Publications by authors named "Ronen Levi"

14 Publications

  • Page 1 of 1

Interleukin-6 contributes to the increase in fibroblast growth factor 23 expression in acute and chronic kidney disease.

Kidney Int 2018 08 31;94(2):315-325. Epub 2018 May 31.

Minerva Center for Calcium and Bone Metabolism, Nephrology Services, Hadassah Hebrew University Medical Center, Jerusalem, Israel. Electronic address:

The high serum fibroblast growth factor 23 (FGF23) levels in patients with acute kidney injury (AKI) and chronic kidney disease (CKD) are associated with increased morbidity and mortality. Mice with folic acid-induced AKI had an increase in bone FGF23 mRNA expression together with an increase in serum FGF23 and several circulating cytokines including interleukin-6 (IL-6). Dexamethasone partially prevented the increase in IL-6 and FGF23 in the AKI mice. IL-6 knock-out mice fed an adenine diet to induce CKD failed to increase bone FGF23 mRNA and had a muted increase in serum FGF23 levels, compared with the increases in wild-type mice with CKD. Therefore, IL-6 contributes to the increase in FGF23 observed in CKD. Hydrodynamic tail injection of IL-6/soluble IL-6 receptor (sIL-6R) fusion protein hyper IL-6 (HIL-6) plasmid increased serum FGF23 levels. Circulating sIL-6R levels were increased in both CKD and AKI mice, suggesting that IL-6 increases FGF23 through sIL-6R-mediated trans-signaling. Renal IL-6 mRNA expression was increased in mice with either AKI or CKD, suggesting the kidney is the source for the increased serum IL-6 levels in the uremic state. HIL-6 also increased FGF23 mRNA in calvaria organ cultures and osteoblast-like UMR106 cells in culture, demonstrating a direct effect of IL-6 on FGF23 expression. HIL-6 increased FGF23 promoter activity through STAT3 phosphorylation and its evolutionarily conserved element in the FGF23 promoter. Thus, IL-6 increases FGF23 transcription and contributes to the high levels of serum FGF23 in both acute and chronic kidney disease.
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http://dx.doi.org/10.1016/j.kint.2018.02.026DOI Listing
August 2018

The gut-kidney axis in chronic renal failure: A new potential target for therapy.

Hemodial Int 2017 07 16;21(3):323-334. Epub 2016 Sep 16.

Department of Medicine, Gastroenterology and Liver Units, Jerusalem, Israel.

Evidence is accumulating to consider the gut microbiome as a central player in the gut-kidney axis. Microbiome products, such as advanced glycation end products, phenols, and indoles, are absorbed into the circulation but are cleared by normal-functioning kidneys. These products then become toxic and contribute to the uremic load and to the progression of chronic kidney failure. In this review, we discuss the gut-kidney interaction under the state of chronic kidney failure as well as the potential mechanisms by which a change in the gut flora (termed gut dysbiosis) in chronic kidney disease (CKD) exacerbates uremia and leads to further progression of CKD and inflammation. Finally, the potential therapeutic interventions to target the gut microbiome in CKD are discussed.
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http://dx.doi.org/10.1111/hdi.12486DOI Listing
July 2017

Implementation of guidelines for metabolic syndrome control in kidney transplant recipients: results at a single center.

Diabetol Metab Syndr 2015 16;7:90. Epub 2015 Oct 16.

Nephrology and Hypertension Services, Hadassah-Hebrew University Medical Center, 91120 Jerusalem, Israel.

Background: Cardiovascular disease is a leading cause of death among kidney transplant recipients. Metabolic syndrome increases the risk for cardiovascular events and decreases graft survival. Lately, guidelines for management of the metabolic syndrome, primarily hypertension, diabetes mellitus (DM) and hypercholesterolemia have dramatically changed in an attempt to decrease cardiovascular risks among kidney transplant recipients. In the present study we examined whether these guideline changes had impact on our management of post-transplantation patients and the subsequent treatment outcomes for these diseases.

Methods: Data were obtained from kidney transplant clinic files from two follow-up (FU) periods-between 1994-1997 and between 2008-2011. Demographic data, monitoring and screening frequency for cardiovascular risk factors, immunosuppression regimen, treatment for hypertension, diabetes and hyperlipidemia, treatment outcomes and graft function changes were compared between the two follow-up periods.

Results: There was a significant increase in the percentage of patients undergoing transplantation due to renal failure secondary to diabetes and/or hypertension. Patient monitoring and screening during the second FU period were less frequent, but more targeted, reflecting changes in clinic routines. Blood pressure was better controlled in the second FU period (p < 0.01), as was hypercholesterolemia (p < 0.001). High fasting glucose levels were more prevalent among patients in the second group (p < 0.005), although more patients received treatment for DM (p < 0.001). Significantly, fewer patients experienced deterioration of kidney functions during the second FU period (p < 0.001).

Conclusions: We found that guideline changes had impact on clinical practice, which translated to better control of the metabolic syndrome. DM control is challenging. Overall, stability of kidney function improved.
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http://dx.doi.org/10.1186/s13098-015-0083-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4609158PMC
October 2015

The fibroblast growth factor receptor mediates the increased FGF23 expression in acute and chronic uremia.

Am J Physiol Renal Physiol 2016 Feb 26;310(3):F217-21. Epub 2015 Aug 26.

Minerva Center for Calcium and Bone Metabolism, Nephrology Services, Hadassah Hebrew University Medical Center, Jerusalem, Israel

Serum FGF23 is markedly elevated in chronic kidney disease and has been associated with poor long-term outcomes. FGF23 expression is increased by activation of the FGF receptor 1 (FGFR1) in rats with normal renal function and in vitro in bone-derived osteoblast-like cells. We studied the regulation of FGF23 by FGFR1 in vivo in acute and chronic uremia in mice and rats. Folic acid-induced acute kidney injury increased calvaria FGF23 mRNA and serum FGF23 and parathyroid hormone (PTH) levels at 6 h. The FGFR1 receptor inhibitor PD173074 prevented the folic acid-induced increase in both FGF23 mRNA and serum levels but had no effect on serum PTH levels. A more prolonged uremia due to an adenine high-phosphorus diet for 14 days resulted in high levels of FGF23 mRNA and serum FGF23 and PTH. PD173074 decreased serum FGF23 and mRNA levels with no effect on PTH in the adenine high phosphorus-induced uremic rats. Therefore, a derangement in FGF23 regulation starts early in the course of acute kidney injury, is in part independent of the increase in serum PTH, and involves activation of FGFR1. It is possible that FGFR1 in the osteocyte is activated by locally produced canonical FGFs, which are increased in uremia. This is the first demonstration that activation of FGFR1 is essential for the high levels of FGF23 in acute and chronic experimental uremia.
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http://dx.doi.org/10.1152/ajprenal.00332.2015DOI Listing
February 2016

A heart breaking case of rapidly developing severe hemophagocytic syndrome secondary to chronic active EBV infection; a case report and review of the literature.

J Clin Virol 2015 Jun 24;67:14-6. Epub 2015 Mar 24.

Department of Nephrology, Hadassah-Hebrew University Medical Center, P.O.B. 12000, Jerusalem IL-91120, Israel. Electronic address:

Epstein-Barr virus (EBV, HHV-4) is a gamma Herpesvirus with a 90% >seroprevalence in adults. Reactivations in non-immuno compromised individuals usually cause mild or no symptoms at all. Rarely, host immunity-virus balance is interrupted, resulting in a chronic active EBV infection. The following case illustrates the rapid development of severe hemophagocytic syndrome during chronic active EBV infection in a 73 year old woman who presented with lower extremity pain and edema, splenomegaly and abnormal liver enzymes. A diagnosis of chronic active EBV infection was made following an extensive investigation and the patient died secondary to rapidly progressive hemophagocytic syndrome.
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http://dx.doi.org/10.1016/j.jcv.2015.03.017DOI Listing
June 2015

Carbapenem-resistant Klebsiella pneumoniae is associated with poor outcome in hemodialysis patients.

J Infect 2012 Oct 18;65(4):318-25. Epub 2012 Jun 18.

Nephrology and Hypertension Services, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.

Background: Hemodialysis (HD) units have become a source of resistant bacteria. One of the most alarming developments is the emergence of carbapenem-resistant Klebsiella pneumoniae (CRKP). Risk factors and outcomes of CRKP isolation in HD patients have not been previously studied.

Methods: A nested case-control study was conducted in maintenance HD patients between January 1st 2006 and June 30th 2009. CRKP-positive patients were matched with randomly selected CRKP-negative HD patients. Demographics, clinical and laboratory data were collected for 24 months prior to the specimen collection. Multivariate analyses identified independent risk factors for CRKP. A prospective follow-up determined CRKP-associated outcome.

Results: Demographics associated with CRKP acquisition in HD patients were age between 65 and 75 and having no living offspring. Clinical conditions associated with CRKP were previous hospitalization, temporary HD catheter and previous isolation of vancomycin-resistant enterococcus. CRKP-related outcome was poor: median survival of one month and a hazard ratio [95% CI] of 5.9 [3.2-11.0] for mortality.

Conclusions: Temporary HD catheters and previous treatment for VRE may predict subsequent CRKP isolation. A microbiological diagnosis of CRKP in HD patients is highly associated with imminent mortality. Meticulous measures to control the spread of CRKP bacteria among HD patients appear particularly warranted.
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http://dx.doi.org/10.1016/j.jinf.2012.06.005DOI Listing
October 2012

Unilateral purpuric rash in a patient with acute renal failure.

Isr Med Assoc J 2011 Aug;13(8):515

Department of Medicine, Hadassah University Hospital, Mt. Scopus, Jerusalem, Israel.

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August 2011

Deletion of the vitamin D receptor specifically in the parathyroid demonstrates a limited role for the receptor in parathyroid physiology.

Am J Physiol Renal Physiol 2009 Nov 19;297(5):F1192-8. Epub 2009 Aug 19.

Minerva Center for Calcium and Bone Metabolism, Nephrology Services, Hadassah Hospital, Jerusalem, Israel.

1,25(OH)2D3 decreases parathyroid hormone (PTH) gene transcription through the vitamin D receptor (VDR). Total body VDR(-/-) mice have high PTH levels, hypocalcemia, hypophosphatemia, and bone malformations. To investigate PTH regulation by the VDR specifically in the parathyroid, we generated parathyroid-specific VDR knockout mice (PT-VDR(-/-)). In both strains, there was a decrease in parathyroid calcium receptor (CaR) levels. The number of proliferating parathyroid cells was increased in the VDR(-/-) mice but not in the PT-VDR(-/-) mice. Serum PTH levels were moderately but significantly increased in the PT-VDR(-/-) mice with normal serum calcium levels. The sensitivity of the parathyroid glands of the PT-VDR(-/-) mice to calcium was intact as measured by serum PTH levels after changes in serum calcium. This indicates that the reduced CaR in the PT-VDR(-/-) mice enables a physiologic response to serum calcium. Serum C-terminal collagen crosslinks, a marker of bone resorption, were increased in the PT-VDR(-/-) mice with no change in the bone formation marker, serum osteocalcin, consistent with a resorptive effect due to the increased serum PTH levels in the PT-VDR(-/-) mice. Therefore, deletion of the VDR specifically in the parathyroid decreases parathyroid CaR expression and only moderately increases basal PTH levels, suggesting that the VDR has a limited role in parathyroid physiology.
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http://dx.doi.org/10.1152/ajprenal.00360.2009DOI Listing
November 2009

Vitamin D supplementation after renal transplantation: how much vitamin D should we prescribe?

Kidney Int 2009 Mar;75(6):576-8

Nephrology Services, Minerva Center for Calcium and Bone Metabolism, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.

Vitamin D deficiency is common in patients with chronic kidney disease after renal transplantation. Vitamin D, essential for mineral and bone metabolism, also has myriad beneficial autocrine effects on intact immune responses and defense against infection, as well as suppression of malignant changes. Supplementation with oral parental vitamin D could correct this problem. Courbebaisse et al. define how much oral vitamin D to prescribe to renal allograft recipients.
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http://dx.doi.org/10.1038/ki.2008.492DOI Listing
March 2009

Increased parathyroid hormone gene expression in secondary hyperparathyroidism of experimental uremia is reversed by calcimimetics: correlation with posttranslational modification of the trans acting factor AUF1.

J Am Soc Nephrol 2006 Jan 16;17(1):107-12. Epub 2005 Nov 16.

Minerva Center for Calcium and Bone Metabolism, Nephrology Services, Hebrew University Hadassah Hospital, P.O. Box 12000, Jerusalem, Israel 91120.

Most patients with chronic kidney disease develop secondary hyperparathyroidism with disabling systemic complications. Calcimimetic agents are effective tools in the management of secondary hyperparathyroidism, acting through allosteric modification of the calcium-sensing receptor (CaR) on the parathyroid gland (PT) to decrease parathyroid hormone (PTH) secretion and PT cell proliferation. This study showed that rats that were fed an adenine high-phosphorus diet had increased serum PTH and PTH mRNA levels at 7 and 21 d. For studying the effect of activation of the CaR by the calcimimetics R-568 on PTH gene expression, R-568 was given by gavage to uremic rats for the last 4 d of a 7-d adenine high-phosphorus diet. R-568 decreased both PTH mRNA and serum PTH levels. The effect of the calcimimetic on PTH gene expression was posttranscriptional and correlated with differences in protein-RNA binding and posttranslational modifications of the trans acting factor AUF1 in the PT. The AUF1 modifications as a result of uremia were reversed by treatment with R-568 to those of normal rats. Therefore, uremia and activation of the CaR mediated by calcimimetics modify AUF1 posttranslationally. These modifications in AUF1 correlate with changes in protein-PTH mRNA binding and PTH mRNA levels.
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http://dx.doi.org/10.1681/ASN.2005070679DOI Listing
January 2006

Regulation of PTH synthesis and secretion relevant to the management of secondary hyperparathyroidism in chronic kidney disease.

Kidney Int Suppl 2005 Jun(95):S8-12

Minerva Center for Calcium and Bone Metabolism, Nephrology and Hypertension Services, Hadassah Hebrew University Medical Center, Jerusalem, Israel 91120.

Regulation of PTH synthesis and secretion relevant to the management of secondary hyperparathyroidism in chronic kidney disease. Small decreases in serum Ca(++) and more prolonged increases in serum phosphate (P) stimulate the parathyroid (PT) to secrete parathyroid hormone (PTH), while 1,25(OH)(2)-vitamin D(3) decreases PTH synthesis and secretion. A prolonged decrease in serum Ca(++) and 1,25(OH)(2)D(3), or increase in serum P, such as in patients with chronic renal failure, leads to the appropriate secondary increase in serum PTH. This secondary hyperparathyroidism involves increases in PTH gene expression, synthesis, and secretion, and, if chronic, to proliferation of the parathyroid cells. A low serum Ca(++) leads to an increase in PTH secretion, PTH mRNA stability, and parathyroid cell proliferation. Pi also regulates the parathyroid in a similar manner. The effect of Ca(++) on the parathyroid is mediated by a membrane Ca(2+) receptor (CaR). 1,25(OH)(2)D(3) decreases PTH gene transcription. Ca(2+) and P regulate the PTH gene post-transcriptionally by regulating the binding of parathyroid cytosolic proteins, trans factors, to a defined cis sequence in the PTH mRNA 3'-untranslated region (UTR), thereby determining the stability of the transcript. The parathyroid trans factors and cis elements have been defined.
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http://dx.doi.org/10.1111/j.1523-1755.2005.09501.xDOI Listing
June 2005

Calcineurin Abeta is central to the expression of the renal type II Na/Pi co-transporter gene and to the regulation of renal phosphate transport.

J Am Soc Nephrol 2004 Dec;15(12):2972-80

Nephrology Services, Hadassah Hospital, P.O. Box 12000, Jerusalem, Israel 91120.

The sensing and response to extracellular phosphate (Pi) concentration is preserved from prokaryotes to mammals and ensures an adequate supply of Pi in the face of large differences in its availability. In mammals, the kidneys are central to Pi homeostasis. Renal Pi reabsorption is mediated by a Na/Pi co-transporter that is regulated by a renal Pi sensing system and humoral factors. The signal transduction by which Pi regulates type II Na/Pi activity is largely unknown. It is shown that calcineurin inhibitors specifically and dramatically decrease type II Na/Pi gene expression in a proximal tubule cell line and in vivo. Mice with genetic deletion of the calcineurin Abeta gene had a marked decrease in type II Na/Pi mRNA levels and remarkably did not show the expected increase in type II Na/Pi mRNA levels after the challenge of a low-Pi diet. In contrast, the regulation of renal 25(OH)-vitamin D 1alpha-hydroxylase gene expression by Pi was intact. This is the first demonstration that calcineurin has a crucial role in the signal transduction pathway regulating renal Pi homeostasis both in vitro and in vivo. These results suggest that the use of calcineurin inhibitors contributes to the renal Pi wasting seen in renal transplant patients.
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http://dx.doi.org/10.1097/01.ASN.0000144207.44469.BEDOI Listing
December 2004

Pathogenesis of parathyroid dysfunction in end-stage kidney disease.

Pediatr Nephrol 2005 Mar 10;20(3):342-5. Epub 2004 Nov 10.

Nephrology and Hypertension Services, Minerva Center for Calcium and Bone Metabolism, Hebrew University Hadassah Medical Center, 91120, Jerusalem, Israel.

Small decreases in serum calcium (Ca(2+)) and more-prolonged increases in serum phosphate (Pi) stimulate the parathyroid (PT) to secrete parathyroid hormone (PTH). 1,25-Dihydroxyvitamin D(3) [1,25(OH)(2) D(3)] decreases PTH synthesis and secretion. The prolonged decrease in serum Ca(2+) and 1,25(OH)(2) D(3), or increase in serum Pi, observed in patients with chronic renal failure leads to a secondary increase in serum PTH. This secondary hyperparathyroidism involves increases in PTH gene expression, synthesis, and secretion and, if chronic, to proliferation of the PT cells. A low serum Ca(2+) leads to an increase in PTH secretion, PTH mRNA stability, and PT cell proliferation. Pi also regulates the PT in a similar manner. The effect of Ca(2+) on the PT is mediated by a membrane Ca(2+) receptor. 1,25(OH)(2) D(3) decreases PTH gene transcription. Ca(2+) and Pi regulate the PTH gene post transcriptionally by regulating the binding of PT cytosolic proteins, trans factors, to a defined cis sequence in the PTH mRNA 3'-untranslated region, thereby determining the stability of the transcript. The PT trans factors and cis elements have been defined.
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http://dx.doi.org/10.1007/s00467-004-1628-4DOI Listing
March 2005

The protein phosphatase calcineurin determines basal parathyroid hormone gene expression.

Mol Endocrinol 2005 Feb 28;19(2):516-26. Epub 2004 Oct 28.

Minerva Center for Calcium and Bone Metabolism, Nephrology Services, Hadassah Hospital, PO Box 12000, Jerusalem 91120, Israel.

Calcium and phosphate regulate PTH mRNA stability through differences in binding of parathyroid (PT) proteins to a minimal 63-nucleotide (nt) cis-acting instability element in its 3'-untranslated region. One of these proteins is adenosine-uridine-rich binding factor (AUF1), whose levels are not regulated in PT extracts from rats fed the different diets. However, two-dimensional gels showed posttranslational modification of AUF1 that included phosphorylation. There is no PT cell line, but in HEK 293 cells the 63-nt element is recognized as an instability element, and RNA interference for AUF1 decreased human PTH secretion in cotransfection experiments. Stably transfected cells with a chimeric GH gene containing the PTH 63-nt cis-acting element were used to study the signal transduction pathway that regulates AUF1 modification and chimeric gene mRNA stability. Cyclosporine A, the calcineurin inhibitor, regulated AUF1 posttranslationally, and this correlated with an increase in the stability of GH-PTH 63-nt mRNA but not of the control GH mRNA. Mice with genetic deletion of the calcineurin Abeta gene had markedly increased PTH mRNA levels that were still regulated by low calcium and phosphorus diets. Therefore, calcineurin regulates AUF1 posttranslationally in vitro and PTH gene expression in vivo but still allows its physiological regulation by calcium and phosphate.
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http://dx.doi.org/10.1210/me.2004-0108DOI Listing
February 2005