Nutrition, inflammation and chronic kidney disease

PURPOSE OF REVIEW: Protein-energy wasting and chronic inflammation are important comorbid conditions that predict poor clinical outcome in patients with advanced chronic kidney disease. The current article aims to provide a brief overview of the etiology and nutritional consequences of chronic inflammation with an outline of potential treatment options. RECENT FINDINGS: The exact mechanisms leading to these unfavorable conditions are not fully elucidated and are most likely multifactorial. Irrespective of the specific etiologic mechanisms, it appears that the common pathway for all the metabolic derangements is related to exaggerated protein degradation relative to protein synthesis. Several studies suggest that chronic inflammation can predispose advanced chronic kidney disease patients to a catabolic state leading to worsening of protein-energy wasting by both increasing protein breakdown and decreasing protein synthesis. Chronic administration of nutritional supplementation, both parenterally and orally, improves nutritional status even in inflamed hemodialysis patients. Several pilot studies indicate that antiinflammatory intervention can also improve the metabolic and nutritional profiles. SUMMARY: While a single common etiology has not been identified in this complex process, nutritional and antiinflammatory interventions can provide potential treatment options to improve the high mortality and morbidity in patients with advanced chronic kidney disease.     

Rapamycin and chronic kidney disease: beyond the inhibition of inflammation

Rapamycin, a potent inhibitor of the mammalian target of rapamycin (mTOR) protein kinase, is a well-known immunosuppressive agent. In this issue, Wu and colleagues report that rapamycin significantly attenuates renal interstitial fibrosis in obstructive nephropathy. Besides its inhibition of renal inflammation, rapamycin is able to block tubular epithelial-mesenchymal transition, thereby shedding new light on the mechanism of its antifibrotic actions.     

Anemia and the heart in chronic kidney disease

Cardiovascular disease is highly prevalent at all stages of chronic kidney disease (CKD) and is the leading cause of morbidity and mortality. Individuals with CKD commonly have multiple risk factors for the development of cardiovascular disease, including both traditional and nontraditional risk factors. Anemia is a nontraditional cardiovascular risk factor found in CKD that contributes to the development and progression of structural abnormalities of the heart, namely left ventricular hypertrophy and dilation. In addition, a deficiency of erythropoietin per se also may have important pathophysiologic consequences. In this review we summarize the evidence from observational studies showing an association between anemia and adverse cardiac outcomes at all stages of CKD. In addition, we provide an overview of the evidence accumulating from randomized controlled trials conducted in both nondialysis and dialysis CKD populations evaluating the effect of anemia correction on cardiac outcomes such as changes in left ventricular hypertrophy.     

Biomarkers of inflammation and progression of chronic kidney disease

BACKGROUND: Chronic kidney disease is associated with higher levels of inflammatory biomarkers. Statins have anti-inflammatory properties and may attenuate loss of kidney function. Although inflammation may mediate progressive renal injury, the relation between statin use, markers of inflammation, and the rate of kidney function loss has not been elucidated. We examined the association between pravastatin use, levels of C-reactive protein (CRP), soluble tumor necrosis factor receptor II (sTNFrii), and the rate of kidney function loss. METHODS: We performed a post hoc analysis of data from a randomized placebo controlled trial of pravastatin 40 mg daily in people with previous myocardial infarction. Glomerular filtration rate (GFR) was estimated using the Modification of Diet in Renal Disease Study (MDRD) GFR equation. We studied 687 subjects with chronic kidney disease (GFR < 60 mL/min/1.73 m(2)) who did not experience a cardiovascular event during follow-up. Multivariate linear regression was used to study the relation between baseline CRP and sTNFrii and the rate of kidney function loss in mL/min/1.73 m(2)/year. Cross-product interaction terms were used to determine if these relations varied with pravastatin use. RESULTS: Median baseline GFR was 54.5 mL/min/1.73 m(2) (interquartile range 49.7, 57.8) and median duration of follow-up was 58 months. Higher baseline CRP level was independently associated with more rapid kidney function loss (highest tertile 0.6 mL/min/1.73 m(2) per year faster than lowest tertile) (P= 0.001). A similar independent relation was observed between tertile of sTNFrii and rate of kidney function loss (highest tertile 0.5 mL/min/1.73 m(2) per year faster than lowest tertile) (P= 0.006). Subjects with both CRP and sTNFrii in the highest tertile ("inflamed" status) appeared to derive more renal benefit from pravastatin than those without (P for interaction 0.047). In these 108 subjects, renal function loss in pravastatin recipients was 0.8 mL/min/1.73 m(2)/year slower than placebo (95% CI 0 to 1.5 mL/min/1.73 m(2)/year slower) (P= 0.039). CONCLUSION: Higher CRP and sTNFrii are independently associated with faster rates of kidney function loss in chronic kidney disease. Pravastatin appears to prevent loss of kidney function to a greater extent in individuals with greater evidence of inflammation, although this was of borderline significance. These data suggest that inflammation may mediate the loss of kidney function among subjects with chronic kidney disease and concomitant coronary disease.     

Hepcidin in anemia and inflammation in chronic kidney disease

Maintaining the correct iron balance is crucial for health. Our understanding of the molecular control of iron metabolism has increased dramatically over the past 5 years due to the discovery of hepcidin. This is a circulating antimicrobial peptide mainly synthesized in the liver, which has been recently proposed as a factor regulating the uptake of dietary iron and its mobilization from macrophages and hepatic stores. Inflammation causes an increase of production of hepcidin, which is a potent mediator of anemia of chronic diseases. Anemia in chronic kidney disease is mainly due to erythropoietin deficiency but these patients often have a chronic inflammatory state. The aim of this review is to summarize the current knowledge dealing with a possible role of hepcidin in iron metabolism and its regulation, particularly in kidney disease. In addition, current methods of determination of hepcidin are reviewed.     

Quotidian hemodialysis and inflammation associated with chronic kidney disease

The mortality rate of chronic dialysis patients in the United States is 24% per year per the 2006 United States Renal Data System. Although there have been marked improvements in dialysis technology, cardiovascular disease is the principal cause of mortality in end-stage renal disease patients. Inflammation and left ventricular hypertrophy both contribute to atherosclerosis. Hemodialysis 3 times a week is the most commonly used form of dialysis in the United States. The multicenter hemodialysis (HEMO) study hypothesized that an increase in dialysis dose and use of high-flux membranes would improve mortality and decrease morbidity. This study failed to show decreases in mortality. In other studies, however, there appears to be improved morbidity with more frequent dialysis including daily nocturnal hemodialysis and short-daily hemodialysis. The more frequent dialysis may have some beneficial effect on the inflammatory process that occurs in end-stage renal disease.     

Posttransplant inflammation associated with onset of chronic kidney disease

Background

Chronic allograft nephropathy (CAN), a major complication in renal transplant patients, is an important cause of graft loss. Inflammation as measured in the pretransplant and posttransplant phases, using various markers, has been associated with worse renal function and a greater risk of cardiovascular disease and of long-term graft loss.

Objective

The objective of our study was to evaluate whether worsening inflammation in the first 3 months postoperatively was a risk factor for developing CAN.

Patients and methods

We performed a cross-sectional study in 207 patients. The following markers of inflammation (MIF) were determined pretransplant and at 3 months after grafting: C-reactive protein (CRP) (mg/L), interleukin (IL)-6 (pg/mL), IL-10 (pg/mL), tumor necrosis factor (TNF)-α (pg/mL), and its soluble receptor (ng/mL), soluble-IL2R (UI/mL), pregnancy-associated plasma protein A (PAPP-A; mUI/L), and IL-4 (pg/mL). We also calculated the ratio at 3 months versus the pre value of MIF.

Results

CAN was diagnosed after the first year in 23 patients (11.3%) always by renal biopsy performed for clinical indications. Patients with CAN showed worse inflammation, eg, MIF ratios over one, with statistically significant differences for the ratios of TNF-α and PAPP-A (P = .032 and P = .051 respectively). Upon multivariate logistic regression analysis, using CAN as the dependent variable and age, sex, donor age, months on dialysis, acute tubular necrosis, acute rejection, and MIF ratios as covariates, we observed that an acute rejection episode (OR = 13.03; CI = 2.8-60.9; P = .001), CRP ratio (OR = 1.36; CI = 1.07-1.73; P = .013), and PAPP-A ratio (OR = 1.80; CI = 0.92-3.53; P = .005) were independent markers of CAN.

Conclusions

Among other factors, inflammation may determine the onset of CAN as diagnosed by renal biopsy.     

Anemia and heart failure in chronic kidney disease

Cardiovascular disease is mainly responsible for the poor long-term survival observed in chronic kidney disease (CKD) patients on dialytic treatment. Anemia is an early complication of CKD and, by inducing important cardiovascular alterations, first of all left ventricular hypertrophy, it does not only impair quality of life, but has also been shown to be an independent risk factor for adverse cardiovascular outcomes in CKD patients. Clinical studies, although with discordant results, have shown that cardiovascular benefits, mainly in terms of left ventricular hypertrophy regression, may be achieved by a partial correction of hemoglobin levels, however, it still is unclear whether starting anemia correction in a very early phase of CKD or aiming for complete normalization of hemoglobin levels higher than the targets recommended by current guidelines may provide further cardiovascular advantages. Results of ongoing, large-scale, prospective, randomized, clinical trials therefore are awaited with much interest to clarify better which practices of anemia correction may provide the best results on the improvement of cardiovascular status and thus of long-term survival of patients with renal disease.     

Long-term, high-dosage candesartan suppresses inflammation and injury in chronic kidney disease: nonhemodynamic renal protection

Recent evidence suggests that higher-than-usual antihypertensive dosages of renin-angiotensin-aldosterone system blockers may provide additional protection from progression of chronic renal disease; however, there have been few long-term studies, and the underlying mechanisms remain uncertain. This study examined the effects of long-term (14 mo) administration of ultrahigh dosages of the angiotensin receptor blocker candesartan on the progression of renal injury in spontaneously hypertensive rats (SHR). Beginning 8 wk after birth, SHR underwent unilateral nephrectomy and were given vehicle (control), or candesartan at a standard 5 mg/kg per d (T5), high 25 mg/kg per d (T25), or ultrahigh 75 mg/kg per d dosage (T75). After 2 wk, BP was reduced in all treated groups; however, it was better controlled in the high-dosage groups (T25 and T75). Urinary protein was significantly reduced in T75 after 2 wk of treatment and was also declined in the other two treatment groups but only after 2 mo. Exogenous angiotensin II test showed that complete angiotensin receptor blockade was achieved only in the high-dosage groups. Renal inflammation and macrophage (ED-1) infiltration were significantly ameliorated in both T25 and T75 but not in T5 rats. This was associated with the changes of tubular expression of monocyte chemoattractant protein-1, RANTES (regulated upon expression normal T cell expressed and secreted), and the phosphorylated NF-kappaB, a marker for activation. Suppression of ED-1, monocyte chemoattractant protein-1, and RANTES expression and NF-kappaB activation were greater in T75 as compared with T25. These findings suggest that candesartan has dosage-dependent, anti-inflammatory effects that are mediated by suppression of NF-kappaB activation and chemokine expression. Renal protection with high-dosage therapy may depend on these nonhemodynamic effects.     

Chemokine/chemokine receptor-mediated inflammation regulates pathologic changes from acute kidney injury to chronic kidney disease

Ischemia–reperfusion injury is a main cause of acute kidney injury. Tubular necrosis and interstitial inflammatory cell infiltration are characteristic pathologic changes of acute kidney injury. The main necrotic area should be repaired with new tubular epithelial cells after the injury. On the other hand, some parts of the injured kidney progress to interstitial fibrosis, a characteristic pathologic change in chronic kidney disease. We hypothesized that interstitial infiltrating leukocytes, that are attracted and activated by chemokines, are key mediators in the pathogenesis of tubular necrosis, regeneration of the necrotic area, or interstitial fibrosis. A large number of chemokines were upregulated after ischemic injury, and chemokine receptor-expressing inflammatory cells were attracted by these chemokines. Genetic or molecular modulating experiments in the mouse model have begun to reveal the key participants and their specific roles at the levels of inflammation, regeneration, and fibrosis. Among these chemokines/chemokine receptors, our data indicated CCR2-mediated macrophage infiltration mainly affected tubular necrosis after ischemic acute kidney injury, interferon-gamma-inducible protein (IP)-10-producing macrophages participate in regeneration of tubular epithelial cells, and CX3CR1-mediated macrophages and platelet infiltration and aggregation play roles in interstitial fibrosis in chronic kidney disease. These chemokines and chemokine receptors on infiltrating inflammatory cells would be novel clinical markers or targets for therapeutic intervention. This article was presented as the Oshima Award memorial lecture at the 51st annual meeting of the Japanese Society of Nephrology, held at Fukuoka, Japan, in 2008.