HLA B27 in health and disease: a double-edged sword?

The strong association of the HLA class 1 allele HLA B27 with ankylosing spondylitis (AS) has been recognized for over 25 yr, however the pathogenic mechanism linking HLA B27 with AS and other spondyloarthropathies remains a mystery. We now know that the principal natural function of HLA B27 is an immunologic one, namely to bind antigenic peptides and then present them to T lymphocytes. I have shown that HLA B27 functions as an excellent antigen-presenting molecule in both spondyloarthropathy patients and healthy individuals. A working molecular model of how T cells recognize HLA B27 has been generated and tested. Evidence that T cells have a role in spondyloarthritis has also been found. First, expanded populations of T lymphocytes were found in both the blood and synovial fluid of patients with reactive arthritis (ReA). Secondly, a strong cytotoxic T-cell response to an HLA B27-restricted peptide epitope from Chlamydia trachomatis was found in a patient with ReA. This peptide, derived from a bacterium known to trigger ReA, is thus a candidate 'arthritogenic' peptide. We have also found evidence that HLA B27 has an unusual cell biology compared with other HLA molecules. HLA B27 demonstrates an unusual ability to form heavy chain homodimers in vitro. Dimerization is dependent upon disulphide bonding through an unpaired cysteine at position 67. Remarkably these dimers lack beta2 microglobulin, previously thought to be an essential component of all mature MHC class 1 molecules. HLA B27 homodimer formation has also been demonstrated in certain cell lines in vivo, and preliminary data suggest that significant numbers of T cells from patients with spondyloarthropathy express a ligand for HLA B27 homodimers. These findings have extended our understanding of the beneficial immunologic function of HLA B27, and have also led us to propose the testable new hypothesis that HLA B27 heavy chain dimerization may be involved in the pathogenesis of spondyloarthritis.     

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.     

Risk of chronic kidney disease in patients with non-alcoholic fatty liver disease: is there a link?

Non-alcoholic fatty liver disease (NAFLD) has emerged as a growing public health problem worldwide. Increasing recognition of the importance of NAFLD and its association with the features of the metabolic syndrome has stimulated an interest in its putative role in the development and progression of chronic kidney disease (CKD). Accumulating evidence suggests that NAFLD and CKD share many important cardio-metabolic risk factors and common pathogenetic mechanisms and that NAFLD is associated with an increased prevalence and incidence of CKD. This association appears to be independent of obesity, hypertension, and other potentially confounding factors, and it occurs both in patients without diabetes and in those with diabetes. Although further research is needed to establish a definitive conclusion, these observations raise the possibility that NAFLD is not only a marker of CKD but also might play a part in the pathogenesis of CKD, possibly through the systemic release of several pro-inflammatory/pro-coagulant mediators from the steatotic/inflamed liver or through the contribution of NAFLD itself to insulin resistance and atherogenic dyslipidemia. However, given the heterogeneity and small number of observational longitudinal studies, further research is urgently required to corroborate the prognostic significance of NAFLD for the incidence of CKD, and to further elucidate the complex and intertwined mechanisms that link NAFLD and CKD. If confirmed in future large-scale prospective studies, the potential adverse impact of NAFLD on kidney disease progression will deserve particular attention, especially with respect to the implications for screening and surveillance strategies in the growing number of patients with NAFLD.     

Vasopeptidase inhibition: a double-edged sword?

The enormous benefits of inhibition of ACE demonstrate that manipulation of the metabolism of peptide hormones is a valuable therapeutic strategy for cardiovascular disease. Recent attempts to expand these benefits have combined ACE inhibition with inhibition of other peptidases such as neutral endopeptidase (NEP) in a single molecule, a strategy known as vasopeptidase inhibition. NEP metabolizes natriuretic peptides, and NEP inhibition offers the prospect of combining the benefits of increased natriuretic peptide levels with those of ACE inhibition. However, peptidases such as ACE and NEP have many different substrates, and there are complex interactions between ACE inhibition and NEP inhibition. Both ACE and NEP metabolize the kinin peptides bradykinin and kallidin, and NEP also converts angiotensin (Ang) I to Ang-(1-7) and metabolizes Ang II and endothelin. Addition of NEP inhibition to ACE inhibition potentiates the ACE inhibitor-induced increase in kinin levels, increases Ang II levels, reduces Ang-(1-7) levels, and may increase endothelin levels. These additional consequences of combined ACE/NEP inhibition increase the risk of angioedema and may counteract any benefit of ACE inhibition that depends on reduced Ang II levels and increased Ang-(1-7) levels. Further considerations are that the ratio of ACE and NEP inhibition is fixed for vasopeptidase inhibitors, and there is uncertainty how these drugs should be compared with ACE inhibitors. Vasopeptidase inhibitors will therefore require careful evaluation before they are introduced to patient care.     

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.     

Does treatment with calcitriol improve survival in predialysis patients with chronic kidney disease?

Treatment of secondary hyperparathyroidism with activated vitamin D analogs has been associated with improved survival of dialysis-dependent patients with chronic kidney disease (CKD). Whether this treatment regimen affords similar benefits to non-dialysis-dependent patients with CKD remains unclear. In this Practice Point commentary, we discuss a study by Kovesdy et al. that reported enhanced survival in predialysis patients with CKD who received calcitriol for a median duration of 2.1 years. Despite the achievement of favorable results in these patients, the study had several limitations that could preclude generalization of the findings to other populations. These limitations included the nonrandomized, observational design, the small patient population, the exclusive enrollment of men (76.5% of whom were white), and the lack of information on cause of death. Here, we place the findings of the study into clinical context and emphasize the urgent need for large, well-designed, randomized trials that aim to assess cardiovascular and mortality end points.     

Risk of cardiovascular disease and chronic kidney disease in diabetic patients with non-alcoholic fatty liver disease: just a coincidence?

Non-alcoholic fatty liver disease (NAFLD) is estimated to afflict ~20-30% of the general population, and over 70% of the patients with Type 2 diabetes. Given the expected rise in the prevalence of obesity and diabetes, NAFLD will be, if not already there, an epidemic. The consequences of NAFLD are numerous, and range from progression to chronic liver disease with its associated morbidity and mortality, to worsening insulin resistance and Type 2 diabetes, to being a contributor to both cardiovascular disease (CVD) and chronic kidney disease (CKD). NAFLD is, therefore, a complex problem with implications far beyond the liver. This review focuses on the rapidly expanding body of clinical evidence suggesting that NAFLD is associated with an increased prevalence and incidence of both CVD and CKD in patients with diabetes. This association appears to be independent of obesity, hypertension, and other potential confounding factors. However, given the heterogeneity and small number of observational studies, further research is urgently required to corroborate the prognostic role of NAFLD in the development and progression of CVD and CKD among patients with diabetes, and to further elucidate the complex and intertwined mechanisms that link NAFLD with these adverse outcomes.     

Does a blood pressure J curve exist for patients with chronic kidney disease?

Aggressive reduction of blood pressure may increase cardiovascular events (the J‐curve phenomenon) in certain populations. In this regard, most studies in patients with chronic kidney disease have shown a J curve for cardiovascular morbidity and mortality, and this phenomenon persists after adjusting for confounding factors. Since there is no evidence that a straighter blood pressure target (<130/70 mm Hg) could improve renal outcomes, the increased cardiovascular risk associated with extreme blood pressure reduction should be seen as undesirable. Moreover, the intensive control of blood pressure may induce an unintended reduction of renal function and this decrease, in turn, may increase cardiovascular risk.     

Could metformin be used in patients with diabetes and advanced chronic kidney disease?

Diabetes is an important cause of end stage renal failure worldwide. As renal impairment progresses, managing hyperglycaemia can prove increasingly challenging, as many medications are contra‐indicated in moderate to severe renal impairment. Whilst evidence for tight glycaemic control reducing progression to renal failure in patients with established renal disease is limited, poor glycaemic control is not desirable, and is likely to lead to progressive complications. Metformin is a first‐line therapy in patients with Type 2 diabetes, as it appears to be effective in reducing diabetes related end points and mortality in overweight patients. Cessation of metformin in patients with progressive renal disease may not only lead to deterioration in glucose control, but also to loss of protection from cardiovascular disease in a cohort of patients at particularly high risk. We advocate the need for further study to determine the role of metformin in patients with severe renal disease (chronic kidney disease stage 4‐5), as well as patients on dialysis, or pre‐/peri‐renal transplantation. We explore possible roles of metformin in these circumstances, and suggest potential key areas for further study.     

Acute kidney injury spectrum in patients with chronic liver disease:Where do we stand?

Acute kidney injury (AKI) is a common complication of liver cirrhosis and is of the utmost clinical and prognostic relevance. Patients with cirrhosis, especially decompensated cirrhosis, are more prone to develop AKI than those without cirrhosis. The hepatorenal syndrome type of AKI (HRS–AKI), a spectrum of disorders in prerenal chronic liver disease, and acute tubular necrosis (ATN) are the two most common causes of AKI in patients with chronic liver disease and cirrhosis. Differentiating these conditions is essential due to the differences in treatment. Prerenal AKI, a more benign disorder, responds well to plasma volume expansion, while ATN requires more specific renal support and is associated with substantial mortality. HRS–AKI is a facet of these two conditions, which are characterized by a dysregulation of the immune response. Recently, there has been progress in better defining this clinical entity, and studies have begun to address optimal care. The present review synopsizes the current diagnostic criteria, pathophysiology, and treatment modalities of HRS–AKI and as well as AKI in other chronic liver diseases (non-HRS–AKI) so that early recognition of HRS–AKI and the appropriate management can be established.     

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.     

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.