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26.  Renal function, uraemia and early arteriovenous fistula failure 
BMC Nephrology  2014;15(1):179.
Guidance varies regarding the optimal timing of arteriovenous fistula (AVF) creation. The aim of this study was to evaluate the association between uraemia, haemodialysis and early AVF failure.
Immunoblotting and cell proliferation assays were performed on vascular smooth muscle cells (VSM) cells isolated from long saphenous vein samples to evaluate the cells’ ability to proliferate when stimulated with uraemic (post-dialysis) and hyperuraemic (pre-dialysis) serum. Clinical data was collected prospectively for 569 consecutive radiocephalic (RCF) and brachiocephalic (BCF) fistulae. The primary outcome was AVF failure at 6 weeks. Dialysis status (haemodialysis (HD); pre-dialysis (Pre-D)), eGFR and serum urea were evaluated to determine if they affected early AVF failure.
Human VSM cells demonstrated increased capacity to proliferate when stimulated with hyperuraemic serum. There was no significant difference in early failure rate of either RCF or BCF depending on dialysis status (pre-D RCF 31.4% (n = 188); pre-D BCF 22.4% (n = 165); HD RCF 29.3% (n = 99); HD BCF 25.9% (n = 116); p = 0.34). There was no difference in mean eGFR between those patients with early AVF failure and those without (11.2+/-0.2 ml/min/1.73 m2 vs. 11.6+/-0.4 ml/min/1.73 m2; p = 0.47). Uraemia was associated with early AVF failure (serum urea: 35.0+/-0.7 mg/dl vs. 26.6+/-0.3 mg/dl (p < 0.001)).
We present the first in vivo evidence of an association between adverse early AVF outcomes and uraemia. This is supported mechanistically by in vitro work demonstrating a pro-mitogenic effect of hyperuraemic serum. We hypothesise that uraemia-driven upregulation of VSM cell proliferation at the site of surgical insult in contributes to higher early AVF failure rates.
PMCID: PMC4239391  PMID: 25403339
Arteriovenous fistula; Uraemia; Renal function; Maturation; Vascular smooth muscle cells
27.  TL1-A can engage death receptor-3 and activate NF-kappa B in endothelial cells 
BMC Nephrology  2014;15(1):178.
Death receptors (DRs) play an important role in renal pathology. We have shown that DR3 is inducibly expressed on renal tubular epithelial cells in the setting of inflammatory injuries. In this study we investigate the expression of DR3 in renal endothelial cells and their response to TL1A, the only known ligand of DR3.
We did RT-PCR, flow cytometry and subcellular immunoblotting to examine the expression and function of DR3 in cells in vitro. We did organ culture of human and mouse tissue to examine expression and signal of DR3 in vivo.
DR3 is expressed in some interstitial vascular endothelial cells (EC) in human kidney in situ; these EC also respond to its ligand TL1A by activating NF-κB. Very low levels of DR3 can be detected on the cell surface of cultured human umbilical vein (HUV) EC, which do not respond to TL1A. HUVEC transfected to overexpress DR3 become responsive to TL1A, assessed by IκBα degradation and E-selectin induction, indicating that the signaling components needed for DR3 responsiveness are expressed. TL1A induces NF-κB activation in EC in renal and cardiac tissue from wild type but not DR3 knock-out mice.
TL1A and DR3 activate NF-κB in vascular endothelial cells, and can be an important regulator of renal interstitial vascular injury.
Electronic supplementary material
The online version of this article (doi:10.1186/1471-2369-15-178) contains supplementary material, which is available to authorized users.
PMCID: PMC4239315  PMID: 25399326
Kidney; Endothelial cells; Death receptor; Inflammation
28.  Actual versus ideal body weight for acute kidney injury diagnosis and classification in critically Ill patients 
BMC Nephrology  2014;15(1):176.
In the current acute kidney injury (AKI) definition, the urine output (UO) criterion does not specify which body weights (BW), i.e. actual (ABW) versus ideal (IBW), should be used to diagnose and stage AKI, leading to heterogeneity across research studies.
This is a single center, retrospective, observational study conducted at a tertiary referral hospital. All adult patients who were admitted to intensive care units (ICUs) at our institution for a minimum of 6 continuous hours between January and March 2010 and had a urinary catheter for hourly urine output monitoring were eligible for this study. Patients’ AKI stages, based on UO criterion, were assessed by calculating each milliliter of urine per kilogram per hour, using ABW versus IBW.
A total of 493 ICU patients were included in the analysis. The median ABW and IBW were 82 (IQR 68-96) and 70 (IQR 60-77) kg, respectively. Using the IBW criterion, 154 patients (31.2%) were diagnosed with AKI, while 204 (41.4%) were diagnosed using the ABW measurement (P-value < .01). Patients who had AKI regardless of BW type had an adjusted odds ratio of 1.76 (95% CI 1.05-2.95) for 90-day mortality, whereas patients who had AKI according to ABW but not IBW had no significant increase in the risk of 90-day mortality, adjusted OR 0.76; (95% CI 0.25-1.91), compared to patients who had no AKI.
Using ABW to diagnose and stage AKI by UO criterion is more sensitive and less specific than IBW. Based on the application of the definition, different BW types could be utilized.
Electronic supplementary material
The online version of this article (doi:10.1186/1471-2369-15-176) contains supplementary material, which is available to authorized users.
PMCID: PMC4236495  PMID: 25398596
Acute kidney injury; Actual body weight; Ideal body weight; Urine output
29.  Association of physical function with predialysis blood pressure in patients on hemodialysis 
BMC Nephrology  2014;15(1):177.
New information from various clinical settings suggests that tight blood pressure control may not reduce mortality and may be associated with more side effects.
We performed cross-sectional multivariable ordered logistic regression to examine the association between predialysis blood pressure and the short physical performance battery (SPPB) in a cohort of 749 prevalent hemodialysis patients in the San Francisco and Atlanta areas recruited from July 2009 to August 2011 to study the relationship between systolic blood pressure and objective measures of physical function. Mean blood pressure for three hemodialysis sessions was analyzed in the following categories: <110 mmHg, 110-129 mmHg (reference), 130-159 mmHg, and ≥160 mmHg. SPPB includes three components: timed repeated chair stands, timed 15-ft walk, and balance tests. SPPB was categorized into ordinal groups (≤6, 7-9, 10-12) based on prior literature.
Patients with blood pressure 130-159 mmHg had lower odds (OR 0.57, 95% CI 0.35-0.93) of scoring in a lower SPPB category than those whose blood pressure was between 110 and 129 mmHg, while those with blood pressure ≥160 mmHg had 0.56 times odds (95% CI 0.33-0.94) of scoring in a lower category when compared with blood pressure 110-129 mmHg. When individual components were examined, blood pressure was significantly associated with chair stand (130-159 mmHg: OR 0.59, 95% CI 0.38-0.92) and gait speed (≥160 mmHg: OR 0.59, 95% CI 0.35-0.98). Blood pressure ≥160 mmHg was not associated with substantially higher SPPB score compared with 130-159 mmHg.
Patients with systolic blood pressure at or above 130 mmHg had better physical performance than patients with lower blood pressure in the normotensive range. The risk-benefit tradeoff of aggressive blood pressure control, particularly in low-functioning patients, should be reexamined.
PMCID: PMC4247716  PMID: 25399253
Blood pressure; End-stage renal disease; Physical function
30.  Whole exome sequencing reveals novel COL4A3 and COL4A4 mutations and resolves diagnosis in Chinese families with kidney disease 
BMC Nephrology  2014;15(1):175.
Collagen IV-related nephropathies, including thin basement membrane nephropathy and Alport Syndrome (AS), are caused by defects in the genes COL4A3, COL4A4 and COL4A5. Diagnosis of these conditions can be hindered by variable penetrance and the presence of non-specific clinical or pathological features.
Three families with unexplained inherited kidney disease were recruited from Shanghai, China. Whole exome sequencing (WES) was performed in the index case from each family and co-segregation of candidate pathogenic mutations was tested by Sanger sequencing.
We identified COL4A4 missense variants [c.G2636A (p.Gly879Glu) and c.C4715T (p.Pro1572Leu)] in the 21-year-old male proband from family 1, who had been diagnosed with mesangial proliferative nephropathy at age 14. COL4A4 c.G2636A, a novel variant, co-segregated with renal disease among maternal relatives. COL4A4 c.C4715T has previously been associated with autosomal recessive AS and was inherited from his clinically unaffected father. In family 2, a novel COL4A3 missense mutation c.G2290A (p.Gly997Glu) was identified in a 45-year-old male diagnosed with focal segmental glomerulosclerosis and was present in all his affected family members, who exhibited disease ranging from isolated microscopic hematuria to end stage renal disease (ESRD). In family 3, ESRD occurred in both male and females who were found to harbor a known AS-causing COL4A5 donor splice site mutation (c.687 + 1G > A). None of these variants were detected among 100 healthy Chinese individuals.
WES identified 2 novel and 2 known pathogenic COL4A3/COL4A4/COL4A5 mutations in 3 families with previously unexplained inherited kidney disease. These findings highlight the clinical range of collagen IV-related nephropathies and resolved diagnostic confusion arising from atypical or incomplete clinical/histological findings, allowing appropriate counselling and treatment advice to be given.
Electronic supplementary material
The online version of this article (doi:10.1186/1471-2369-15-175) contains supplementary material, which is available to authorized users.
PMCID: PMC4233041  PMID: 25381091
Collagen IV-related nephropathies; Whole exome sequencing; Novel mutation; Misdiagnosis
31.  The glomerular parietal epithelial cell’s responses are influenced by SM22 alpha levels 
BMC Nephrology  2014;15(1):174.
Studies have shown in several diseases initially affecting podocytes, that the neighboring glomerular parietal epithelial cells (PECs) are secondarily involved. The PEC response might be reparative under certain circumstances, yet injurious under others. The factors governing these are not well understood. We have shown that SM22α, an actin-binding protein considered a marker of smooth muscle differentiation, is upregulated in podocytes and PECs in several models of podocyte disease. However, the impact of SM22α levels on PECs is not known.
Experimental glomerular disease, characterized by primary podocyte injury, was induced in aged-matched SM22α +/+ and SM22α -/- mice by intraperitoneal injection of sheep anti-rabbit glomeruli antibody. Immunostaining methods were employed on days 7 and 14 of disease.
The number of PEC transition cells, defined as cells co-expressing a PEC protein (PAX2) and podocyte protein (Synaptopodin) was higher in diseased SM22α -/- mice compared with SM22α +/+ mice. WT1 staining along Bowman’s capsule is higher in diseased SM22α -/- mice. This was accompanied by increased PEC proliferation (measured by ki-67 staining), and an increase in immunostaining for the progenitor marker NCAM, in a subpopulation of PECs in diseased SM22α -/- mice. In addition, immunostaining for vimentin and alpha smooth muscle actin, markers of epithelial-to-mesenchymal transition (EMT), was lower in diseased SM22α -/- mice compared to diseased SM22α+/+ mice.
SM22α levels may impact how PECs respond following a primary podocyte injury in experimental glomerular disease. Absent/lower levels favor an increase in PEC transition cells and PECs expressing a progenitor marker, and a lower EMT rate compared to SM22α +/+ mice, where SM22 levels are markedly increased in PECs.
PMCID: PMC4247743  PMID: 25376243
Regeneration; WT-1; Podocyte; Glomerulus; Progenitor
32.  Increased peritoneal permeability at peritoneal dialysis initiation is a potential cardiovascular risk in patients using biocompatible peritoneal dialysis solution 
BMC Nephrology  2014;15(1):173.
Cardiovascular disease is a frequent cause of death in peritoneal dialysis patients. Biocompatible peritoneal dialysis solutions with neutral pH have been anticipated to reduce cardiovascular disease more than conventional peritoneal dialysis solutions with low pH, but it remains unclear which factors at peritoneal dialysis initiation increase cardiovascular risk in patients using biocompatible peritoneal dialysis solutions. This study was undertaken to investigate which clinical factors at peritoneal dialysis initiation, including peritoneal transport status, are associated with cardiovascular event in patients using biocompatible peritoneal dialysis solution.
This retrospective cohort study of peritoneal dialysis patients using biocompatible solutions with neutral pH assessed relations of clinical parameters at peritoneal dialysis initiation to cardiovascular event during the subsequent five years.
Of 102 patients who started peritoneal dialysis, cardiovascular event occurred in 18. Age, history of cardiovascular disease before peritoneal dialysis initiation, hemoglobin, serum albumin, C-reactive protein, peritoneal permeability defined by the ratio of dialysate to plasma creatinine concentration at 4 hr (D/Pcre) in peritoneal equilibration test (PET), number of patients in each PET category defined by D/Pcre, and peritoneal protein clearance significantly differed between patients with and without cardiovascular event. For patients divided according to PET category using Kaplan–Meier method, the group of high average to high peritoneal transporters exhibited significantly high incidence of cardiovascular event and mortality compared with the groups of low and low-average peritoneal transporters (Log rank; p = 0.0003 and 0.005, respectively). A Cox proportional hazards model showed independent association of PET category classification with cardiovascular event.
Peritoneal permeability expressed as PET category at peritoneal dialysis initiation is an independent cardiovascular risk factor in peritoneal dialysis patients using biocompatible peritoneal dialysis solution with neutral pH. Greater peritoneal permeability at peritoneal dialysis initiation might reflect subclinical vascular disorders.
Electronic supplementary material
The online version of this article (doi:10.1186/1471-2369-15-173) contains supplementary material, which is available to authorized users.
PMCID: PMC4230909  PMID: 25361694
Biocompatible peritoneal dialysis solution; Cardiovascular disease; Peritoneal dialysis; Peritoneal equilibration test; Peritoneal permeability
33.  The incremental treatment of ESRD: a low-protein diet combined with weekly hemodialysis may be beneficial for selected patients 
BMC Nephrology  2014;15(1):172.
Infrequent dialysis, namely once-a-week session combined with very low-protein, low-phosphorus diet supplemented with ketoacids was reported as a useful treatment schedule for ESRD patients with markedly reduced residual renal function but preserved urine output. This study reports our findings from the application of a weekly dialysis schedule plus less severe protein restriction (standard low-protein low-phosphorus diet) in stage 5 CKD patients with consistent dietary discipline.
This is a multicenter, prospective controlled study, including 68 incident CKD patients followed in a pre-dialysis clinic with Glomerular Filtration Rate 5 to 10 ml/min/1.73/ m2 who became unstable on the only medical treatment. They were offered to begin a Combined Diet Dialysis Program (CDDP) or a standard thrice-a-week hemodialysis (THD): 38 patients joined the CDDP, whereas 30 patients chose THD. Patients were studied at baseline, 6 and 12 months; hospitalization and survival rate were followed-up for 24 months.
Volume output and residual renal function were maintained in the CDDP Group while those features dropped quickly in THD Group. Throughout the study, CDDP patients had a lower erythropoietin resistance index, lower β2 microglobulin levels and lower need for cinacalcet of phosphate binders than THD, and stable parameters of nutritional status. At 24 month follow-up, 39.4% of patients were still on CDDP; survival rates were 94.7% and 86.8% for CDDP and THD patients, respectively, but hospitalization rate was much higher in THD than in CDDP patients. The cost per patient per year resulted significantly lower in CDDP than in THD Group.
This study shows that a CDDP served to protect the residual renal function, to maintain urine volume output and to preserve a good nutritional status. CDDP also blunted the rapid β2 microglobulin increase and resulted in better control of anemia and calcium-phosphate abnormalities. CDDP was also associated with a lower hospitalization rate and reduced need of erythropoietin, as well as of drugs used for treatment of calcium-phosphate abnormalities, thus leading to a significant cost-saving. We concluded that in selected ESRD patients with preserved urine output attitude to protein restriction, CDDP may be a beneficial choice for an incremental hemodialysis program.
PMCID: PMC4232716  PMID: 25352299
Nutrition; Low protein diet; Hemodialysis; CKD; ESRD; Incremental dialysis
34.  The RaDIANT community study protocol: community-based participatory research for reducing disparities in access to kidney transplantation 
BMC Nephrology  2014;15(1):171.
The Southeastern United States has the lowest kidney transplant rates in the nation, and racial disparities in kidney transplant access are concentrated in this region. The Southeastern Kidney Transplant Coalition (SEKTC) of Georgia, North Carolina, and South Carolina is an academic and community partnership that was formed with the mission to improve access to kidney transplantation and reduce disparities among African American (AA) end stage renal disease (ESRD) patients in the Southeastern United States.
We describe the community-based participatory research (CBPR) process utilized in planning the Reducing Disparities In Access to kidNey Transplantation (RaDIANT) Community Study, a trial developed by the SEKTC to reduce health disparities in access to kidney transplantation among AA ESRD patients in Georgia, the state with the lowest kidney transplant rates in the nation. The SEKTC Coalition conducted a needs assessment of the ESRD population in the Southeast and used results to develop a multicomponent, dialysis facility-randomized, quality improvement intervention to improve transplant access among dialysis facilities in GA. A total of 134 dialysis facilities are randomized to receive either: (1) standard of care or “usual” transplant education, or (2) the multicomponent intervention consisting of transplant education and engagement activities targeting dialysis facility leadership, staff, and patients within dialysis facilities. The primary outcome is change in facility-level referral for kidney transplantation from baseline to 12 months; the secondary outcome is reduction in racial disparity in transplant referral.
The RaDIANT Community Study aims to improve equity in access to kidney transplantation for ESRD patients in the Southeast.
Trial registration number NCT02092727.
PMCID: PMC4230631  PMID: 25348614
Kidney transplantation; Dialysis facility; Randomized trial; Education; Staff; Community-based participatory research
35.  The incidence and risk factors of acute kidney injury after hepatobiliary surgery: a prospective observational study 
BMC Nephrology  2014;15(1):169.
Although intraperitoneal surgery is a major operation associated with postoperative acute kidney injury (AKI), the incidence, risk factors, and long-term renal outcome are not well known. We aimed to determine the risk factors and 6 months renal outcome in patients with clinical or subclinical AKI after hepatobiliary surgery. We also assessed the validity of urine neutrophil gelatinase-associated lipocalin (NGAL) in the early detection of AKI or prediction of renal outcome.
This prospective observational study enrolled patients with normal renal function who underwent hepatobiliary surgeries. Urine and serum samples were collected for NGAL measurement.
Among 131 patients, 10 (7.6%) developed postoperative AKI. Urine NGAL at 12 h postsurgery was the most predictive parameter for the diagnosis of AKI (cutoff, 92.85 ng/mL). With the cutoff value, subclinical AKI was diagnosed in 42 (32.1%) patients. Patients with clinical AKI and those with subclinical AKI were assigned to the AKI group. The AKI group had significantly higher model for end-stage liver disease and sodium (MELD-Na) score, lower albumin level, and longer hospital stay after surgery than the non-AKI group. Older age and higher MELD-Na score were independent risk factors for the development of postoperative AKI. At 6 months postsurgery, the estimated glomerular filtration rate (eGFR) in the AKI group was significantly lower than that in the non-AKI group, although the baseline eGFR was not different. In multiple linear regression analysis, the maximum urine NGAL level during 24 h postsurgery, intraoperative fluid balance, and having liver transplantation were significantly associated with a poor 6 months renal outcome.
Urine NGAL was useful in the early diagnosis of postoperative AKI as well as in predicting the 6 months renal outcome after hepatobiliary surgery. A considerable proportion of patients developed subclinical AKI, and these patients showed worse renal outcome compared with the non-AKI group.
Electronic supplementary material
The online version of this article (doi:10.1186/1471-2369-15-169) contains supplementary material, which is available to authorized users.
PMCID: PMC4221681  PMID: 25342079
Acute kidney injury; Postoperative complications; Neutrophil gelatinase-associated lipocalin
36.  Summary adherence estimates do not portray the true incongruity between drug intake, nurse documentation and physicians’ orders 
BMC Nephrology  2014;15(1):170.
Hemodialysis patients (HD) need to adhere to a complex medication regimen. Because their daily pill burden is one of the highest reported, poor compliance is a major cause of therapeutic failure. The primary aim of this study was to define patterns of medication prescription, intake and documentation among HD patients.
HD patients treated between 2007 and 2009 and assigned to the largest health service provider in Israel were randomly selected. Drug practices were abstracted from their records and compared to electronic pharmacy data. The discrepancy between drug intake reports and the actual purchase was measured to estimate adherence. Drug purchase, intake report and physician order were plotted in complementing diagrams to appreciate consistency and discrepancy patterns.
The study included full analysis of 75 patients. The mean overall drug adherence was 56.7% (95% CI 53.6-59.9%), varying among drug families and over time. Often, there was a systematic disengagement between the nurses’ documentation and the actual patient purchase. Specifically, we observed either different quantities of medication use, improper documentation of a non-purchased drug, drug purchase without nurse documentation and futile physician attempts to modify prescriptions of unpurchased medication. We found a high rate of physician order turbulence for active vitamin D and calcium.
Drug prescription, documentation and adherence are incongruent and their mismatches are diverse. Summary estimates do not divulge the extent of these disparities. These system-wide communication failures compromise patient care. Strategies to promote system reconciliation and reasonable medication prescription are in need.
Electronic supplementary material
The online version of this article (doi:10.1186/1471-2369-15-170) contains supplementary material, which is available to authorized users.
PMCID: PMC4230519  PMID: 25342142
Hemodialysis; Adherence; Medications; Pharmacy; Physician orders
37.  Observational multicenter study to evaluate the prevalence and prognosis of subclinical atheromatosis in a Spanish chronic kidney disease cohort: baseline data from the NEFRONA study 
BMC Nephrology  2014;15(1):168.
Cardiovascular events (CVE) are more prevalent in chronic kidney disease (CKD) than in general population, being the main cause of morbimortality. Specific risk factors related to CKD have been suggested, because traditional factors do not fully explain this increase in cardiovascular disease rates. However, the role of atheromatosis, its pathogenesis and evolution are still unclear. The potential use of diagnostic tests to detect subclinical atheromatosis has to be determined.
NEFRONA is a prospective multicenter cohort study. 2445 CKD subjects were enrolled from 81 Spanish hospitals and dialysis clinics, from 2010 to 2012. Eligibility criteria included: 18 to 74 years old, CKD stage 3 or higher, and no previous CVE. 559 non-CKD controls were also recruited. Demographical, clinical and analytical data were collected. Carotid and femoral ultrasounds were performed by a single trained team to measure carotid intima-media thickness (cIMT) and detect atheromatous plaques. Ankle-brachial index (ABI) was measured.
Differences in age, sex and prevalence and control of cardiovascular risk factors were found between controls and CKD patients. These differences are similar to those described in epidemiological studies.
No difference was found regarding cIMT between controls and CKD (when subjects with plaques in common carotid arteries were omitted); earlier CKD stages had higher values. CKD patients had a higher rate of atheromatous plaques, with no difference between stages in the unadjusted analysis. A group of patients had plaques in femoral arteries but were plaque-free in carotid arteries, and would have gone underdiagnosed without the femoral study. The percentage of pathologic ABI was higher in CKD, with higher prevalence in more advanced stages, and a higher rate of ABI >1.4 than <0.9, suggesting more vascular calcification.
NEFRONA is the first large study describing the actual prevalence of subclinical atheromatosis across different CKD stages. There is a very high rate of atheromatous plaques and pathologic ABI in CKD. Prospective data will add important information to the pathogenesis and evolution of atheromatosis in CKD, compared to non-CKD subjects.
PMCID: PMC4210528  PMID: 25326683
Chronic kidney disease; Cardiovascular disease; Atheromatosis; Vascular calcification; Intima-media thickness; Ankle-brachial index
38.  Plasmapheresis in a patient with antiphospholipid syndrome before living-donor kidney transplantation: a case report 
BMC Nephrology  2014;15(1):167.
Early graft thrombosis and bleeding complications remain important causes of early graft loss following kidney transplantation in patients with antiphospholipid syndrome. Anti-β2-glycoprotein I IgG is a disease-specific antibody in patients with antiphospholipid syndrome. Although plasmapheresis is partially effective for antibody removal, the optimal treatment allowing successful transplantation in patients with antiphospholipid syndrome has not been established. This is the first report of a patient with antiphospholipid syndrome who successfully underwent living-donor kidney transplantation following prophylactic plasmapheresis for removal of anti-β2-glycoprotein I IgG.
Case presentation
A 37-year-old Japanese female was scheduled to undergo a living-donor kidney transplant from her mother. At age 25 years, she experienced renal vein thrombosis, was diagnosed with antiphospholipid syndrome secondary to systemic lupus erythematosus, and was subsequently treated with prednisolone and warfarin. At age 37 years, she was diagnosed with end stage kidney disease, requiring maintenance hemodialysis because of recurrent renal vein thrombosis despite taking anticoagulation therapy. The pretreatment protocol consisted of prophylactic plasmapheresis plus full anticoagulation therapy to counteract the risks of early graft thrombosis. Anticardiolipin and anti-β2-glycoprotein I IgGs were successfully removed by both double filtration plasmapheresis and plasma exchange. The allograft kidney began to function soon after transplantation. No obvious thrombotic complications were observed after transplantation, although anti-β2-glycoprotein I IgG increased to the level observed before plasmapheresis. One year after transplantation, the patient’s kidney function remains stable while receiving anticoagulation therapy as well as a maintenance immunosuppressive regimen.
Prophylactic plasmapheresis plus full anticoagulation therapy may be an effective strategy in patients with antiphospholipid syndrome undergoing living-donor kidney transplantation.
PMCID: PMC4216348  PMID: 25319344
Antiphospholipid syndrome; Living-donor kidney transplantation; Plasmapheresis; Anti-β2-glycoprotein I IgG
39.  Your Path to Transplant: a randomized controlled trial of a tailored computer education intervention to increase living donor kidney transplant 
BMC Nephrology  2014;15(1):166.
Because of the deceased donor organ shortage, more kidney patients are considering whether to receive kidneys from family and friends, a process called living donor kidney transplantation (LDKT). Although Blacks and Hispanics are 3.4 and 1.5 times more likely, respectively, to develop end stage renal disease (ESRD) than Whites, they are less likely to receive LDKTs. To address this disparity, a new randomized controlled trial (RCT) will assess whether Black, Hispanic, and White transplant patients’ knowledge, readiness to pursue LDKT, and receipt of LDKTs can be increased when they participate in the Your Path to Transplant (YPT) computer-tailored intervention.
Nine hundred Black, Hispanic, and White ESRD patients presenting for transplant evaluation at University of California, Los Angeles Kidney and Pancreas Transplant Program (UCLA-KPTP) will be randomly assigned to one of two education conditions, YPT or Usual Care Control Education (UC). As they undergo transplant evaluation, patients in the YPT condition will receive individually-tailored telephonic coaching sessions, feedback reports, video and print transplant education resources, and assistance with reducing any known socioeconomic barriers to LDKT. Patients receiving UC will only receive transplant education provided by UCLA-KPTP. Changes in transplant knowledge, readiness, pros and cons, and self-efficacy to pursue LDKT will be assessed prior to presenting at the transplant center (baseline), during transplant evaluation, and 4- and 8-months post-baseline, while completion of transplant evaluation and receipt of LDKTs will be assessed at 18-months post-baseline. The RCT will determine, compared to UC, whether Black, Hispanic, and White patients receiving YPT increase in their readiness to pursue LDKT and transplant knowledge, and become more likely to complete transplant medical evaluation and pursue LDKT. It will also examine how known patient, family, and healthcare system barriers to LDKT act alone and in combination with YPT to affect patients’ transplant decision-making and behavior. Statistical analyses will be performed under an intent-to-treat approach.
At the conclusion of the study, we will have assessed the effectiveness of an innovative and cost-effective YPT intervention that could be utilized to tailor LDKT discussion and education based on the needs of individual patients of different races in many healthcare settings.
Trial registration, number NCT02181114.
PMCID: PMC4213461  PMID: 25315644
Kidney transplantation; Living donor; Racial disparities; African-Americans; Hispanics; Patient education; Health knowledge/attitudes; Transtheoretical model
40.  Urinary albumin excretion and prevalence of microalbuminuria in a general Chinese population: a cross-sectional study 
BMC Nephrology  2014;15(1):165.
Microalbuminuria has been shown to be a risk factor for cardiovascular and renal disease in patients with hypertension and diabetes as well as in the general population. Urinary albumin excretion over 24 h is considered a ‘gold standard’ to detect microalbuminuria. Few studies have used 24-h urinary albumin excretion to analyze the prevalence of and related factors for microalbuminuira in a general Chinese population.
This study included 1980 adults aged 18–69 years from the Shandong-Ministry of Health Action on Salt and Hypertension (SMASH) Project 2011 survey. Blood pressure, height, weight and waist circumference were measured, and a venous blood and timed 24-h urine samples were collected from each participant. Linear and logistic regression analyses were used to test associations between established cardiovascular risk factors and microalbuminuria.
The median (25th–75th percentile) of 24-h urinary albumin excretion was 6.1 mg/d (4.5–8.7 mg/d) for all adults, 6.0 mg/d (4.4–8.5 mg/d) for men and 6.2 mg/d (4.6–8.9 mg/d) for women. The overall prevalence of microalbuminuria was 4.1% (95% confidence interval [CI]: 3.2–5.0%), 3.7% (95% CI: 2.9–4.5%) for men and 4.6% (95% CI: 3.7–5.5%) for women. Microalbuminuria was present in 8.1% (95% CI: 6.9–9.3%) of individuals with hypertension, 11.4% (95% CI: 10.0–12.8%) of those with diabetes and 15.6% (95% CI: 14.0–17.2%) of those with both. Multiple logistic regression analysis indicated that systolic blood pressure (odds ratio [OR] 1.02; 95% CI: 1.01–1.03) and fasting blood glucose (OR 1.19; 95% CI: 1.05–1.35) were the independent risk factors for microalbuminuria.
Adults in the general population of Shandong Province have a moderate prevalence of microalbuminuria. Those with hypertension and diabetes are at high risk of having microalbuminuria, suggesting the need for screening and early intervention for microalbuminuria among these individuals.
PMCID: PMC4209030  PMID: 25308236
Diabetes; Hypertension; Microalbuminuria
41.  Hyperuricemia and acute kidney injury secondary to spontaneous tumor lysis syndrome in low risk myelodysplastic syndrome 
BMC Nephrology  2014;15(1):164.
This is a rare instance of acute kidney injury caused by hyperuricemia due to spontaneous tumor lysis syndrome and also the first case of spontaneous tumor lysis syndrome reported in association with myelodysplastic syndrome.
Case presentation
A 53-year-old man presented with abrupt oliguria. Laboratory findings on admission included hyperuricemia, hyperphosphatemia, hypocalcemia, metabolic acidosis and rapidly rising serum creatinine, which were consistent with acute tumor lysis syndrome in the absence of precipitating chemotherapy or radiotherapy. After hemodialysis and oral uric acid lowering therapy, serum uric acid levels returned to normal range and renal function rapidly recovered. The patient was diagnosed as myelodysplastic syndrome eleven months later.
Occult malignancy including solid tumors and hematological malignancies should be carefully evaluated in the case of unexplainable acute kidney injury with hyperuricemia. Aggressive investigations should be thoroughly considered and repeated in this population.
PMCID: PMC4209058  PMID: 25304761
Acute kidney injury; Hyperuricemia; Myelodysplastic syndrome; Spontaneous tumor lysis syndrome
42.  The gap between calculated and actual calcium substitution during citrate anticoagulation in an immobilised patient on renal replacement therapy reflects the extent of bone loss – a case report 
BMC Nephrology  2014;15(1):163.
Demineralisation and bone density loss during immobilisation are known phenomena. However information concerning the extent of calcium loss during immobilisation remains inconsistent within literature. This may explain why treatment of bone loss and prevention of further demineralisation is often initiated only when spontaneous bone fracture occurred.
Continuous renal replacement therapy is commonly utilised in critically ill patients with acute kidney injury requiring RRT. Regional anticoagulation with citrate for CRRT is well-established within the intensive care setting. Due to calcium free dialysate, calcium is eliminated directly as well as indirectly via citrate binding necessitating calcium substitution. In anuric patients declining calcium requirements over time reflect bone calcium liberation secondary to immobilisation. The difference between the expected and actual need for calcium infusion corresponds to calcium release from bone which is particularly impressive in patients exposed to long-term immobilisation and CRRT. We report a dialysis period in excess of 250 days with continuous renal replacement therapy and anticoagulation with citrate.
Case presentation
We present a 30-year old male with prolonged multisystem organ failure after bilateral lung transplantation, in whom during a period of 254 days the cumulative difference between expected and actual need for calcium infusion was 14.25 mol, representing an estimated calcium loss of about 571 g. Comparison of computed tomographic imaging of the lower thoracic vertebrae over this period depicts a radiographically discernible decrease in bone density from 238 to 52 Hounsfield Units. The first spontaneous fracture occurred after 6 months of immobilisation. Despite subsequent treatment with bisphosphonates and androgen therapy resulting in an increase in bone density to 90 HU a further fracture occurred.
In immobilised patients receiving CRRT and anticoagulation with citrate, decreasing need for calcium substitution reflects the degree of bone demineralisation corresponding with radiographic assessment of declining bone mineral density. Such a declining need for calcium substitution could be useful in clinical practice highlighting relevant bone loss which results in spontaneous fractures in immobilised critically ill patients.
PMCID: PMC4192282  PMID: 25281195
Bone loss; Citrate anticoagulation; Immobilisation; Renal replacement therapy
43.  High levels of mannose-binding lectin are associated with lower pulse wave velocity in uraemic patients 
BMC Nephrology  2014;15(1):162.
Uraemia is associated with a highly increased risk of cardiovascular disease. Mannose-binding lectin (MBL) has been shown to be involved in cardiovascular pathophysiology and a protective effect of MBL is suggested. The purpose of the present study was to evaluate a potential impact of MBL on vascular parameters in uraemic patients.
A cohort of 98 patients with end stage renal disease (ESRD) awaiting kidney transplantation had pulse wave velocity (PWV) and augmentation index (AIX) examined by tonometry and endothelial dependent flow-mediated (FMD) and endothelial independent nitroglycerin-induced (NID) dilatory capacities of the brachial artery measured by ultrasound. An oral glucose tolerance test (OGTT) was performed and serum levels of MBL were measured using Luminex xMAP bead array technology.
The cohort was divided in two groups according to MBL-concentration below or above the median concentration. These groups were comparable regarding age, BMI, and duration of ESRD. PWV was significantly lower in the group with high MBL levels compared to the group with low MBL levels and trends toward better AIX and higher insulin sensitivity (ISI) was also seen in the group with high MBL levels. No difference was seen in FMD and NID.
High levels of MBL are associated with lower PWV and the use of antihypertensive drugs in a cohort of patients with ESRD awaiting kidney transplantation suggesting a beneficial role of high levels of MBL on arterial stiffness in uraemia.
PMCID: PMC4197330  PMID: 25281004
Arterial stiffness; Augmentation index; Endothelial function; Glucose intolerance; Mannose-binding lectin
44.  Renal “hyperfiltrators” are at elevated risk of death and chronic diseases 
BMC Nephrology  2014;15(1):160.
The definition of glomerular hyperfiltration has not been agreed upon and the pathophysiological mechanisms have not been well explored. Low serum creatinine concentrations may be associated with increased risk of coronary heart disease (CHD) or cardiopulmonary events the impact of which needs further study.
Consecutive applicants to a cardiovascular hospital free of moderate/severe chronic kidney disease (age 55.6 ± 8.2 years) were grouped into those without (“healthy”, n = 469) and with CHD (320 stable and acute coronary syndrome cases) at baseline and into sex-specific quartiles of CKD-EPI equation-estimated glomerular filtration rate (eGFR). New or recurrent cardiovascular (myocardial infarction, stroke, heart failure [HF]) events, obstructive pulmonary disease (COPD) and death were determined during 3-years’ follow-up.
Among 25 deaths and 75 cardiopulmonary events, HF was the leading nonfatal event. Age, serum uric acid and left ventricular ejection fraction proved the best independent inverse covariates of eGFR in the “healthy” sample. The highest eGFR quartile (“hyperfiltrators”), exhibiting significantly lower serum LDL-cholesterol levels, significantly predicted the combined outcome (at a RR of 6) in “healthy” subjects, after adjustment for sex, age, body mass index, smoking status and presence of hypertension. This finding was paralleled by the highest eGFR quartile calculated also by the MDRD equation, replicating this also in the CHD group.
Renal “hyperfiltrators” represent individuals with autoimmune activation (involving serum creatinine, partly escaping assay), are misclassified into optimal renal function and actually are at significantly higher risk of death, HF or cardiopulmonary events. Low serum creatinine levels may represent a clue to the existence of autoimmune activation.
PMCID: PMC4190443  PMID: 25278185
Autoimmune activation; Cardiovascular disease; Chronic obstructive pulmonary disease; Glomerular filtration rate; Heart failure; Renal hyperfiltration
45.  The financial impact of increasing home-based high dose haemodialysis and peritoneal dialysis 
BMC Nephrology  2014;15(1):161.
Evidence suggests that high dose haemodialysis (HD) may be associated with better health outcomes and even cost savings (if conducted at home) versus conventional in-centre HD (ICHD). Home-based regimens such as peritoneal dialysis (PD) are also associated with significant cost reductions and are more convenient for patients. However, the financial impact of increasing the use of high dose HD at home with an increased tariff is uncertain. A budget impact analysis was performed to investigate the financial impact of increasing the proportion of patients receiving home-based dialysis modalities from the perspective of the England National Health Service (NHS) payer.
A Markov model was constructed to investigate the 5 year budget impact of increasing the proportion of dialysis patients receiving home-based dialysis, including both high dose HD at home and PD, under the current reimbursement tariff and a hypothetically increased tariff for home HD (£575/week). Five scenarios were compared with the current England dialysis modality distribution (prevalent patients, 14.1% PD, 82.0% ICHD, 3.9% conventional home HD; incident patients, 22.9% PD, 77.1% ICHD) with all increases coming from the ICHD population.
Under the current tariff of £456/week, increasing the proportion of dialysis patients receiving high dose HD at home resulted in a saving of £19.6 million. Conducting high dose HD at home under a hypothetical tariff of £575/week was associated with a budget increase (£19.9 million). The costs of high dose HD at home were totally offset by increasing the usage of PD to 20–25%, generating savings of £40.0 million – £94.5 million over 5 years under the increased tariff. Conversely, having all patients treated in-centre resulted in a £172.6 million increase in dialysis costs over 5 years.
This analysis shows that performing high dose HD at home could allow the UK healthcare system to capture the clinical and humanistic benefits associated with this therapy while limiting the impact on the dialysis budget. Increasing the usage of PD to 20-25%, the levels observed in 2005-2008, will totally offset the additional costs and generate further savings.
PMCID: PMC4194367  PMID: 25278356
End-stage renal disease; In-centre haemodialysis; High dose haemodialysis; Home haemodialysis; Peritoneal dialysis; Budget impact analysis
46.  The relationship between asymptomatic organ damage, and serum soluble tumor necrosis factor-like weak inducer of apoptosis (sTWEAK) and Interleukin-17A (IL-17A) levels in non-diabetic hypertensive patients 
BMC Nephrology  2014;15(1):159.
This study aimed to measure the serum soluble tumor necrosis factor-like weak inducer of apoptosis (sTWEAK) and interleukin-17A (IL-17A) levels in hypertensive patients with/without asymptomatic organ damage (AOD), as well as to determine the relationship between the serum sTWEAK and IL17-A levels, and carotid intima media thickness (CIMT), proteinuria, retinopathy, and the left ventricle mass index (LVMI).
The study included 159 patients diagnosed with and followed-up for primary hypertension (HT); 79 of the patients had AOD (61 female and 18 male) and 80 did not (52 female and 28 male). sTWEAK and IL-17A levels were measured in all patients.
The sTWEAK level was significantly lower in the patients with AOD than in those without AOD (858.4 pg/mL vs. 1151.58 pg/mL, P = 0.001). The sTWEAK level was negatively correlated with the mean microalbuminuria level and LVMI. The median IL-17A level was significantly higher in the patients with AOD than in those without AOD (2.34 pg/mL vs. 1.80 pg/mL, P = 0.001). There was a positive correlation between mean IL-17A level, and mean microalbuminuria level, CIMT, and LVMI. Multivariate logistic regression analysis showed that patient age, sTWEAK level, and mean 24-h systolic blood pressure were predictors of AOD.
The sTWEAK level was lower and IL-17A level was higher in the patients with AOD. It remains unknown if sTWEAK and IL-17A play a role in the pathophysiology of AOD. Prospective observational studies are needed to determine the precise role of sTWEAK and IL-17A in the development of target organ damage.
PMCID: PMC4190353  PMID: 25273526
Asymptomatic organ damage; Hypertension; Interleukin-17; Tumor necrosis factor-like weak inducer of apoptosis
47.  A rare association between Fabry’s disease and granulomatosis with polyangiitis: a potential pathogenic link 
BMC Nephrology  2014;15(1):157.
Fabry’s disease is a rare X-linked, hereditary lysosomal storage disease caused by a deficiency of the enzyme α-galactosidase A. Granulomatosis with polyangiitis is characterized by the involvement of the respiratory tract and kidneys. Here, we report the first case of the coexistence of these diseases.
Case presentation
We describe a 29-year-old man suffering from fever with maxillary sinusitis, multiple lung nodules, and proteinuria. He was diagnosed with Fabry’s disease accompanying granulomatosis with polyangiitis on the basis of the low activity of peripheral leukocyte α-galactosidase A and pathological findings in the lung and kidney. Glucocorticoid and cyclophosphamide were administered, followed by enzyme replacement therapy. Progression to end-stage renal disease has not been observed for 6 years until the time of drafting this manuscript.
Because both Fabry’s disease and granulomatosis with polyangiitis or crescentic glomerulonephritis are rare diseases, their concurrence in this and related cases suggests there may be a pathogenic link between these two conditions. Fabry’s disease may be underdiagnosed, particularly in cases of granulomatosis with polyangiitis or crescentic glomerulonephritis.
PMCID: PMC4190398  PMID: 25270872
Crescentic glomerulonephritis; Enzyme replacement therapy; Fabry’s disease; Granulomatosis with polyangiitis
48.  Detection of renal allograft rejection using blood oxygen level-dependent and diffusion weighted magnetic resonance imaging: a retrospective study 
BMC Nephrology  2014;15(1):158.
Acute rejection (AR) and acute tubular necrosis (ATN) are main causes of early renal allograft dysfunction. Blood oxygen level-dependent magnetic resonance imaging (BOLD MRI) and Diffusion weighted (DW) MRI can provide valuable information about changes of oxygen bioavailability and water diffusion by measuring R2* or apparent diffusion coefficient (ADC) respectively. We aimed to determine the value of BOLD MRI and DW MRI in detecting causes for early allograft dysfunction in renal allograft recipients.
Fifty patients received renal allografts from deceased donors were analyzed, including 35 patients with normal renal function (control group), 10 AR patients and 5 ATN patients. Cortical R2* (CR2*) and medullary R2* (MR2*) were measured by BOLD MRI. Ten diffusion gradient b values (0, 5, 10, 20, 50, 100, 200, 400, 800, 1200s/mm2) were used in DW MRI. ADC values were measured in renal cortex (CADC) and medulla (MADC). CADCl and MADCl were measured under low b values (b ≤ 200 s/mm2), while CADCh and MADCh were measured under high b values (b > 200 s/mm2).
MR2* was significantly lower in AR group (18.2 ± 1.5/s) than control group (23.8 ± 5.0/s, p = 0.001) and ATN group (25.8 ± 5.0/s, p = 0.004). There was a tendency of lower levels on CADCl, MADCl, CADCh or MADCh in AR group than in control group. There were no differences on ADC values between AR group and ATN group.
BOLD MRI was a valuable method in detection of renal allografts with acute rejection.
PMCID: PMC4192395  PMID: 25270976
49.  Renal thrombotic microangiopathy and podocytopathy associated with the use of carfilzomib in a patient with multiple myeloma 
BMC Nephrology  2014;15(1):156.
Proteasome inhibitors are a relatively new class of chemotherapeutic agents. Bortezomib is the first agent of this class and is currently being used for the treatment of multiple myeloma. However, recent reports have linked exposure to bortezomib with the development of thrombotic microangiopathy. A new agent in this class, carfilzomib, has been recently introduced as alternative therapy for relapsing and refractory multiple myeloma. We report a case of renal thrombotic microangiopathy associated with the use of carfilzomib in a patient with refractory multiple myeloma.
Case presentation
A 62 year-old Caucasian man with hypertension and a 4-year history of multiple myeloma, had been previously treated with lenalidomide, bortezomib and two autologous hematopoietic stem cell transplants. After the second hematopoietic stem cell transplant, he developed acute kidney injury secondary to septic shock and required dialysis for 4 weeks. Subsequently, his serum creatinine stabilized at 2.1 mg/dL (185.64 μmol/L). Seventeen months after the second hematopoietic stem cell transplant, he was initiated on carfilzomib for relapse of multiple myeloma. Six weeks later, he developed abrupt worsening of lower extremity edema and hypertension, and new onset proteinuria. His kidney function remained stable. Kidney biopsy findings were consistent with thrombotic microangiopathy. Eight weeks after discontinuation of carfilzomib, proteinuria and hypertension improved. Due to progression of multiple myeloma, he died a few months later.
In view of the previously reported association of bortezomib with thrombotic microangiopathy, the temporal association of the clinical picture with the initiation of carfilzomib, and the partial resolution of symptoms after discontinuation of the drug, we conclude that carfilzomib may have precipitated a case of clinically evident renal thrombotic microangiopathy in our patient.
PMCID: PMC4190298  PMID: 25267524
Thrombotic microangiopathy; Malignant hypertension; Proteasome inhibitor; Proteinuria
50.  Adequate hemodialysis improves anemia by enhancing glucose-6-phosphate dehydrogenase activity in patients with end-stage renal disease 
BMC Nephrology  2014;15(1):155.
We conducted this study to determine the erythrocyte glucose-6-phosphate dehydrogenase (G6PD) activity level in patients with end-stage renal disease (ESRD) on maintenance hemodialysis (HD) and to determine the effect of hemodialysis adequacy on G6PD activity levels and its impact on anemia.
Eighty-two patients (48 men and 34 women) receiving regular hemodialysis for ESRD through arteriovenous fistulae for at least one year prior to the start of the study were enrolled in this study. G6PD activity levels were measured in all patients and the average Kt/V was used as a parameter of HD adequacy. Patients were divided into two groups according to Kt/V values. Group 1 included 45 patients with Kt/V˃1.2 (adequate HD), and group 2 included 37 patients with Kt/V˃1.2 (inadequate HD). The average hemoglobin level and the weekly dose of an erythropoietin-stimulating agent, epoetin alpha (ESA), for each patient were calculated for one year.
The mean (SD) erythrocyte G6PD activity for all patients on hemodialysis was 7.64 ± 1.85 U/g Hb. Patients who had received adequate hemodialysis had a significantly higher average erythrocyte G6PD (mean (SD) = 9.2 ± 0.7 U/g Hb) compared to patients who had inadequate hemodialysis (mean (SD) = 5.7 ± 0.7U/g Hb) (P-value <0.005). The mean hemoglobin concentration was significantly higher in patients with adequate hemodialysis compared to those with inadequate hemodialysis.
Our study demonstrated the beneficial effect of adequate hemodialysis in correcting anemia by enhancing the erythrocyte G6PD activity in patients.
PMCID: PMC4181374  PMID: 25261071
Anemia; Glucose-6-phosphate dehydrogenase; Hemodialysis

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