Animal Models Of Chronic Kidney Disease Research Articles

Plasma renalase in chronic kidney disease: differences and similarities between humans and rats.

Renalase was described in 2005 as a new flavoprotein expressed mainly in the kidney that functions as a flavin adenine dinucleotide (FAD)- and nicotinamide adenine dinucleotide (NADH)-dependent amine oxidase. In contrast to other monoamine oxidases, renalase can be secreted into both plasma and urine where it has been suggested to metabolise catecholamines and contribute to blood pressure control. Renalase was first reported to be undetectable in patients with chronic kidney disease (CKD) and end-stage renal disease (ESRD), suggesting a causal link between the reduced plasma renalase levels, increased plasma catecholamine, and heightened cardiovascular risk that are well documented in this population. Plasma renalase deficiency has been consistently reported in studies using animal models of CKD. However, in studies with 3/4 nephrectomised (3/4nx) rats, the reduced circulating renalase levels were accompanied by increased plasma renalase activity that appeared to be related to decreased inhibition of circulating enzyme. By contrast, a series of recent studies in human subjects provides evidence suggesting that plasma renalase levels are negatively correlated with renal function. Though, similar to that found in the rat remnant kidney, the increased plasma renalase activity in patients with ESRD was associated with decreased inhibition of the circulating enzyme.

Melatonin and renal protection: novel perspectives from animal experiments and human studies (review).

Chronic kidney disease (CKD) is a serious public health problem. Current therapies are designed to slow down progression of the disease and avoid the necessity of dialysis or kidney transplantation. CKD is characterized by chronic inflammation and progressive cell death resulting in fibrotic rebuilding of renal tissue. Melatonin, the primary product of the pineal gland, has been shown to have pluripotent protective effects in many organs and tissues. It exerts anti-hypertensive, anti-inflammatory, anti-apoptotic, and antiremodelling actions. A principal mechanism of these numerous melatonin benefits resides in its extraordinary high efficacy as an antioxidant and scavenger protecting cells both extracellularly and in all subcellular structures. In addition to these receptor-independent actions, the effects of melatonin via specific MT-receptors may be beneficial. In several animal models of CKD, involving experimental hypertension, diabetes mellitus and various models of nephrotoxicity, melatonin reduced the oxidative burden, attenuated the chronic inflammation and limited apoptosis. These effects were associated with the reduction of proteinuria, damage of parenchymal cells and fibrosis. In humans, melatonin's chronobiological action attenuates sleep disturbances in hemodialyzed patients suffering from a relative melatonin deficiency. Moreover, melatonin reduces the oxidative burden and improves iron metabolism in hemodialyzed patients. In conclusion, the pleiotropic physiological actions of melatonin induce beneficial effects at numerous pathophysiological levels related to CKD both under experimental and clinical conditions. It is hoped that this review will prompt a large clinical trial to determine the efficacy of this nontoxic indoleamine as a potential treatment for this debilitating disease.

Anti-sclerostin antibody treatment in a rat model of progressive renal osteodystrophy.

Chronic kidney disease (CKD) is associated with abnormalities in bone quantity and quality, leading to increased fractures. Recent studies suggest abnormalities of Wnt signaling in animal models of CKD and elevated sclerostin levels in patients with CKD. The goal of this study was to evaluate the effectiveness of anti-sclerostin antibody treatment in an animal model of progressive CKD with low and high parathyroid hormone (PTH) levels. Cy/+ male rats (CKD) were treated without or with calcium in the drinking water at 25 weeks of age to stratify the animals into high PTH and low PTH groups, respectively, by 30 weeks. Animals were then treated with anti-sclerostin antibody at 100 mg/kg i.v. weekly for 5 doses, a single 20-µg/kg subcutaneous dose of zoledronic acid, or no treatment, and were then euthanized at 35 weeks. As a positive control, the efficacy of anti-sclerostin antibody treatment was also evaluated in normal littermates. The results demonstrated that the CKD animals with high PTH had lower calcium, higher phosphorus, and lower FGF23 compared to the CKD animals with low PTH. Treatment with anti-sclerostin antibody had no effect on any of the biochemistries, whereas zoledronic acid lowered dkk-1 levels. The anti-sclerostin antibody increased trabecular bone volume/total volume (BV/TV) and trabecular mineralization surface in animals with low PTH, but not in animals with high PTH. Neither anti-sclerostin antibody nor zoledronic acid improved biomechanical properties in the animals. Cortical porosity was severe in high-PTH animals and was unaffected by either treatment. In contrast, in normal animals treated with anti-sclerostin antibody, there was an improvement in bone volume, cortical geometry, and biomechanical properties. In summary, this is the first study to test the efficacy of anti-sclerostin antibody treatment on animals with advanced CKD. We found efficacy in improving bone properties only when the PTH levels were low.

FGF23 directly impairs endothelium-dependent vasorelaxation by increasing superoxide levels and reducing nitric oxide bioavailability.

Fibroblast growth factor 23 (FGF23) is secreted primarily by osteocytes and regulates phosphate and vitamin D metabolism. Elevated levels of FGF23 are clinically associated with endothelial dysfunction and arterial stiffness in chronic kidney disease (CKD) patients; however, the direct effects of FGF23 on endothelial function are unknown. We hypothesized that FGF23 directly impairs endothelial vasorelaxation by hindering nitric oxide (NO) bioavailability. We detected expression of all four subtypes of FGF receptors (Fgfr1-4) in male mouse aortas. Exogenous FGF23 (90-9,000 pg/ml) did not induce contraction of aortic rings and did not relax rings precontracted with PGF2α. However, preincubation with FGF23 (9,000 pg/ml) caused a ∼36% inhibition of endothelium-dependent relaxation elicited by acetylcholine (ACh) in precontracted aortic rings, which was prevented by the FGFR antagonist PD166866 (50 nM). Furthermore, in FGF23-pretreated (9,000 pg/ml) aortic rings, we found reductions in NO levels. We also investigated an animal model of CKD (Col4a3(-/-) mice) that displays highly elevated serum FGF23 levels and found they had impaired endothelium-dependent vascular relaxation and reduced nitrate production compared with age-matched wild types. To elucidate a mechanism for the FGF23-induced impairment, we measured superoxide levels in endothelial cells and aortic rings and found that they were increased following FGF23 treatment. Crucially, treatment with the superoxide scavenger tiron reduced superoxide levels and also restored aortic relaxation to ACh. Therefore, our data suggest that FGF23 increases superoxide, inhibits NO bioavailability, and causes endothelial dysfunction in mouse aorta. Together, these data provide evidence that high levels of FGF23 contribute to cardiovascular dysfunction.

Treatment of established left ventricular hypertrophy with fibroblast growth factor receptor blockade in an animal model of CKD.

Activation of fibroblast growth factor receptor (FGFR)-dependent signalling by FGF23 may contribute to the complex pathogenesis of left ventricular hypertrophy (LVH) in chronic kidney disease (CKD). Pan FGFR blockade by PD173074 prevented development of LVH in the 5/6 nephrectomy rat model of CKD, but its ability to treat and reverse established LVH is unknown. CKD was induced in rats by 5/6 nephrectomy. Two weeks later, rats began treatment with vehicle (0.9% NaCl) or PD173074, 1 mg/kg once-daily for 3 weeks. Renal function was determined by urine and blood analyses. Left ventricular (LV) structure and function were determined by echocardiography, histopathology, staining for myocardial fibrosis (Sirius-Red) and investigating cardiac gene expression profiles by real-time PCR. Two weeks after inducing CKD by 5/6 nephrectomy, rats manifested higher (mean ± SEM) systolic blood pressure (208 ± 4 versus 139 ± 3 mmHg; P < 0.01), serum FGF23 levels (1023 ± 225 versus 199 ± 9 pg/mL; P < 0.01) and LV mass (292 ± 9 versus 220 ± 3 mg; P < 0.01) when compared with sham-operated animals. Thereafter, 3 weeks of treatment with PD173074 compared with vehicle did not significantly change blood pressure, kidney function or metabolic parameters, but significantly reduced LV mass (230 ± 14 versus 341 ± 33 mg; P < 0.01), myocardial fibrosis (2.5 ± 0.7 versus 5.4 ± 0.95% staining/field; P < 0.01) and cardiac expression of genes associated with pathological LVH, while significantly increasing ejection fraction (18 versus 2.5% post-treatment increase; P < 0.05). FGFR blockade improved cardiac structure and function in 5/6 nephrectomy rats with previously established LVH. These data support FGFR activation as a potentially modifiable, blood pressure-independent molecular mechanism of LVH in CKD.

Angiotensin Blockade—A Double-Edged Sword in Renal Failure

Angiotensin receptor suppression in macrophages infiltrating damaged kidneys exacerbates renal fibrosis.

Changes in gene expression profiles in chronic kidney disease patients treated with tetrahydrobiopterin versus placebo: a randomized controlled trial (912.11)

Chronic kidney disease (CKD) patients are at significantly higher risk of cardiovascular mortality. One major contributing factor is decreased nitric oxide (NO) bioavailability, which leads to endothelial dysfunction and sympathetic nervous system (SNS) overactivity. Tetrahydrobiopterin (BH4) is a cofactor for endothelial NO synthase activity that has been shown to improve NO bioavailability and endothelial function in animal models of CKD; however, BH4 treatment had never before been tested in humans with CKD. We hypothesized that BH4 treatment alters gene expression profiles in CKD; particularly, the RNA activity of genes involved in the regulation of NO and SNS activity. In a randomized, double‐masked, placebo‐controlled trial, we randomized 36 hypertensive CKD patients to 12 weeks of: a) BH4 200 mg twice daily + folic acid 1 mg daily; versus b) identical placebo twice daily + folic acid 1 mg daily. Physiologic measures and blood collected in tempus tubes were obtained before and after treatment. Total RNA will be extracted, and gene expression profiling will be performed using the Illumina HT12 BeadChip technology at the Emory Integrative Genomics Core laboratory. We anticipate that expression of candidate genes involved in NO and SNS regulation may be altered with time in CKD patients treated with BH4.Grant Funding Source: Supported by K grant HL098744

Effects of pyrophosphate delivery in a peritoneal dialysis solution on bone tissue of apolipoprotein-E knockout mice with chronic kidney disease

Vascular calcification (VC) is a risk factor for cardiovascular mortality in the setting of chronic kidney disease (CKD). Pyrophosphate (PPi), an endogenous molecule that inhibits hydroxyapatite crystal formation, has been shown to prevent the development of VC in animal models of CKD. However, the possibility of harmful effects of exogenous administration of PPi on bone requires further investigation. To this end, we examined by histomorphometry the bone of CKD mice after intraperitoneal PPi administration. After CKD creation or sham surgery, 10-week-old female apolipoprotein-E knockout (apoE(-/-)) mice were randomized to one non-CKD group or 4 CKD groups (n = 10-35/group) treated with placebo or three distinct doses of PPi, and fed with standard diet. Eight weeks later, the animals were killed. Serum and femurs were sampled. Femurs were processed for bone histomorphometry. Placebo-treated CKD mice had significantly higher values of osteoid volume, osteoid surface and bone formation rate than sham-placebo mice with normal renal function. Slightly higher osteoid values were observed in CKD mice in response to very low PPi dose (OV/BV, O.Th and ObS/BS) and, for one parameter measured, to high PPi dose (O.Th), compared to placebo-treated CKD mice. Treatment with PPi did not modify any other structural parameters. Mineral apposition rates, and other parameters of bone formation and resorption were not significantly different among the treated animal groups or control CKD placebo group. In conclusion, PPi does not appear to be deleterious to bone tissue in apoE(-/-) mice with CKD, although a possible stimulatory PPi effect on osteoid formation may be worth further investigation.

The role of sleep and sildenafil in the progression of chronic kidney disease: A new therapeutic approach

Introduction The prevalence of chronic kidney disease (CKD) is increasing rapidly throughout the world. Also, CKD is associated with comorbidities such as sexual dysfunction and sleep disorders which may impact the patients’ quality of life. Although sleep loss is inherent to the lifestyle of people suffering from CKD, its effects on the disease progression are unknown. Moreover, there are few studies evaluating potential alternative treatments that could attenuate some CKD comorbidities. Thus, the aim of this study was to evaluate the outcomes of a chronic treatment with sildenafil in an animal model of CKD subjected to sleep restriction (SR). Materials and methods The study was performed using 140 male adult Wistar rats distributed into 4 groups: sham treated with vehicle (SHAM + V), sham treated with sildenafil (SHAM + S), CKD treated with vehicle (CKD + V) and CKD treated with sildenafil (CKD + S). After 46 days, all groups were sub distributed in sleep control (SC) and SR. Blood pressure and heart rate was assessed once a week. In the end, we performed the evaluation of the sexual behavior followed by euthanasia and collection of blood. Results Sildenafil was able to prevent the disease progression, demonstrated by higher levels of serum creatinine in CKD + V + SC compared to SHAM + V + SC and CKD + S + SC groups. Nevertheless, creatinine levels of CKD + S + SR was significantly higher than SHAM + S + SR group. Moreover, sildenafil prevented the development of systemic hypertension, although this was not sustained after SR. Heart rate was only affected by disease and SR, both contributing to tachycardia. Sildenafil treatment also reduced the excessive body weight loss, the iron deficit, the dyslipidemia, the decrease of serum testosterone and LH and the increase of proinflammatory cytokines IL-1 α , TNF α e IL-17. However, many of these effects were attenuated or abolished by SR. Regarding the sexual behavior, CKD + V + SC group had lower sexual activity index than SHAM + V + SC and CKD + S + SC. Overall, SR had a stimulant-like effect on sexual behavior by increasing the sexual motivation and performance in the animals. This effect was also followed by increased corticosterone, progesterone and FSH levels. Conclusion The early chronic treatment with sildenafil in CKD plays a role as possible adjuvant in the therapy for CKD and its comorbidities. Importantly, its effectiveness demands the maintenance of the sleep quality. Acknowledgements This work was supported by grants from AFIP , FAPESP , CAPES and CNPq .

Adverse Mandibular Bone Effects Associated with Kidney Disease Are Only Partially Corrected with Bisphosphonate and/or Calcium Treatment

Background/Aims: Patients with chronic kidney disease (CKD) have a high prevalence of periodontal disease that may predispose to tooth loss and inflammation. The goal of this study was to test the hypotheses that a genetic rat model of progressive CKD would exhibit altered oral bone properties and that treatment with either bisphosphonates or calcium could attenuate these adverse changes. Methods: At 25 weeks of age, rats were treated with zoledronate (ZOL), calcium gluconate, or their combination for 5 or 10 weeks. Mandible bone properties were assessed using micro-computed tomography to determine bone volume (BV/TV) and cementum-enamel junction to alveolar crest distance (CEJ-AC). Results: Untreated CKD animals had significantly lower BV/TV at both 30 (-5%) and 35 (-14%) weeks of age and higher CEJ-AC (+27 and 29%) compared to normal animals. CKD animals had a significantly higher parathyroid hormone (PTH) compared to normal animals, yet similar levels of C-reactive protein (CRP). ZOL treatment normalized BV/TV over the first 5 weeks but this benefit was lost by 10 weeks. Calcium treatment, alone or in combination with ZOL, was effective in normalizing BV/TV at both time points. Neither ZOL nor calcium was able to correct the higher CEJ-AC caused by CKD. Calcium, but not ZOL, significantly reduced serum PTH, while neither treatment affected CRP. Conclusions: (i) This progressive animal model of CKD shows a clear mandibular skeletal phenotype consistent with periodontitis, (ii) the periodontitis is not associated with systemic inflammation as measured by CRP, and (iii) reducing PTH has positive effects on the mandible phenotype.

Warfarin-related nephropathy is the tip of the iceberg: direct thrombin inhibitor dabigatran induces glomerular hemorrhage with acute kidney injury in rats

Excessive anticoagulation with warfarin can result in acute kidney injury (AKI) by causing glomerular hemorrhage and renal tubular obstruction by red blood cell (RBC) casts in some patients, especially in those with chronic kidney disease (CKD). This condition was described as warfarin-related nephropathy (WRN). Recent evidence suggests that WRN-like syndromes are not confined to anticoagulation with warfarin, but may be seen with other anticoagulants, such as dabigatran. The aim of this study was to investigate dabigatran effects on kidney function in an animal model of CKD and possible pathogenic mechanisms of AKI. Control and 5/6 nephrectomy rats were treated with different doses of dabigatran and protease-activated receptor 1 (PAR-1) inhibitor SCH79797. Dabigatran resulted in changes in coagulation in rats similar to those in humans at 50 mg/kg/day. Dabigatran resulted in a dose-dependent increase in serum creatinine (Scr) and hematuria in both control and 5/6 nephrectomy rats. SCH79797 also increased Scr and hematuria, more prominent in animals with CKD. Morphologically, numerous RBC tubular casts were seen in 5/6 nephrectomy rats treated with either dabigatran or SCH79797 and only occasional RBC casts in control rats. Our data indicate that WRN represents part of a broader syndrome, anticoagulant-related nephropathy (ARN). ARN, at least partially, is mediated via PAR-1. Our findings suggest that not only CKD patients, but other patients as well, are at high risk of developing AKI if the therapeutic range of anticoagulation with dabigatran is exceeded. Close monitoring of kidney function in patients on dabigatran therapy is warranted.

Excisional Wound Healing Is Delayed in a Murine Model of Chronic Kidney Disease

BackgroundApproximately 15% of the United States population suffers from chronic kidney disease (CKD), often demonstrating an associated impairment in wound healing. This study outlines the development of a surgical murine model of CKD in order to investigate the mechanisms underlying this impairment.MethodsCKD was induced in mice by partial cauterization of one kidney cortex and contralateral nephrectomy, modifying a previously published technique. After a minimum of 6-weeks, splinted, dorsal excisional wounds were created to permit assessment of wound healing parameters. Wounds were harvested on postoperative days (POD) 0, 3, 7, and 14 for histological, immunofluorescent, and quantitative PCR (qPCR).ResultsCKD mice exhibited deranged blood chemistry and hematology profiles, including profound uremia and anemia. Significant decreases in re-epithelialization and granulation tissue deposition rates were found in uremic mice wounds relative to controls. On immunofluorescent analysis, uremic mice demonstrated significant reductions in cellular proliferation (BrdU) and angiogenesis (CD31), with a concurrent increase in inflammation (CD45) as compared to controls. CKD mice also displayed differential expression of wound healing-related genes (VEGF, IL-1β, eNOS, iNOS) on qPCR.ConclusionsThese findings represent the first reported investigation of cutaneous healing in a CKD animal model. Ongoing studies of this significantly delayed wound healing phenotype include the establishment of renal failure model in diabetic strains to study the combined effects of CKD and diabetes.

Acid–base status and progression of chronic kidney disease

Most patients with reduced glomerular filtration rate (GFR) have progressive GFR decline despite currently recommended kidney-protective interventions. Recent studies support that dietary acid reduction with Na(+)-based alkali or food types that yield base when metabolized provides kidney protection that is additive to currently recommended interventions. We review these recent studies in light of current kidney-protective recommendations for chronic kidney disease (CKD). Animal models of CKD show that metabolic acidosis and/or dietary acid induce intrakidney mechanisms that cause kidney injury and mediate progressive GFR decline. Translational studies in patients show that NaHCO(3) ameliorates kidney injury in patients with CKD and reduced GFR, with and without metabolic acidosis; NaHCO(3) and base-inducing food types each ameliorate kidney injury in patients with reduced GFR without metabolic acidosis; and NaHCO(3) and Na(+) citrate each slow GFR decline in CKD patients with reduced GFR, with and without metabolic acidosis. Recently published studies in animals and humans suggest that acid-base-related mechanisms mediate nephropathy progression. These studies support that dietary acid reduction with Na(+)-based alkali or alkali-inducing food is an effective kidney-protective adjunct to current strategies and support re-examination of current recommendations for CKD management.

Target organ cross talk in cardiorenal syndrome: animal models

The combination of chronic kidney disease (CKD) and heart failure (HF) is associated with an adverse prognosis. Although clinical studies hint at a specific bidirectional interaction between HF and CKD, insight into the pathogenesis of cardiorenal syndrome (CRS) remains limited. We review available evidence on cardiorenal interactions from animal models of CKD and HF and discuss several studies that employed a "double-hit" model to research organ cross talk between the heart and kidneys. Regarding cardiac changes in CKD models, parameters of cardiac remodeling are equivocal and cardiac systolic function generally remains preserved. Structural changes include hypertrophy, fibrosis, and microvasculopathy. In models of HF, data on renal pathology are mostly limited to functional hemodynamic changes. Most double-hit models were unable to show that combined renal and cardiac injury induces additive damage to both organs, perhaps because of the short study duration or absence of organ failure. Because of this lack of "dual-failure" models, we have developed two rat models of combined CKD and HF in which renal dysfunction induced by a subtotal nephrectomy preceded cardiac dysfunction. Cardiac dysfunction was induced either functionally by nitric oxide depletion or structurally by myocardial infarction. In both models, we found that cardiac remodeling and failure were worse in CKD rats compared with controls undergoing the same cardiac insult. Variables of renal damage, like glomerulosclerosis and proteinuria, were also further worsened by combined cardiorenal injury. These studies show that target organ cross talk does occur in CRS. These models may be useful for interventional studies in rats.

FGF23 induces left ventricular hypertrophy

Chronic kidney disease (CKD) is a public health epidemic that increases risk of death due to cardiovascular disease. Left ventricular hypertrophy (LVH) is an important mechanism of cardiovascular disease in individuals with CKD. Elevated levels of FGF23 have been linked to greater risks of LVH and mortality in patients with CKD, but whether these risks represent causal effects of FGF23 is unknown. Here, we report that elevated FGF23 levels are independently associated with LVH in a large, racially diverse CKD cohort. FGF23 caused pathological hypertrophy of isolated rat cardiomyocytes via FGF receptor-dependent activation of the calcineurin-NFAT signaling pathway, but this effect was independent of klotho, the coreceptor for FGF23 in the kidney and parathyroid glands. Intramyocardial or intravenous injection of FGF23 in wild-type mice resulted in LVH, and klotho-deficient mice demonstrated elevated FGF23 levels and LVH. In an established animal model of CKD, treatment with an FGF-receptor blocker attenuated LVH, although no change in blood pressure was observed. These results unveil a klotho-independent, causal role for FGF23 in the pathogenesis of LVH and suggest that chronically elevated FGF23 levels contribute directly to high rates of LVH and mortality in individuals with CKD.

Quantification of glomerular number and size distribution in normal rat kidneys using magnetic resonance imaging

Glomerular number and size are important risk factors for chronic kidney disease (CKD) and cardiovascular disease and have traditionally been estimated using invasive techniques. Here, we report a novel technique to count and size every glomerulus in the rat kidney using magnetic resonance imaging (MRI). The ferromagnetic nature of cationized ferritin allowed visualization of single glomeruli in high-resolution susceptibility-weighted MRI. A segmentation algorithm was used to identify and count all glomeruli within the whole kidney. To prove our concept, we estimated total glomerular number and mean glomerular volume of each kidney using design-based stereology. The glomerular counts obtained with MRI agreed well with estimates obtained using traditional methods [MRI, 32 785 (3117); stereology, 35 132 (3123)]. For the first time, the glomerular volume distribution for the entire kidney is shown. Additionally, the method is substantially faster than the current methods. MRI provides a new method for measuring these important microanatomical markers of disease risk and leads the way to in vivo analysis of these parameters, including longitudinal studies of animal models of CKD.

Vitamin D in Chronic Kidney Disease: New Potential for Intervention

Prevention of progressive renal function loss and its complications remains the main challenge in clinical nephrology. Although current therapeutic strategies aiming at reduction of blood pressure and proteinuria often slow down deterioration of renal function, still many patients progress to end-stage renal disease. The development of novel pharmacological approaches for treatment of chronic kidney disease (CKD) is therefore instrumental. Here we review the renoprotective potential of vitamin D and its analogues. In CKD patients, vitamin D deficiency is common and progression of CKD is associated with low (active) vitamin D levels. Moreover, in animal models of CKD, treatment with vitamin D (analogues) alone or in combination with renin-angiotensin-aldosterone system (RAAS) blockade reduces proteinuria, glomerulosclerosis and tubulointerstitial fibrosis. Potential underlying mechanisms include suppression of the RAAS, modulation of immune cell function and direct protective effects on renal cells such as podocytes. Whether vitamin D analogues could further optimize existing therapies in human renal disease is currently under investigation.

Association of Asymmetric Dimethylarginine with Severity of Kidney Injury and Decline in Kidney Function in IgA Nephropathy

Background: Asymmetric dimethylarginine (ADMA) plays important roles in the pathogenesis of chronic kidney disease (CKD). We have recently found that ADMA is involved in glomerular sclerosis and tubulointerstitial fibrosis in an animal model of CKD. However, relationship between plasma ADMA levels and severity of renal damage in CKD patients remains unknown. Methods: Relatively young 109 biopsy-proven IgA nephropathy (IgAN) patients (age: 32.7 ± 13.2; estimated glomerular filtration rate, eGFR: 86.5 ± 28.8 ml/min/1.73 m²) were enrolled. We retrospectively investigated whether plasma levels of ADMA were associated with severity of the renal tissue damage and could be a predictor of the disease progression in our subjects. Results: ADMA levels were higher in IgAN patients than age-, sex- and mean eGFR-matched healthy volunteers (0.53 ± 0.14 vs. 0.43 ± 0.08 µM, p < 0.01). ADMA levels were associated with the severity of glomerular and tubulointerstitial injury. Multiple stepwise regression analysis revealed that ADMA, but not proteinuria was an independent determinant for the disease progression assessed by annual reduction rates of eGFR. In univariate analyses, ADMA levels were correlated with proteinuria, total cholesterol, triglycerides, and uric acid. Proteinuria was a sole independent correlate of ADMA in multiple stepwise regression analysis. Conclusion: The present study demonstrated that ADMA was correlated with the severity of the renal tissue damage and could be a predictor of disease progression in IgAN patients.

Aldosterone blockade in chronic kidney disease: can it improve outcome?

The purpose of this review is to explain the rationale and limitations for use of mineralocorticoid receptor blockers (MRBs) for the treatment of chronic kidney disease (CKD) and its complications. Recent studies in animal models of CKD demonstrate that blockade of the mineralocorticoid receptor using spironolactone or eplerenone decreases inflammation, oxidative stress, proteinuria and glomerular and tubular injury. Patients with CKD are at very high risk for progression of kidney disease and major cardiovascular events. Recent studies in patients with CKD demonstrate that administration of low doses of MRBs added onto an angiotensin-converting enzyme inhibitor-based regimen reduces proteinuria--a risk marker for both progressive kidney disease and cardiovascular events. However, incident hyperkalemia, an unwanted side effect, dampened enthusiasm for this approach. There are no large-scale, long-term outcome trials examining whether MRB can slow progression of kidney disease or prevent cardiovascular events. At this time it is unknown whether mineralocorticoid receptor blockade can improve outcomes in patients with CKD. To move this field forward and determine whether these agents can improve the lives of patients with kidney disease, novel strategies to prevent or ameliorate hyperkalemia are needed.

HDL metabolism and activity in chronic kidney disease

Chronic kidney disease (CKD) is associated with development of atherosclerosis and premature death from cardiovascular disease. The predisposition of patients with CKD to atherosclerosis is driven by inflammation, oxidative stress and dyslipidemia, all of which are common features of this condition. Markers of dyslipidemia in patients with advanced CKD are impaired clearance and heightened oxidation of apolipoprotein-B-containing lipoproteins and their atherogenic remnants, and a reduction of the plasma concentration, antioxidant, and anti-inflammatory properties of high-density lipoprotein (HDL). Studies in animal models of CKD indicate that the disease promotes lipid accumulation in the artery wall and kidney, leading to atherosclerosis, glomerulosclerosis and tubulointerstitial injury. These effects seem to be mediated by an increased cellular influx of lipids, elevated cellular production and reduced cellular catabolism of fatty acids, and impaired antioxidant, anti-inflammatory and reverse lipid transport properties of HDL. Available pharmacological therapies have been largely ineffective in ameliorating oxidative stress, inflammation, HDL deficiency and/or dysfunction, and the associated atherosclerosis and cardiovascular disease in patients with end-stage renal disease. This Review aims to provide an overview of the mechanisms and consequences of CKD-induced HDL deficiency and dysfunction.