Mechanisms Of Chronic Kidney Disease Research Articles

Relationship of Pruritus with Biochemical and Haematological Parameters in Haemodialysis Patients (A Single Center Study).

Background: Pruritus often constitutes a major problem for patients with end stage renal disease. The pathophysiological mechanism of chronic kidney disease -associated pruritus is poorly defined.Objectives: To evaluate the prevalence of uremic pruritus in dialysis patients and their correlation with the laboratory and clinical parameters in some Iraqi patients with chronic renal disease.Patients & methods: This analytic, descriptive, cross-sectional study was performed on 103 patients on haemodialysis. Blood urea, creatinine, calcium, phosphorus, alkaline phosphatase and parathyroid hormone were determined. Complete blood count was also performed.Results: Of the 103 patients included in the study the, 79 patients (76.7%) had pruritus of whom, 27 (34.1%) had mild pruritus, 30 (38%) had moderate and 22 (27.9%) had severe pruritus. No significant association (p> 0.05) was found between pruritus and each of age and haemodialysis duration. There was no significant difference (p > 0.05) in the urea, creatinine, calcium, phosphorus, alkaline phosphatase, parathyroid hormone, hemoglobin, hematocrit, white blood cells, neutrophils, eoisinophils, basophils mean values among patients who had no pruritus, mild, moderate and severe pruritus. A significant positive correlation (p > 0.05) was found between severity of pruritus in pruritic patients and each of age, hemoglobin and hematocrit levels.Conclusion: Our study showed that age, hemoglobin and hematocrit levels had a significant positive correlation with the severity of pruritus in pruritic patients.

The Role of the Gut Microbiome on Chronic Kidney Disease.

Chronic kidney disease (CKD) is estimated to affect nearly 500 million people worldwide and cardiovascular (CV) disease is a major cause of death in this population. However, therapeutic interventions targeting traditional CV risks are not effective at lowering the incidence of CV events or at delaying the progression of the disease in CKD patients. In recent years, disturbances of normal gut microbiome were recognized in the pathogenesis of diverse chronic diseases. Gut dysbiosis is being unraveled in CKD and pointed as a nontraditional risk factor for CV risk and CKD progression. The most often reported changes in gut microbiome in CKD are related to the lower levels of Bifidobacteriaceae and Lactobacillaceae and to higher levels of Enterobacteriaceae. Although metagenomics brought us an amplified vision on the microbial world that inhabits the human host, it still lacks the sensitivity to characterize the microbiome up to species level, not revealing alterations that occur within specific genus. Here, we review the current state-of-the-art concerning gut dysbiosis in CKD and its role in pathophysiological mechanisms in CKD, particularly in relation with CV risk. Also, the strategies towards prevention and treatment of gut dysbiosis in CKD progression will be discussed.

علاقة الحكة بالمعايير الكيميائية الحياتية والدموية لدى مرضى غسيل الدم (دراسة أجريت في مركز واحد)

Background: Pruritus often constitutes a major problem for patients with end stage renal disease. The pathophysiological mechanism of chronic kidney disease -associated pruritus is poorly defined.Objectives: To evaluate the prevalence of uremic pruritus in dialysis patients and their correlation with the laboratory and clinical parameters in some Iraqi patients with chronic renal disease.Patients & methods: This analytic, descriptive, cross-sectional study was performed on 103 patients on haemodialysis. Blood urea, creatinine, calcium, phosphorus, alkaline phosphatase and parathyroid hormone were determined. Complete blood count was also performed.Results: Of the 103 patients included in the study the, 79 patients (76.7%) had pruritus of whom, 27 (34.1%) had mild pruritus, 30 (38%) had moderate and 22 (27.9%) had severe pruritus. No significant association (p> 0.05) was found between pruritus and each of age and haemodialysis duration. There was no significant difference (p > 0.05) in the urea, creatinine, calcium, phosphorus, alkaline phosphatase, parathyroid hormone, hemoglobin, hematocrit, white blood cells, neutrophils, eoisinophils, basophils mean values among patients who had no pruritus, mild, moderate and severe pruritus. A significant positive correlation (p > 0.05) was found between severity of pruritus in pruritic patients and each of age, hemoglobin and hematocrit levels.Conclusion: Our study showed that age, hemoglobin and hematocrit levels had a significant positive correlation with the severity of pruritus in pruritic patients.

High prevalence of and potential mechanisms for chronic kidney disease in patients with acute intermittent porphyria

Acute intermittent porphyria (AIP) is a genetic disorder of the synthesis of heme caused by a deficiency in hydroxymethylbilane synthase (HMBS), leading to the overproduction of the porphyrin precursors δ-aminolevulinic acid and porphobilinogen. The aim of this study is to describe the clinical and biological characteristics, the renal pathology, and the cellular mechanisms of chronic kidney disease associated with AIP. A total of 415 patients with HMBS deficiency followed up in the French Porphyria Center were enrolled in 2003 in a population-based study. A follow-up study was conducted in 2013, assessing patients for clinical, biological, and histological parameters. In vitro models were used to determine whether porphyrin precursors promote tubular and endothelial cytotoxicity. Chronic kidney disease occurred in up to 59% of the symptomatic AIP patients, with a decline in the glomerular filtration rate of ~1 ml/min per 1.73 m(2) annually. Proteinuria was absent in the vast majority of the cases. The renal pathology was a chronic tubulointerstitial nephropathy, associated with a fibrous intimal hyperplasia and focal cortical atrophy. Our experimental data provide evidence that porphyrin precursors promote endoplasmic reticulum stress, apoptosis, and epithelial phenotypic changes in proximal tubular cells. In conclusion, the diagnosis of chronic kidney disease associated with AIP should be considered in cases of chronic tubulointerstitial nephropathy and/or focal cortical atrophy with severe proliferative arteriosclerosis.

Cellular and Molecular Mechanisms of Chronic Kidney Disease with Diabetes Mellitus and Cardiovascular Diseases as Its Comorbidities.

Chronic kidney disease (CKD), diabetes mellitus (DM), and cardiovascular diseases (CVD) are complex disorders of partly unknown genesis and mostly known progression factors. CVD and DM are the risk factors of CKD and are strongly intertwined since DM can lead to both CKD and/or CVD, and CVD can lead to kidney disease. In recent years, our knowledge of CKD, DM, and CVD has been expanded and several important experimental, clinical, and epidemiological associations have been reported. The tight cellular and molecular interactions between the renal, diabetic, and cardiovascular systems in acute or chronic disease settings are becoming increasingly evident. However, the (patho-) physiological basis of the interactions of CKD, DM, and CVD with involvement of multiple endogenous and environmental factors is highly complex and our knowledge is still at its infancy. Not only single pathways and mediators of progression of these diseases have to be considered in these processes but also the mutual interactions of these factors are essential. The recent advances in proteomics and integrative analysis technologies have allowed rapid progress in analyzing complex disorders and clearly show the opportunity for new efficient and specific therapies. More than a dozen pathways have been identified so far, including hyperactivity of the renin–angiotensin (RAS)–aldosterone system, osmotic sodium retention, endothelial dysfunction, dyslipidemia, RAS/RAF/extracellular-signal-regulated kinase pathway, modification of the purinergic system, phosphatidylinositol 3-kinase (PI 3-kinase)-dependent signaling pathways, and inflammation, all leading to histomorphological alterations of the kidney and vessels of diabetic and non-diabetic patients. Since a better understanding of the common cellular and molecular mechanisms of these diseases may be a key to successful identification of new therapeutic targets, we review in this paper the current literature about cellular and molecular mechanisms of CKD.

A crystal-clear mechanism of chronic kidney disease

Knauf et al. demonstrate that prolonged activation of the intrarenal inflammasome is responsible for the loss of kidney function in oxalate crystal nephropathy. These findings suggest new therapeutic opportunities for patients suffering from severe hereditary kidney diseases such as primary hyperoxaluria, and reveal a previously unappreciated general mechanism of kidney disease progression that may also contribute to conditions other than crystal nephropathy.

Evidence for the involvement of epigenetics in the progression of renal fibrogenesis

Epigenetics are omnipresent in eukaryotic cells and influence cell differentiation and maintenance of cell metabolism in health and disease. Here, we discuss how the 'second genetic code' impacts the fate of the injured kidney. We provide a glimpse of how recent insights into epigenetic mechanisms of chronic kidney disease might lead to novel diagnostic and therapeutic tools.

Chronic kidney disease accelerates endothelial barrier dysfunction in a mouse model of an arteriovenous fistula

Hemodialysis patients depend on arteriovenous fistulas (AVF) for vascular access. Unfortunately, their 2-yr primary patency rate is only 60% because of AVF clog due to intimal hyperplasia at the venous anastomosis. Chronic kidney disease (CKD) can increase neointima formation by unknown mechanisms. A new AVF mouse model was created, and the mechanisms of CKD on neointima formation in AVFs were investigated. We created AVFs in mice by anastomosing the common carotid artery to the internal jugular vein. CKD was induced [BUN (blood urea nitrogen) in control and CKD mice, 33.3 ± 3.9 vs. 114.2 ± 12.1 mg/dl, P < 0.05]. After 1 day, there was endothelial cell loss and CD41-positive platelet aggregation, especially in the venous anastomosis. An invasion of macrophages and neutrophils peaked at 1 wk after surgery. Neointima formation (smooth muscle cell accumulation and extracellular matrix deposition) increased progressively over 4 wk. Mice with CKD had ~45% (P < 0.05) more neointima formation than control mice. CKD decreased vascular endothelial-cadherin expression in endothelial cells and delayed regeneration of the endothelium. CKD also increased inflammatory cells (Mac-2-positive or CD45-positive) in AVFs at 2 wk. Finally, AVFs were "leakier" (increased accumulation of Evans blue) in CKD mice at 7 and 14 days than control mice. We find that CKD increases neointima formation and endothelial barrier dysfunction. We have created a mouse model of AVF with characteristics similar to failed AVFs in patients. The model will allow testing of strategies directed at improving AVF function in CKD patients.

Uric acid-induced phenotypic transition of renal tubular cells as a novel mechanism of chronic kidney disease

Recent experimental and clinical studies suggest a causal role of uric acid in the development of chronic kidney disease. Most studies have focused on uric acid-induced endothelial dysfunction, oxidative stress, and inflammation in the kidney. The direct effects of uric acid on tubular cells have not been studied in detail, and whether uric acid can mediate phenotypic transition of renal tubular cells such as epithelial-to-mesenchymal transition (EMT) is not known. We therefore investigated whether uric acid could alter E-cadherin expression and EMT in the kidney of hyperuricemic rats and in cultured renal tubular cells (NRK cells). Experimental hyperuricemia was associated with evidence of EMT before the development of significant tubulointerstitial fibrosis at 4 wk, as shown by decreased E-cadherin expression and an increased α-smooth muscle actin (α-SMA). Allopurinol significantly inhibited uric acid-induced changes in E-cadherin and α-SMA with an amelioration of renal fibrosis at 6 wk. In cultured NRK cells, uric acid induced EMT, which was blocked by the organic anion transport inhibitor probenecid. Uric acid increased expression of transcriptional factors associated with decreased synthesis of E-cadherin (Snail and Slug). Uric acid also increased the degradation of E-cadherin via ubiquitination, which is of importance since downregulation of E-cadherin is considered to be a triggering mechanism for EMT. In conclusion, uric acid induces EMT of renal tubular cells decreasing E-cadherin synthesis via an activation of Snail and Slug as well as increasing the degradation of E-cadherin.

Acute changes in home blood pressure after the Great East Japan Earthquake among patients with chronic kidney disease in Fukushima City

Blood pressure (BP) transiently increases after major earthquakes. Although home BP increased in hypertensive patients after the Great East Japan Earthquake (measuring 9.0 on the Richter scale) on March 11th, 2011, such profiles in patients with chronic kidney disease (CKD) have not been investigated. This retrospective single-center observational study included 38 patients with CKD at the predialysis stage [male, n=27 (71%); mean age 66.0 years; mean estimated glomerular filtration rate (eGFR) 46.0 mL/min/1.73 m²] who lived in Fukushima City. We compared their morning BP between two and four weeks after the quake with that of a control group of 39 non-CKD patients with hypertension. Systolic BP (SBP) remained elevated for one week after the quake in the CKD and non-CKD groups [before vs. after the quake 133.7±15.6 vs. 136.9±16.9 (p=0.017) and 129.9±7.8 vs. 133.3±9.3 mmHg (p=0.009), respectively]. Increases in SBP in the morning after the quake were statistically significant in the group with but not in that without CKD (7.1 and 3.4 mmHg; p=0.038 and 0.221, respectively). Multivariate analysis revealed that a low eGFR was an independent risk factor for elevated SBP after the quake. The quake caused acute changes in the home BP and the fact that BP elevation correlated with renal function suggests a possible mechanism of CKD, such as enhanced activity of the sympathetic nervous system in such patients.

Investigating mechanisms of chronic kidney disease in mouse models.

Animal models of chronic kidney disease (CKD) are important experimental tools that are used to investigate novel mechanistic pathways and to validate potential new therapeutic interventions prior to pre-clinical testing in humans. Over the past several years, mouse CKD models have been extensively used for these purposes. Despite significant limitations, the model of unilateral ureteral obstruction (UUO) has essentially become the high-throughput in vivo model, as it recapitulates the fundamental pathogenetic mechanisms that typify all forms of CKD in a relatively short time span. In addition, several alternative mouse models are available that can be used to validate new mechanistic paradigms and/or novel therapies. Here, we review several models-both genetic and experimentally induced-that provide investigators with an opportunity to include renal functional study end-points together with quantitative measures of fibrosis severity, something that is not possible with the UUO model.

Oxidized high‐density lipoprotein enhances inflammatory activity in rat mesangial cells

Inflammation is a mechanism of glomerular damage in chronic glomerulopathies, in which dyslipidaemia plays an important role. Unlike native high-density lipoprotein (HDL), oxidized HDL is thought to be an adverse factor in chronic ischaemic disease and may increase the production of inflammatory cytokines in atheromatous plaques and plasma, but the effect of oxidized HDL on mesangial cells remains unclear. Intracellular reactive oxygen species level was measured. The inflammatory and proapoptotic effects of oxidized HDL were detected in rat mesangial cells by measuring levels of tumour necrosis factor-alpha, regulated upon activation, normal T-cell expressed and secreted, monocyte chemoattractant protein-1, CXC chemokine ligand-1 and early apoptosis. The expression of mitogen-activated protein kinase (MAPK) (p38/MAPK, extracellular-regulated kinase/MAPK and c-Jun N-terminal kinase/MAPK), nuclear factor-kappaB activity and lipoprotein scavenger receptors (CD36, low-density lipoprotein receptor-1 and scavenger receptor BI) were also detected. Oxidized HDL enhanced reactive oxygen species production and upregulated expression of proinflammatory factors, including tumour necrosis factor-alpha, regulated upon activation, normal T-cell expressed and secreted (RANTES), monocyte chemoattractant protein-1 and CXC chemokine ligand-1 by rat mesangial cells dose in a dependent fashion. Incubation with oxidized HDL also increased rat mesangial cells apoptosis in a dose-dependent manner. These effects partly depended on scavenger receptors CD36 and low-density lipoprotein receptor-1, but not scavenger receptor BI. In addition, co-culture with oxidized HDL activated P38/MAPK, extracellular-regulated kinase (ERK)/MAPK and nuclear factor-kappaB (NF-kappaB). The results of the present study suggest that oxidized HDL enhanced proinflammatory properties in mesangial cells partly via CD36 and low-density lipoprotein receptor-1. MAPK and nuclear factor-kappaB pathways were involved in the process. The ability of oxidized HDL to negatively influence mesangial cell biology may represent an important mechanism of chronic kidney disease.

Targeting the renin angiotensin system for remission/regression of chronic kidney disease.

In the last few years great progress has been made in the search for the cellular and molecular mechanisms of chronic kidney disease and its progression to end-stage renal failure. The possibility of remission/regression of chronic nephropathy has become a reality for some patients on therapy based on renin-angiotensin system blockade - an example of how a public health concern can be successfully addressed by translational medicine. This review describes experimental and clinical investigations documenting the advances achieved in the management of chronic kidney diseases by targeting angiotensin II.

The glomerular proteome in a model of chronic kidney disease

Adequate kidney function is crucial in sustaining vertebrate homeostasis. Certain diseases can diminish renal function and lead to end-stage renal disease. Diabetes mellitus and hypertension are the main causes of glomerulosclerosis and albuminuria in adults. The molecular mechanisms that trigger these maladaptive changes are still unsatisfyingly described. We previously introduced 2-D DIGE in combination with focused tissue isolation methods to analyze protein expression in glomeruli. Glomeruli, the crucial compartments in albuminuric renal diseases, were extracted using magnetic particles from subtotally nephrectomized FVB mice (n = 6); this 5/6 nephrectomy in FVB mice is a model of chronic kidney disease. Analysis of protein expression levels from glomerular protein lysates was performed using 2-D DIGE and compared with glomerular protein lysates from mice that underwent sham surgery. The comparison of about 2100 detectable spots between both groups revealed 48 protein spots that showed significant differential expression. Of those, 33 proteins could be identified using nanoLC-ESI MS. The metalloproteinase meprin 1 alpha, the beta galactoside-binding-lectin galectin-1 and dimethylarginine dimethylaminohydrolase 1, a key enzyme in NO metabolism, were found to be differentially regulated, thus implying a role in the pathogenesis and pathophysiology of progressive kidney disease. In conclusion, 2-D DIGE protein analysis of smallest sample sizes from specific organ compartments provides focused protein expression results, which help in gaining an understanding of the molecular mechanisms of chronic kidney disease.

Hyperbaric oxygen treatment augments the efficacy of cilazapril and simvastatin regimens in an experimental nephrotic syndrome model

Oxidative stress plays a role in the mechanism of chronic kidney disease (CKD), and antioxidant regimes are regarded as promising treatment modalities. We compared the effects of cilazapril, simvastatin, and hyperbaric oxygen (HBO) treatment on proteinuria and on oxidative stress in adriamycine (ADR)-induced proteinuria. Seventy male Sprague-Dawley rats were housed, and 60 were injected with ADR to induce nephrosis. After the stabilization of proteinuria, rats were treated for 6 weeks with simvastatin (n = 10, 4 mg/kg/day), cilazapril (n = 10, 10 mg/kg/day), HBO (n = 10, 2.8 athmosphere absolute, 90 min/daily), HBO + cilazapril (n = 10), HBO + simvastatin (n = 10), and vehicle (n = 10). After euthanization at 12 weeks, protein carbonyl (PCO), superoxide dismutase (SOD), and glutathion peroxidase (GPx) levels were analyzed from tissues. The histological alterations in the kidneys were determined by semiquantitative scoring. Protein carbonyl (PCO) levels were higher (p < 0.001), and the GPx and SOD levels were lower (p < 0.001 for all) in the nephrotic rats. Proteinuria was correlated to PCO (r = 0.483), GPx (r = -0.686), or SOD (r = -0.620) (p < 0.001 for all). Superoxide dismutase (SOD) (beta = -0.381, p = 0.02) and GPx (beta = -0.509, p < 0.001) were independently related to proteinuria levels. Both cilazapril and simvastatin significantly improved GPx, SOD, PCO, and proteinuria. When HBO was combined with either drug, the above markers further improved (p < 0.001). Both regimens caused distinct histological features, while the combination of HBO made much significant histological improvement. Both cilazapril and simvastatin regimens improve oxidative stress and proteinuria, while the effects significantly increase with the combination of HBO treatment. HBO seems to be a candidate antioxidant strategy in glomerular diseases.

Animal Models of Obesity-Associated Chronic Kidney Disease

Dramatic advances in basic science have been made in the past 50 years on the basis of animal models of obesity and type II diabetes. Positional-cloning strategies in rodents with spontaneous obesity have enabled landmark scientific breakthroughs and defined the molecular scaffolding for the regulation of energy homeostasis. Recently, studies in the general population suggest that obesity is an independent risk factor for chronic kidney disease. To date, most of the animal studies that investigated chronic kidney disease associated with obesity and type II diabetes have largely been descriptive. We aim to provide an overview of animal models used to investigate the mechanisms of obesity-associated chronic kidney disease. Our overview is not meant to be an exhaustive list of all animal models in the literature on this subject, but rather to illustrate the experimental approaches. Because of space limitations, we have chosen to concentrate on rodent models. These animal models will provide excellent tools for in vivo testing of molecular mechanisms. Further hypothesis-driven research into the mechanism of chronic kidney disease and their progression by use of these models will provide important insights necessary to develop therapeutic strategies for this significant complication of the worldwide epidemic of obesity and type II diabetes.

Genetic and Genomic Approaches to Glomerulosclerosis

Chronic kidney disease (CKD) is common, progressive and expensive to manage. Although modifiable risk factors can be treated and outcomes improved, CKD remains a chronic disease with excessive morbidity and mortality. The completion of the human genome sequence and the advent of methodologies to define gene function provide new opportunities to manage and treat patients with CKD and other chronic diseases. Despite the lack of clear correspondence between genotype and phenotype and an obvious Mendelian inheritance pattern, CKD susceptibility has a genetic basis. In this review, we focus on recent studies of familial focal segmental glomerulosclerosis and the discoveries that have resulted from both genetic and genomic approaches used to understand its pathogenesis. Key slit diaphragm proteins were discovered using linkage analyses of these rare causes of glomerulosclerosis and subsequent work has characterized slit diaphragm function in health and disease. Podocyte dysfunction is now recognized as a key contributor to the functional and histologic derangements that characterize glomerular dysfunction in many common causes of CKD. In aggregate, these studies provide a paradigm for approaches to better define mechanisms of CKD and to identify novel therapeutic targets.