Acute kidney injury (AKI) is a complex disorder for which currently there is no accepted definition. Having a uniform standard for diagnosing and classifying AKI would enhance our ability to manage these patients. Future clinical and translational research in AKI will require collaborative networks of investigators drawn from various disciplines, dissemination of information via multidisciplinary joint conferences and publications, and improved translation of knowledge from pre-clinical research. We describe an initiative to develop uniform standards for defining and classifying AKI and to establish a forum for multidisciplinary interaction to improve care for patients with or at risk for AKI. Members representing key societies in critical care and nephrology along with additional experts in adult and pediatric AKI participated in a two day conference in Amsterdam, The Netherlands, in September 2005 and were assigned to one of three workgroups. Each group's discussions formed the basis for draft recommendations that were later refined and improved during discussion with the larger group. Dissenting opinions were also noted. The final draft recommendations were circulated to all participants and subsequently agreed upon as the consensus recommendations for this report. Participating societies endorsed the recommendations and agreed to help disseminate the results. The term AKI is proposed to represent the entire spectrum of acute renal failure. Diagnostic criteria for AKI are proposed based on acute alterations in serum creatinine or urine output. A staging system for AKI which reflects quantitative changes in serum creatinine and urine output has been developed. We describe the formation of a multidisciplinary collaborative network focused on AKI. We have proposed uniform standards for diagnosing and classifying AKI which will need to be validated in future studies. The Acute Kidney Injury Network offers a mechanism for proceeding with efforts to improve patient outcomes.

Acute Kidney Injury Network: report of an initiative to improve outcomes in acute kidney injury

Epidemiology of cardiovascular disease in chronic renal disease

BACKGROUND\nStatins reduce the incidence of cardiovascular events in persons with type 2 diabetes mellitus. However, the benefit of statins in such patients receiving hemodialysis, who are at high risk for cardiovascular disease and death, has not been examined.\n\n\nMETHODS\nWe conducted a multicenter, randomized, double-blind, prospective study of 1255 subjects with type 2 diabetes mellitus receiving maintenance hemodialysis who were randomly assigned to receive 20 mg of atorvastatin per day or matching placebo. The primary end point was a composite of death from cardiac causes, nonfatal myocardial infarction, and stroke. Secondary end points included death from all causes and all cardiac and cerebrovascular events combined.\n\n\nRESULTS\nAfter four weeks of treatment, the median level of low-density lipoprotein cholesterol was reduced by 42 percent among patients receiving atorvastatin, and among those receiving placebo it was reduced by 1.3 percent. During a median follow-up period of four years, 469 patients (37 percent) reached the primary end point, of whom 226 were assigned to atorvastatin and 243 to placebo (relative risk, 0.92; 95 percent confidence interval, 0.77 to 1.10; P=0.37). Atorvastatin had no significant effect on the individual components of the primary end point, except that the relative risk of fatal stroke among those receiving the drug was 2.03 (95 percent confidence interval, 1.05 to 3.93; P=0.04). Atorvastatin reduced the rate of all cardiac events combined (relative risk, 0.82; 95 percent confidence interval, 0.68 to 0.99; P=0.03, nominally significant) but not all cerebrovascular events combined (relative risk, 1.12; 95 percent confidence interval, 0.81 to 1.55; P=0.49) or total mortality (relative risk, 0.93; 95 percent confidence interval, 0.79 to 1.08; P=0.33).\n\n\nCONCLUSIONS\nAtorvastatin had no statistically significant effect on the composite primary end point of cardiovascular death, nonfatal myocardial infarction, and stroke in patients with diabetes receiving hemodialysis.

Atorvastatin in Patients With Type 2 Diabetes Mellitus Undergoing Hemodialysis

Heart Disease A Textbook of Cardiovascular Medicine

BACKGROUND\nB-type natriuretic peptide levels are higher in patients with congestive heart failure than in patients with dyspnea from other causes.\n\n\nMETHODS\nWe conducted a prospective, randomized, controlled study of 452 patients who presented to the emergency department with acute dyspnea: 225 patients were randomly assigned to a diagnostic strategy involving the measurement of B-type natriuretic peptide levels with the use of a rapid bedside assay, and 227 were assessed in a standard manner. The time to discharge and the total cost of treatment were the primary end points.\n\n\nRESULTS\nBase-line demographic and clinical characteristics were well matched between the two groups. The use of B-type natriuretic peptide levels reduced the need for hospitalization and intensive care; 75 percent of patients in the B-type natriuretic peptide group were hospitalized, as compared with 85 percent of patients in the control group (P=0.008), and 15 percent of those in the B-type natriuretic peptide group required intensive care, as compared with 24 percent of those in the control group (P=0.01). The median time to discharge was 8.0 days in the B-type natriuretic peptide group and 11.0 days in the control group (P=0.001). The mean total cost of treatment was 5,410 dollars (95 percent confidence interval, 4,516 dollars to 6,304 dollars) in the B-type natriuretic peptide group, as compared with 7,264 dollars (95 percent confidence interval, 6,301 dollars to 8,227 dollars) in the control group (P=0.006). The respective 30-day mortality rates were 10 percent and 12 percent (P=0.45).\n\n\nCONCLUSIONS\nUsed in conjunction with other clinical information, rapid measurement of B-type natriuretic peptide in the emergency department improved the evaluation and treatment of patients with acute dyspnea and thereby reduced the time to discharge and the total cost of treatment.

Use of B-type natriuretic peptide in the evaluation and management of acute dyspnea

Cardiovascular diseases such as coronary artery disease, congestive heart failure, arrhythmias and sudden cardiac death represent main causes of morbidity and mortality in patients with chronic kidney disease (CKD). Pathogenesis includes close linkage between heart and kidneys and involves traditional and non-traditional cardiovascular risk factors. According to a well-established classification of cardiorenal syndrome, cardiovascular involvement in CKD is known as "type-4 cardiorenal syndrome" (chronic renocardiac). The following review makes an overview about epidemiology, pathophysiology, diagnosis and treatment of cardiovascular complications in CKD patients.

Chronic kidney disease and cardiovascular complications.

Cardiovascular diseases represent the main causes of morbidity and mortality in patients with chronic kidney disease (CKD). According to a well-established classification, cardiovascular involvement in CKD can be set in the context of cardiorenal syndrome type 4. Left ventricular hypertrophy (LVH) represents a key feature to provide an accurate picture of systolic-diastolic left heart involvement in CKD patients. Cardiovascular involvement is present in about 80% of prevalent hemodialysis patients, and it is evident in CKD patients since stage IIIb-IV renal disease (according to the K/DOQI CKD classification). According to the definition of cardiorenal syndrome type 4, kidney disease is detected before the development of heart failure, although timing of the diagnosis is not always possible. The evaluation of LVH is a bit heterogeneous, and few standard imaging methods can provide the accuracy of either CT- or MRI-derived left ventricular mass. Key principles in the treatment of LVH in CKD patients are mainly based on anemia and blood pressure control, together with the management of secondary hyperparathyroidism and sudden cardiac death prevention. This review is mainly focused on the clinical aspects of CKD-related LVH to provide practical guidelines both for cardiologists and nephrologists in the daily clinical approach to CKD patients.

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Left Ventricular Hypertrophy in Chronic Kidney Disease Patients: From Pathophysiology to Treatment

Background: Cardiac valve calcifications are present in dialysis patients and regarded as dependent on a deranged mineral metabolism. Few data are available for patients with chronic kidney disease (CKD) not on dialysis. This study evaluates the potential association between the extent of cardiac valve calcification and levels of intact parathyroid hormone (i-PTH), phosphorus, calcium, 25-OH vitamin D, fibroblast growth factor 23 (FGF-23), Klotho and C-reactive protein (CRP) simultaneously measured in patients with mild to moderate CKD. Methods: Consecutive non-hospitalized patients referring to five nephrology units were evaluated. Inclusion criteria were age >18years,CKDStages3–4,andthepresenceofaorticand/ormitralvalvecalcificationassessedbyechocardiographyasroutinely clinical evaluation. Patients underwent clinical examination and routine biochemistry. Baseline i-PTH, phosphorus, calcium, 25-OH vitamin D, FGF-23, Klotho and CRP were simultaneously ascertained. Results: Extent of aortic valve calcification (n=100 patients) was moderate in 68 patients and mild in the remaining patients. Mitral valve calcification (n=96 patients) score was 1, 2 and 3 in 61, 34 and 1 patients, respectively. In univariate analysis, no association was found between extent of mitral valve calcification and markers of mineral metabolism and CRP; aortic valve extent of calcification was positively associated with i-PTH (r 2 =0.212; P =0.03) and FGF-23 (r 2 =0.272;P=0.01), and negatively with Klotho (r 2 = −0.208; P=0.04). In multivariable analysis, extent of aortic valve calcification was associated with FGF-23 (P=0.01) and PTH (P=0.01) levels. Conclusions: Extent of aortic valve calcification is associated to FGF-23 and PTH in naive CKD patients with mild to moderate CKD. Further studies should examine whether FGF-23 assay should be included in routine clinical evaluation of CKD as part of cardiovascular risk stratification.

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Fibroblast growth factor 23 and parathyroid hormone predict extent of aortic valve calcifications in patients with mild to moderate chronic kidney disease

tion (p<0.0001) and phosphorus excretion (p<0.0001) were observed. Conclusions: One-year treatment with a non-calcium- containing phosphate binder may hamper the pro- gression of cardiac valve calcification and slow the decline of renal function, as well as reduce serum con- centration of FGF-23 and CRP and urinary phosphorus excretion. AbstrAct Background: No study has evaluated the efficacy of non-calcium-containing phosphate binders in slowing progression of cardiac valve calcification or deteriora- tion of kidney function in patients with chronic kidney disease not on dialysis. This study addressed these issues. Methods: Outpatients (n = 170) with stage 3-4 chronic kidney disease and either mitral or aortic valve calci- fication were evaluated in this single-center, single- arm, prospective observational study. Patients received sevelamer hydrochloride (1,600 mg/day) for 1 year. Car- diac valve calcification progression was assessed by echocardiography, and decline of renal function by es- timated glomerular filtration rate. Parathyroid hormone, FGF-23 and C-reactive protein (CRP) serum concentra- tion and urinary phosphorus excretion were assayed. Results: At the end of treatment with sevelamer (12th month), mitral valve calcification had decreased by 79.3% from baseline. At baseline, 69 patients had grade 1, 97 patients grade 2 and 4 patients grade 3 calcification scores; at the end of the study, 60 pa- tients showed grade 1, and no mitral valve calcifi- cation was registered in the remaining patients. An aortic valve score of 1 was found in 32%, score of 2 in 58%, score of 3 in 9% and score of 4 in 1% of pa- tients at baseline; at the end of the study, a score of 1 was found in 95% and a score of 2 in 5% of patients. Significant slowing down of renal function decline (p<0.001), reduction of FGF-23 and CRP concentra-

Progression of cardiac valve calcification and decline of renal function in CKD patients.

Pulmonary hypertension is defined as an increased systolic pulmonary pressure of >30 mm Hg, and it shows a 40% prevalence in hemodialysis patients due to vascular access (both central venous catheter and arteriovenous fistula). Secondary pulmonary hypertension in chronic kidney disease patients is strictly related to pulmonary circulation impairment together with chronic volume overload and increased levels of cytokines and growth factors, such as FGF, PDGF, and TGF-β, leading to fibrosis. Endothelial dysfunction, together with lower activation of NOS, increased levels of serum endothelin and fibrin storages, involves an extensive growth of endothelial cells leading to complete obliteration of pulmonary vessels. Pulmonary hypertension has no pathognomonic and distinctive symptoms and signs; standard transthoracic echocardiography allows easy assessment of compliance of the right heart chambers. The therapeutic approach is based on traditional drugs such as digitalis-derived drugs, vasodilatory agents (calcium channel blockers), and oral anticoagulants. New pharmacological agents are under investigation, such as prostaglandin analogues, endothelin receptor blockers, and phosphodiesterase-5 inhibitors.

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Alberto Santoboni

Papers

Chronic kidney disease and cardiovascular complications.

Left Ventricular Hypertrophy in Chronic Kidney Disease Patients: From Pathophysiology to Treatment

Fibroblast growth factor 23 and parathyroid hormone predict extent of aortic valve calcifications in patients with mild to moderate chronic kidney disease

Progression of cardiac valve calcification and decline of renal function in CKD patients.

Pulmonary Hypertension and Right Heart Failure in Chronic Kidney Disease: New Challenge for 21st-Century Cardionephrologists