Iranian Journal of Kidney Diseases
Volume:9 Issue: 3, May 2015

Patients with chronic kidney disease (CKD) have high incidence rates of cardiovascular disease and malignancy. Several factors contribute to these conditions. Structural characteristics in CKD, loss of renal energy, and uremia result in an imbalance between free radical production and antioxidant defenses. Also, CKD patients usually have multiple cardiovascular risk factors like diabetes mellitus, dyslipidemia, and hypertension. These conditions are associated with oxidative stress, which can trigger the inflammatory process and accelerate renal injury progression. There are some clinical biomarkers to detect oxidative stress and antioxidant status in CKD patients. Antioxidant therapies may be beneficial in reducing oxidative stress, lowering uremic cardiovascular toxicity, and improving survival. Therefore, their roles in CKD patients have been evaluated in several studies as a new target for therapeutic intervention. This review provides an overview of oxidative stress mechanisms, clinical squeals, biomarkers, and possible antioxidant therapies in CKD patients.

Chronic kidney disease represents a dramatic worldwide resource-consuming problem. This problem is of increasing importance even in preterm infants, since nephrogenesis may go on only for a few weeks (4 to 6 weeks) after birth. Recent literature focusing on traditional regenerative medicine does not take into account the presence of a high number of active endogenous stem cells in the preterm kidney, which represents a unique opportunity for starting regenerative medicine in the perinatal period. Pluripotent cells of the blue strip have the capacity to generate new nephrons, improving kidney function in neonates and potentially protecting them from developing chronic kidney disease and end-stage renal disease in adulthood. There is a marked interindividual neonatal variability of nephron numbers. Moreover, the renal stem/progenitor cells appear as densely-packed small cells with scant cytoplasm, giving rise to a blue-appearing strip in hematoxylin-eosin-stained kidney sections ("the blue strip"). There are questions concerning renal regenerative medicine: among preliminary data, the simultaneous expression of Wilms tumor 1 and thymosin β4 in stem/progenitor cells of the neonatal kidney may bring new prospects for renal regeneration applied to renal stem cells that reside in the kidney itself. A potential approach could be to prolong the 6 weeks of postnatal renal growth of nephrons or to accelerate the growth of nephrons during the weeks or both. Considering what we know today about perinatal programming, this could be an important step for the future to reduce the incidence and global health impact of chronic kidney disease.

Chronic kidney disease (CKD) is a general health problem with high rates of mortality and morbidity. The increasing prevalence of CKD has led to the recognition of the fact that it needs special care. One approach to CKD management is to present a model of care for the disease. A model of care for CKD was developed by drawing on the literature, including guidelines for CKD care, and by using previous experiences in providing care for patients with diabetes mellitus and CKD. The model focuses on training, identification of patients, care, follow-up, and evaluation of patients. In this study, two levels were defined for providing care to patients with CKD. The first level involves care provided by family physicians, while the second level was defined as community health services for CKD. Establishment of at least 1 CKD community health service at each capital city of any province seems to be an effective factor in improving services provided to patients with CKD.

This study aimed to investigate the effect of vitamin D on the pathologic changes of podocyte β-catenin and P-cadherin and podocyte permeability induced by diabetic conditions. We cultured mouse podocytes under normal glucose (5 mM, control); high glucose (HG, 30 mM); advanced glycosylation end products (AGE)-added; and HG plus AGE-added conditions and treated with vitamin D. The distribution of podocyte β-catenin and P-cadherin was shown by confocal microscopy, and protein levels of β-catenin and P-cadherin by Western blotting. Podocytes were incubated with vitamin D at the concentrations of 10 nM and 50 nM for 6, 24, and 48 hours. The dextran filtration through monolayered podocytes tended to increase in AGE and HG condition compared to that in B5 at 16 hours in permeability assay, which was improved by vitamin D. In confocal imaging, the distribution of β-catenin and P-cadherin were internally concentrated by diabetic conditions, which was ameliorated by vitamin D. In Western blotting, HG and AGE decreased β-catenin protein levels at 6, 24, and 48 hours and vitamin D improved the decreased β-catenin protein levels at 6, 24, and 48 hours. Advanced glycosylation end products also decreased P-cadherin protein amount by 22.9% and 59.1% (P <.01) at 24 hours, respectively, which was improved by vitamin D. Our results suggest that HG and AGE have an influence on the redistribution of β-catenin and P-cadherin and amount of β-catenin protein of podocytes, thereby causing hyperpermeability, which can be reversed by vitamin D.

Emodin, an anthraquinone derivative from the Chinese herb Radix et Rhizoma Rhe, has been reported to possess anti-inflammatory property in vivo and in vitro. However, the effect of emodin on inflammation in lipopolysaccharide (LPS)- induced acute kidney injury as an immunomodulator has yet to be determined. This study aimed to investigate whether emodin had protective effects against LPS-induced acute kidney injury by inhibiting toll-like receptor 2 (TLR2) signal pathway in normal rat kidney epithelial cells (NRK-52E). The NRK-52E cells were incubated with LPS with and without the indicated concentrations of emodin for 24 hours. The TLR2 and NF-κB protein level was detected by Western blot method. Tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and IL-6 protein levels were measured using an enzymelinked immunosorbent assay. The mRNA expression of TLR2, NF-κB, TNF-α, IL-1β, and IL-6 was detected using a real-time polymersase chain reaction. A concentration of 102 ng/mL of LPS significantly upregulated mRNA and protein levels of TLR2 and NF-κB and increased TNF-α, IL-1β, and IL-6 mRNA and protein levels. At doses of 20 μM and 40μM, emodin was able to inhibit LPS-induced TLR2, NF-κB, TNF-α, IL-1β and IL-6 mRNA and protein expressions in cultured NRK-52E cells.These results demonstrate that an elevated expression of inflammatory cytokines and TLR2 in cells stimulated by LPS were simultaneously inhibited by emodin. Therefore, emodin attenuates the inflammation by inhibiting TLR2-mediated NF-κB signal pathway, which may contribute to the immune inflammation regulation of emodin in LPS-induced acute kidney injury.

It has been shown that gene polymorphisms influence the development and progression of chronic kidney disease (CKD). Many studies have indicated that aldosterone synthase CYP11B2 gene polymorphism (-344C>T) influences the aldosterone level, urinary aldosterone excretion, blood pressure, and left ventricular size and mass. We aimed to investigate whether there is an effect of CYP11B2 -344 C>T polymorphism on the development of CKD in a Turkish population. A total of 240 patients with stage 5 CKD and 240 age- and sex-matched healthy individuals were included in the study. Genotyping of CYP11B2 gene -344 T>C promoter polymorphism was carried out using polymerase chain reaction and restriction fragment length polymorphism methods. No significant differences were found in the genotype distribution of CYP11B2 -344 C>T polymorphism between the patients and controls; however, -344 C>T polymorphism was significantly more frequent among the CKD patients with diabetes mellitus as compared to those with it (P =. 02). Diabetic CKD patients with TC genotype had a 2-fold increased risk for development of the disease than the CKD patients without diabetes mellitus (odds ratio, 2.21; 95% confidence interval, 1.04 to 4.67). Our study suggests that the CYP11B2 gene -344 C>T polymorphism may have an effect on the development of CKD in diabetic patients.

Atorvastatin has antioxidant activity and has been reported to increase blood antioxidant capacity. This study aimed to evaluate the effect of different doses of atorvastatin on gentamicin-induced kidney injury. In this experimental study, 30 male Wistar rats were designated into 6 equal groups for a 7-day period of intraperitoneal injections of gentamicin and atorvastatin. Group 1 received gentamicin, 80 mg/kg. Group 2 received phosphate buffer as the vehicle of atorvastatin. All rats in groups 3, 4, and 5 received gentamicin, 80 mg/kg/d, and then, after a 1-hour interval, atorvastatin was injected for 7 days as follow: group 3, 10 mg/kg/d; group 4, 50 mg/kg/d; and group 5, 150 mg/kg/d. Rats in group 6 received only 150 mg of atorvastatin. On the 8th day, blood samples were collected for evaluation of creatinine and blood urea nitrogen levels, and the animal's kidneys were dissected out for histopathological examinations. Morphological damages to the tubular cells in groups 3 and 4 were less than those in groups 1 and 5. Injuries to the renal tubular cells in the rats of group 5 (gentamicin and atorvastatin, 150 mg/kg/d) and in group 6 (atorvastatin 150 mg/kg/d alone) were more extensive than those in group 1. The none-dose-dependent effect of atorvastatin in inducing renal tubular cell protection and renal tubular toxicity of atorvastatin in higher dose suggest administration of low-dose atorvastatin in critical conditions associated with renal tubular cell protection.

Methotrexate, an antagonist of folic acid used in the treatment of many cancers and inflammatory diseases, is associated with side effects that limit its usage. Infliximab has been reported to have a protective effect against nephrotoxicity induced by some drugs and ischemic reperfusion. We aimed to investigate whether infliximab has a protective effect against methotrexate-induced nephrotoxicity. We administered methotrexate at a dose of 20 mg/kg as a single intraperitoneal injection in 10 rats (methotrexate group). Another group of 10 rats received a single dose of infliximab, 7 mg/kg, intraperitoneally (infliximab group). The methotrexate and infliximab group received a similar single injection of infliximab 72 hours prior to methotrexate injection. After 72 hours a single dose of methotrexate, 20 mg/kg, was administered intraperitoneally. Five days after methotrexate injection, blood samples were collected and the kidney tissues were removed for biochemical and histological examination. The methotrexate group had significantly higher tissue levels of tumor necrosis factor-α (P =. 008), interleukin-1β (P =. 036), nitric oxide (P <. 001), and adenosine deaminase (P <. 001) than the methotrexate and infliximab group after the 5-day study. The methotrexate group also had significantly higher total histological scores (P <. 001) and carbonic anhydrase-II activity (P <. 001) when compared to the methotrexate and infliximab group. Infliximab has a strong protective effect against methotrexate-induced nephrotoxicity by suppressing cytokines release. It may decrease methotrexate-induced nephrotoxicity by regulating carbonic anhydrase-II enzyme activities and slowing down purine metabolism.

Mutations of the anion exchanger 1 (AE1) gene encoding the kidney anion exchanger 1 can result in autosomal dominant or autosomal recessive form of distal renal tubular acidosis (DRTA). This study aimed to report deletion mutations of the AE1 and its impact on Iranian children with DRTA. Twelve children with DRTA referred to Ali Asghar Children Hospital were investigated for all AE1 gene exons through polymerase chain reaction amplification, DNA sequencing, and bioinformatics analysis. Eleven of 12 patients (91.7%) showed an alteration in AE1 gene with a real hot spot in its exons 11 or 15. Homozygote and heterozygote deletions were confirmed in exon 15 in 5 (41.7%) and 3 (25.0%), respectively. Two patients (16.7%) showed homozygote deletions in exon 11 of AE1 gene, and 1 patient (8.3%) showed point mutation in exon 11. The 3-dimensional structures of the native and these mutant kidney AE1 proteins were determined by the multitemplate method using the Phyre and Hidden Markov Model algorithms. Parent's consanguinity of these patients reveals that cousins are at a high risk for DRTA. This study is considered as a pilot study showing the importance of AE1 mutations in Iranian children with DRTA and further studies is recommended in this geographic region of the world. These models suggest that alteration in the structures leads to alteration in function and change in the current role of AE1.

Immunoglobulin A (IgA) nephropathy, the most common type of glomerulonephritis, is only diagnosed by invasive kidney biopsy. Urine proteome panel might help in noninvasive diagnosis and also better understanding of pathogenesis of IgA nephropathy. Second mid-stream urine samples of 13 patients with biopsy-proven IgA nephropathy and 8 healthy controls were investigated by means of nanoscale liquid chromatography tandem mass spectrometry. Multivariate analysis of quantified label-free proteins was performed by the principal component analysis and partial least squares models. A total number of 493 unique proteins were quantified by nanoscale liquid chromatography tandem mass spectrometry, of which 46 proteins were considered as putative biomarkers of IgA nephropathy, after multivariate analysis and additional filter criterion and comparing the patients and the controls. Some of the significant differentially expressed proteins were CD44, glycoprotein 2, vasorin, epidermal growth factor, CLM9, protocadherin, utreoglobin, dipeptidyl peptidase IV, NHL repeat-containing protein 3, and SLAM family member 5. These proteins were related to various involved pathogenic pathways of inflammatory response and complement system. This proteome profile could be utilized in the diagnosis of IgA nephropathy. In addition, providing a noninvasive diagnostic tool, it may shed light on the pathogenesis of IgA nephropathy.

Plasma protein growth arrest-specific 6 (GAS6) and matrix Gla protein (MGP) are crucial mediators of vascular calcification and are involved in the development of vascular complications in chronic kidney diseases. This study was set out to investigate the relationship between plasma GAS6 levels and MGP in patients with end-stage renal disease on maintenance hemodialysis. Forty-six hemodialysis and 46 healthy individuals with normal kidneys were recruited. Plasma GAS6 and MGP concentrations and related biochemical factors were quantified as well as collection of data on clinical characteristics. Plasma GAS6 levels were significantly higher in the hemodialysis patients as compared with the control group (763.52 ± 187.91 pg/mL versus 421.63 ± 189.91 pg/mL, P <. 001). Plasma MGP concentration was significantly lower in the hemodialysis patients than the control group (52.35 ± 12.35 ng/mL versus 6.60 ± 19.54 ng/mL, P <. 001). The levels of GAS6 were inversely associated with MGP (r = -0.341, P =. 02) in the hemodialysis patients. Increased GAS6 and decreased MGP levels in hemodialysis patients, as mediators of induction or prevention of vascular calcification, and their inverse correlation may suggest that there might be a role in increased calcification process in hemodialysis patients or only as a secondary phenomenon of advanced kidney failure. Their direct role on vascular calcification needs further studies in the future.

Chronic hypernatremia due to adipsia is very rare and occasionally presents with muscle weakness and rhabdomyolysis. We report a patient with chronic hypernatremia without thirst sensation who presented with muscle weakness and was treated successfully with prescribed water intake.