From cardiorenal syndrome to nephrocardiology: The journey of exploring the interconnection between nephrology and cardiovascular medicine.

The knowledge about the pathophysiology of cardiorenal syndrome has evolved remarkably over the past two decades. However, cardiorenal syndrome is only one subject within a much broader field of nephrocardiology, which encompasses the interconnection between nephrology and cardiovascular medicine from nine different standpoints of pathophysiology, epidemiology, prevention, prognosis, diagnosis, therapy, monitoring, risk factors and systemic diseases. The complexities of these nine elements of the interaction between nephrology and cardiovascular medicine are not adequately addressed in either of those two fields of medicine. Nephrocardiology is an emerging field in medicine aiming at addressing those subtleties to improve prognosis and quality of life of a large and vulnerable patient population with combined cardiovascular and nephrology related conditions.

Introduction to Nephrocardiology.

The interaction between nephrology and cardiovascular medicine is much broader than the cardiorenal syndrome. Many different aspects of cardiovascular medicine are interconnected with and substantially influenced by the conditions that fall into the realm of nephrology, and vice versa. Those aspects include pathophysiology, risk factors, epidemiology, prognosis, prevention, diagnosis, monitoring, and therapy. Discovery of the interconnected areas and development of appropriate knowledge and skill to optimally approach those circumstances can improve the quality of care and outcome of a large population of patients. Therefore, establishment of the distinct subspeciality of nephrocardiology is imperative.

Cardiorenal Syndrome: An Important Subject in Nephrocardiology.

Coexisting dysfunction of heart and kidney, the cardiorenal syndrome, is a common condition and is associated with worsening of outcomes and complexities of diagnostic, preventive, and therapeutic approaches. The knowledge of the physiology of heart and kidney and their interaction with each other and with other organ systems has progressed significantly in recent years, resulting in a better understanding of the pathogenesis of cardiorenal syndrome. A robust knowledge of the pathophysiology and of the latest practical advancements about cardiorenal syndrome is necessary for cardiologists, nephrologists, and other practitioners who provide medical care to the patients with heart and kidney diseases.

Iron indices and survival in maintenance hemodialysis patients with and without polycystic kidney disease.

BACKGROUND: Anemia is less prominent in patients with polycystic kidney disease (PKD). Such iron indices as ferritin and transferrin saturation (TSAT) values are used to guide management of anemia in individuals on maintenance hemodialysis (MHD). Optimal levels of correction of anemia and optimal levels of TSAT and ferritin are unclear in chronic kidney disease patients and have not been studied specifically in PKD. METHODS: We studied 2969 MHD patients with and 128 054 patients without PKD from 580 outpatient hemodialysis facilities between July 2001 and June 2006. Using baseline, time-dependent and time-averaged values with unadjusted and multivariable adjusted analysis models, the survival predictabilities of TSAT and ferritin were studied. RESULTS: PKD patients were 58 ± 13 years old and included 46% women, whereas non-PKD patients were 62 ± 15 years old and 45% women. In both PKD and non-PKD patients, a time-averaged TSAT between 30 and 40% was associated with the lowest mortality. Time-averaged ferritin between 100 and <800 ng/mL was associated with the lowest mortality in PKD patients, although this range was 500 to <800 ng/mL in non-PKD patients. CONCLUSIONS: In MHD patients with and without PKD, there was a U-shaped relationship between the average TSAT and mortality, and a TSAT of 30-40% was associated with the best survival. However, an average ferritin of 100-800 ng/mL was associated with the best survival in PKD patients, whereas that of non-PKD patients was 500-800 ng/mL. Further studies in PKD and non-PKD patients are necessary to determine whether or not therapeutic attempts to keep TSAT and ferritin levels in these ranges will improve survival.

Differences in clinical profile of African-American women with peripartum cardiomyopathy in the United States.

BACKGROUND: Peripartum cardiomyopathy (PPCM) is a rare and heterogeneous disease with a higher prevalence in African Americans (AAs) in the USA. The clinical features and prognosis of PPCM in AAs have not been sufficiently characterized. METHODS: We studied 52 AA patients with PPCM and compared clinical characteristics and outcome with those of 104 white patients. RESULTS: AA patients were significantly younger (26 ± 7 vs 30 ± 6 years; P < .001), had a higher prevalence of gestational hypertension (61% vs 41%; P = .03), and were diagnosed more commonly postpartum rather then antepartum (83% vs 64%; P = .03). The rate of left ventricular (LV) recovery (LV ejection fraction [LVEF] ≥50%) was significantly lower in AAs (40% vs 61%; P = .02). AA women also had a larger LV end-diastolic diameter (57 ± 10 vs 51 ± 6 mm; P = .004) as well as lower LVEF (40% ± 16.7% vs 46% ± 14%; P = .002) at the last follow-up. Moreover, AA patients had a significantly higher incidence of the combined end points of mortality and cardiac transplantation (P = .03) and showed a strong trend (P = .09) for increased mortality. CONCLUSIONS: AA patients with PPCM in the USA have a different clinical profile and worse prognosis compared with white patients. Further research to evaluate potentially correctable causes for these differences is warranted.

Recipient-related predictors of kidney transplantation outcomes in the elderly.

BACKGROUND: It is not clear whether in old people with end-stage renal disease kidney transplantation is superior to dialysis therapy. METHODS: We compared mortality rates between kidney transplant recipients (KTRs) and the general population across different age categories. We also examined patient and allograft survival in 15 667 elderly KTRs (65-<90 yr old, 36% female) within three age subgroups (65-<70, 70-<75, and ≥75 yr). RESULTS: The rise in the relative risk of death in older age groups was substantially less in KTRs than in the general population, that is, 1.8 and 2.0 vs. 21.4 and 76.6 in those aged 65-<75 and ≥75 yr, respectively, compared with 15- to <65-yr-old people (reference group). In 65- to <70-yr-old KTRs, obesity (BMI>30 kg/m(2) ) was associated with 19% higher risk of graft failure (HR: 1.19 [1.07-1.33], p = 0.002). Diabetes was a predictor of worse patient survival in all age groups but poorer allograft outcome in the youngest age group (65-<70 yr old) only. None of the examined risk factors affected allograft outcome in the oldest group (≥75 yr old) although there was a 49% lower trend of graft failure in very old Hispanic recipients (HR: 0.51 [0.26-1.01], p = 0.05). CONCLUSIONS: Kidney transplantation may attenuate the age-associated increase in mortality, and its superior survival gain is most prominent in the oldest recipients (≥75 yr old). The potential protective effect of kidney transplantation on longevity in the elderly deserves further investigation.

Association of coronary artery calcium score and vascular dysfunction in long-term hemodialysis patients.

Long-term hemodialysis patients are prone to an exceptionally high burden of cardiovascular disease and mortality. The novel temperature-based technology of digital thermal monitoring (DTM) of vascular reactivity appears associated with the severity of coronary artery disease in asymptomatic population. We hypothesized that in hemodialysis patients, the DTM and coronary artery calcium (CAC) score have a gradient association that follows that of subjects without kidney disease. We examined the cross-sectional DTM-CAC associations in a group of long-term hemodialysis patients, and their 1:1 matched normal counterpart. Area under the curve for temperature (TMP-AUC), the surrogate of the DTM index of vascular function, was assessed after a 5-minute arm-cuff reactive hyperemia test. Coronary calcium score was measured via electron beam computed tomography or multidetector computed tomography scan. We studied 105 randomly recruited hemodialysis patients (age: 58 ± 13 years, 47% men) and 105 age- and gender-matched controls. In hemodialysis patients vs. controls, TMP-AUC was significantly worse (114 ± 72 vs. 143 ± 80, P = 0.001) and CAC score was higher (525 ± 425 vs. 240 ± 332, P < 0.001). Hemodialysis patients were 14 times more likely to have CAC score >1000 as compared with controls. After adjustment for known confounders, the relative risk for case vs. control for each standard deviation decrease in TMP-AUC was 1.46 (95% confidence interval: 1.12-1.93, P = 0.007). Vascular reactivity measured via the novel DTM technology is incrementally worse across CAC scores in hemodialysis patients, in whom both measures are even worse than their age- and gender-matched controls. The DTM technology may offer a convenient and radiation-free approach to risk-stratify hemodialysis patients.

Cardiorenal syndrome: pathophysiology and potential targets for clinical management.

Combined dysfunction of the heart and the kidneys, which can be associated with haemodynamic impairment, is classically referred to as cardiorenal syndrome (CRS). Cardiac pump failure with resulting volume retention by the kidneys, once thought to be the major pathophysiologic mechanism of CRS, is now considered to be only a part of a much more complicated phenomenon. Multiple body systems may contribute to the development of this pathologic constellation in an interconnected network of events. These events include heart failure (systolic or diastolic), atherosclerosis and endothelial cell dysfunction, uraemia and kidney failure, neurohormonal dysregulation, anaemia and iron disorders, mineral metabolic derangements including fibroblast growth factor 23, phosphorus and vitamin D disorders, and inflammatory pathways that may lead to malnutrition-inflammation-cachexia complex and protein-energy wasting. Hence, a pathophysiologically and clinically relevant classification of CRS based on the above components would be prudent. With the existing medical knowledge, it is almost impossible to identify where the process has started in any given patient. Rather, the events involved are closely interrelated, so that once the process starts at a particular point, other pathways of the network are potentially activated. Current therapies for CRS as well as ongoing studies are mostly focused on haemodynamic adjustments. The timely targeting of different components of this complex network, which may eventually lead to haemodynamic and vascular compromise and cause refractoriness to conventional treatments, seems necessary. Future studies should focus on interventions targeting these components.

Relative contributions of inflammation and inadequate protein intake to hypoalbuminemia in patients on maintenance hemodialysis.

PURPOSE: Serum albumin is one of the strongest mortality predictors in maintenance hemodialysis (MHD) patients. Yet, the degree to which serum albumin represents dietary protein intake or an inflammatory state, among others, is not clear. We hypothesize that these inadequate protein intake and inflammation contribute somewhat equally to hypoalbuminemia. METHODS: In a cross-sectional analysis, we examined correlates of low serum albumin, <3.8 g/dL, in 812 MHD patients in whom interleukin-6 (IL-6) and normalized protein nitrogen appearance (nPNA), also known as normalized protein catabolic rate (nPCR), were also measured. Logistic regression estimated odds ratios were employed, and spline models were plotted to examine the likelihood of relatively low serum albumin <3.8 g/dL. RESULTS: Mean age (±SD) of patients was 54 ± 15 years; 53 % of patients were men, 50 % Hispanic, 31 % African-American, and 55 % diabetic. The mean dialysis vintage was 31 ± 34 months (median: 19, inter-quartile range: 7-44 months). The baseline serum albumin, averaged over a 3-month period (mean ± SD), was 3.88 ± 0.38 g/mL. The unadjusted correlation coefficients of l IL-6 and nPNA with serum albumin were -0.36 and +0.20, respectively (p < 0.001 for each comparison). The likelihood for an albumin <3.8 gr/dL increased linearly with decreasing nPNA and rising serum IL-6. This trend was steeper with increasing serum IL-6 up to a concentration of 30 ng/mL. CONCLUSIONS: Both low protein intakes and a high state of inflammation are associated with low serum albumin in MHD patients.

Association of malnutrition-inflammation complex and responsiveness to erythropoiesis-stimulating agents in long-term hemodialysis patients.

BACKGROUND: Protein-energy wasting, inflammation and refractory anemia are common in long-term hemodialysis patients. A decreased responsiveness to erythropoiesis-stimulating agents (ESA) is often the cause of the refractory anemia. We hypothesized that the malnutrition-inflammation complex is an independent predictor of decreased responsiveness to ESAs in hemodialysis patients. METHODS: This cohort study of 754 hemodialysis patients was examined for an association between inflammatory and nutritional markers, including the malnutrition-inflammation score (MIS) and responsiveness to ESA. Cubic spline models were fitted to verify found associations. RESULTS: The mean (±SD) age of patients was 54 ± 15 years, 53% were diabetic and 32% blacks. MIS was worse in the highest quartile of ESAs responsiveness index (ERI, ESA dose divided by hemoglobin) when compared with 1st quartile (6.5 ± 4.5 versus 4.4 ± 3.4; P < 0.001). Both C-reactive protein (log CRP) (ß = 0.19) and interleukin-6 (log IL-6) (ß = 0.32) were strong and independent predictors of ERI using multivariate linear regression. Serum albumin (ß = -0.30) and prealbumin levels (ß = -0.14) were inversely associated with ERI. Each 1 SD higher MIS, higher CRP and lower albumin were associated with 86, 44 and 97% higher likelihood of having highest versus three lowest ERI quartiles in fully adjusted models [odds ratio (and 95% confidence interval) of 1.86 (1.31-2.85), 1.44 (1.08-1.92) and 1.97 (1.41-2.78)], respectively. Cubic splines confirmed the continuous and incremental nature of these associations. CONCLUSIONS: Malnutrition-inflammation complex is an incremental predictor of poor responsiveness to ESAs in hemodialysis patients. Further studies are needed to assess whether modulating inflammatory or nutritional processes can improve anemia management.

Estimated glomerular filtration rate at reinitiation of dialysis and mortality in failed kidney transplant recipients.

BACKGROUND: Recent observational studies and a controlled trial suggest more favorable outcomes upon later dialysis initiation in chronic kidney disease. The role of estimated glomerular filtration rate (eGFR) in predicting outcome at reinitiation of dialysis in failed kidney transplant recipients is unclear. METHODS: Five-year data in a large dialysis organization was linked to the 'Scientific Registry of Transplant Recipients' to identify 747 failed kidney transplant patients with CKD Stage 5, who had restarted dialysis therapy. A propensity score for early (eGFR>10.5 mL/min/1.73 m2) versus late reinitiation of dialysis was fit by logistic regression. The mortality hazard ratio (HR) was estimated across tertiles of the fitted score. RESULTS: Patients were 44±14 years old and included 42% women. Male gender {odds ratio (OR), [95% confidence interval (CI)]: 1.82 (1.22-2.73)}, diabetes mellitus [OR: 1.75 (1.14-2.68)] and peripheral vascular disease [OR: 3.55 (1.17-10.77)] were associated with higher odds of early dialysis reinitiation. Each mL/min/1.73 m2 higher eGFR was associated with 6% higher death risk in unadjusted model [HR: 1.06 (1.01-1.11)], and although not significant in fully adjusted models [HR: 1.02 (0.96-1.07)], it was significant in some subgroups including women and younger patients. The death HR of higher eGFR across lowest to highest tertiles of propensity score of early dialysis initiation (corresponding healthiest to sickest patients) were 1.10 (0.98-1.24), 1.00 (0.91-1.10) and 0.99 (0.92-1.07), respectively (P for trend<0.05), indicating a trend toward higher mortality risk with earlier dialysis initiation in the healthiest patients. CONCLUSIONS: Earlier return to dialysis therapy in failed kidney transplant patients tends to correlate with worse dialysis survival especially among healthiest and younger patients and women. Additional studies need to verify these findings.

Cardiorenal syndrome and vitamin D receptor activation in chronic kidney disease.

Cardiorenal syndrome (CRS) refers to a constellation of conditions whereby heart and kidney diseases are pathophysiologically connected. For clinical purposes, it would be more appropriate to emphasize the pathophysiological pathways to classify CRS into: (1) hemodynamic, (2) atherosclerotic, (3) uremic, (4) neurohumoral, (5) anemic-hematologic, (6) inflammatory-oxidative, (7) vitamin D receptor (VDR) and/or FGF23-, and (8) multifactorial CRS. In recent years, there have been a preponderance data indicating that vitamin D and VDR play an important role in the combination of renal and cardiac diseases. This review focuses on some important findings about VDR activation and its role in CRS, which exists frequently in chronic kidney disease patients and is a main cause of morbidity and mortality. Pathophysiological pathways related to suboptimal or defective VDR activation may play a role in causing or aggravating CRS. VDR activation using newer agents including vitamin D mimetics (such as paricalcitol and maxacalcitol) are promising agents, which may be related to their selectivity in activating VDR by means of attracting different post-D-complex cofactors. Some, but not all, studies have confirmed the survival advantages of D-mimetics as compared to non-selective VDR activators. Higher doses of D-mimetic per unit of parathyroid hormone (paricalcitol to parathyroid hormone ratio) is associated with greater survival, and the survival advantages of African American dialysis patients could be explained by higher doses of paricalcitol (>10 µg/week). More studies are needed to verify these data and to explore additional avenues for CRS management via modulating VDR pathway.

Clinical profile and predictors of complications in peripartum cardiomyopathy.

BACKGROUND: Clinical profile and predictors of major adverse events (MAE) associated with peripartum cardiomyopathy (PPCM) have not been characterized. METHODS AND RESULTS: A retrospective review and analysis of clinical data of 182 patients with PPCM. Forty-six patients had >or=1 MAE, including death (13), heart transplantation (11), temporary circulatory support (4), cardiopulmonary arrest (6), fulminant pulmonary edema (17), thromboembolic complications (4), and defibrillator or pacemaker implantation (10). Diagnosis of PPCM was delayed >or=1 week in 48% of patients with MAE that preceded the diagnosis in 50% of these patients. Seven (32%) of the surviving patients who had MAE and did not undergo heart transplantation had residual brain damage. Significant predictors of MAE were: left ventricular ejection fraction

Impact of acute serum creatinine elevation in patients treated with nesiritide.

BACKGROUND: We assessed the effect of increases in serum creatinine on mortality in nesiritide-treated versus control subjects with acute decompensated heart failure (ADHF). HYPOTHESIS: Mortality effect of nesiritide-related increases in serum creatinine differs from that of standard therapies. METHODS: Scios Inc., granted unrestricted access to data from all 5 randomized, controlled nesiritide infusion trials completed to date in patients hospitalized with ADHF. We used 2 different definitions of acute serum creatinine increase: >0.3 mg/dL and > 0.5mg/dL within 30 days of study enrollment and determined 30-day mortality risk for nesiritide-treated versus control subjects utilizing each definition. RESULTS: A total of 1,270 subjects participated in the 5 trials. A >0.3 mg/dL increase in serum creatinine was associated with a significant increase in mortality risk in control subjects, (hazard ratio [HR]: 3.47, 95% confidence interval [CI]: 1.49-8.09) but not in nesiritide-treated subjects (HR: 1.65, 95% CI: 0.90-3.05). Results were similar for a >0.5 mg/dL increase (control HR: 5.12, 95% CI: 2.09-12.57 and nesiritide HR: 1.77, 95% CI: 0.90-3.51). In subjects with >0.3 mg/dL and >0.5 mg/dL increases in serum creatinine, respectively, the 30-day mortality odds ratios for nesiritide relative to control were 0.73 (95% CI: 0.29-1.93) and 0.52 (95% CI: 0.17-1.63) using a stratified Mantel-Haenszel analysis. CONCLUSIONS: The impact of increased serum creatinine on mortality was attenuated in nesiritide-treated patients compared to control, suggesting that the mechanism and clinical significance of increases in serum creatinine associated with nesiritide treatment may differ from those associated with standard therapies. Further investigation is warranted.

Vasodilators in the management of acute heart failure.

Recent guidelines by the Heart Failure Society of America have recommended consideration for use of nitroprusside, nitroglycerin, or nesiritide in addition to diuretics to achieve hemodynamic and symptomatic improvement. This article reviews the results of previous studies evaluating the pharmacologic and clinical effects and safety profiles of these drugs in patients with heart failure.

Renal Vasodilatory Action of Dopamine in Patients With Heart Failure: Magnitude of Effect and Site of Action.

BACKGROUND: A "renal dose" of dopamine is often used to increase renal blood flow; however, data on the magnitude of effect and site of action in patients with heart failure are scarce. METHODS AND RESULTS: Renal effects of intravenous dopamine (1, 2, 3, 5, and 10 mug . kg(-1) . min(-1)) were evaluated in 13 patients with chronic heart failure. Renal blood flow was calculated from renal artery cross-sectional area measured with intravascular ultrasound and renal blood flow velocity-time integral measured by the intravascular Doppler technique. Cross-sectional area increased and was significantly higher than baseline (0.30+/-0.04 cm(2)) at 5 mug . kg(-1) . min(-1) (0.36+/-0.05 cm(2)) and 10 mug . kg(-1) . min(-1) (0.38+/-0.06 cm(2)). The velocity-time integral was significantly higher than baseline (22+/-3 cm) at doses of 3 and 5 mug . kg(-1) . min(-1) (both 31+/-4 cm). Renal blood flow increased, whereas renal vascular resistance decreased, reaching statistical significance at 2 mug . kg(-1) . min(-1) through 10 mug . kg(-1) . min(-1). Cardiac output gradually increased, reaching statistical significance at doses of 5 and 10 mug . kg(-1) . min(-1) (5.5+/-0.5 and 6.1+/-0.7 versus 4.5+/-5.2 L/min at baseline), but the increase in renal blood flow appeared proportionately larger than corresponding increases in cardiac output. CONCLUSIONS: Dopamine is associated with an increase in renal blood flow in patients with heart failure. This effect is due to dilation of both the large conductance and small resistance renal blood vessels. Further evaluation of the efficacy and safety of dopamine for improvement of renal function in hospitalized patients with heart failure is warranted.

Assessment of renal hemodynamic effects of nesiritide in patients with heart failure using intravascular Doppler and quantitative angiography.

OBJECTIVES: We evaluated the magnitude and site of action of the nesiritide mediated renal vasodilatory effect in patients with heart failure (HF). BACKGROUND: Nesiritide, a recombinant human B-type natriuretic peptide is approved for the treatment of acute decompensated HF and has been shown to exert favorable hemodynamic, neurohormonal, and symptomatic effects. The renal effect of nesiritide in HF patients has not been well defined. METHODS: In 15 patients with acute decompensated HF, intravascular Doppler and quantitative angiography of the renal artery were used to assess the effect of nesiritide on renal artery diameter and velocity time integral as well as renal blood flow and vascular resistance. Nesiritide was administered intravenously at a standard dose of 2 microg/kg bolus followed by a continuous infusion at a rate of 0.01 microg/kg/min. Assessment of nesiritide effect was made at 15 min. RESULTS: Nesiritide infusion was associated with a significant central hemodynamic effect including a fall in mean pulmonary artery pressure (36 +/- 12 mm Hg to 31 +/- 13 mm Hg, p < 0.001), mean pulmonary capillary wedge pressure (21 +/- 2 mm Hg to 15 +/- 10 mm Hg, p < 0.001), and systemic vascular resistance (1,995 +/- 532 dynes s cm(-5) to 1,563 +/- 504 dynes s cm(-5), r < 0.001), and an increase in cardiac output from 3.9 +/- 1.2 l/min to 4.6 +/- 1.6 l/min (p = 0.001). Nesiritide was also associated with a significant vasodilatory effect on the large conductance renal arteries resulting in an increase in renal artery diameter from 6.2 +/- 0.7 mm to 6.7 +/- 0.8 mm (p < 0.001). At the same time, there was a concomitant fall in mean renal artery pressure (99 +/- 17 mm Hg to 89 +/- 13 mm Hg, p = 0.002) and renal blood flow velocity time integral (27 +/- 15 cm/beat to 23 +/- 15 cm/beat, p = 0.008) and, therefore, no significant change in renal blood flow or renal vascular resistance. CONCLUSIONS: The nesiritide effect on the renal circulation in patients with HF is complex, with a marked vasodilatory action on the large, conductance renal arteries but a concomitant fall in velocity time integral and no effect on renal vascular resistance or renal blood flow. Lack of increase in renal blood flow may be due to a fall in renal blood pressure or an intrarenal vasoconstrictive effect.