in part to the reliance on functional markers (serum creatinine and blood urea nitrogen) that are neither sensitive nor specific to diagnose AKI. This limitation has created a great deal of interest and intense investigation to identify a “troponin-like marker” that would facilitate recognition of AKI and allow for timely implementation of the precise therapeutic agent. The other major obstacle in this field is the diverse and complex nature of AKI that involves multiple independent and overlapping pathways, making it difficult to cure AKI with a single approach. In this review, we will summarize the advances, ongoing studies and future perspectives in the field of translational research of AKI.
doi:10.1111/j.1752-8062.2011.00302.x
PMCID: PMC3292183  PMID: 22376265
9.  Dietary Salt Activates An Endothelial Pyk2/c-Src/PI3-Kinase Complex To Promote Endothelial NO Synthase Phosphorylation 
Hypertension  2008;52(6):1134-1141.
While many laboratories have shown that dietary NaCl (salt) intake increases nitric oxide (NO) production in rodents and humans, the mechanism has not been uncovered. In the present study, pharmacological and dominant-negative strategies were used to show that feeding a formulated diet containing increased amounts of salt to young male Sprague-Dawley rats induced the formation of an endothelial cell-signaling complex that contained proline-rich tyrosine kinase 2 (Pyk2), c-Src (also known as pp60c-src) and phosphatidylinositol 3-kinase (PI3-kinase). In the setting of a high-salt diet, Pyk2 served as the scaffold for c-Src-mediated PI3-kinase activation. PI3-kinase was the upstream activator of protein kinase B (Akt), which was responsible for phosphorylation of the rat endothelial isoform of nitric oxide synthase (NOS3) at S1176 and thereby promoted the increase in NO production. The combined findings illustrated the crucial role for a Pyk2-signaling complex in the endothelial response to salt intake.
doi:10.1161/HYPERTENSIONAHA.108.121582
PMCID: PMC2680421  PMID: 18981321
nitric oxide; cell signaling; cell biology; Animal models of human disease
10.  A Propensity-Matched Study of the Comparative Effectiveness of Angiotensin Receptor Blockers versus Angiotensin-Converting Enzyme Inhibitors in Heart Failure Patients Age ≥65 Years 
The American Journal of Cardiology  2011;108(10):1443-1448.
The comparative effectiveness of angiotensin-converting enzyme inhibitors (ACEIs) versus angiotensin receptor blockers (ARBs) in real-world older heart failure (HF) patients remains unclear. Of the 8049 hospitalized HF patients ≥65 years discharged alive from 106 Alabama hospitals, 4044 received discharge prescriptions of either ACEIs (n=3383) or ARBs (n=661). Propensity scores for ARB use, calculated for each of 4044 patients, were used to match 655 (99% of 661) patients receiving ARBs with 661 patients receiving ACEIs. The assembled cohort of 655 pairs of patients was well-balanced on 56 baseline characteristics. During over 8 years of follow-up, all-cause mortality occurred in 63% and 68% of matched patients receiving ARBs and ACEIs respectively (hazard ratio {HR} associated with ARB use, 0.86; 95% confidence interval {CI}, 0.75–0.99; p=0.031). Among the 956 matched patients with data on left ventricular ejection fraction (LVEF), the association between ARB (versus ACEI) use was significant only in 419 patients with LVEF≥45% (HR, 0.65; 95% CI, 0.51–0.84; p=0.001) but not in the 537 patients with LVEF <45% (HR, 1.00; 95% CI, 0.81–1.23; p=0.999; p for interaction= 0.012). HRs (95% CIs) for HF hospitalization associated with ARBs use were 0.99 (0.86–1.14; p=0.876) overall, 0.80 (0.63–1.03; p=0.080) among those with LVEF≥45% and 1.14 (0.91–1.43; p=0.246) among those with LVEF <45% (p for interaction, 0.060). In conclusion, in older HF patients with preserved LVEF, a discharge prescription of ARBs (versus ACEI) was associated with lower mortality and a trend toward lower HF hospitalization, findings which need replication in other HF populations.
doi:10.1016/j.amjcard.2011.06.066
PMCID: PMC3324349  PMID: 21890091
Heart failure; Older; Mortality; ACEI; ARB
11.  Effect of Aging and Dietary Salt and Potassium Intake on Endothelial PTEN (Phosphatase and Tensin Homolog on Chromosome 10) Function 
PLoS ONE  2012;7(11):e48715.
Aging promotes endothelial dysfunction, defined as a reduction in bioavailable nitric oxide (NO) produced by the endothelial isoform of nitric oxide synthase (NOS3). This enzyme is critically regulated by phosphorylation by protein kinase B (Akt), which in turn is regulated by the lipid phosphatase, PTEN. The present series of studies demonstrated a reduction in bioavailable NO as the age of rats increased from 1 to 12 months. At 12 months of age, rats no longer demonstrated increases in phosphorylated NOS3 in response to high dietary salt intake. Endothelial cell levels of PTEN increased with age and became refractory to change with increased salt intake. In contrast to the reduction in NO production, endothelial cell production of transforming growth factor-ß (TGF-ß) relative to NO increased progressively with age. In macrovascular endothelial cells, PTEN was regulated in a dose-dependent fashion by TGF-ß, which was further regulated by extracellular [KCl]. When combined with prior studies, the present series of experiments suggested an integral role for PTEN in endothelial cell pathobiology of aging and an important mitigating function of TGF-ß in endothelial PTEN regulation. The findings further supported a role for diet in affecting vascular function through the production of TGF-ß and NO.
doi:10.1371/journal.pone.0048715
PMCID: PMC3492426  PMID: 23144940
12.  Detection of early changes in renal function using 99mTc-MAG3 imaging in a murine model of ischemia-reperfusion injury 
Accurate determination of renal function in mice is a major impediment to the use of murine models in acute kidney injury. The purpose of this study was to determine whether early changes in renal function could be detected using dynamic gamma camera imaging in a mouse model of ischemia-reperfusion (I/R) injury. C57BL/6 mice (n = 5/group) underwent a right nephrectomy, followed by either 30 min of I/R injury or sham surgery of the remaining kidney. Dynamic renal studies (21 min, 10 s/frame) were conducted before surgery (baseline) and at 5, 24, and 48 h by injection of 99mTc-mercaptoacetyltriglycine (MAG3; ~1.0 mCi/mouse) via the tail vein. The percentage of injected dose (%ID) in the kidney was calculated for each 10-s interval after MAG3 injection, using standard region of interest analyses. A defect in renal function in I/R-treated mice was detected as early as 5 h after surgery compared with sham-treated mice, identified by the increased %ID (at peak) in the I/R-treated kidneys at 100 s (P < 0.01) that remained significantly higher than sham-treated mice for the duration of the scan until 600 s (P < 0.05). At 48 h, the renal scan demonstrated functional renal recovery of the I/R mice and was comparable to sham-treated mice. Our study shows that using dynamic imaging, renal dysfunction can be detected and quantified reliably as early as 5 h after I/R insult, allowing for evaluation of early treatment interventions.
doi:10.1152/ajprenal.00083.2007
PMCID: PMC3373432  PMID: 17634403
acute kidney injury; nuclear imaging; mice models of acute renal failure
13.  Hyperuricaemia, chronic kidney disease, and outcomes in heart failure: potential mechanistic insights from epidemiological data 
European Heart Journal  2011;32(6):712-720.
Aim
To determine if the association between hyperuricaemia and poor outcomes in heart failure (HF) varies by chronic kidney disease (CKD).
Methods and results
Of the 2645 systolic HF patients in the Beta-Blocker Evaluation of Survival Trial with data on baseline serum uric acid, 1422 had hyperuricaemia (uric acid ≥6 mg/dL for women and ≥8 mg/dL for men). Propensity scores for hyperuricaemia, estimated for each patient, were used to assemble a matched cohort of 630 pairs of patients with and without hyperuricaemia who were balanced on 75 baseline characteristics. Associations of hyperuricaemia with outcomes during 25 months of median follow-up were examined in all patients and in those with and without CKD (estimated glomerular filtration rate of <60 mL/min/1.73 m2). Hyperuricaemia-associated hazard ratios (HRs) and 95% confidence intervals (CI) for all-cause mortality and HF hospitalization were 1.44 (1.12–1.85, P = 0.005) and 1.27 (1.02–1.58, P = 0.031), respectively. Hazard ratios (95% CIs) for all-cause mortality among those with and without CKD were 0.96 (0.70–1.31, P = 0.792) and 1.40 (1.08–1.82, P = 0.011), respectively (P for interaction, 0.071), and those for HF hospitalization among those with and without CKD were 0.99 (0.74–1.33, P = 0.942) and 1.49 (1.19–1.86, P = 0.001), respectively (P for interaction, 0.033).
Conclusion
Hyperuricaemia has a significant association with poor outcomes in HF patients without CKD but not in those with CKD, suggesting that hyperuricaemia may predict poor outcomes when it is primarily a marker of increased xanthine oxidase activity, but not when it is primarily due to impaired renal excretion of uric acid.
doi:10.1093/eurheartj/ehq473
PMCID: PMC3056205  PMID: 21199831
Heart failure; Hyperuricaemia; Chronic kidney disease; Outcomes
14.  Mechanisms and Consequences of Salt Sensitivity and Dietary Salt Intake 
Purpose of review
Investigation into the underlying mechanisms of salt sensitivity has made important advances in recent years. This review examines in particular the effects of sodium and potassium on vascular function.
Recent findings
Sodium chloride (salt) intake promotes cutaneous lymphangiogenesis mediated through tissue macrophages and directly alters endothelial cell function, promoting increased production of transforming growth factor-β (TGF-β) and nitric oxide (NO). In the setting of endothelial dysfunction, such as occurs with aging, diminished NO production exacerbates the vascular effects of TGF-β, promoting decreased arterial compliance and hypertension. Dietary potassium intake may serve as an important countervailing influence on the effects of salt in the vasculature.
Summary
There is growing appreciation that, independently of alterations in blood pressure, dietary intake of sodium and potassium promote functional changes in the vasculature and lymphatic system. These changes may serve as compensatory changes that protect against development of salt-sensitive hypertension. While salt sensitivity cannot be ascribed exclusively to these factors, perturbation of these processes promote hypertension during high-salt intake. These studies add to the list of genetic and environmental factors that are associated with salt sensitivity, but in particular provide insight into adaptive mechanisms during high salt intake.
doi:10.1097/MNH.0b013e32834122f1
PMCID: PMC3089903  PMID: 21088577
dietary sodium; dietary potassium; nitric oxide; TGF-β; arterial compliance
15.  Mild hyperkalemia and outcomes in chronic heart failure: A propensity matched study 
International journal of cardiology  2009;144(3):383-388.
Background
Compared with serum potassium levels 4–5.5 mEq/L, those <4 mEq/L have been shown to increase mortality in chronic heart failure (HF). Expert opinions suggest that serum potassium levels >5.5 mEq/L may be harmful in HF. However, little is known about the safety of serum potassium 5–5.5 mEq/L.
Methods
Of the 7788 chronic HF patients in the Digitalis Investigation Group trial, 5656 had serum potassium 4–5.5 mEq/L. Of these, 567 had mild hyperkalemia (5–5.5 mEq/L) and 5089 had normokalemia (4–4.9 mEq/L). Propensity scores for mild hyperkalemia were used to assemble a balanced cohort of 548 patients with mild hyperkalemia and 1629 patients with normokalemia. Cox regression models were used to estimate hazard ratios (HR) and 95% confidence intervals (CI) for association between mild hyperkalemia and mortality during a median follow-up of 38 months.
Results
All-cause mortality occurred in 36% and 38% of matched patients with normokalemia and mild hyperkalemia respectively (HR, 1.07; 95% CI, 0.90–1.26; P= 0.458). Unadjusted, multivariable-adjusted, and propensity-adjusted HRs for mortality associated with mild hyperkalemia were 1.33 (95% CI, 1.15–1.52; P<0.0001), 1.16 (95% CI, 1.01–1.34; P=0.040) and 1.13 (95% CI, 0.98–1.31; P=0.091) respectively. Mild hyperkalemia had no association with cardiovascular or HF mortality or all-cause or cardiovascular hospitalization.
Conclusion
Serum potassium 4–4.9 mEq/L is optimal and 5–5.5 mEq/L appears relatively safe in HF. Despite lack of an intrinsic association, the bivariate association of mild-hyperkalemia with mortality suggests that it may be useful as a biomarker of poor prognosis in HF.
doi:10.1016/j.ijcard.2009.04.041
PMCID: PMC2888731  PMID: 19500863
Mild hyperkalemia; heart failure; mortality; hospitalization
16.  Association between hyperuricemia and incident heart failure among older adults: A propensity-matched study 
International journal of cardiology  2009;142(3):279-287.
Background
The association between hyperuricemia and incident heart failure (HF) is relatively unknown.
Methods
Of the 5461 community-dwelling older adults, ≥65 years, in the Cardiovascular Health Study without HF at baseline, 1505 had hyperuricemia (baseline serum uric acid ≥6 mg/dL for women and ≥7 mg/dL for men). Using propensity scores for hyperuricemia, estimated for each participant using 64 baseline covariates, we were able to match 1181 pairs of participants with and without hyperuricemia.
Results
Incident HF occurred in 21% and 18% of participants respectively with and without hyperuricemia during 8.1 years of mean follow-up (hazard ratio {HR} for hyperuricemia versus no hyperuricemia, 1.30; 95% confidence interval {CI}, 1.05–1.60; P=0.015). The association between hyperuricemia and incident HF was significant only in subgroups with normal kidney function (HR, 1.23; 95% CI, 1.02–1.49; P=0.031), without hypertension (HR, 1.31; 95% CI, 1.03–1.66; P=0.030), not receiving thiazide diuretics (HR, 1.20; 95% CI, 1.01–1.42; P=0.044), and without hyperinsulinemia (HR, 1.35; 95% CI, 1.06–1.72; P=0.013). Used as a continuous variable, each 1 mg/dL increase in serum uric acid was associated with a 12% increase in incident HF (HR, 1.12; 95% CI, 1.03–1.22; P=0.006). Hyperuricemia had no association with acute myocardial infarction or all-cause mortality.
Conclusions
Hyperuricemia is associated with incident HF in community-dwelling older adults. Cumulative data from our subgroup analyses suggest that this association is only significant when hyperuricemia is a marker of increased xanthine oxidase activity but not when hyperuricemia is caused by impaired renal elimination of uric acid.
doi:10.1016/j.ijcard.2009.01.010
PMCID: PMC2906633  PMID: 19201041
Uric acid; incident heart failure; kidney function; propensity score
17.  Hypokalemia and Outcomes in Patients with Chronic Heart Failure and Chronic Kidney Disease: Findings from Propensity-Matched Studies 
Circulation. Heart failure  2010;3(2):253-260.
Background
Little is known about the effects of hypokalemia on outcomes in patients with chronic heart failure (HF) and chronic kidney disease (CKD).
Methods and Results
Of the 7788 chronic HF patients in the Digitalis Investigation Group trial, 2793 had CKD, defined as estimated glomerular filtration rate (eGFR) <60 ml/min/1.73 m2. Of these, 527 had hypokalemia (serum potassium <4 mEq/L) and 2266 had normokalemia (4–4.9 mEq/L). Propensity scores for hypokalemia were used to assemble a balanced cohort of 522 pairs of patients with hypokalemia and normokalemia. All-cause mortality occurred in 48% and 36% of patients with hypokalemia and normokalemia respectively during 57 months of follow-up (matched hazard ratio {HR} when hypokalemia was compared with normokalemia, 1.56, 95% confidence interval {CI}, 1.25–1.95; P<0.0001). Matched HR’s (95% CI’s) for cardiovascular and HF mortalities, and all-cause, cardiovascular and HF hospitalizations were 1.65 (1.29–2.11; P<0.0001), 1.82 (1.28–2.57; P<0.0001), 1.16 (1.00–1.35; P=0.036), 1.27 (1.08–1.50; P=0.004) and 1.29 (1.05–1.58; P=0.014) respectively. Among 453 pairs of balanced patients with HF and CKD, all-cause mortality occurred in 47% and 38% of patients with mild hypokalemia (3.5–3.9 mEq/L) and normokalemia respectively (matched HR, 1.31, 95% CI, 1.03–1.66; P=0.027). Among 169 pairs of balanced patients with eGFR <45 ml/min/1.73 m2, all-cause mortality occurred in 57% and 47% of patients with hypokalemia (<4 mEq/L) and normokalemia respectively (matched HR, 1.53, 95% CI, 1.07–2.19; P=0.020).
Conclusions
In patients with HF and CKD, hypokalemia is common and associated with increased mortality and hospitalization.
doi:10.1161/CIRCHEARTFAILURE.109.899526
PMCID: PMC2909749  PMID: 20103777
18.  Potassium Inhibits Dietary Salt-Induced Transforming Growth Factor-β Production 
Hypertension  2009;54(5):1159-1163.
Human and animal studies demonstrate an untoward effect of excess dietary NaCl (salt) intake on cardiovascular function and life span. The endothelium in particular augments the production of transforming growth factor (TGF)-β, a fibrogenic growth factor, in response to excess dietary salt intake. This study explored the initiating mechanism that regulates salt-induced endothelial cell production of TGF-β. Male Sprague-Dawley rats were given diets containing different amounts of NaCl and potassium for 4 days. A bioassay for TGF-β demonstrated increased (35.2%) amounts of active TGF-β in the medium of aortic ring segments from rats on the high-salt diet compared with rats maintained on a 0.3% NaCl diet. Inhibition of the large-conductance, calcium-activated potassium channel inhibited dietary salt-induced vascular production of TGF-β but did not affect production of TGF-β by ring segments from rats on the low-salt diet. Immunohistochemical and Western analyses demonstrated the α subunit of the calcium-activated potassium channel in endothelial cells. Increasing medium [K+] inhibited production of dietary salt-induced vascular production levels of total and active TGF-β but did not alter TGF-β production by aortic rings from rats on the 0.3% NaCl diet. Increasing dietary potassium content decreased urinary active TGF-β in animals receiving the high-salt diet but did not change urinary active TGF-β in animals receiving the low-salt diet. The findings demonstrated an interesting interaction between the dietary intake of potassium and excess NaCl and further showed the fundamental role of the endothelial calcium-activated potassium channel in the vascular response to excess salt intake.
doi:10.1161/HYPERTENSIONAHA.109.138255
PMCID: PMC2766016  PMID: 19738156
dietary sodium chloride; potassium channel; endothelium; aorta; iberiotoxin; physiology
19.  Isolated Systolic Hypertension and Incident Heart Failure in Older Adults: A Propensity-Matched Study 
Hypertension  2009;53(3):458-465.
The association between isolated systolic hypertension (ISH) and incident heart failure (HF) has not been prospectively studied in a propensity-matched population of ambulatory older adults. Of the 5,795 participants in the public-use copy of the Cardiovascular Health Study (CHS) dataset, 5248 has diastolic blood pressure <90 mm Hg and were free of HF at baseline. Of these, 2000 (38%) has ISH, defined as average seated systolic blood pressure ≥ 140 mm Hg. Propensity scores for baseline ISH were calculated for each participant (based on 64 baseline covariates), and were used to match 1,260 pairs of participants with and without ISH. Matched Cox regression models were used to estimate association of ISH with incident HF during a mean follow-up of 8.7 years. Matched participants (n=2,520) had a mean (±SD) age of 74 (±6) years, 60% were women, 16% were nonwhites, 18% developed new-onset HF, and 35% died. Incident HF developed in 20% (rate, 242/10,000 person-years) and 16% (rate, 194/10,000 person-years) of participants with and without ISH respectively (matched hazard ratio {HR} when ISH was compared with no-ISH, 1.26; 95% confidence interval {CI}, 1.04–1.51; P=0.016). Pre-match unadjusted, multivariable-adjusted and propensity-adjusted HRs (95% CI) for ISH-associated incident HF were respectively 1.72 (1.51–1.97; P<0.0001), 1.35 (1.18–1.56; P<0.0001) and 1.22 (1.04–1.44; P=0.016). ISH had no association with all-cause mortality (matched HR, 1.03; 95% CI, 0.88–1.19; P=0.732). In conclusion, in a propensity-matched cohort of community-dwelling older adults who were well-balanced in 64 baseline covariates, ISH was associated with increased risk of incident HF but had no association with all-cause mortality.
doi:10.1161/HYPERTENSIONAHA.108.119792
PMCID: PMC2887759  PMID: 19188527
Heart failure; isolated systolic hypertension; mortality; coronary artery disease; cerebrovascular disease; propensity score
20.  Association of chronic kidney disease with outcomes in chronic heart failure: a propensity-matched study 
Background. Chronic kidney disease (CKD) is associated with increased mortality in patients with heart failure (HF). However, its association with hospitalization in HF patients has not been well studied.
Methods. Of 7788 patients in the Digitalis Investigation Group trial, 3527 had CKD, defined by an estimated glomerular filtration rate (GFR) <60 ml/min/1.73 m2 body surface area (BSA). Propensity scores for CKD were calculated using a multivariable logistic regression model and used to match 2399 pairs of patients with and without CKD. Matched Cox regression analyses were used to estimate association of CKD with outcomes.
Results. All-cause hospitalization occurred in 1636 (rate, 4233/10 000 person-years) and 1587 (rate, 3733/10 000 person-years) patients respectively, with and without CKD (matched hazard ratio [HR] for CKD, 1.18, 95% confidence interval [CI], 1.08–1.29; P < 0.0001). Matched HR for cardiovascular and HF hospitalization were respectively 1.17 (95% CI, 1.06–1.28, P = 0.002) and 1.28 (95% CI, 1.13–1.45, P < 0.0001). Compared to GFR ≥60 ml/min/1.73 m2 BSA, HR for all-cause hospitalization for GFR 45–59 and <45 ml/min/1.73 m2 BSA were respectively 1.04 (95% CI, 0.94–1.16; P = 0.422) and 1.58 (95% CI, 1.34–1.87; P < 0.0001). Similarly, HR for all-cause death for GFR 45–59 and <45 ml/min/1.73 m2 BSA were respectively 1.03 (95% CI, 0.90–1.18; P = 0.651) and 1.70 (95% CI, 1.40–2.07; P < 0.0001). Matched HR for death due to cardiovascular causes and progressive HF were respectively 1.24 (95% CI, 1.09–1.40; P = 0.001) and 1.42 (95% CI, 1.16–1.72; P = 0.001).
Conclusion. CKD was associated with increased mortality and hospitalization in ambulatory patients with chronic HF, which increased progressively with worsening kidney function.
doi:10.1093/ndt/gfn445
PMCID: PMC2721423  PMID: 18711222
chronic kidney disease; heart failure; hospitalization; mortality
21.  Chronic Kidney Disease Associated Mortality in Diastolic Versus Systolic Heart Failure: A Propensity Matched Study 
Chronic kidney disease (CKD) is common and associated with increased mortality in heart failure (HF). However, it is unknown whether the effect of CKD on mortality varies by left ventricular ejection fraction (LVEF). We evaluated the effect of CKD on mortality in systolic (LVEF ≤45%) and diastolic (LVEF >45%) HF patients. Of the 7788 patients in the Digitalis Investigation Group trial, 3527 (45%) had CKD (estimated glomerular filtration rate <60 ml/min/1.73m2). We calculated propensity score for CKD for each patient, using a multivariable logistic regression model (c statistic=0.76; post-match absolute standardized differences <5% for all 32 covariates). We matched 2399 pairs of patients with and without CKD with similar propensity scores. There were 757 (rate, 1,049/10,000 person-year) and 882 (rate, 1,282/10,000 person-year) deaths respectively in patients without and with CKD (hazard ratio=1.22, 95% confidence interval {CI}=1.09–1.36; p<0.0001). CKD-associated mortality was higher in diastolic HF (371 extra deaths/10,000 person-year; hazard ratio=1.71; 95% CI=1.21–2.41; p=0.002) than in systolic HF (214 extra deaths/10,000 person-year; hazard ratios =1.19; 95% CI =1.07–1.32; p=0.001), which was significant (adjusted p for interaction=0.034). There was a graded association between CKD-related deaths and LVEF. Hazard ratios (95% CI) for CKD-associated mortality for LVEF subgroups <35%, 35–55% and >55% were respectively 1.15 (1.02–1.29), 1.35 (1.11–1.64), and 2.33 (1.34–4.06). In conclusion, CKD-associated mortality was higher in diastolic than in systolic HF. Diastolic HF patients should be evaluated for CKD and the role of inhibitors of the renin-angiotensin system in these patients needs to be investigated.
doi:10.1016/j.amjcard.2006.08.042
PMCID: PMC2708087  PMID: 17261405
heart failure; chronic kidney disease; ejection fraction; and mortality
22.  Activation of the Fas/Fas ligand pathway in hypertensive renal disease in Dahl/Rapp rats 
BMC Nephrology  2002;3:1.
Background
Hypertensive nephrosclerosis is the second most common cause of end-stage renal failure in the United States. The mechanism by which hypertension produces renal failure is incompletely understood. Recent evidence demonstrated that an unscheduled and inappropriate increase in apoptosis occurred in the Dahl/Rapp rat, an inbred strain of rat that uniformly develops hypertension and hypertensive nephrosclerosis; early correction of the hypertension prevents the renal injury. The present study examined the role of the Fas/FasL pathway in this process.
Methods
Young male Dahl/Rapp salt-sensitive (S) and Sprague-Dawley rats were fed diets that contained 0.3% or 8.0% NaCl diets. Kidneys were examined at days 7 and 21 of the study.
Results
An increase in Fas and FasL expression was observed in glomerular and tubular compartments of kidneys of hypertensive S rats, whereas dietary salt did not change expression of either of these molecules in normotensive Sprague-Dawley rats. Associated with this increase was cleavage of Bid and activation of caspase-8, the initiator caspase in this apoptotic pathway, by day 21 of the study.
Conclusions
Augmented expression of apoptotic signaling by the Fas/FasL pathway occurred during development of end-stage renal failure in this model of hypertensive nephrosclerosis.
doi:10.1186/1471-2369-3-1
PMCID: PMC64784  PMID: 11818026
23.  The pathogenesis and diagnosis of acute kidney injury in multiple myeloma 
Nature Reviews. Nephrology  2011;8(1):43-51.
Renal failure remains a principal cause of morbidity for patients with multiple myeloma. Once reversible factors such as hypercalcemia have been corrected, the most common cause of severe renal failure in these patients is a tubulointerstitial pathology that results from the very high circulating concentrations of monoclonal immunoglobulin free light chains. These endogenous proteins can result in isolated proximal tubule cell cytotoxicity, tubulointerstitial nephritis and cast nephropathy (myeloma kidney). Less frequently, high levels of free light chains can lead to immunoglobulin light chain amyloidosis and light chain deposition disease, although these conditions are usually associated with insidious progression of renal failure rather than acute kidney injury. Unless there is rapid intervention, progressive and irreversible damage occurs, particularly interstitial fibrosis and tubular atrophy. Despite advances in our understanding of the pathogenesis of these processes there has been a gap in translating these achievements into improved patient outcomes. The International Kidney and Monoclonal Gammopathy Research Group was formed to address this need. In this Review, we discuss the mechanisms of disease and diagnostic approaches to patients with acute kidney injury complicating multiple myeloma.
doi:10.1038/nrneph.2011.168
PMCID: PMC3375610  PMID: 22045243
24.  Relationship between Stage of Kidney Disease and Incident Heart Failure in Older Adults 
American Journal of Nephrology  2011;34(2):135-141.
Background
The relationship between stage of chronic kidney disease (CKD) and incident heart failure (HF) remains unclear.
Methods
Of the 5,795 community-dwelling adults ≥65 years in the Cardiovascular Health Study, 5,450 were free of prevalent HF and had baseline estimated glomerular filtration rate (eGFR: ml/min/1.73 m2) data. Of these, 898 (16%) had CKD 3A (eGFR 45–59 ml/min/1.73 m2) and 242 (4%) had CKD stage ≥3B (eGFR <45 ml/min/1.73 m2). Data on baseline proteinuria were not available and 4,310 (79%) individuals with eGFR ≥60 ml/min/1.73 m2 were considered to have no CKD. Propensity scores estimated separately for CKD 3A and ≥3B were used to assemble two cohorts of 1,714 (857 pairs with CKD 3A and no CKD) and 557 participants (148 CKD ≥3B and 409 no CKD), respectively, balanced on 50 baseline characteristics.
Results
During 13 years of follow-up, centrally-adjudicated incident HF occurred in 19, 24 and 38% of pre-match participants without CKD (reference), with CKD 3A [unadjusted hazard ratio (HR) 1.40; 95% confidence interval (CI) 1.20–1.63; p < 0.001] and with CKD ≥3B (HR 3.37; 95% CI 2.71–4.18; p < 0.001), respectively. In contrast, among matched participants, incident HF occurred in 23 and 23% of those with CKD 3A and no CKD, respectively (HR 1.03; 95% CI 0.85–1.26; p = 0.746), and 36 and 28% of those with CKD ≥3B and no CKD, respectively (HR 1.44; 95% CI 1.04–2.00; p = 0.027).
Conclusions
Among community-dwelling older adults, CKD is a marker of incident HF regardless of stage; however, CKD ≥3B, not CKD 3A, has a modest independent association with incident HF.
doi:10.1159/000328905
PMCID: PMC3136373  PMID: 21734366
Chronic kidney disease; Heart failure
25.  Downregulation of FIP200 Induces Apoptosis of Glioblastoma Cells and Microvascular Endothelial Cells by Enhancing Pyk2 Activity 
PLoS ONE  2011;6(5):e19629.
The expression of focal adhesion kinase family interacting protein of 200-kDa (FIP200) in normal brain is limited to some neurons and glial cells. On immunohistochemical analysis of biopsies of glioblastoma tumors, we detected FIP200 in the tumor cells, tumor-associated endothelial cells, and occasional glial cells. Human glioblastoma tumor cell lines and immortalized human astrocytes cultured in complete media also expressed FIP200 as did primary human brain microvessel endothelial cells (MvEC), which proliferate in culture and resemble reactive endothelial cells. Downregulation of endogenous expression of FIP200 using small interfering RNA resulted in induction of apoptosis in the human glioblastoma tumor cells, immortalized human astrocytes, and primary human brain MvEC. It has been shown by other investigators using cells from other tissues that FIP200 can interact directly with, and inhibit, proline-rich tyrosine kinase 2 (Pyk2) and focal adhesion kinase (FAK). In the human glioblastoma tumor cells, immortalized human astrocytes, and primary human brain MvEC, we found that downregulation of FIP200 increased the activity of Pyk2 without increasing its expression, but did not affect the activity or expression of FAK. Coimmunoprecipitation and colocalization studies indicated that the endogenous FIP200 was largely associated with Pyk2, rather than FAK, in the glioblastoma tumor cells and brain MvEC. Moreover, the pro-apoptotic effect of FIP200 downregulation was inhibited significantly by a TAT-Pyk2-fusion protein containing the Pyk2 autophosphorylation site in these cells. In summary, downregulation of endogenous FIP200 protein in glioblastoma tumor cells, astrocytes, and brain MvECs promotes apoptosis, most likely due to the removal of a direct interaction of FIP200 with Pyk2 that inhibits Pyk2 activation, suggesting that FIP200 expression may be required for the survival of all three cell types found in glioblastoma tumors.
doi:10.1371/journal.pone.0019629
PMCID: PMC3094350  PMID: 21602932

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