Mohamed E. Suliman

Elevated serum levels of S-adenosylhomocysteine, but not homocysteine, are associated with cardiovascular disease in stage 5 chronic kidney disease patients.

OBJECTIVE The putative role of sulfur amino acids such as homocysteine (tHcy) as cardiovascular risk factors is controversial in chronic kidney disease (CKD). Although, S-adenosylhomocysteine (SAH) levels have been linked to CVD in non-renal populations, such relationship has not been evaluated in CKD. DESIGN Serum concentrations of S-adenosylmethionine (SAM), SAH and total homocysteine (tHcy) were determined by HPLC in 124 CKD stage 5 patients (GFR range 1-11 m/min) and 47 control subjects, and related to renal function, presence of CVD, inflammation and protein-energy wasting (PEW). RESULTS The levels of SAM and SAH were higher in CKD patients than in controls. Both SAM (rho=-0.19; P<0.05) and SAH (rho=-0.37, P<0.001) were inversely related to GFR. The concentrations of SAH were significantly higher (P<0.001) in patients with CVD than in non-CVD patients, (683 (201-3057) vs 485 (259-2620) nmol/L; median (range)) as opposed to tHcy levels, which were lower in CVD patients. While SAH was not associated with the presence of inflammation or PEW, it was a significant contributor (OR; 4.9 (CI 1.8-12.8), P<0.001) to CVD in a multinomial logistic regression model (pseudo r(2)=0.31). CONCLUSION Concentrations of serum SAH and SAM in CKD stage 5 patients are associated with renal function, but not with inflammation or PEW. Among the investigated sulfur amino acids, only SAH was independently associated with the presence of clinical signs of CVD. These findings suggest that while tHcy might be influenced by a number of confounding uremic factors, SAH levels may better reflect the putative increased cardiovascular risk of sulfur amino acid alterations in CKD patients.

Predictors of carotid artery intima-media thickness in chronic kidney disease and kidney transplant patients without overt cardiovascular disease.

Background/Aims: Carotid intima-media thickness (IMT) assessed using ultrasonography is a widely used marker of atherosclerosis. In the largest study to date of IMT and chronic kidney disease (CKD), we assessed correlates of IMT in CKD patients with a wide range of renal dysfunction, and also investigated what happens to IMT following renal transplantation. Methods: We studied 406 patients with different stages of nondiabetic CKD (50% males, 46 ± 12 years), and 58 kidney transplant recipients (27 ± 6 years), testing relationships between IMT, assessed by ultrasonography, and selected biomarkers. Results: Despite a lack of overt CVD, patients had significantly higher IMT as compared to controls (0.9 [0.7–1.0] vs. 0.6 [0.4–0.7] mm; p > 0.001). Furthermore, in multivariate analysis IMT was independently associated with CKD stage, mean arterial pressure (MAP) and calcium-phosphate product, but not with Framingham risk factors. Following kidney transplantation, IMT decreased rapidly, reaching levels comparable to those in the controls within 90 days. In a time-dependent multivariate analysis, this decrease was predicted by changes in GFR, MAP, and uric acid levels. Conclusion: Our data does not exclude IMT as a predictor of mortality in CKD, but suggests that other etiologies than atherosclerosis may be more important in determining IMT levels in the population with CKD.

Interleukin-6 Is a Better Predictor of Mortality as Compared to C-Reactive Protein, Homocysteine, Pentosidine and Advanced Oxidation Protein Products in Hemodialysis Patients

Inflammatory markers predict mortality in hemodialysis (HD) patients, whereas a possible association between oxidative stress (OS) markers and survival is less clear. We assessed the impact on all-cause mortality of baseline inflammatory [high-sensitivity C-reactive protein and interleukin-6 (IL-6)] and OS markers (advanced oxidation protein products, pentosidine, homocysteine) in 112 HD patients. We found no significant correlations between inflammatory and OS markers. During the 5.5 years of follow-up, 51 patients died. In a Kaplan-Meier analysis, the survival rate was reduced in patients with IL-6 higher than the median (IL-6 >4.2 pg/ml) (log- rank = 6.47; p = 0.01), in diabetics (log-rank = 12.26; p = 0.0005) and in older patients (log-rank = 11.22; p = 0.0008). Moreover, in Cox analysis only IL-6 and age were independently associated with mortality. We conclude that in this group of prevalent Brazilian HD patients, IL-6 was a better predictor of survival than other inflammatory and OS markers.

Effect of hepatitis C serology on C-reactive protein in a cohort of Brazilian hemodialysis patients.

Hepatitis C (HCV) is not an uncommon feature in hemodialysis (HD) patients and may be a cause of systemic inflammation. Plasma cytokine interleukin-6 (IL-6) is mainly produced by circulating and peripheral cells and induces the hepatic synthesis of C-reactive protein (CRP), which is the main acute phase reactant. The aim of this study was to investigate the influence of HCV on two markers of systemic inflammation, serum CRP and IL-6, in HD patients. The study included 118 HD patients (47% males, age 47 +/- 13 years, 9% diabetics) who had been treated by standard HD for at least 6 months. The patients were divided into two groups depending on the presence (HCV+) or absence (HCV-) of serum antibodies against HCV. Serum albumin (S-Alb), plasma high sensitivity CRP (hsCRP), IL-6, and alanine aminotransferase (ALT) were measured and the values were compared with those for 22 healthy controls. Median hsCRP and IL-6 values and hsCRP/IL-6 ratio were: 3.5 vs 2.1 mg/l, P < 0.05; 4.3 vs 0.9 pg/ml, P < 0.0001, and 0.8 vs 2.7, P < 0.0001, for patients and controls, respectively. Age, gender, S-Alb, IL-6 and hsCRP did not differ between the HCV+ and HCV- patients. However, HCV+ patients had higher ALT (29 +/- 21 vs 21 +/- 25 IU/l) and had been on HD for a longer time (6.1 +/- 3.0 vs 4.0 +/- 2.0 years, P < 0.0001). Moreover, HCV+ patients had a significantly lower median hsCRP/IL-6 ratio (0.7 vs 0.9, P < 0.05) compared to the HCV- group. The lower hsCRP/IL-6 ratio in HCV+ patients than in HCV- patients suggests that hsCRP may be a less useful marker of inflammation in HCV+ patients and that a different cut-off value for hsCRP for this population of patients on HD may be required to define inflammation.

The kidney is the major site of S-adenosylhomocysteine disposal in humans

S-adenosylhomocysteine (SAH), the metabolic precursor of homocysteine in the body, is a potent inhibitor of methylation reactions. Several methylation reactions play a major role in epigenetic regulation of protein expression, atherosclerosis, and cancer development. Here we studied the mechanisms responsible for the maintenance of circulating SAH levels by measurement of the arterio-venous differences across the kidney, splanchnic organs, and the lung in humans. The lungs did not remove or add any circulating SAH, whereas the liver released it into the hepatic veins. The kidney extracted 40% of SAH and the SAH arterio-venous difference across the kidney was directly and significantly related to its arterial levels. Thus, the kidney plays a major role in maintaining SAH levels and may, indirectly, control tissue transmethylation reactions. Our findings of a pivotal role for the human kidney in sulfur amino acid metabolism may also account for the increased plasma levels of SAH in patients with chronic kidney diseases.

Chapter 6 Vascular Calcification Inhibitors In Relation To Cardiovascular Disease With Special Emphasis On Fetuin‐A In Chronic Kidney Disease

The mortality rate is extremely high in chronic kidney disease (CKD), primarily due to the high prevalence of cardiovascular disease (CVD) in this patient group. Apart from traditional Framingham risk factors, evidences suggest that nontraditional risk factors, such as inflammation, oxidative stress, endothelial dysfunction, and vascular calcification also contribute to this extremely high risk of CVD. Disturbance in the mineral metabolism, especially in the ions of Ca and PO4, are linked to enhanced calcification of blood vessels. Although the mechanism(s) of this enhanced calcification process are not fully understood, current knowledge suggests that a large number (and an imbalance between them) of circulating promoters and inhibitors of the calcification process, that is, fetuin-A (or alpha 2-Heremans-Schmid glycoprotein, AHSG), matrix-Gla protein (MGP), osteoprotegerin (OPG), osteopontin (OPN), bone morphogenetic proteins (BMPs), and inorganic pyrophosphate (PPi), are involved in the deterioration of vascular tissue. Thus, an imbalance in these factors may contribute to the high prevalence of vascular complications in CKD patients. Among these mediators, studies on fetuin-A deserve further attention as clinical studies consistently show that fetuin-A deficiency is associated with vascular calcification, all-cause and cardiovascular mortality in CKD patients. Both chronic inflammation and the uremic milieu per se may contribute to fetuin-A depletion, as well as specific mutations in the AHSG gene. Recent experimental and clinical studies also suggest an intriguing link between fetuin-A, insulin resistance, and the metabolic syndrome.

Bone Mineral Density in End-Stage Renal Disease Patients : Association with Wasting, Cardiovascular Disease and Mortality

Background: Bone and mineral disorders may contribute to extraosseous ossifications and cardiovascular disease (CVD) in end-stage renal disease (ESRD) patients. We have investigated the relationship between bone mineral density (BMD) and inflammation, wasting, CVD and mortality in ESRD patients. Methods: BMD (dual energy X-ray absorptiometry) and biochemical, nutritional and inflammatory markers were assessed in 277 incident ESRD patients (GFR 7.1 ± 0.2 ml/min) who were then followed prospectively for a mean of 27 (range 1–60) months. Carotid plaques were determined in 103 patients. Results: Patients with carotid plaques, clinical manifestation of CVD and wasting (assessed by subjective global assessment) had significantly lower BMD than their counterparts. Low BMD was associated with high all-cause and cardiovascular mortality. Even after adjustment for several confounders and risk factors, all-cause (HR = 2.1, CI: 1.1–3.9, p = 0.02) and cardiovascular (HR = 2.8, CI: 1.2–6.3, p = 0.02) mortality remained significantly associated with low BMD. Conclusions: Low BMD is associated with wasting and CVD, and is an independent predictor of all-cause and cardiovascular mortality in ESRD patients.

CARDIOVASCULAR AND SURVIVAL PARADOXES IN DIALYSIS PATIENTS: Homocysteine-Lowering Is Not a Primary Target for Cardiovascular Disease Prevention in Chronic Kidney Disease Patients

The homocysteine (Hcy) theory states that total homocysteine (tHcy) is a risk factor for atherosclerosis. Chronic kidney disease (CKD) is one of the most frequent causes of hyperhomocysteinemia in the presence of high prevalence of cardiovascular disease (CVD). However, there is not yet any conclusive answer to the question whether Hcy may contribute to, or predict, cardiovascular events or mortality in CKD patients or whether it is just an innocent bystander biologically related to other potential risk factors for CVD. Moreover, tHcy levels in CKD are influenced by several commonly occurring confounding factors, such as inflammation and protein‐energy wasting (PEW). These factors are also associated with morbidity and mortality and altogether this may explain why Hcy does not show up as a cardiovascular risk but in fact is reversely associated with clinical outcome. Thorough evaluation of such reverse association may not necessarily imply that the principles of Hcy being a contributor to vascular pathophysiology are different in CKD patients but rather indicate that other superimposed factors, such as PEW and inflammation, are more important. These confounders contribute significantly to the unacceptably high mortality rate in this patient population and may require nutritional and anti‐inflammatory interventions to improve clinical outcome. So far, the results of recent folic acid intervention trials do not support the use of folic acid supplementation for lowering tHcy and improving survival in CKD patients. Although we are still waiting for the results from several ongoing controlled randomized trials in this area, future studies are needed to evaluate if thiol‐exchange agents, besides folic acid, as part of a future multifactorial intervention regime targeting inflammation, PEW, oxidative stress as well as hyperhomocysteinemia may decrease CVD risk in this high‐risk patient population.