Precision engineered peptide targeting leukocyte extracellular traps mitigate acute kidney injury in Crush syndrome.

Crush syndrome induced by skeletal muscle compression causes fatal rhabdomyolysis-induced acute kidney injury (RIAKI) that requires intensive care, including hemodialysis. However, access to crucial medical supplies is highly limited while treating earthquake victims trapped under fallen buildings, lowering their chances of survival. Developing a compact, portable, and simple treatment method for RIAKI remains an important challenge. Based on our previous finding that RIAKI depends on leukocyte extracellular traps (ETs), we aimed to develop a novel medium-molecular-weight peptide to provide clinical treatment of Crush syndrome. We conducted a structure-activity relationship study to develop a new therapeutic peptide. Using human peripheral polymorphonuclear neutrophils, we identified a 12-amino acid peptide sequence (FK-12) that strongly inhibited neutrophil extracellular trap (NET) release in vitro and further modified it by alanine scanning to construct multiple peptide analogs that were screened for their NET inhibition ability. The clinical applicability and renal-protective effects of these analogs were evaluated in vivo using the rhabdomyolysis-induced AKI mouse model. One candidate drug [M10Hse(Me)], wherein the sulfur of Met10 is substituted by oxygen, exhibited excellent renal-protective effects and completely inhibited fatality in the RIAKI mouse model. Furthermore, we observed that both therapeutic and prophylactic administration of M10Hse(Me) markedly protected the renal function during the acute and chronic phases of RIAKI. In conclusion, we developed a novel medium-molecular-weight peptide that could potentially treat patients with rhabdomyolysis and protect their renal function, thereby increasing the survival rate of victims affected by Crush syndrome.

Controlling gene activation by enhancers through a drug-inducible topological insulator.

While regulation of gene-enhancer interaction is intensively studied, its application remains limited. Here, we reconstituted arrays of CTCF-binding sites and devised a synthetic topological insulator with tetO for chromatin-engineering (STITCH). By coupling STITCH with tetR linked to the KRAB domain to induce heterochromatin and disable the insulation, we developed a drug-inducible system to control gene activation by enhancers. In human induced pluripotent stem cells, STITCH inserted between MYC and the enhancer down-regulated MYC. Progressive mutagenesis of STITCH led to a preferential escalation of the gene-enhancer interaction, corroborating the strong insulation ability of STITCH. STITCH also altered epigenetic states around MYC. Time-course analysis by drug induction uncovered deposition and removal of H3K27me3 repressive marks follows and reflects, but does not precede and determine, the expression change. Finally, STITCH inserted near NEUROG2 impaired the gene activation in differentiating neural progenitor cells. Thus, STITCH should be broadly useful for functional genetic studies.

Klotho supplementation ameliorates blood pressure and renal function in DBA/2-pcy mice, a model of polycystic kidney disease.

Klotho interacts with various membrane proteins such as receptors for transforming growth factor-ß (TGF-ß) and insulin-like growth factor (IGF). Renal expression of klotho is diminished in polycystic kidney disease (PKD). In the present study, the effects of klotho supplementation on PKD were assessed. Recombinant human klotho protein (10 µg·kg-1·day-1) or a vehicle was administered daily by subcutaneous injection to 6-wk-old mice with PKD (DBA/2-pcy). Blood pressure was measured using tail-cuff methods. After 2 mo, mice were killed, and the kidneys were harvested for analysis. Exogenous klotho protein supplementation reduced kidney weight, cystic area, systolic blood pressure, renal angiotensin II levels, and 8-epi-PGF2α excretion (P < 0.05). Klotho protein supplementation enhanced glomerular filtration rate, renal expression of superoxide dismutase, and klotho itself (P < 0.05). Klotho supplementation attenuated renal expressions of TGF-ß and collagen type I and diminished renal abundance of Twist, phosphorylated Akt, and mammalian target of rapamycin (P < 0.05). Pathological examination revealed that klotho decreased the fibrosis index and nuclear staining of Smad in PKD kidneys (P < 0.05). Our data indicate that klotho protein supplementation ameliorates the renin-angiotensin system, reducing blood pressure in PKD mice. Furthermore, the present results implicate klotho supplementation in the suppression of Akt/mammalian target of rapamycin signaling, slowing cystic expansion. Finally, our findings suggest that klotho protein supplementation attenuated fibrosis at least partly by inhibiting epithelial mesenchymal transition in PKD.

Klotho protein supplementation reduces blood pressure and renal hypertrophy in db/db mice, a model of type 2 diabetes.

AIMS: Klotho interacts with various membrane proteins, such as receptors for transforming growth factor (TGF)-ß and insulin-like growth factor (IGF), to alter their function. Renal expression of klotho is diminished in diabetes. The present study examined whether exogenous klotho protein supplementation ameliorates kidney injury and renin-angiotensin system (RAS) in db/db mice. METHODS: We investigated the effects of klotho supplementation on diabetic kidney injury and RAS. Recombinant human klotho protein (10 µg/kg/d) was administered to db/db mice daily. RESULTS: Klotho protein supplementation reduced kidney weight, systolic blood pressure (SBP), albuminuria, glomerular filtration rate, and 8-epi-prostaglandin F2α excretion without affecting body weight. Although klotho supplementation did not alter glycated albumin, it reduced renal angiotensin II levels associated with reduced renal expression of angiotensinogen. Klotho supplementation improved renal expression of superoxide dismutase (SOD), and endogenous renal expression of klotho. Klotho supplementation reduced the levels of hypoxia-inducible factor, phosphorylated Akt, and phosphorylated mTOR and decreased the renal expression of TGF-ß, tumour necrosis factor (TNF), and fibronectin. CONCLUSIONS: These data indicate that klotho supplementation reduces blood pressure and albuminuria along with ameliorating renal RAS activation in db/db mice. Furthermore, these results suggest that klotho inhibits IGF signalling, induces SOD expression to reduce oxidative stress, and suppresses Akt-mTOR signalling to inhibit abnormal kidney growth. Collectively, the results suggest that klotho inhibits TGF-ß and TNF signalling, resulting in a decline in renal fibrosis.

Klotho Ameliorates Medullary Fibrosis and Pressure Natriuresis in Hypertensive Rat Kidneys.

Renal expression of klotho is reduced in hypertension. Experiments were performed to examine whether exogenous klotho protein supplementation ameliorates pressure natriuresis in early phase of hypertension, using stroke-prone spontaneously hypertensive rats (sp-SHR). The interactions between klotho protein and renal renin-Ang (angiotensin) system were examined with immunoprecipitation and cell culture methods. Uninephrectomy was performed in sp-SHRs to induce nephrosclerosis, and they were treated with exogenous klotho protein or vehicle. Exogenous klotho protein supplementation to sp-SHR decreased blood pressure, renal Ang II levels, AGT (angiotensinogen) expression, HIF (hypoxia-inducible factor)-1α abundance, and medullary fibronectin levels, with increased renal klotho expression and serum and urine klotho levels. Klotho supplementation also reduced kidney weight, renal phosphorylated Akt, and mTOR (mammalian target of rapamycin) abundance. Furthermore, klotho supplementation restored renal autoregulation of glomerular filtration rate and enhanced pressure-induced natriuresis in sp-SHR. Klotho protein bound to AT1R (Ang II type-1 receptor) and decreased the presence of AT1R on HK-2 (human proximal tubular) cells, attenuating inositol triphosphate generation. Klotho protein suppressed Ang II-induced increments of AGT expression in HK-2 cells. Collectively, the present data demonstrate that klotho binds with the AT1R to suppress Ang signal transduction, participating in inactivating renal renin-Ang system. Our results also suggest that exogenous klotho supplementation represses Akt-mTOR signaling to reduce renal hypertrophy and restore the autoregulatory ability of glomerular filtration rate in uninephrectomized sp-SHRs. Finally, the present findings implicate that klotho supplementation inhibits HIF-1α pathway and medullary fibrosis, contributing to enhancements of pressure natriuresis and reduction in blood pressure.

Expanding Phenotype of Nephronophthisis-Related Ciliopathy: an Elderly Patient with Homozygous RPGRIP1L Mutation.

Nephronophthisis-related ciliopathies (NPHP-RC) are autosomal recessive disorders characterized by renal corticomedullary cysts with the extrarenal symptoms. Typically, patients with NPHP-RC reach end-stage kidney disease (ESKD) before the age of 30 years. We herein report a Japanese woman with NPHP-RC who had unusually delayed progression to ESKD after 6 decades. She exhibited liver dysfunction at the age of 23 years. She also showed mild renal dysfunction at the age of 43 years. Ultrasonography revealed bilateral multiple renal cysts with loss of corticomedullary differentiation. Her liver and renal functions gradually deteriorated. She was diagnosed with liver fibrosis as a result of biopsy, and initiated the maintenance hemodiafiltration therapy for ESKD at the age of 61 years. Because of a unique combination of multiple renal cysts and liver fibrosis, ciliopathy was suspected and medical exome analysis was performed. A novel homozygous missense mutation was identified in RPGRIP1L (c.1810G>A p.Glu604Lys), a causative gene for NPHP-RC. To the best of our knowledge, this patient is the oldest one who progressed to ESKD in NPHP-RC. Our case illustrates that NPHP-RC should be included in the differential diagnosis of the patient with corticomedullary polycystic kidneys accompanied by the extrarenal organ involvements, even if the patient is elderly.

Macrophage extracellular trap formation promoted by platelet activation is a key mediator of rhabdomyolysis-induced acute kidney injury.

Rhabdomyolysis is a serious syndrome caused by skeletal muscle injury and the subsequent release of breakdown products from damaged muscle cells into systemic circulation. The muscle damage most often results from strenuous exercise, muscle hypoxia, medications, or drug abuse and can lead to life-threatening complications, such as acute kidney injury (AKI). Rhabdomyolysis and the AKI complication can also occur during crush syndrome, an emergency condition that commonly occurs in victims of natural disasters, such as earthquakes, and man-made disasters, such as wars and terrorism. Myoglobin released from damaged muscle is believed to trigger renal dysfunction in this form of AKI. Recently, macrophages were implicated in the disease pathogenesis of rhabdomyolysis-induced AKI, but the precise molecular mechanism remains unclear. In the present study, we show that macrophages released extracellular traps (ETs) comprising DNA fibers and granule proteins in a mouse model of rhabdomyolysis. Heme-activated platelets released from necrotic muscle cells during rhabdomyolysis enhanced the production of macrophage extracellular traps (METs) through increasing intracellular reactive oxygen species generation and histone citrullination. Here we report, for the first time to our knowledge, this unanticipated role for METs and platelets as a sensor of myoglobin-derived heme in rhabdomyolysis-induced AKI. This previously unknown mechanism might be targeted for treatment of the disease. Finally, we found a new therapeutic tool for prevention of AKI after rhabdomyolysis, which might rescue some sufferers of this pathology.

Pre-operative and post-operative estimated glomerular filtration rate in Japanese patients with urological malignancies.

BACKGROUND: The suitable methods evaluating glomerular filtration rate (GFR) have not been established in patients undergoing radical nephrectomy (RN) or radical nephroureterectomy (RNU) due to urological malignancies in Japan as well as worldwide. METHODS: We examined the relationship between creatinine clearance-based measured GFR (mGFR) versus estimated GFR (eGFR) calculated by 3 popular equations, 4-variable Modification of Diet in Renal Disease equation adjusted by Japanese correction coefficient (cmMDRD), 3-variable MDRD equation for Japanese population (eGFRcreat), and Chronic Kidney Disease-Epidemiology Collaboration equation adjusted by Japanese correction coefficient (cmCKD-EPI) in Japanese patients who had undergone RN or RNU due to renal cell carcinoma or upper tract urothelial carcinoma before and after surgery. RESULTS: Among the 3 equations examined, eGFRcreat was the closest to mGFR, although each eGFR was significantly higher than mGFR in the pre-operative period. In the post-operative period, cmMDRD and eGFRcreat, but not cmCKD-EPI, were comparable to mGFR. Each of eGFR was significantly correlated with mGFR in both the pre-operative and post-operative periods. Similar results were obtained by the subanalysis of the patients with pre-operative mGFR of < 60 mL/min/1.73 m2. Results of κ statistics also showed that eGFRcreat was most appropriate to estimate GFR both before and after heminephrectomy, when cut-off value of GFR of < 60 mL/min/1.73 m2 was used. CONCLUSION: Results of the present study suggest that eGFRcreat is likely to be the most appropriate equation for patients undergoing RN or RNU due to urological malignancies. However, more precise equations will be required for accurately estimating GFR.

Klotho suppresses the renin-angiotensin system in adriamycin nephropathy.

BACKGROUNDS: Klotho protein interacts with the transforming growth factor ß (TGF-ß) receptor and Wnt, which contribute to the progression of renal disease, inhibiting their signals. Renal and circulating klotho levels are diminished in chronic kidney disease. METHODS: Experiments were performed to assess whether supplementation of klotho protein could have protective effects on the kidney. Rats were injected with adriamycin (5 mg/kg) and divided into three groups: those treated with vehicle, those treated with klotho protein and those treated with klotho plus 4-benzyl-2-methyl-1,2,4-thiadiazolidine-3,5-dione (TDZD). Rats without adriamycin treatment were used as a control. RESULTS: Adriamycin reduced the serum klotho concentration and renal expression of klotho and E-cadherin. Adriamycin also increased the renal expression of Wnt, TGF-ß, and angiotensinogen, as well as the renal abundance of ß-catenin and angiotensin II. Klotho supplementation suppressed adriamycin-induced elevations of ß-catenin and angiotensin II with sustained Wnt expression. Combined treatment with klotho and TDZD reversed the klotho-induced improvements in the renal abundance of ß-catenin and angiotensin II as well as the expression of TGF-ß and angiotensinogen without affecting E-cadherin. CONCLUSIONS: Our data indicate that Wnt is involved in the pathogenesis of adriamycin nephropathy. Furthermore, klotho supplementation inhibited Wnt signaling, ameliorating renal angiotensin II. Finally, klotho protein appears to suppress epithelial-mesenchymal transition by inhibiting TGF-ß and Wnt signaling.

Anemia Treatment by Erythropoiesis-stimulating Agents during the 6 Months before the Initiation of Hemodialysis: Comparison of Darbepoetin Alfa and Continuous Erythropoietin Receptor Activator.

Anemia in chronic kidney disease (CKD) is a risk factor for cardiovascular diseases and is treated by long-acting erythropoiesis-stimulating agents (ESAs). Although the results of previous studies have shown that hemoglobin levels could not be maintained at the initiation of dialysis in CKD patients treated with recombinant human erythropoietin, it remains undetermined whether long-acting ESAs are effective in preventing the progression of anemia at the initiation of dialysis. In the present study, hemoglobin levels in 40 CKD patients treated with darbepoetin alfa (DA) and 15 CKD patients treated with a continuous erythropoietin receptor activator (CERA) were retrospectively compared during the 6 months period before the initiation of dialysis. Results showed that DA and CERA both maintained hemoglobin levels at around 10 g/dL from 6 months to 1 month before dialysis. However, hemoglobin levels at the initiation of dialysis significantly decreased to 9.1 ± 1.2 g/dL in the DA group and to 9.0 ± 1.0 g/dL in the CERA group. Although the total doses of ESAs used during the 6-month period were similar between the two groups, DA-treated CKD patients received subcutaneous injections more frequently than did patients treated with CERA. These results suggest that CKD patients require more intense ESA therapy to prevent a decline in hemoglobin levels at the initiation of dialysis, including those treated with long-acting ESAs. The results also raise the possibility that CERA is more useful than DA for reducing the number of injections during the pre-dialysis period.

Podocyte NF-κB is dispensable for the pathogenesis of renal ischemia-reperfusion injury.

Podocytes play a central role in the formation of the glomerular filtration barrier in the kidney, and their dysfunction has been shown to result in multiple proteinuric kidney diseases. In this study, we sought to determine whether NF-κB, a proinflammatory signaling, within podocytes was involved in renal ischemia-reperfusion (I/R) injury. Podocyte-specific IκBΔN transgenic (Pod-IκBΔN) mice, in which NF-κB was inhibited specifically in podocytes, were generated by the Cre-loxP technology, and their phenotype was compared with control mice after bilateral renal ischemia. The effect of systemic administration of a NF-κB inhibitor, pyrrolidinedithiocarbamate (PDTC), on renal I/R injury was also examined. Pod-IκBΔN mice were phenotypically normal before surgery. Following renal I/R injury, serum concentrations of urea nitrogen and creatinine were elevated in both Pod-IκBΔN and control mice to a similar extent, whereas PDTC treatment attenuated the elevation of these parameters. Renal histological damage in I/R-injured Pod-IκBΔN mice was also similar to I/R-injured control mice, although it was improved by PDTC treatment. Moreover, I/R induced accumulation of inflammatory cells, such as neutrophils and macrophages, was reduced by PDTC treatment, but not by podocyte-specific NF-κB inhibition. These results provide evidence that the NF-κB activity in podocytes does not contribute to the pathogenesis of renal I/R injury.

Endothelial Krüppel-Like Factor 4 Mediates the Protective Effect of Statins against Ischemic AKI.

Endothelial cells participate in the pathophysiology of ischemic AKI by increasing the expression of cell adhesion molecules and by recruiting inflammatory cells. We previously showed that endothelial Krüppel-like factor 4 (Klf4) regulates vascular cell adhesion molecule 1 (Vcam1) expression and neointimal formation after carotid injury. In this study, we determined whether endothelial Klf4 is involved in ischemic AKI using endothelial Klf4 conditional knockout (Klf4 cKO) mice generated by breeding Tek-Cre mice and Klf4 floxed mice. Klf4 cKO mice were phenotypically normal before surgery. However, after renal ischemia-reperfusion injury, Klf4 cKO mice exhibited elevated serum levels of urea nitrogen and creatinine and aggravated renal histology compared with those of Klf4 floxed controls. Moreover, Klf4 cKO mice exhibited enhanced accumulation of neutrophils and lymphocytes and elevated expression of cell adhesion molecules, including Vcam1 and Icam1, in injured kidneys. Notably, statins ameliorated renal ischemia-reperfusion injury in control mice but not in Klf4 cKO mice. Mechanistic analyses in cultured endothelial cells revealed that statins increased KLF4 expression and that KLF4 mediated the suppressive effect of statins on TNF-α-induced VCAM1 expression by reducing NF-κB binding to the VCAM1 promoter. These results provide evidence that endothelial Klf4 is renoprotective and mediates statin-induced protection against ischemic AKI by regulating the expression of cell adhesion molecules and concomitant recruitment of inflammatory cells.

A case of severe osteomalacia caused by Tubulointerstitial nephritis with Fanconi syndrome in asymptomotic primary biliary cirrhosis.

BACKGROUND: Primary biliary cirrhosis (PBC) is an immune-mediated chronic cholestatic liver disease, characterized by increased concentrations of serum IgM and the presence of circulating anti-mitochondrial antibodies. Although bone diseases such as osteoporosis or osteodystrophy are commonly associated with PBC, osteomalacia which is caused by abnormal vitamin D metabolism, mineralization defects, and phosphate deficiency has not been recognized as a complication of PBC. CASE PRESENTATION: We report the case of a 49-year-old Japanese woman who complained of multiple fractures. Hypophosphatemic osteomalacia was diagnosed from a low serum phosphorus level, 1,25-dihydroxyvitamin D3 level, high levels of bone specific alkaline phosphatase and the findings of bone scintigraphy, although a bone biopsy was not performed. Twenty four hour urine demonstrated a low renal fractional tubular reabsorption of phosphate, increased fractional excretion of uric acid and generalized aminoaciduria. An intravenous bicarbonate loading test suggested the presence of proximal renal tubular acidosis (RTA). These biochemical data indicated Fanconi syndrome with proximal RTA. A kidney biopsy demonstrated the features of tubulointerstitial nephritis (TIN). The patient was also suspected as having primary biliary cirrhosis (PBC) because of high levels of alkaline phosphatase, IgM and the presence of anti-mitochondrial M2 antibody, though biochemical liver function was normal. Sequential liver biopsy was compatible with PBC and the diagnosis of PBC was definite. After administration of 1,25 dihydroxyvitamin D3, neutral potassium phosphate, sodium bicarbonate for osteomalacia and subsequent predonizolone for TIN, symptoms of fractures were relieved and renal function including Fanconi syndrome was ameliorated. CONCLUSION: In this case, asymptomatic PBC was shown to induce TIN with Fanconi syndrome with dysregulation of electrolytes and vitamin D metabolism, which in turn led to osteomalacia with multiple fractures. Osteomalacia has not been recognized as a result of the renal involvement of PBC. PBC and its rare complication of TIN with Fanconi syndrome should be considered in adult patients with unexplained osteomalacia even in the absence of liver dysfunction.

Inhalation of Hydrogen Gas Is Beneficial for Preventing Contrast-Induced Acute Kidney Injury in Rats.

Background: The present study aimed at investigating the effect of a novel antioxidant, hydrogen (H2) gas, on the severity of contrast-induced acute kidney injury (CIAKI) in a rat model. Methods: CIAKI was induced in rats by intravenous injection of a contrast medium, Ioversol, in addition to reagents inhibiting prostaglandin and nitric oxide synthesis. During the injection of these reagents, the rats inhaled H2 gas or control gas. Results: One day after the injection, serum levels of urea nitrogen were significantly lower in H2 gas-inhaling CIAKI rats (17.6 ± 2.3 mg/dl) than those in control gas-treated CIAKI rats (36.0 ± 7.3 mg/dl), although they both were elevated as compared to untreated rats (14.9 ± 0.9 mg/dl). Consistently, creatinine clearance in H2 gas-treated CIAKI rats was higher than that in control gas-treated counterparts. Renal histological analysis revealed that the formation of proteinaceous casts and tubular necrosis was improved by H2 gas inhalation. Mechanistic analyses showed that inhalation of H2 gas significantly reduced renal cell apoptosis, expression of cleaved caspase 3, and expression of an oxidative stress marker, 8-hydroxydeoxyguanosine, in injured kidneys. Conclusion: Results suggest that H2 gas inhalation is effective in ameliorating the severity of CIAKI in rats by reducing renal cell apoptosis and oxidative stress. © 2015 S. Karger AG, Basel.

Role of Krüppel-like factor 4 and its binding proteins in vascular disease.

Krüppel-like factor 4(KLF4) is a zinc-finger transcription factor that plays a key role in cellular differentiation and proliferation during normal development and in various diseases, such as cancer. The results of recent studies have revealed that KLF4 is expressed in multiple vascular cell types, including phenotypically modulated smooth muscle cells(SMCs), endothelial cells and monocytes/macrophages and contributes to the progression of vascular diseases by activating or repressing the transcription of multiple genes via its associations with a variety of partner proteins. For example, KLF4 decreases the expression of markers of SMC differentiation by interacting with serum response factor, ELK1 and histone deacetylases. KLF4 also suppresses SMC proliferation by associating with p53. In addition, KLF4 enhances arterial medial calcification in concert with RUNX2. Furthermore, endothelial KLF4 represses arterial inflammation by binding to nuclear factor-κB. This article summarizes the role of KLF4 in vascular disease with a particular focus on in vivo studies and reviews recent progress in our understanding of the regulatory mechanisms involved in KLF4- mediated gene transcription.

Deletion of Krüppel-like factor 4 in endothelial and hematopoietic cells enhances neointimal formation following vascular injury.

BACKGROUND: Krüppel-like factor 4 (Klf4) is involved in a variety of cellular functions by activating or repressing the transcription of multiple genes. Results of previous studies showed that tamoxifen-inducible global deletion of the Klf4 gene in mice accelerated neointimal formation following vascular injury, in part via enhanced proliferation of smooth muscle cells (SMCs). Because Klf4 is also expressed in non-SMCs including endothelial cells (ECs), we determined if Tie2 promoter-dependent deletion of Klf4 in ECs and hematopoietic cells affected injury-induced neointimal formation. METHODS AND RESULTS: Klf4 conditional knockout (cKO) mice were generated by breeding Tie2-Cre mice and Klf4 floxed mice, and their phenotype was analyzed after carotid ligation injury. Results showed that injury-induced repression of SMC differentiation markers was unaffected by Tie2 promoter-dependent Klf4 deletion. However, of interest, neointimal formation was significantly enhanced in Klf4-cKO mice 21 days following carotid injury. Moreover, Klf4-cKO mice exhibited an augmented proliferation rate, enhanced accumulation of macrophages and T lymphocytes, and elevated expression of cell adhesion molecules including vascular cell adhesion molecule-1 (Vcam1) and E-selectin in injured arteries. Mechanistic analyses in cultured ECs revealed that Klf4 inhibited tumor necrosis factor-α-induced expression of Vcam1 through blocking the binding of nuclear factor-κB to the Vcam1 promoter. CONCLUSIONS: These results provide evidence that Klf4 in non-SMCs such as ECs regulates neointimal formation by repressing arterial inflammation following vascular injury.

Disturbed tumor necrosis factor system is linked with lower eGFR and chronic inflammation in hypertension.

BACKGROUND: The relationship between tumor necrosis factor (TNF)-related parameters and cardiorenal metabolic factors is still controversial in clinical hypertension. METHODS: Normotensive men (NT, n=60) and treated stage 2 and 3 essential hypertensive men (HT, n=89) were enrolled in this study. The relationship between TNF-related parameters and cardiorenal metabolic factors was examined in NT and HT, separately. RESULTS: HT showed higher rates of insulin resistance and enhanced chronic inflammation compared with NT. The levels of soluble TNF receptor 1 and 2 were significantly higher in HT than in NT, although TNF-α levels were unexpectedly lower in HT than in NT. Regression analysis indicated that the TNF-related parameters were closely linked with mild renal dysfunction both in NT and HT, and moderately related to chronic inflammation only in HT. HT taking inhibitors of the renin-angiotensin system showed improved insulin resistance, but no difference in the TNF-related parameters. CONCLUSION: These results suggest that the disturbed TNF system is closely linked with chronic inflammation rather than with insulin resistance in HT.

Renal thrombotic microangiopathy in a patient with septic disseminated intravascular coagulation.

BACKGROUND: The mechanism for the development of thrombotic microangiopathy (TMA) during sepsis has only been partially elucidated. TMA is recognized as a disease caused by various factors, and may be involved in the emergence of organ damage in severe sepsis. Here we report a case of TMA that followed disseminated intravascular coagulation (DIC) due to severe infection in a patient with a reduced ADAMTS-13 activity level. CASE PRESENTATION: An 86-year-old Japanese woman was admitted to our hospital because of low back pain and fever. A careful evaluation led to a diagnosis of acute obstructive pyelonephritis due to a ureteral stone. Proteus mirabilis was isolated from both blood and urine cultures. The patient developed systemic inflammatory response syndrome and DIC, and was treated with antibiotics and daily continuous hemodiafiltration. Although infection and the coagulation abnormalities due to DIC were successfully controlled, renal failure persisted and her consciousness level deteriorated progressively in association with severe thrombocytopenia and microangiopathic hemolytic anemia. We therefore suspected the presence of TMA and started plasma exchange, which resulted in an impressive improvement in consciousness as well as the laboratory abnormalities. The ADAMTS-13 activity was 44% and the patient tested negative for the ADAMTS-13 inhibitor prior to the initiation of plasma exchange. A renal biopsy was performed to determine the etiology of acute renal injury, which revealed findings that were interpreted to be compatible with the sequelae of TMA. The follow-up studies performed after the successful treatment of TMA showed that her plasma ADAMTS-13 activity level remained persistently low. It is surmised that septic DIC occurring in the presence of preexisting reduced ADAMTS-13 activity have led to the development of secondary TMA in the present case. CONCLUSION: The present case suggests that TMA can be superimposed on sepsis-induced DIC, and plasma exchange is expected to be beneficial in such situations. Clinicians should consider the possibility of secondary TMA that follows sepsis-induced DIC in certain indicative clinical settings.

High glucose concentration does not modulate the formation of arterial medial calcification in experimental uremic rats.

High phosphate-induced phenotypic switching of smooth muscle cells (SMCs) into osteogenic cells is critical for the formation of arterial medial calcification in chronic kidney disease. Because vascular calcification is also prevalent in type 2 diabetes, we examined whether glucose concentration affects high phosphate-induced SMC phenotypic switching and calcification. First, the formation of arterial medial calcification was compared among 4 groups: adenine-fed uremic rats, streptozotocin-injected hyperglycemic rats, adenine-fed and streptozotocin-injected uremic/hyperglycemic rats, and control rats. Calcification was obvious in uremic and uremic/hyperglycemic rats, whereas it was undetectable in the others. Aortic calcium contents were significantly elevated in uremic and uremic/hyperglycemic rats, but they were not different between the two groups. Moreover, hyperglycemia had no effects on the reduced expression of SMC differentiation markers including smooth muscle α-actin and SM22α and on the increased expression of osteogenic markers, such as Runx2, in uremic rats. Second, cultured SMCs were incubated in the medium with various concentrations of phosphate (0.9-4.5 mmol/l) and glucose (5-50 mmol/l), and calcium deposition was measured. Although high phosphate dose-dependently increased calcium contents, they were unaffected by glucose concentration. Results suggest that glucose concentration does not directly modulate high phosphate-induced SMC phenotypic switching and arterial medial calcification.