Robert G. Fassett

Biomarkers in chronic kidney disease: a review

Chronic kidney disease (CKD) is a major public health problem. The classification of CKD by KDOQI and KDIGO and the routine eGFR reporting have resulted in increased identification of CKD. It is important to be able to identify those at high risk of CKD progression and its associated cardiovascular disease (CVD). Proteinuria is the most sensitive marker of CKD progression in clinical practice, especially when combined with eGFR, but these have limitations. Hence, early, more sensitive, biomarkers are required. Recently, promising biomarkers have been identified for CKD progression and its associated CVD morbidity and mortality. These may be more sensitive biomarkers of kidney function, the underlying pathophysiological processes, and/or cardiovascular risk. Although there are some common pathways to CKD progression, there are many primary causes, each with its own specific pathophysiological mechanism. Hence, a panel measuring multiple biomarkers including disease-specific biomarkers may be required. Large, longitudinal observational studies are needed to validate candidate biomarkers in a broad range of populations prior to implementation into routine CKD management. Recent renal biomarkers discovered include neutrophil gelatinase-associated lipocalin, kidney injury molecule-1, and liver-type fatty acid-binding protein. Although none are ready for use in clinical practice, it is timely to review the role of such biomarkers in predicting CKD progression and/or CVD risk in CKD.

Astaxanthin: A Potential Therapeutic Agent in Cardiovascular Disease

Astaxanthin is a xanthophyll carotenoid present in microalgae, fungi, complex plants, seafood, flamingos and quail. It is an antioxidant with anti-inflammatory properties and as such has potential as a therapeutic agent in atherosclerotic cardiovascular disease. Synthetic forms of astaxanthin have been manufactured. The safety, bioavailability and effects of astaxanthin on oxidative stress and inflammation that have relevance to the pathophysiology of atherosclerotic cardiovascular disease, have been assessed in a small number of clinical studies. No adverse events have been reported and there is evidence of a reduction in biomarkers of oxidative stress and inflammation with astaxanthin administration. Experimental studies in several species using an ischaemia-reperfusion myocardial model demonstrated that astaxanthin protects the myocardium when administered both orally or intravenously prior to the induction of the ischaemic event. At this stage we do not know whether astaxanthin is of benefit when administered after a cardiovascular event and no clinical cardiovascular studies in humans have been completed and/or reported. Cardiovascular clinical trials are warranted based on the physicochemical and antioxidant properties, the safety profile and preliminary experimental cardiovascular studies of astaxanthin.

DETECTION OF GLOMERULAR BLEEDING BY PHASE-CONTRAST MICROSCOPY

Midstream urine specimens from 303 consecutive patients with haematuria were examined with phase-contrast microscopy to determine whether the source of the haematuria could be predicted on the basis of urinary red-cell morphology. In 253 patients a definite diagnosis was made but the data for the other 50 were inadequate to allow a definite diagnosis. With phase-contrast microscopy the origin of haematuria was considered to be glomerular in 120 patients (115 had proven glomerulonephritis and 5 had lesions of the lower urinary tract) and non-glomerular in 105 patients (100 had lesions of the lower urinary tract and 5 had proven glomerulonephritis). A mixed picture of glomerular and non-glomerular red cells was seen in 28 patients, most commonly in association with IgA nephropathy and renal calculi. The assessment of urinary red-cell morphology by means of phase-contrast microscopy can add importantly to clinical information and, together with the presence of red-cell casts and protein in the urine, can help the clinician decide on initial investigations in patients with haematuria.

Relationships between single nucleotide polymorphisms of antioxidant enzymes and disease

The presence and progression of numerous diseases have been linked to deficiencies in antioxidant systems. The relationships between single nucleotide polymorphisms (SNPs) arising from specific antioxidant enzymes and diseases associated with elevated oxidative stress have been studied with the rationale that they may be useful in screening for diseases. The purpose of this narrative review is to analyse evidence from these studies. The antioxidant enzyme SNPs selected for analysis are based on those most frequently investigated in relation to diseases in humans: superoxide dismutase (SOD2) Ala16Val (80 studies), glutathione peroxidise (GPx1) Pro197Leu (24 studies) and catalase C-262T (22 studies). Although the majority of evidence supports associations between the SOD2 Ala16Val SNP and diseases such as breast, prostate and lung cancers, diabetes and cardiovascular disease, the presence of the SOD2 Ala16Val SNP confers only a small, clinically insignificant reduction (if any) in the risk of these diseases. Other diseases such as bladder cancer, liver disease, nervous system pathologies and asthma have not been consistently related to this SOD SNP genotype. The GPx1 Pro197Leu and catalase C-262T SNP genotypes have been associated with breast cancer, but only in a small number of studies. Thus, currently available evidence suggests antioxidant enzyme SNP genotypes are not useful for screening for diseases in humans.

Effects of uric acid-lowering therapy on renal outcomes: a systematic review and meta-analysis.

BACKGROUND Non-randomized studies suggest an association between serum uric acid levels and progression of chronic kidney disease (CKD). The aim of this systematic review is to summarize evidence from randomized controlled trials (RCTs) concerning the benefits and risks of uric acid-lowering therapy on renal outcomes. METHODS Medline, Excerpta Medical Database and Cochrane Central Register of Controlled Trials were searched with English language restriction for RCTs comparing the effect of uric acid-lowering therapy with placebo/no treatment on renal outcomes. Treatment effects were summarized using random-effects meta-analysis. RESULTS Eight trials (476 participants) evaluating allopurinol treatment were eligible for inclusion. There was substantial heterogeneity in baseline kidney function, cause of CKD and duration of follow-up across these studies. In five trials, there was no significant difference in change in glomerular filtration rate from baseline between the allopurinol and control arms [mean difference (MD) 3.1 mL/min/1.73 m2, 95% confidence intervals (CI) -0.9, 7.1; heterogeneity χ2=1.9, I2=0%, P=0.75]. In three trials, allopurinol treatment abrogated increases in serum creatinine from baseline (MD -0.4 mg/dL, 95% CI -0.8, -0.0 mg/dL; heterogeneity χ2=3, I2=34%, P=0.22). Allopurinol had no effect on proteinuria and blood pressure. Data for effects of allopurinol therapy on progression to end-stage kidney disease and death were scant. Allopurinol had uncertain effects on the risks of adverse events. CONCLUSIONS Uric acid-lowering therapy with allopurinol may retard the progression of CKD. However, adequately powered randomized trials are required to evaluate the benefits and risks of uric acid-lowering therapy in CKD.

Oxidative stress biomarkers as predictors of cardiovascular disease

Evidence for the role of oxidative stress in the pathogenesis of cardiovascular disease (CVD) is primarily based on experimental and observational human studies. The aim of this review is to examine the observational longitudinal studies that have investigated the relationship between oxidative stress biomarkers and CVD. Fifty-one studies were identified with twenty-six of these measuring oxidized (Ox)-LDL, fifteen assessing myeloperoxidase, seven using lipid peroxidation measures and three quantifying protein oxidation. Results of studies using Ox-LDL have been equivocal with sixteen of the twenty-six studies reporting that this measure is predictive of cardiovascular events. These inconsistent results are not explained by differences in the study populations (primary or secondary CVD) or the type of assay used (auto or monoclonal antibodies). Six of the seven lipid peroxidation, and two of three protein oxidation studies found associations. Twelve of fifteen studies assessing the role of myeloperoxidase reported it to be predictive of CVD. However, issues surrounding the specificity of myeloperoxidase as a marker of oxidative stress and the small number of research groups reporting these results, limit this finding. In summary, the ability of oxidative stress biomarkers to predict CVD has yet to be established. Furthermore, it is important to note that the methods used to assess oxidative stress in these studies are indirect, and the evidence that the various methods actually reflect oxidative stress in vivo is limited.

Astaxanthin, oxidative stress, inflammation and cardiovascular disease.

It is accepted that oxidative stress and inflammation play an integral role in the pathophysiology of many chronic diseases including atherosclerotic cardiovascular disease. The xanthophyll carotenoid dietary supplement astaxanthin has demonstrated potential as an antioxidant and anti-inflammatory therapeutic agent in models of cardiovascular disease. There have been at least eight clinical studies conducted in over 180 humans using astaxanthin to assess its safety, bioavailability and clinical aspects relevant to oxidative stress, inflammation or the cardiovascular system. There have been no adverse outcomes reported. Studies have demonstrated reduced markers of oxidative stress and inflammation and improved blood rheology. A larger number of experimental studies have been performed using astaxanthin. In particular, studies in a variety of animals using a model of myocardial ischemia and reperfusion have demonstrated protective effects from prior administration of astaxanthin both intravenously and orally. Future clinical studies and trials will help determine the efficacy of antioxidants such as astaxanthin on vascular structure, function, oxidative stress and inflammation in a variety of patients at risk of, or with, established cardiovascular disease. These may lead to large intervention trials assessing cardiovascular morbidity and mortality.

Effect of Intradialytic Versus Home-Based Aerobic Exercise Training on Physical Function and Vascular Parameters in Hemodialysis Patients: A Randomized Pilot Study

BACKGROUND Hemodialysis patients show reduced physical function and greater risk of increased arterial stiffness because of hypertension, metabolic disturbances, and vascular calcification. Exercise interventions potentially could improve their vascular risk profile. STUDY DESIGN Randomized controlled pilot clinical study comparing the effects of 6 months of supervised intradialytic exercise training versus home-based exercise training or usual care on physical function and arterial stiffness in hemodialysis patients. SETTING & PARTICIPANTS 70 hemodialysis patients from 3 renal units. INTERVENTION Intradialytic-exercise patients trained 3 times/wk for 6 months on a cycle ergometer and home-based-exercise patients followed a walking program to achieve the same weekly physical activity. Usual-care patients received no specific intervention. OUTCOMES & MEASUREMENTS Primary outcome measures were distance traveled during a 6-minute walk test and aortic pulse wave velocity. Secondary outcome measures included augmentation index (augmentation pressure as a percentage of central pulse pressure), peripheral (brachial) and central blood pressures (measured noninvasively using radial tonometry), physical activity, and self-reported physical functioning. Measurements were made at baseline and 6 months. RESULTS At 6 months, there were no significant differences between changes in 6-minute walk test distance (intradialytic exercise, +14%; home-based exercise, +11%; usual care, +5%), pulse wave velocity (intradialytic exercise, -4%; home-based exercise, -2%; usual care, +5%), or any secondary outcome measure. LIMITATIONS Lack of medication data limited the analysis of vascular parameters in this study. CONCLUSION There were no differences between intradialytic or home-based exercise training and usual care for either physical function or vascular parameters.

Omega-3 Polyunsaturated Fatty Acids in the Treatment of Kidney Disease

After more than 25 years of published investigation, including randomized controlled trials, the role of omega-3 polyunsaturated fatty acids in the treatment of kidney disease remains unclear. In vitro and in vivo experimental studies support the efficacy of omega-3 polyunsaturated fatty acids on inflammatory pathways involved with the progression of kidney disease. Clinical investigations have focused predominantly on immunoglobulin A (IgA) nephropathy. More recently, lupus nephritis, polycystic kidney disease, and other glomerular diseases have been investigated. Clinical trials have shown conflicting results for the efficacy of omega-3 polyunsaturated fatty acids in IgA nephropathy, which may relate to varying doses, proportions of eicosapentaenoic acid and docosahexaenoic acid, duration of therapy, and sample size of the study populations. Meta-analyses of clinical trials using omega-3 polyunsaturated fatty acids in IgA nephropathy have been limited by the quality of available studies. However, guidelines suggest that omega-3 polyunsaturated fatty acids should be considered in progressive IgA nephropathy. Omega-3 polyunsaturated fatty acids decrease blood pressure, a known accelerant of kidney disease progression. Well-designed, adequately powered, randomized, controlled clinical trials are required to further investigate the potential benefits of omega-3 polyunsaturated fatty acids on the progression of kidney disease and patient survival.

Sulforaphane: translational research from laboratory bench to clinic

Cruciferous vegetables are widely acknowledged to provide chemopreventive benefits in humans, but they are not generally consumed at levels that effect significant change in biomarkers of health. Because consumers have embraced the notion that dietary supplements may prevent disease, this review considers whether an appropriately validated sulforaphane-yielding broccoli sprout supplement may deliver clinical benefit. The crucifer-derived bioactive phytochemical sulforaphane is a significant inducer of nuclear factor erythroid 2-related factor 2 (Nrf2), the transcription factor that activates the cells endogenous defenses via a battery of cytoprotective genes. For a broccoli sprout supplement to demonstrate bioactivity in vivo, it must retain both the sulforaphane-yielding precursor compound, glucoraphanin, and the activity of glucoraphanins intrinsic myrosinase enzyme. Many broccoli sprout supplements are myrosinase inactive, but current labeling does not reflect this. For the benefit of clinicians and consumers, this review summarizes the findings of in vitro studies and clinical trials, interpreting them in the context of clinical relevance. Standardization of sulforaphane nomenclature and assay protocols will be necessary to remove inconsistency and ambiguity in the labeling of currently available broccoli sprout products.