Publications by authors named "Vecihi Batuman"

70 Publications

Free light chains injure proximal tubule cells through the STAT1/HMGB1/TLR axis.

JCI Insight 2020 07 23;5(14). Epub 2020 Jul 23.

John W. Deming Department of Medicine, Tulane University School of Medicine, New Orleans, Louisiana, USA.

Free light chains (FLCs) induce inflammatory pathways in proximal tubule cells (PTCs). The role of TLRs in these responses is unknown. Here we present findings on the role of TLRs in FLC-induced PTC injury. We exposed human kidney PTC cultures to κ and λ FLCs and used cell supernatants and pellets for ELISA and gene expression studies. We also analyzed tissues from Stat1-/- and littermate control mice treated with daily i.p. injections of a κ FLC for 10 days. FLCs increased the expression of TLR2, TLR4, and TLR6 via HMGB1, a damage-associated molecular pattern. Countering TLR2, TLR4, and TLR6 through GIT-27 or specific TLR siRNAs reduced downstream cytokine responses. Blocking HMGB1 through siRNA or pharmacologic inhibition, or via STAT1 inhibition, reduced FLC-induced TLR2, TLR4, and TLR6 expression. Blocking endocytosis of FLCs through silencing of megalin/cubilin, with bafilomycin A1 or hypertonic sucrose, attenuated FLC-induced cytokine responses in PTCs. IHC showed decreased TLR4 and TLR6 expression in kidney sections from Stat1-/- mice compared with their littermate controls. PTCs exposed to FLCs released HMGB1, which induced expression of TLR2, TLR4, and TLR6 and downstream inflammation. Blocking FLCs' endocytosis, Stat1 knockdown, HMGB1 inhibition, and TLR knockdown each rescued PTCs from FLC-induced injury.
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http://dx.doi.org/10.1172/jci.insight.137191DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7453901PMC
July 2020

The evaluation of monoclonal gammopathy of renal significance: a consensus report of the International Kidney and Monoclonal Gammopathy Research Group.

Nat Rev Nephrol 2019 01;15(1):45-59

Division of Nephrology, Hematology, Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA.

The term monoclonal gammopathy of renal significance (MGRS) was introduced by the International Kidney and Monoclonal Gammopathy Research Group (IKMG) in 2012. The IKMG met in April 2017 to refine the definition of MGRS and to update the diagnostic criteria for MGRS-related diseases. Accordingly, in this Expert Consensus Document, the IKMG redefines MGRS as a clonal proliferative disorder that produces a nephrotoxic monoclonal immunoglobulin and does not meet previously defined haematological criteria for treatment of a specific malignancy. The diagnosis of MGRS-related disease is established by kidney biopsy and immunofluorescence studies to identify the monotypic immunoglobulin deposits (although these deposits are minimal in patients with either C3 glomerulopathy or thrombotic microangiopathy). Accordingly, the IKMG recommends a kidney biopsy in patients suspected of having MGRS to maximize the chance of correct diagnosis. Serum and urine protein electrophoresis and immunofixation, as well as analyses of serum free light chains, should also be performed to identify the monoclonal immunoglobulin, which helps to establish the diagnosis of MGRS and might also be useful for assessing responses to treatment. Finally, bone marrow aspiration and biopsy should be conducted to identify the lymphoproliferative clone. Flow cytometry can be helpful in identifying small clones. Additional genetic tests and fluorescent in situ hybridization studies are helpful for clonal identification and for generating treatment recommendations. Treatment of MGRS was not addressed at the 2017 IKMG meeting; consequently, this Expert Consensus Document does not include any recommendations for the treatment of patients with MGRS.
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http://dx.doi.org/10.1038/s41581-018-0077-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7136169PMC
January 2019

Fatal Hypermagnesemia Due to Laxative Use.

Am J Med Sci 2018 Apr 12;355(4):390-395. Epub 2017 Sep 12.

Tulane University School of Medicine, New Orleans, Louisiana.; Southeast Louisiana Veterans Healthcare System, New Orleans, Louisiana.. Electronic address:

We report a case of fatal hypermagnesemia in a 53-year-old woman admitted for acute exacerbation of chronic obstructive pulmonary disease and with a history of chronic constipation treated regularly with magnesium-containing laxatives. On admission, her magnesium level was 2.0mg/dL, which rose to a peak of 10.8mg/dL despite hydration and diuresis in the presence of a normal kidney function. Continuous renal replacement therapy was promptly initiated, which reduced her serum magnesium levels, but her condition continued to deteriorate precipitously progressing to shock leading to oligoanuric renal failure, and she died 2 days later. A review of the literature shows that though rare and often unsuspected, severe hypermagnesemia frequently results in death even in individuals with normal renal function despite renal replacement therapy. In patients with constipation, retention of magnesium-based laxative in the gut apparently serves as a reservoir for continuous magnesium absorption and contributes to mortality.
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http://dx.doi.org/10.1016/j.amjms.2017.08.013DOI Listing
April 2018

Animal models of monoclonal immunoglobulin-related renal diseases.

Nat Rev Nephrol 2018 04 19;14(4):246-264. Epub 2018 Feb 19.

CNRS UMR 7276-CRIBL, University of Limoges, Limoges, France, and French National Reference Centre for "AL Amyloidosis and Other Monoclonal Immunoglobulin Deposition Diseases", University Hospital Dupuytren, Limoges, France.

The renal deposition of monoclonal immunoglobulins can cause severe renal complications in patients with B cell and plasma cell lymphoproliferative disorders. The overproduction of a structurally unique immunoglobulin can contribute to the abnormal propensity of monoclonal immunoglobulins to aggregate and deposit in specific organs. A wide range of renal diseases can occur in multiple myeloma or monoclonal gammopathy of renal significance, including tubular and glomerular disorders with organized or unorganized immunoglobulin deposits. The development of reliable experimental models is challenging owing to the inherent variability of immunoglobulins and the heterogeneity of the pathologies they produce. However, although imperfect, animal models are invaluable tools to understand the molecular pathogenesis of these diseases, and advances in creating genetically modified animals might provide novel approaches to evaluate innovative therapeutic interventions. We discuss the strategies employed to reproduce human monoclonal immunoglobulin-induced kidney lesions in animal models, and we highlight their advantages and shortcomings. We also discuss how these models have affected the management of these deposition diseases and might do so in the future. Finally, we discuss hypotheses that explain some limitations of the various models, and how these models might improve our understanding of other nephropathies without immunoglobulin involvement that have similar pathogenic mechanisms.
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http://dx.doi.org/10.1038/nrneph.2018.8DOI Listing
April 2018

Paraprotein-Related Kidney Disease: Kidney Injury from Paraproteins-What Determines the Site of Injury?

Clin J Am Soc Nephrol 2016 12 15;11(12):2288-2294. Epub 2016 Aug 15.

Department of Medicine, Nephrology Research and Training Center and

Disorders of plasma and B cells leading to paraproteinemias are associated with a variety of renal diseases. Understanding the mechanisms of injury and associated nephropathies provides a framework that aids clinicians in prompt diagnosis and appropriate adjunctive treatment of these disorders. Glomerular diseases that may be associated with paraproteinemias include amyloid deposition, monoclonal Ig deposition disease, proliferative GN with monoclonal Ig deposits, C3 glomerulopathy caused by alterations in the complement pathway, immunotactoid glomerulopathy, fibrillary GN, and cryoglobulinemia. Tubular lesions include the classic Fanconi syndrome, light-chain proximal tubulopathy, interstitial fibrosis, and cast nephropathy. These paraproteinemic renal diseases are distinct in their pathogenesis as well as their urinary and kidney biopsy findings. Renal pathology is usually initiated by deposition and direct involvement of the intact monoclonal Ig or Ig fragments with resident cells of the nephron. Our review summarizes current insights into the underlying molecular pathogenesis of these interesting kidney lesions.
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http://dx.doi.org/10.2215/CJN.02560316DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5142058PMC
December 2016

Anemia and risk for cognitive decline in chronic kidney disease.

BMC Nephrol 2016 Jan 28;17:13. Epub 2016 Jan 28.

Department of Epidemiology and Biostatistics, University of California San Francisco, San Francisco, CA, USA.

Background: Anemia is common among patients with chronic kidney disease (CKD) but its health consequences are poorly defined. The aim of this study was to determine the relationship between anemia and cognitive decline in older adults with CKD.

Methods: We studied a subgroup of 762 adults age ≥55 years with CKD participating in the Chronic Renal Insufficiency Cohort (CRIC) study. Anemia was defined according to the World Health Organization criteria (hemoglobin <13 g/dL for men and <12 g/dL for women). Cognitive function was assessed annually with a battery of six tests. We used logistic regression to determine the association between anemia and baseline cognitive impairment on each test, defined as a cognitive score more than one standard deviation from the mean, and mixed effects models to determine the relation between anemia and change in cognitive function during follow-up after adjustment for demographic and clinical characteristics.

Results: Of 762 participants with mean estimated glomerular filtration rate of 42.7 ± 16.4 ml/min/1.73 m(2), 349 (46 %) had anemia. Anemia was not independently associated with baseline cognitive impairment on any test after adjustment for demographic and clinical characteristics. Over a median 2.9 (IQR 2.6-3.0) years of follow-up, there was no independent association between anemia and change in cognitive function on any of the six cognitive tests.

Conclusions: Among older adults with CKD, anemia was not independently associated with baseline cognitive function or decline.
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http://dx.doi.org/10.1186/s12882-016-0226-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4730636PMC
January 2016

Association of C-reactive protein, tumor necrosis factor-alpha, and interleukin-6 with chronic kidney disease.

BMC Nephrol 2015 May 30;16:77. Epub 2015 May 30.

Department of Medicine, Tulane University School of Medicine, New Orleans, LA, USA.

Background: We studied the association of inflammatory biomarkers including C-reactive protein (CRP), tumor necrosis factor-alpha (TNF-α), and interleukin-6 (IL-6) with chronic kidney disease (CKD).

Methods: We conducted a case-control study among 201 CKD patients and 201 community-based controls in the greater New Orleans area. CKD was defined as estimated-glomerular filtration rate (eGFR) <60 mL/min/1.73 m(2) or albuminuria ≥30 mg/24-h. Serum CRP, TNF-α, and IL-6 were measured using standard methods. Multivariable regression models were used to examine associations between the inflammatory biomarkers and CKD adjusting for important CKD risk factors, history of cardiovascular disease, and use of antihypertensive, antidiabetic, and lipid-lowering agents and aspirin.

Results: The multivariable-adjusted medians (interquartile-range) were 2.91 (1.47, 5.24) mg/L in patients with CKD vs. 1.91 (0.99, 3.79) mg/L in controls without CKD (p = 0.39 for group difference) for CRP; 1.86 (1.51, 2.63) pg/mL vs. 1.26 (1.01, 1.98) pg/mL (p < 0.0001) for TNF-α; and 2.53 (1.49, 4.42) pg/mL vs. 1.39 (0.95, 2.15) pg/mL (p = 0.04) for IL-6, respectively. Compared to the lowest tertile, the highest tertile of TNF-α (OR 7.1, 95% CI 3.2 to 15.5) and IL-6 (OR 2.5, 95% CI 1.1 to 5.5) were significantly associated with higher odds of CKD in multivariable-adjusted models. Additionally, higher TNF-α and IL-6 were independently and significantly associated with lower eGFR and higher albuminuria.

Conclusions: Our data suggest that TNF-α and IL-6, but not CRP, are associated with the prevalence and severity of CKD, independent from established CKD risk factors, history of cardiovascular disease, and use of antihypertensive, antidiabetic, and lipid-lowering agents and aspirin.
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http://dx.doi.org/10.1186/s12882-015-0068-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4449580PMC
May 2015

Non-diabetic renal disease in diabetic patients: How to identify? When to biopsy?

J Diabetes Complications 2015 Jul 25;29(5):613-4. Epub 2015 Apr 25.

Southeast Louisiana Veterans Healthcare System and, Tulane University Medical School, New Orleans, LA 70112. Electronic address:

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http://dx.doi.org/10.1016/j.jdiacomp.2015.04.015DOI Listing
July 2015

Sodium and cardiovascular disease.

Authors:
Vecihi Batuman

N Engl J Med 2014 11;371(22):2134-5

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http://dx.doi.org/10.1056/NEJMc1412113DOI Listing
November 2014

Salt and hypertension: why is there still a debate?

Authors:
Vecihi Batuman

Kidney Int Suppl (2011) 2013 Dec;3(4):316-320

Section of Nephrology and Hypertension, Southeast Louisiana Veterans Healthcare System, Tulane University Medical School , New Orleans, Louisiana, USA.

More than a quarter of human populations now suffer from hypertension paralleling the marked increase in the dietary intake of salt during the recent several decades. Despite overwhelming experimental and epidemiological evidence, some still debate the relation between salt and hypertension. Pointing to some conflicting data in a few flawed studies, they argue that policy interventions to reduce the dietary intake of salt are premature and maybe unsafe without further studies. A brief review of data relating salt intake to hypertension, along with an overview of the history of the introduction of salt to human diet on an historic and evolutionary time scale, should help dispel doubts on the effectiveness and safety of low-salt diet. The recorded history confirms how rare and inaccessible salt has been until recent times. Like all other terrestrial life forms, humans evolved in a salt-free environment under intense evolutionary pressure for the selection of salt-conserving genes. Hypertension is a prototypical evolutionary maladaptation disorder of the modern man-a species exquisitely well adapted to low salt conditions suddenly confronted with salt excess. The World Health Organization and many governments have finally taken action to reduce dietary intake of salt, which already has started to reduce the burden of hypertension and the associated cardiovascular morbidity and mortality. This brief review is to broadly look at the evidence linking salt to hypertension from a historic and evolutionary perspective as well as touching upon some of the epidemiological and experimental data.
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http://dx.doi.org/10.1038/kisup.2013.66DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4089608PMC
December 2013

Hypertension and chronic kidney disease in Turkey.

Kidney Int Suppl (2011) 2013 Dec;3(4):308-311

Department of Nephrology, Ankara University School of Medicine , Ankara, Turkey.

Worldwide, both hypertension and chronic kidney disease are major public health problems, due to their epidemic proportions and their association with high cardiovascular mortality. In 2003, the first Prevalence, awareness, treatment, and control of hypertension in Turkey (the PatenT) study was conducted in a nationally representative population (=4910) by the Turkish Society of Hypertension and Renal Diseases, and showed that overall age- and sex-adjusted prevalence of hypertension in Turkey was 31.8%. The PatenT study also reported that overall awareness (40.7%), treatment (31.1%), and control rates (8.1%) of hypertension were strikingly low. Only 20.7% of the patients who were aware of their hypertension and receiving treatment had their blood pressure controlled to <140/90 mm Hg. In the Chronic Renal Disease in Turkey (CREDIT) study (=10,748), the overall prevalence of chronic kidney (including all stages) disease was 15.7% and increased with advancing age. In the same population, the prevalence of hypertension, diabetes mellitus, dyslipidemia, obesity, and metabolic syndrome were reported as 32.7%, 12.7%, 76.3%, 20.1%, and 31.3%, respectively. The prevalence and awareness of hypertension in CREDIT population was 32.7% and 48.6%, respectively. According to the data obtained from national surveys, the prevalence of hypertension and chronic kidney disease in Turkey is alarmingly high. To improve prevention, early diagnosis, and treatment of these major public health problems, appropriate health strategies should be implemented by the government, together with medical societies, non-governmental organizations, industry, health-care providers, and academia.
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http://dx.doi.org/10.1038/kisup.2013.64DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4089601PMC
December 2013

The persistence of chronic lead nephropathy.

Am J Kidney Dis 2014 Jul;64(1):1-3

Rutgers University - The New Jersey Medical School, Newark, New Jersey.

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http://dx.doi.org/10.1053/j.ajkd.2014.04.004DOI Listing
July 2014

Incidence and predictive factors of Balkan endemic nephropathy: a longitudinal study.

Saudi J Kidney Dis Transpl 2014 Mar;25(2):343-52

Department of Epidemiology and Biostatistics, University of South Carolina, Columbia, South Carolina, USA.

Balkan endemic nephropathy (BEN) is a chronic kidney disease that progresses slowly. There are no known clinical markers to identify an early disease development. We evaluated the relationship between parental history of BEN and clinical markers as predictors of new occurrences of BEN. A 5-year prospective study in the offsprings of BEN and control patients was conducted in Vratza, Bulgaria, between 2003 and 2009 using markers in years one and three to predict new cases of BEN in the year five. We defined incident cases of BEN based on parental history, reduced kidney size and reduced kidney function, distinguishing probable and definite BEN, both combined as total incidence. The data were analyzed by Cox regression models using age as time scale and controlling for gender. We estimated hazard ratios and their 95% confidence intervals. The incidence of BEN was 17.4%. Paternal history was strongly associated with all three incidence groups (hazards ratio: 27-68, P <0.05). A reduction of kidney size of 1 mm resulted in a 5% increased hazard. However, taking parental history of BEN into account, these associations lost their significance. No kidney function measures were associated with new onset of BEN. A parental history of BEN is more important than clinical markers predicting the incidence of BEN. Without this information, kidney length forecasts probable BEN and the total incidence, while none of any clinical markers was related to definite BEN.
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http://dx.doi.org/10.4103/1319-2442.128539DOI Listing
March 2014

Prostaglandin D2 synthase: Apoptotic factor in alzheimer plasma, inducer of reactive oxygen species, inflammatory cytokines and dialysis dementia.

J Nephropathol 2013 Jul 1;2(3):166-80. Epub 2013 Jul 1.

Department of Anatomy, Cell Biology and Physiological Sciences, American University of Beirut, Beirut, Lebanon.

Background: Apoptosis, reactive oxygen species (ROS) and inflammatory cytokines have all been implicated in the development of Alzheimer's disease (AD).

Objectives: The present study identifies the apoptotic factor that was responsible for the fourfold increase in apoptotic rates that we previously noted when pig proximal tubule, LLC-PK1, cells were exposed to AD plasma as compared to plasma from normal controls and multi-infarct dementia.

Patients And Methods: The apoptotic factor was isolated from AD urine and identified as lipocalin-type prostaglandin D2 synthase (L-PGDS). L-PGDS was found to be the major apoptotic factor in AD plasma as determined by inhibition of apoptosis approximating control levels by the cyclo-oxygenase (COX) 2 inhibitor, NS398, and the antibody to L-PGDS. Blood levels of L-PGDS, however, were not elevated in AD. We now demonstrate a receptor-mediated uptake of L-PGDS in PC12 neuronal cells that was time, dose and temperature-dependent and was saturable by competition with cold L-PGDS and albumin. Further proof of this endocytosis was provided by an electron microscopic study of gold labeled L-PGDS and immunofluorescence with Alexa-labeled L-PGDS.

Results: The recombinant L-PGDS and wild type (WT) L-PGDS increased ROS but only the WTL-PGDS increased IL6 and TNFα, suggesting that differences in glycosylation of L-PGDS in AD was responsible for this discrepancy.

Conclusions: These data collectively suggest that L-PGDS might play an important role in the development of dementia in patients on dialysis and of AD.
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http://dx.doi.org/10.12860/JNP.2013.28DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3891133PMC
July 2013

Pituitary adenylate cyclase-activating polypeptide prevents contrast-induced nephropathy in a novel mouse model.

Physiol Rep 2013 Nov 19;1(6):e00163. Epub 2013 Nov 19.

Department of Medicine, Section of Nephrology and Hypertension, Tulane University School of Medicine New Orleans, Louisiana ; Department of Veterans Affairs, Southeast Louisiana Veterans Health Care System New Orleans, Louisiana.

We determined whether pituitary adenylate cyclase-activating polypeptide 38 (PACAP38) prevents contrast-induced nephropathy using human renal proximal tubule epithelial (HK-2) cells and homozygous endothelial nitric oxide synthase-deficient (eNOS(-/-)) mice as a novel in vivo model. Cultured HK-2 cells were pretreated with 10(-9)-10(-6) mol/L PACAP or vasoactive intestinal peptide (VIP) for 1 h, and then exposed to ionic (Urografin) or nonionic (iohexol) contrast media at 50 mg iodine/mL for 24 h. Male eNOS(-/-) mice received Urografin (1.85 g iodine/kg) intravenously after water deprivation for 24 h, and PACAP38 (10 μg) intraperitoneally 1 h before and 12 h after Urografin injection. Urografin and iohexol increased lactate dehydrogenase and kidney injury molecule 1 in the culture medium, induced apoptosis, and inhibited cell proliferation in HK-2 cell cultures. PACAP38 and VIP reduced these changes in a dose-dependent manner. PACAP38 was more potent than VIP. In eNOS(-/-) mice, Urografin raised serum creatinine and cystatin C levels, caused renal tubule damage, induced apoptosis, and promoted neutrophil influx. Urografin also increased kidney protein levels of proinflammatory cytokines, and kidney mRNA levels of proinflammatory cytokines, kidney injury biomarkers, and enzymes responsible for reactive oxygen and nitrogen species. PACAP38 significantly reduced these Urografin-induced changes in eNOS(-/-) mice. This study shows that both Urografin and iohexol are toxic to HK-2 cells, but Urografin is more toxic than iohexol. Urografin causes acute kidney injury in eNOS(-/-) mice. PACAP38 protects HK-2 cells and mouse kidneys from contrast media and is a potential therapeutic agent for contrast-induced nephropathy.
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http://dx.doi.org/10.1002/phy2.163DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3871477PMC
November 2013

Receptor-associated protein blocks internalization and cytotoxicity of myeloma light chain in cultured human proximal tubular cells.

PLoS One 2013 23;8(7):e70276. Epub 2013 Jul 23.

Department of Nephrology, Ankara University School of Medicine, Ankara, Turkey.

Background: Free light chains (LCs) are among the many ligands that bind to cubilin/megalin for endocytosis via the clathrin-dependent endosomal/lysosomal pathway. Receptor associated protein (RAP), is a 39 kDA high-affinity, chaperone-like ligand for megalin that assists in the proper folding and functioning of megalin/cubilin. Although RAP is known to inhibit ligand binding to megalin/cubilin, its effect on LC endocytosis has not been shown directly.

Methods And Principal Findings: We investigated whether RAP can block the endocytosis of LC in cultured human proximal tubule cells and whether this can prevent LC cytotoxicity. Immunofluorescence microscopy and flow cytometry showed that fluorescently labeled LC endocytosis was markedly inhibited in HK-2 cells pretreated with human RAP. The effect of RAP was dose-dependent, and was predominantly on endocytosis as it had no effect on the small acid-washable fraction of LC bound to cell membrane. RAP significantly inhibited LC induced cytokine production and phosphorylation of ERK1/2 and p38 MAPK. Prolonged exposure to LC for 48 h resulted in epithelial-to-mesenchymal transformation in HK-2 cells as evidenced by marked reduction in the expression of the epithelial cell marker E-cadherin, and increased the expression of the mesenchymal marker α-SMA, which was also prevented by RAP in the endocytosis medium.

Conclusions: RAP inhibited LC endocytosis by ∼88% and ameliorated LC-induced cytokine responses and EMT in human PTCs. The results not only provide additional evidence that LCs endocytosis occurs via the megalin/cubilin endocytic receptor system, but also show that blocking LC endocytosis by RAP can protect proximal tubule cells from LC cytotoxicity.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0070276PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3720907PMC
March 2014

Delayed administration of pituitary adenylate cyclase-activating polypeptide 38 ameliorates renal ischemia/reperfusion injury in mice by modulating Toll-like receptors.

Peptides 2012 Dec 28;38(2):395-403. Epub 2012 Sep 28.

Division of Nephrology and Hypertension, Department of Medicine, Tulane University, School of Medicine, New Orleans, LA 70112, USA.

We investigated whether pituitary adenylate cyclase-activating polypeptide 38 (PACAP38) ameliorates kidney injury after ischemia/reperfusion (IR) by modulating Toll-like receptor (TLR)-associated signaling pathways. Male C57BL/6 mice were subjected to bilateral renal ischemia for 45 min. PACAP38, 20 μg in 100 μl of saline, was administered i.p. at 24 and 48 h after IR, and mice were euthanized at 72h. In IR mice, PACAP38 maintained serum creatinine near control levels (0.81 ± 0.08 vs. 0.69 ± 0.17 mg/dl in controls, p=NS, vs. 1.8 ± 0.03 in saline-treated IR mice, p<0.01) and significantly reduced the expression of kidney injury biomarkers. PACAP38 significantly reduced the levels of apoptosis and neutrophil infiltration, and protected against tubular damage. With PCR arrays, 59 of 83 TLR-related genes significantly changed their expression after IR. TLR2 increased 162 fold, followed by Fas-associated death domain (37 fold) and TLR6 (24 fold), while ubiquitin-conjugating enzyme E2 variant 1 (UBE2V1) decreased 55 fold. PACAP38 given 24 and 48 h after IR injury significantly reversed these changes in 56 genes, including TLR2, TLR3, TLR4, TLR6, and genes in the NF-κB pathways. The alterations in TLR2, TLR3, TLR6, and UBE2V1 were confirmed by RT-PCR. After IR, PACAP38 also suppressed protein levels of TLR-associated cytokines. PACAP38 reversed the changes in IR-activated TLR-associated NF-κB signaling pathways even when treatment was delayed 24h. Therefore, PACAP38 could be an effective therapeutic for unexpected IR-mediated renal injury. The prominently IR-induced TLR-related genes identified in this study could be novel drug targets.
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http://dx.doi.org/10.1016/j.peptides.2012.09.023DOI Listing
December 2012

The pathogenesis of acute kidney impairment in patients with multiple myeloma.

Authors:
Vecihi Batuman

Adv Chronic Kidney Dis 2012 Sep;19(5):282-6

Section of Nephrology and Hypertension, Department of Medicine, Tulane University School of Medicine, New Orleans, LA 70112, USA.

Acute kidney injury in myeloma, a serious complication associated with poor prognosis, is generally mediated by the toxic and inflammatory effects of monoclonal free light chains (FLCs) on kidney proximal tubule cells and by the formation of intratubular casts through interaction with Tamm-Horsfall proteins. Production of excessive quantities of FLCs is seen in most cases of FLC-associated kidney injury, although a direct relation between quantity and nephrotoxicity does not exist, indicating variable toxicity among light chain species. Toxic effects of FLCs include inhibition of transport functions, Fanconi syndrome, generation of reactive oxygen species, cytoskeletal abnormalities, and apoptosis and necrosis in proximal tubule cells. Excessive endocytosis of FLCs in proximal tubule cells also induces cell stress responses that result in stimulation of inflammatory pathways through activation of nuclear transcription factors κB and mitogen-activated protein kinases, induction of proinflammatory cytokines, and epithelial to mesenchymal transition. The mechanisms of nephrotoxicity of FLC described here explain the basis of acute kidney injury seen in patients with multiple myeloma and provide the rationale for eliminating or reducing the FLC burden in myeloma patients with renal involvement. The inflammatory pathways that are activated as a result of FLC toxicity also show clearly how severe chronic tubulointerstitial nephritis can occur in patients with myeloma kidney and identify several attractive opportunities for novel therapeutic interventions.
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http://dx.doi.org/10.1053/j.ackd.2012.04.009DOI Listing
September 2012

Renal ischemia and transplantation predispose to vascular constriction mediated by angiotensin II type 1 receptor-activating antibodies.

Transplantation 2012 Jul;94(1):8-13

Medical Clinic for Nephrology and Internal Intensive Care, Charité Campus Virchow Klinikum, Berlin, Germany.

Background: We previously described angiotensin II type 1 receptor-activating antibodies (AT1R-Abs) in renal transplant recipients with vascular rejection and malignant hypertension. In this study, we tested the hypothesis that AT1R-Abs can cause renal artery contraction by AT1R activation with renal ischemia representing a key permissive factor and therefore contribute to renal pathologic condition.

Methods: Isolated renal and mesenteric arteries from Lewis rats were incubated with purified AT1R-Abs from patients with human leukocyte antigen antibody-negative vascular rejection. Vascular contraction was measured using small vessel myography. The measurements were repeated with renal arteries derived from native kidneys subjected to ischemia-reperfusion or after transplantation in a low-responder Fischer 344-to-Lewis rat kidney-transplantation model.

Results: AT1R-Abs acted in a vascular bed-specific manner and caused small contractions only in native rat renal arteries but not in mesenteric arteries. AT1R-Abs did not alter the vascular reactivity to phenylephrine, angiotensin II, or acetylcholine in native renal arteries. In contrast, AT1R-Abs caused a pronounced (>10-fold) contraction of renal arteries after ischemia and after allogeneic transplantation. Pretreatment with pharmacologic AT1R blocker only partially inhibited the AT1R-Abs-induced contraction, which was almost completely abolished by neutralizing peptides targeting epitopes of AT1R-Abs on the second loop of AT1R.

Conclusions: These data demonstrate that AT1R-Abs can induce renal vascular contraction under predisposing conditions such as in ischemic or transplanted kidneys. Neutralizing antibodies against specific epitopes in the AT1R can ameliorate this contraction.
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http://dx.doi.org/10.1097/TP.0b013e3182529bb7DOI Listing
July 2012

The role of a parental history of Balkan endemic nephropathy in the occurrence of BEN: a prospective study.

Int J Nephrol Renovasc Dis 2012 4;5:61-8. Epub 2012 Apr 4.

Department of Epidemiology and Biostatistics, University of South Carolina, Columbia, SC, USA.

Balkan endemic nephropathy (BEN) is a chronic kidney disease that affects persons living in the Balkans. Despite the unique geographical specificity of this disease, its etiology has remained unclear. Even if a positive family history of BEN has been identified, it is still uncertain how the disease develops in offspring. In this paper, we examine clinical mechanisms related to the onset of BEN in individuals who have a parental history of BEN to identify early detection of the disease and formulate interventions. We conducted a 5-year prospective study, using markers in years one and three to predict new cases of BEN in year five. New cases of BEN were defined based on three criteria: parental history of BEN, reduced kidney size, and reduced kidney function. Incident cases were divided into (1) probable, (2) definite, and (3) combined labeled total incidence. We evaluated parental history in relation to BEN and tested the potentially intervening effects of kidney length, kidney cortex width, β(2)-microglobulin, C-reactive protein, and creatinine clearance, using path analyses. The findings of the path analyses suggested that parental history of BEN had both direct and indirect effects. The direct effect was significant for all three modes of parental history (biparental, maternal, and paternal; odds ratios 71.5, 52.3, and 50.1, respectively). The indirect effects of maternal BEN acted via kidney length and creatinine clearance. Biparental BEN was mediated by (1) kidney length and creatinine clearance, and (2) creatinine clearance alone. Paternal BEN had three indirect effects: (1) through kidney length and creatinine clearance, (2) via kidney cortex width and creatinine clearance, and (3) via kidney cortex width only. In conclusion, a family history of BEN led to reduced kidney length and cortex width, and a decline in creatinine clearance, which in turn predicted the onset of BEN.
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http://dx.doi.org/10.2147/IJNRD.S30615DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3333804PMC
October 2012

Increased urinary excretion of angiotensinogen is associated with risk of chronic kidney disease.

Nephrol Dial Transplant 2012 Aug 6;27(8):3176-81. Epub 2012 Mar 6.

Department of Epidemiology, Tulane University School of Public Health and Tropical Medicine, New Orleans, LA, USA.

Background: The effect of intrarenal renin-angiotensin system (RAS) activity on risk of chronic kidney disease (CKD) has not been well studied in human subjects.

Methods: We investigated the association between urinary angiotensinogen, a reliable biomarker of intrarenal RAS activity, and risk of CKD in 201 patients and 201 controls. CKD was defined as estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73 m(2) or presence of albuminuria ( ≥ 30 mg/24 h).

Results: Compared to controls, median urinary angiotensinogen excretion (45.4 versus 7.4 μg/24 h, P < 0.0001) and angiotensinogen-to-creatinine ratio (26.3 versus 4.4 μg/g, P < 0.0001) were significantly higher in patients with CKD. Log-transformed urinary angiotensinogen excretion and angiotensinogen-to-creatinine ratio were inversely correlated with eGFR (r = -0.59 and -0.57, both P < 0.0001) and positively correlated with log-transformed urinary albumin excretion (r = 0.89 and 0.87, both P < 0.0001). After adjusting for multiple covariables, including the use of angiotensin-converting enzyme inhibitors and/or angiotensin II receptor blockers, diuretics and statins, the odds ratios (95% confidence interval) for CKD comparing the highest tertile to the lowest two tertiles of urinary angiotensinogen excretion and angiotensinogen-to-creatinine ratio were 6.70 (3.43, 13.1; P < 0.0001) and 6.45 (3.34, 12.4; P < 0.0001), respectively.

Conclusions: These data indicate the intrarenal RAS may play an important role in the etiology of CKD, and urinary angiotensinogen may be a useful clinical biomarker for the identification of patients at a high risk for CKD.
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http://dx.doi.org/10.1093/ndt/gfs011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3408937PMC
August 2012

The pathogenesis and diagnosis of acute kidney injury in multiple myeloma.

Nat Rev Nephrol 2011 Nov 1;8(1):43-51. Epub 2011 Nov 1.

Renal Institute of Birmingham, University Hospital Birmingham and University of Birmingham, Birmingham, UK.

Renal failure remains a principal cause of morbidity for patients with multiple myeloma. Once reversible factors such as hypercalcemia have been corrected, the most common cause of severe renal failure in these patients is a tubulointerstitial pathology that results from the very high circulating concentrations of monoclonal immunoglobulin free light chains. These endogenous proteins can result in isolated proximal tubule cell cytotoxicity, tubulointerstitial nephritis and cast nephropathy (myeloma kidney). Less frequently, high levels of free light chains can lead to immunoglobulin light chain amyloidosis and light chain deposition disease, although these conditions are usually associated with insidious progression of renal failure rather than acute kidney injury. Unless there is rapid intervention, progressive and irreversible damage occurs, particularly interstitial fibrosis and tubular atrophy. Despite advances in our understanding of the pathogenesis of these processes there has been a gap in translating these achievements into improved patient outcomes. The International Kidney and Monoclonal Gammopathy Research Group was formed to address this need. In this Review, we discuss the mechanisms of disease and diagnostic approaches to patients with acute kidney injury complicating multiple myeloma.
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http://dx.doi.org/10.1038/nrneph.2011.168DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3375610PMC
November 2011

Renoprotection with pituitary adenylate cyclase-activating polypeptide in cyclosporine A-induced nephrotoxicity.

J Investig Med 2011 Jun;59(5):793-802

Section of Nephrology and Hypertension, Department of Medicine, Tulane University School of Medicine, New Orleans, LA 70112-2632, USA.

Background: Acute and long-term nephrotoxicity is the major dose-limiting factor for cyclosporine A (CsA). We evaluated the protective effects of pituitary adenylate cyclase-activating polypeptide (PACAP)38 on CsA-induced nephrotoxicity in human renal proximal tubule epithelial (human kidney-2) cells and in intact mice.

Methods: Confluent (human kidney-2 cells were exposed to CsA (25-50 μmol/L) in the presence or absence of PACAP38 or vasoactive intestinal peptide (10(-10) to 10(-6) M). For studies in vivo, male BALB/c mice (n = 5 in each group) were given a single intraperitoneal injection of CsA (5 mg/kg body weight). Treatment group received 20 μg of PACAP38 2 hours before exposure to CsA and additional doses daily for 10 days.

Results: Cyclosporine A caused oxidative injury, marked morphological alterations, apoptosis, and increased expression of transforming growth factor (TGF)-β1 in cell cultures. Pituitary adenylate cyclase-activating polypeptide 38 at 10(-8) mol/L restored cell confluency, reduced TGF-β1 secretion, and preserved cell integrity. In mice, CsA caused tubular injury characterized by loss of tubular epithelial cell brush border membranes, tubular collapse, cellular necrosis, interstitial fibrosis, increased production of TGF-β1, and elevated serum creatinine (3.39 ± 0.21 vs 0.13 ± 0.02 mg/dL in controls, P < 0.01). Treatment with PACAP38 reduced TGF-β1 and tumor necrosis factor-α production in kidney, prevented epithelial-mesenchymal transition of the renal cells, and reduced serum creatinine levels to 1.01 ± 0.18 mg/dL, P < 0.01 versus CsA group.

Conclusions: Pituitary adenylate cyclase-activating polypeptide 38 ameliorated renal tubular injury, reduced oxidative injury, and inhibited the expression of TGF-β1 in CsA-exposed murine kidneys. Pituitary adenylate cyclase-activating polypeptide could be a novel renoprotective and antifibrotic agent for CsA nephrotoxicity.
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http://dx.doi.org/10.2310/JIM.0b013e31821452a2DOI Listing
June 2011

Role of proximal tubules in the pathogenesis of kidney disease.

Contrib Nephrol 2011 20;169:37-50. Epub 2011 Jan 20.

The proximal tubules make up a significant portion of the kidneys; proximal tubule epithelial cells are the most populous cell type in the kidney, and carry out diverse regulatory and endocrine functions where numerous transporters are located. Under normal circumstances, more than two thirds of filtered salt and water, and all filtered bicarbonate is reabsorbed in the proximal tubule. A number of inherited and acquired acid-base and tubule disorders are linked to impaired transporters in the proximal tubule cells. Equally important is the intrinsic immune characteristics of proximal tubule cells that give them the ability to also function as immune responders to a wide range of immunologic, ischemic or toxic injury. It is therefore not surprising that proximal tubule-related phenomena are closely related to the pathogenesis of a vast array of kidney diseases. Many kidney diseases, acute and chronic, first manifest with proximal tubule disorders. Recent insight into molecular characteristics of transport functions in the proximal tubules, and the recognition that proximal tubule cells possess intrinsic immune responses have contributed to an improved understanding of important areas in nephrology, such as Fanconi's syndrome, renal tubular acidosis, phosphate wasting syndromes, Dent's disease, cystinuria and other amino acid transport disorders, acute kidney injury, and the role of proximal tubules in progressive kidney disease. Megalin/ cubilin-mediated endocytosis by proximal tubule cells of increased quantities of filtered proteins (protein overloading) in glomerular diseases appears to evoke cell stress responses resulting in increased inflammatory cytokines leading to tubulointerstitial inflammation and fibrosis. Finally, the proximal tubule may be the site of both active vitamin D synthesis through the action of 1-α-hydroxylase, and the site where erythropoietin synthesis takes place. Thus, proximal tubule injury also contributes to two distressing consequences of chronic kidney disease: mineral-bone disorder and anemia.
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http://dx.doi.org/10.1159/000313944DOI Listing
June 2011

Emergence of biomarkers in nephropharmacology.

Biomark Med 2010 Dec;4(6):805-14

Tulane University Medical School, Department of Medicine, Nephrology Section 1430 Tulane Avenue, New Orleans, LA, USA.

Blood-urea nitrogen, serum creatinine and urine output have long been used as markers of kidney function despite their known limitations. In the past few years, a number of novel biomarkers have been identified in the urine and blood that can detect kidney injury early. Although, to date, none of these biomarkers are in clinical use, many have been validated as reliable and sensitive, allowing detection of kidney injury before serum creatinine levels rise and urine output drops. These markers have been evaluated in great detail in animal models and to a lesser extent in humans in postcardiopulmonary bypass and sepsis. There is relatively scarse data on the use of these biomarkers in the detection of kidney injury associated with the use of pharmacologic agents. The purpose of this article is to summarize these data and highlight the potential utility of these biomarkers in nephropharmacology.
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http://dx.doi.org/10.2217/bmm.10.115DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3041514PMC
December 2010

The effect of PACAP38 on MyD88-mediated signal transduction in ischemia-/hypoxia-induced acute kidney injury.

Am J Nephrol 2010 28;32(6):522-32. Epub 2010 Oct 28.

Section of Nephrology and Hypertension, Department of Medicine, Tulane University School of Medicine, New Orleans, La., 70112 USA.

Background/aims: toll-like receptor 4 (TLR4) and its adaptor protein MyD88 play an important role in ischemia/reperfusion (I/R) injury in the kidney, and pituitary adenylate cyclase-activating polypeptide (PACAP) could ameliorate renal I/R injury.

Methods: primary cultures of proximal tubule epithelial cells (PTEC) were prepared from wild-type and MyD88(-/-) mice, and subjected to hypoxia in vitro. Acute kidney injury (AKI) was induced by I/R in vivo in wild-type mice only.

Results: hypoxia resulted in significant increases in cytokine production and apoptosis/necrosis in wild-type PTEC, but these responses were markedly blunted in MyD88(-/-) PTEC. Treatment with PACAP38 before or after hypoxia further suppressed the hypoxia-induced cytokine responses and apoptosis in both MyD88(+/+) and MyD88(-/-) PTEC cultures. PACAP38 significantly inhibited TLR4/MyD88/TRAF6 as well as TRIF and IRF3 expression in mouse kidney and PTEC, and inhibited the secretion and mRNA expression of cytokines in kidneys from mice after I/R, paralleling the cytokine responses in vitro. Moreover, treatment with PACAP38 protected mice from renal failure, histological damage, neutrophil influx and tubule cell apoptosis after I/R.

Conclusion: our data reveal that the TLR4-mediated cytokine responses to hypoxia are primarily dependent on MyD88 signaling and highlight the pivotal role of MyD88-dependent mechanisms in the coordination of the innate immune responses to ischemic/hypoxic acute renal tubular injury. The renoprotective effect of PACAP in AKI involves both MyD88-dependent and -independent pathways.
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http://dx.doi.org/10.1159/000321491DOI Listing
April 2011

Myeloma light chain-induced renal injury in mice.

Nephron Exp Nephrol 2010 29;116(2):e32-41. Epub 2010 Jun 29.

Section of Nephrology and Hypertension, Department of Medicine, Tulane University School of Medicine, New Orleans, La 70112, USA.

We investigated the effects of human light chain (LC) protein-overload in mice kidney to gain further insights into the molecular mechanisms involved in the pathogenesis of myeloma kidney. Intact male C57BL/6, 10- to 12-week-old mice were given daily intraperitoneal (i.p.) injections of 1 ml of human κ-LCs (1.5 mg/ml, low dose), or (100 mg/ml, high dose) to uninephrectomized mice for 2 weeks. Intact, sham-operated or uninephrectomized control animals were given the same volume (1 ml/day) of saline, human serum albumin (10 mg/ml) or bovine serum albumin (100 mg/ml) i.p. for 2 weeks in place of LCs. The low-dose LC-treated mice had human LCs in their urine and a significant increase in monocyte chemoattractant protein-1 (MCP-1) mRNA in the kidneys. Uninephrectomized mice treated with high-dose κ-LCs showed tubule casts, and foci of intracytoplasmic rhomboid crystals within the proximal tubules, along with cytoskeletal disruptions and alterations in the brush-border membrane, and high concentrations of human κ-LC were present in their sera. High-dose LC treatment also led to increases in serum creatinine and tumor necrosis factor-α levels, and marked increases in interleukin-6 and MCP-1 expression as well as cellular apoptosis in the kidneys. These studies demonstrate that myeloma LC overload over a range of LC concentrations in mice causes significant functional and morphological kidney injury. The model should be helpful in investigating pathophysiologic mechanisms and exploring therapeutic interventions for myeloma kidney and other LC-associated renal disorders.
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http://dx.doi.org/10.1159/000317129DOI Listing
January 2011

Reduced kidney size in adult offspring of Balkan endemic nephropathy patients and controls: a prospective study.

Am J Med Sci 2010 Aug;340(2):94-102

Department of Epidemiology and Biostatistics, University of South Carolina, Columbia, USA.

Introduction: Reduced kidney size has been proposed as a criterion for clinical diagnosis of Balkan endemic nephropathy (BEN). Some studies suggest that smaller kidneys are found in advanced stages of BEN, whereas others reported them in earlier stages. To investigate the clinical course of kidney sizes in the offspring of BEN and non-BEN parents, we followed up a cohort of adult offspring over 5 years. We hypothesized that parental history affects kidney dimensions.

Methods: Four repeated ultrasound measurements of kidney length and cortex width were conducted in 121 offspring of BEN and 98 offspring of non-BEN parents. Repeated measurements were analyzed using mixed models adjusting for gender and time-dependent information on other kidney diseases, diabetes, age, height and year of follow-up.

Results: A reduction of kidney length was associated with maternal BEN (-4 mm, P = 0.001). We detected a parallel decline in kidney length in the various offspring groups. However, kidney cortex width was significantly smaller when both parents or the mother had BEN and offspring age > or =60 years (-1.88 mm, P = 0.0003; -1.03 mm, P = 0.05). In the 5th year of follow-up, 37 participants developed BEN (14 confirmed, 23 suspected). Kidney cortex width at baseline was smaller in offspring who developed BEN (P = 0.0001).

Conclusions: The development of kidney dimensions depends on the parental BEN status and offspring age. In BEN offspring, ultrasound measurements of the kidney cortex width seem to have a prognostic value.
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http://dx.doi.org/10.1097/MAJ.0b013e3181e2353eDOI Listing
August 2010