Obesity in chronic kidney disease: good or bad?

Cardiovascular disease (CVD) remains the major cause of morbidity and mortality in chronic kidney disease (CKD) patients. As traditional risk factors cannot alone explain the high prevalence and incidence of CVD in this high-risk population, the complex of insulin resistance, oxidative stress, and endothelial dysfunction has increasingly been studied as important non-traditional risk factors. Recent studies show that the adipose tissue is a complex organ with functions far beyond the mere storage of energy. Indeed, it has recently been shown that fat tissue secretes a number of adipokines - including leptin, adiponectin and retinol-binding protein, as well as cytokines such as resistin, visfatin, tumor necrosis factor and interleukin-6. Adipokine serum levels are furthermore markedly elevated in CKD, likely due to a decreased renal excretion. Evidence suggests that these pluripotent signaling molecules may have multiple effects modulating insulin signaling, endothelial health and putatively CVD. As fat tissue is also a storage depot for energy, much needed in the catabolic milieu of uremia, further research is still needed to elucidate the likely complex interactions between these signaling networks, vascular health and outcome in this high-risk population.     

Valvular and perivalvular involvement in patients with chronic kidney disease

Mitral annular calcification (MAC) and aortic valve calcification (AVC) are the most common valvular and perivalvular abnormalities in patients with chronic kidney disease (CKD). Both MAC and AVC occur at a younger age in CKD patients than in the general population. AVC progresses to aortic stenosis and mild aortic stenosis progresses to severe aortic stenosis at a more rapid rate in patients with CKD than in the general population. The use of calcium-free phosphate binders in such patients may reduce the calcium burden in valvular and perivalvular structures and retard the rate of progression of aortic stenosis. Despite high rates of morbidity and mortality, the prognosis associated with valve surgery in patients with CKD is better than without valve surgery. Infective endocarditis remains an important complication of CKD, particularly in those treated with hemodialysis.     

Obesity--the risk factor of cardiovascular disease in patients with chronic kidney disease?

In general population obesity is regarded as a predisposing factor for chronic disease such as type 2 diabetes and cardiovascular disease. Obesity increases the risk of kidney disease and adversely affects the progress of kidney disease among patients with diagnosed kidney disease. The main reason of mortality in chronic kidney disease patients is cardiovascular disease, however, the real meaning of obesity as a risk factor of cardiovascular diseases is still uncertain. While in a general population obesity causes higher cardiovascular mortality, many studies reflect inverse association in chronic kidney disease patients. Obesity is associated with better survival, contrary to general population obesity appears to be a protective factor of cardiovascular disease. The name of this phenomenon is "reverse epidemiology" or "obesity paradox", in dialysis patients known as a "risk-factor-paradox". Some studies do not confirm this paradox association in patients with chronic kidney disease.     

Anemia treatment and left ventricular hypertrophy in non-dialysis chronic kidney disease

To this day, the target hemoglobin level that minimizes cardiovascular risk in chronic kidney disease (CKD) patients remains unclear. When one examines the many randomized trials of epoetin therapy in aggregate, enhanced quality of life provides the most cogent argument for hemoglobin levels above 110 g/L. It remains unclear whether treatment of anemia improves longevity, or even a surrogate marker (such as left ventricular [LV] mass index), especially when applied at earlier phases of CKD.     

Does treating obesity stabilize chronic kidney disease?

Background

Much epidemiological evidence suggests that hydrocarbon exposure may induce glomerulonephritis and worsen its course in many patients. The mechanisms are unknown, however, no specific microscopic pattern has been identified, and it has also been argued that hydrocarbon exposure causes tubular damage mainly. Studying experimental animals may best answer these questions, and as no systematic review of glomerulonephritis produced experimentally by hydrocarbon exposure has been performed previously, I found it relevant to search for and analyse such studies.

Methods

Animal experiments having mimicked human glomerulonephritis by hydrocarbon exposure were sought on Medline and Toxnet

Results

Twenty-six experiments using thirteen different hydrocarbons were identified. Several human subtypes were observed including IgA nephritis, mesangial, proliferative and extracapillary glomerulonephritis, focal and focal-segmental sclerosis, minimal change nephropathy, anti-GBM and anti-TBM nephritis, and glomerulonephritis associated with peiarteritis nodosa. Glomerular proteinuria was seen in 10/12 experiments that included urine analyses, and renal failure in 5/8 experiments that included measurements of glomerular function. All experiments resulted in various degrees of tubular damage as well. In most studies, where the animals were examined at different times during or after the exposure, the renal microscopic and functional changes were seen immediately, whereas deposits of complement and immunoglobulins appeared late in the course, if at all.

Conclusion

These experiments are in accord with epidemiological evidence that hydrocarbon exposure may cause glomerulonephritis and worsen renal function. Probable mechanisms include an induction of autologous antibodies and a disturbance of normal immunological functions. Also, tubular damage may increase postglomerular resistance, resulting in a glomerular deposition of macromolecules. In most models a causal role of glomerular immune complex formation was unlikely, but may rather have been a secondary phenomenon. As most glomerulonephritis subgroups were seen and as some of the hydrocarbons produced more than one subgroup, the microscopic findings in a patient cannot be used as a clue to the causation of his disease. By the same reason, the lack of a specific histological pattern in patients with glomerulonephritis assumed to have been caused by hydrocarbon exposure is not contradictive.     

Anaemia in diabetic patients with chronic kidney disease—prevalence and predictors

Aims/hypothesis We investigated the relationship between haemoglobin (Hb) and diabetes in patients with renal disease.Subjects, materials and methods All adult patients with stable chronic kidney disease attending renal or diabetic outpatient clinics in a six-month period were identified. Patients’ notes and electronic patient records were used to build a comprehensive biochemical and clinical database. Results were analysed for the predictors of Hb, the severity of anaemia in both groups and the relative impact of diabetes on haemoglobin and anaemia.Results The study group consisted of 468 patients, of whom 204 had diabetes and 264 did not. At every level of renal function haemoglobin levels were lower by an average of 10 g/l in subjects with diabetes than in those without. Likewise, anaemia was found to occur at an earlier stage of chronic kidney disease (and to be of greater severity) in diabetic patients. Independent predictors of haemoglobin included female sex, diabetes, renal function and serum albumin, with diabetes and renal function being the greatest predictors. Multiple logistic regression showed that patients with diabetes had an odds ratio of 4 for being anaemic. Had we used an estimated GFR of less than 60 ml/min to trigger investigation of anaemia, we would have detected 85% of anaemic patients.Conclusions/interpretation Anaemia is frequently found in diabetic patients with renal disease, occurs earlier and is more severe than in similar but non-diabetic subjects. In contrast to previous publications, our findings suggest that anaemia is prevalent at the earliest stages of chronic kidney disease. We advocate an estimated GFR threshold of <60 ml/min to trigger investigation for anaemia in diabetic subjects.     

Endothelial dysfunction and cardiovascular disease in early-stage chronic kidney disease: Cause or association?

Chronic kidney disease (CKD) is strongly associated with cardiovascular disease (CVD); a graded inverse relationship between estimated glomerular filtration rate (eGFR) and cardiovascular event rates has emerged from large-scale observational studies. Chronic kidney disease is also associated with endothelial dysfunction (ED) although the precise relationship with GFR and the "threshold" at which ED begins are contentious. Abnormal endothelial function is certainly present in late-stage CKD but data in early-stage CKD appear confounded by disease states such as diabetes and hypertension which themselves promote ED. Thus, the direct effect of a reduction in GFR on endothelial function and, therefore, cardiovascular (CV) risk is far from completely established. In human studies, the precise duration of kidney impairment is seldom known and the onset of CVD often insidious, making it difficult to determine exactly when CVD first appears in the context of CKD. Kidney donors provide a near-ideal experimental model of CKD; subjects undergo an acute change from normal to modestly impaired renal function at the time of nephrectomy and lack the confounding co-morbidity that has made observational studies of CKD patients so challenging to interpret. By examining changes in endothelial function in living kidney donors before and after nephrectomy, useful insight might be gained into the pathophysiology of CVD in CKD and help determine whether targeting ED or the renal disease itself has the potential to reduce CV risk.     

Does ALLHAT change the management of hypertension in chronic kidney disease?

ALLHAT was designed to test the hypothesis that “newer” antihypertensive agents are superior to a thiazide diuretic for cardiovascular outcomes. Pre-specified secondary outcomes included the development of endstage renal disease (ESRD) (dialysis, renal transplantation, or death from renal cause) and estimated glomerular filtration rate (GFR). ALLHAT showed no differences in the overall rates of ESRD between those randomized to chlorthalidone, amlodipine, or lisinopril. It showed a slower rate of decline of GFR among those randomized to amlodipine in both diabetics and nondiabetics, and in the composite end point (ESRD or ≥ 50% decline in GFR) in nondiabetics. The results of ALLHAT are consistent with other studies that, for the patient population studied (presumably largely nonalbuminuric patients with and without diabetes), at systolic BP < 130 mm Hg, there is no difference for renal outcomes between a thiazide diuretic, dihydropyridine calcium channel blocker, and ACEI-initiated treatment for 5 to 6 years of follow-up. These results suggest that BP control per se remains the most important objective for this patient population.     

Time for a comeback of NSAIDs in proteinuric chronic kidney disease?

Before the introduction of renin-angiotensin-aldosterone system (RAAS) inhibitors in the 1980s, non-steroidal anti-inflammatory drugs (NSAIDs) were the only class of drugs available for the reduction of symptomatic proteinuria. Long-term data from those days suggested sustained renoprotective properties in proteinuric chronic kidney disease (CKD), but this potential has not been further explored, due to the adverse effects of NSAIDs, and due to the successful introduction of RAAS blockade for blood pressure control and renoprotection. The renoprotective potential of NSAIDs may seem surprising for the present generation of clinicians, as NSAIDs are well known for their adverse effects on the kidney. Interestingly, the newer selective COX-2 inhibitors (coxibs), such as non-selective (ns) NSAIDs, exert an antiproteinuric effect in CKD patients. This review discusses the role of NSAIDs as a class of drugs representing an old concept for renoprotection in the light of current insights on renoprotection. It has become increasingly clear during the last two decades, from evidence obtained almost exclusively in studies using RAAS blockade, that not only reduction of blood pressure, but also of proteinuria is a prerequisite for long-term renoprotection. Ns-NSAIDs and coxibs reduce proteinuria without reduction of blood pressure. Their possible role as an adjunct in individualised treatment strategies, particularly for individual patients resistant or intolerant to current therapy, will be discussed.     

Effects of PPARγ on hypertension, atherosclerosis, and chronic kidney disease

Peroxisome proliferator-activated receptor (PPAR) γ is a nuclear hormone receptor that is trans-activated by its ligands including insulin-sensitizing thiazolidinediones. PPARγ has recently been reported to demonstrate pleiotropic beneficial effects in the vasculatures, independent of its blood glucose-lowering effects. Firstly, PPARγ ligands have been shown to lower blood pressure in both animals and human. The effect may possibly be mediated via the PPARγ-mediated inhibition of the angiotensin (Ang) II type 1 receptor expression as well as Ang II-mediated signaling pathways, which may result in the suppression of the renin-angiotensin system (RAS). Secondly, the progression of atherosclerosis was also prevented by PPARγ ligands in both animals and human. In addition to the PPARγ-mediated suppression of the RAS and the thromboxane A(2) system, protective effects of PPARγ ligands on endothelial function may also be involved. Thirdly, reno-protective effects of PPARγ ligands, especially on reducing urinary albumin, have been observed in both animals and human not only in diabetic nephropathy but also in non-diabetic renal diseases. The reno-protective effects may be mediated, at least in part, via the PPARγ ligand-induced blood pressure-lowering effects, protective effects on endothelial function, and vasodilating effects on the glomerular efferent arterioles. Additionally, anti-cancer effects of PPARγ ligands have recently been reported. Taken together, usefulness and effectiveness of PPARγ ligands on lifestyle related diseases will be increasingly appreciated.     

A prospective,multi-centre,observational study to examine kidney disease progression in adults with chronic kidney disease – CKDOD - Study design and preliminary results

Background

The objective of this article is to describe the organisation of an international, clinical registry, the Chronic Kidney Disease Observational Database (CKDOD), the processes of enrolling patients and entering data and preliminary results to date.

Design

The Chronic Kidney Disease Observational Database (CKDOD) is designed to assess the association between different factors with a known influence on chronic kidney disease (CKD) progression as well as treatment strategies such as dietary modifications, blood pressure control and pharmacological interventions in Asian countries (India, China, Malaysia and Thailand). The only inclusion criterion is the presence of CKD stage 2 or higher as defined by the KDIGO guidelines. Demographic and clinical information are collected by a standardised electronic questionnaire, available in English and Chinese. The data are transferred to the CKDOD database either by e-mail or via web access. All data are checked for consistency and missing values.Collection of data started in September 2011 and by April 2015, data on 1323 individual patients had been submitted. The mean age at inclusion was 57?±?14 years, 67 % were male and 36 % were diabetic. The baseline estimated glomerular filtration rate was 26 ml/min/1.73 m². Of all enrolled patients, 324 (24 %) received ketoanalogue supplementation during at least one recorded visit.

Discussion

The CKDOD is a very large and comprehensive data repository, currently focused in subjects recruited from Asia. The database is expected to provide important long-term information on CKD progression, nutritional and metabolic derangements that accompany CKD progression and treatment strategies to ameliorate progression and complications of CKD.

Trial Registration

Clinical Trial Registry – India: CTRI/2012/06/002743; 25th July 2012

     

Arrhythmias,chronic kidney disease and the elderly:a triple jeopardy

Crdiovascular diseases (CVD) incur a heavy burden of morbidity and mortality among patients with chronic kidney disease (CKD), particularly among the elderly. It is estimated that about 22-25% of all adults beyond the age of 65 years have moderate or severe renal dysfunction. Traditional risk factors such as hypertension, hypertriglyceridemia, low HDL levels and physical inactivity have a stronger association with cardiovascular mortality; however this association is weaker with risk factors such as high CRP, fibrinogen, interleukin 6 (IL-6), factor VIIIc and lipoprotein(α) which are novel for patients with CKD.     

Cytokine dysregulation in chronic kidney disease: how can we treat it?

As the kidney is the major site for elimination of many cytokines, the delicate equilibrium of pro-inflammatory cytokines and their inhibitors is clearly dysregulated in chronic kidney disease (CKD) patients. The consequences of the altered immune response in uremia lead to a state of persistent inflammation which is highly prevalent among CKD patients and is linked to complications such as the development of protein-energy wasting and atherosclerotic vascular disease. The present review aims at reviewing this complex orchestration of uremic cytokines beyond the well-studied interleukin-6 and tumor necrosis factor-alpha. Finally, we update our current understanding on anti-inflammatory treatment strategies in CKD patients, including nutritional and lifestyle measurements, pharmacological intervention and specific anticytokine strategies targeting the dialytic procedure.     

Anaemia, diabetes and chronic kidney disease: where are we now?

Anaemia is a common finding in people with diabetes and chronic kidney disease and failure of the kidney to produce erythro-poietin in response to a falling haemoglobin concentration is a key component, correlating with the degree of albuminuria, renal dysfunction and iron deficiency. Anaemia in diabetes is associated with a number of adverse outcomes, including increased risk of all cause and cardiovascular mortality. Whether or not anaemia is a marker or mediator of adverse outcome still remains to be completely resolved. Treatment of anaemia in diabetes has quality of life benefits and reduces transfusion requirements. Correction of anaemia to normal haemoglobin concentrations is associated with significant adverse cardiovascular outcomes and is not recommended, escalating doses of erythropoiesis-stimulating agents should be avoided. The treatment of anaemia in people with diabetes and chronic kidney disease should begin with optimisation of iron stores. An aspirational haemoglobin concentration range of 10-12 g/dl with anaemia management, balances proven benefits of anaemia treatment with potential cardiovascular risk.