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1.  Culture-negative subacute bacterial endocarditis masquerades as granulomatosis with polyangiitis (Wegener’s granulomatosis) involving both the kidney and lung 
BMC Nephrology  2012;13:174.
Subacute bacterial endocarditis (SBE) occasionally exhibits positive cytoplasmic anti-neutrophil cytoplasmic antibody (c-ANCA) of the anti-proteinase-3 (PR-3) type. Clinically, it mimics ANCA-associated vasculitis, such as Wegener's disease with glomerulonephritis. Lung abscesses are the most common manifestation of lung involvement. We herein report a case of culture-negative SBE strongly c-ANCA/PR3-positive accompanied by pulmonary involvement and glomerulonephritis. In this case, we took biopsies of both the lung and kidney, although renal biopsy is usually preferred over lung biopsy. The lung biopsy showed severe alveolar capillaritis, suggesting vasculitis consistent with polyangiitis. The renal biopsy revealed glomerulonephritis with a membranoproliferative pattern. To our knowledge, this is the first such reported case.
Case presentation
A 68-year-old Chinese male patient presented to our hospital with a fever, cough, chest pain, and recurrent peripheral edema. He had a past medical history significant for treated schistosomiasis 20 years previously. Physical examination revealed palpable purpura, mild hypertension, hepatosplenomegaly, and a holosystolic cardiac murmur (Levine 2/6). Echocardiography showed tricuspid valve vegetations with moderate to severe regurgitation. Serum c-ANCA/PR3 and cryoglobulin were strongly positive. Renal biopsy results indicated membranoproliferative glomerulonephritis with several crescents. Chest CT revealed multiple intraparenchymal and subpleural nodules, and lung biopsy showed polyangiitis. The patient’s ANCA titers, glomerulonephritis, and pulmonary injury all resolved after antibiotic therapy.
SBE may present with positive c-ANCA/PR3, multiple pulmonary nodules, pulmonary polyangiitis, and glomerulonephritis clinically mimicking granulomatosis with polyangiitis (Wegener's granulomatosis).
PMCID: PMC3574827  PMID: 23268737
Subacute bacterial endocarditis; PR3/c-ANCA; Granulomatosis with polyangiitis (Wegener's granulomatosis); Glomerulonephritis
2.  Hypertension and the development of New onset chronic kidney disease over a 10 year period: a retrospective cohort study in a primary care setting in Malaysia 
BMC Nephrology  2012;13:173.
Little is known about the rate of progression to chronic kidney disease (CKD) among hypertensive patients, particularly at the primary care level. This study aims to examine risk factors associated with new onset CKD among hypertensive patients attending a primary care clinic.
This is a 10-year retrospective cohort study of 460 patients with hypertension who were on treatment. Patient information was collected from patient records. CKD was defined as a glomerular filtration rate <60 ml/min per 1.73 m2 (Cockcroft-Gault equation). Multiple logistic regression statistics was used to test the association in newly diagnosed CKD.
The incidence of new CKD was 30.9% (n = 142) with an annual rate of 3%. In multivariate logistic regression analysis, factors associated with development of new onset of CKD among hypertensive patients were older age (odds ratio [OR] 1.123, 95% confidence interval [CI] 1.078-1.169), presence of diabetes (OR 2.621, 95% CI 1.490-4.608), lower baseline eGFR (OR 1.041, 95% CI 0.943-0.979) and baseline hyperuricaemia (OR 1.004, 95% CI 1.001-1.007).
The progression to new onset CKD is high among urban multiethnic hypertensive patients in a primary care population. Hence every effort is needed to detect the presence of new onset CKD earlier. Hypertensive patients who are older, with underlying diabetes, hyperuricaemia and lower baseline eGFR are associated with the development of CKD in this population.
PMCID: PMC3543163  PMID: 23259489
Hypertension; Chronic kidney disease; Primary care; Estimated glomerular filtration rate; Cohort, Malaysia
3.  Membranoproliferative glomerulonephritis complicating Waldenström’s macroglobulinemia 
BMC Nephrology  2012;13:172.
Lymphoproliferative disorders causing paraproteinemia can be associated with various kidney injuries including the deposition of monoclonal immunoglobulins (Ig). A known glomerular manifestation of Waldenström’s macroglobulinemia is characterized by prominent intracapillary hyaline thrombi and lack of conspicuous glomerular proliferation. The present case was special in 2 aspects: 1. the diagnosis of glomerulonephritis was unexpected before renal biopsy, 2. the prominent glomerular proliferation paired with large intracapillary hyaline thrombi is uncommon in Waldenström’s macroglobulinemia-associated glomerulonephritis.
Case presentation
A 73-year-old Caucasian woman with a long-standing history of rheumatoid arthritis and Waldenström’s macroglobulinemia was admitted for acute renal failure (ARF), which initially was presumed to be the consequence of extrarenal causes. Proteinuria and hematuria were only mild. In renal core biopsy, a membranoproliferative glomerulonephritis (MPGN) and prominent intracapillary hyaline monoclonal IgM thrombi were found in addition to acute tubular necrosis. Of note, the patient’s history was positive for purpuric skin changes, suspicious for cryoglobulinemia. However, serological tests for cryoglobulins were repeatedly negative. The ARF resolved before the start of immunomodulatory therapy for Waldenström’s macroglobulinemia.
The presence of MPGN with prominent hyaline thrombi in the context of Waldenström’s macroglobulinemia is uncommon and can be oligosymptomatic. We discuss this case in the context of previous literature and classifications suggested for monoclonal Ig-related renal pathologies.
PMCID: PMC3541200  PMID: 23259458
Waldenström’s macroglobulinemia; MPGN; Hyaline thrombi
4.  Impact of heavy proteinuria on clinical outcomes in patients on incident peritoneal dialysis 
BMC Nephrology  2012;13:171.
There are few reports on the nutritional status changes and residual renal function (RRF) according to proteinuria levels in patients on peritoneal dialysis (PD).
A total of 388 patients on PD were enrolled. The patients were divided into 3 groups with respect to initial proteinuria: the A (n = 119; <500 mg/day), B (n = 218; 500–3,500 mg/day), and C groups (n = 51; >3,500 mg/day).
The patients with higher proteinuria levels had a higher incidence of male sex, diabetes mellitus, and icodextrin use than those with lower proteinuria levels. Although initial peritoneal albumin loss in C group was lower than that detected in the other groups, no significant difference was observed in peritoneal albumin loss among the 3 groups at the end of follow-up period. At the time of PD initiation, the Geriatric nutritional risk index (GNRI) was lower in the C group than in the other 2 groups. However, at the end of the follow-up period, there was no significant difference in GNRI between the 3 groups. The GNRI increased, and the proteinuria level or RRF decreased more in the C group than in the other 2 groups. There were no significant differences in lean mass index or fat mass index change from the time of PD initiation to the end of the follow-up period. However, fat mass index and nPNA showed greater increases in the C group. The multivariate analysis revealed that proteinuria was negatively correlated with GNRI at the time of PD initiation and at the end of the follow-up period. The initial RRF and proteinuria were negatively correlated with the RRF decline during the follow-up.
The attenuation of the nephrotic proteinuria, along with the RRF decline, was associated with the improvement of the malnutrition.
PMCID: PMC3538719  PMID: 23245677
Peritoneal dialysis; Proteinuria; Residual renal function; Nutrition
5.  Association between serum insulin-like growth factor I or IGF-binding protein 3 and estimated glomerular filtration rate: results of a population-based sample 
BMC Nephrology  2012;13:169.
Insulin-like growth factor I (IGF-I), which is mostly carried in blood by IGF-binding protein 3 (IGFBP-3), was associated to the glomerular filtration rate and chronic kidney disease in a multiethnic study among US adults. The aim of the present study was to investigate whether serum IGF-I or IGFBP-3 are associated with estimated glomerular filtration rate (eGFR) in a population-based study of Caucasian adults.
Data from 4028 subjects (2048 women) aged 20 to 81 years from the Study of Health in Pomerania (SHIP) were analyzed. Total serum IGF-I and IGFBP-3 concentrations were determined by chemiluminescence immunoassays and categorized into sex- and age-specific quartiles.
After adjusting for age, waist circumference and type 2 diabetes mellitus, analysis of variance (ANOVA) revealed inverse associations between serum IGF-I concentrations and eGFR in men as well as between serum IGFBP-3 concentrations and eGFR in men and women. Logistic regression analyses confirmed these findings and showed that high IGF-I or IGFBP-3 concentrations were associated with an increased risk of decreased eGFR (<60 mL/min/1.73 m2) in men or women. These relations became stronger when lower eGFR cut-offs were used for the analyses.
Our data revealed associations of increased serum IGF-I concentrations and decreased eGFR in men but not in women and an association of increased serum IGFBP-3 concentrations and decreased eGFR in both sexes.
PMCID: PMC3563443  PMID: 23237568
eGFR; Insulin-like growth factor; IGF-I; IGFBP-3; Renal function; Study of health in Pomerania
6.  Cultural adaptation and validation of the “Kidney Disease and Quality of Life - Short Form (KDQOL-SF™) version 1.3” questionnaire in Egypt 
BMC Nephrology  2012;13:170.
Health Related Quality of Life (HRQOL) instruments need disease and country specific validation. In Arab countries, there is no specific validated questionnaire for assessment of HRQOL in chronic kidney disease (CKD) patients. The aim of this study was to present an Arabic translation, adaptation, and the subsequent validation of the kidney disease quality of life-short form (KDQOL-SFTM) version 1.3 questionnaire in a representative series of Egyptian CKD patients.
KDQOL-SFTM version 1.3 was translated into Arabic by two independent translators, and then subsequently translated back into English. After translation disparities were reconciled, the final Arabic questionnaire was tested by interviewing 100 pre-dialysis CKD (stage 1-4) patients randomly selected from outpatients attending the Nephrology clinic at the Main Alexandria University Hospital. Test re-test reliability was performed, with a subsample of 50 consecutive CKD patients, by two interviews 7 days apart and internal consistency estimated by Cronbach’s α. Discriminant, concept, and construct validity were assessed.
All items of SF-36 met the criterion for internal consistency and were reproducible. Of the 10 kidney disease targeted scales, only three had Cronbach’s α <0.7: quality of social interaction (0.23), work status (0.28), and cognitive function (0.60). All disease specific scales were reproducible. Results from discriminant validity showed that the study questionnaire could discriminate between patients’ subgroups. As for concept validity, the correlation between all domains of the questionnaire with overall health ratewas significant for all domains except for the work status, sexual function, emotional wellbeing, and role emotional. Furthermore, the correlation between the disease specific domains and the two composite summaries of SF-36 (physical and mental composite summaries) was significant for all domains except for sexual function with mental composite summary. Construct validity was indicated by the observation that the majority of the domains of the kidney disease targeted scale of KDQOL-SFTM 1.3 were significantly inter-correlated. Finally, principal component analysis of the kidney disease targeted scale indicated that this part of the questionnaire could be summarized into 10 factors that together explained 70.9% of the variance.
The results suggest that this Arabic version of the KDQOL-SFTM 1.3 questionnaire is a valid and reliable tool for use in Egyptian patients with CKD.
PMCID: PMC3583144  PMID: 23237591
Chronic kidney disease; Egypt; Health-related quality of life; KDQOL-SFTM 1.3; Questionnaire validation
7.  Assessment of renal function in mice with unilateral ureteral obstruction using 99mTc-MAG3 dynamic scintigraphy 
BMC Nephrology  2012;13:168.
Renal scintigraphy using 99mTc-mercaptoacetyltriglycine (99mTc-MAG3) is widely used for the assessment of renal function in humans. However, the application of this method to animal models of renal disease is currently limited, especially in rodents. Here, we have applied 99mTc-MAG3 renal scintigraphy to a mouse model of unilateral ureteral obstruction (UUO) and evaluated its utility in studying obstructive renal disease.
UUO mice were generated by complete ligation of the left ureter. Sham-operated mice were used as a control. Renal function was investigated on days 0, 1, 3, and 6 post-surgery using dynamic planar imaging of 99mTc-MAG3 activity following retro-orbital injection. Time-activity curves (TACs) were produced for individual kidneys and renal function was assessed by 1) the slope of initial 99mTc-MAG3 uptake (SIU), which is related to renal perfusion; 2) peak activity; and 3) the time-to-peak (TTP). The parameters of tubular excretion were not evaluated in this study as 99mTc-MAG3 is not excreted from UUO kidneys.
Compared to sham-operated mice, SIU was remarkably (>60%) reduced in UUO kidneys at day 1 post surgery and the TACs plateaued, indicating that 99mTc-MAG3 is not excreted in these kidneys. The plateau activity in UUO kidneys was relatively low (~40% of sham kidney’s peak activity) as early as day1 post surgery, demonstrating that uptake of 99mTc-MAG3 is rapidly reduced in UUO kidneys. The time to plateau in UUO kidneys exceeded 200 sec, suggesting that 99mTc-MAG3 is slowly up-taken in these kidneys. These changes advanced as the disease progressed. SIU, peak activity and TTPs were minimally changed in contra-lateral kidneys during the study period.
Our data demonstrate that renal uptake of 99mTc-MAG3 is remarkably and rapidly reduced in UUO kidneys, while the changes are minimal in contra-lateral kidneys. The parametric analysis of TACs suggested that renal perfusion as well as tubular uptake is reduced in UUO kidneys. This imaging technique should allow non-invasive assessments of UUO renal injury and enable a more rapid interrogation of novel therapeutic agents and protocols.
PMCID: PMC3542003  PMID: 23228112
Nuclear imaging; Renal scintigraphy; 99mTc-MAG3; Mouse model; Unilateral ureteral obstruction; Renal function
8.  Comparative effectiveness studies to improve clinical outcomes in end stage renal disease: the DEcIDE patient outcomes in end stage renal disease study 
BMC Nephrology  2012;13:167.
Evidence is lacking to inform providers’ and patients’ decisions about many common treatment strategies for patients with end stage renal disease (ESRD).
The DEcIDE Patient Outcomes in ESRD Study is funded by the United States (US) Agency for Health Care Research and Quality to study the comparative effectiveness of: 1) antihypertensive therapies, 2) early versus later initiation of dialysis, and 3) intravenous iron therapies on clinical outcomes in patients with ESRD. Ongoing studies utilize four existing, nationally representative cohorts of patients with ESRD, including (1) the Choices for Healthy Outcomes in Caring for ESRD study (1041 incident dialysis patients recruited from October 1995 to June 1999 with complete outcome ascertainment through 2009), (2) the Dialysis Clinic Inc (45,124 incident dialysis patients initiating and receiving their care from 2003–2010 with complete outcome ascertainment through 2010), (3) the United States Renal Data System (333,308 incident dialysis patients from 2006–2009 with complete outcome ascertainment through 2010), and (4) the Cleveland Clinic Foundation Chronic Kidney Disease Registry (53,399 patients with chronic kidney disease with outcome ascertainment from 2005 through 2009). We ascertain patient reported outcomes (i.e., health-related quality of life), morbidity, and mortality using clinical and administrative data, and data obtained from national death indices. We use advanced statistical methods (e.g., propensity scoring and marginal structural modeling) to account for potential biases of our study designs. All data are de-identified for analyses. The conduct of studies and dissemination of findings are guided by input from Stakeholders in the ESRD community.
The DEcIDE Patient Outcomes in ESRD Study will provide needed evidence regarding the effectiveness of common treatments employed for dialysis patients. Carefully planned dissemination strategies to the ESRD community will enhance studies’ impact on clinical care and patients’ outcomes.
PMCID: PMC3554422  PMID: 23217181
9.  Disruption of the endothelin A receptor in the nephron causes mild fluid volume expansion 
BMC Nephrology  2012;13:166.
Endothelin, via endothelin A receptors (ETA), exerts multiple pathologic effects that contribute to disease pathogenesis throughout the body. ETA antagonists ameliorate many experimental diseases and have been extensively utilized in clinical trials. The utility of ETA blockers has been greatly limited, however, by fluid retention, sometimes leading to heart failure or death. To begin to examine this issue, the effect of genetic disruption of ETA in the nephron on blood pressure and salt handling was determined.
Mice were generated with doxycycline-inducible nephron-specific ETA deletion using Pax8-rtTA and LC-1 transgenes on the background of homozygous loxP-flanked ETA alleles. Arterial pressure, Na metabolism and measures of body fluid volume status (hematocrit and impedance plethysmography) were assessed.
Absence of nephron ETA did not alter arterial pressure whether mice were ingesting a normal or high Na diet. Nephron ETA disruption did not detectably affect 24 hr Na excretion or urine volume regardless of Na intake. However, mice with nephron ETA knockout that were fed a high Na diet had mild fluid retention as evidenced by an increase in body weight and a fall in hematocrit.
Genetic deletion of nephron ETA causes very modest fluid retention that does not alter arterial pressure. Nephron ETA, under normal conditions, likely do not play a major role in regulation of Na excretion or systemic hemodynamics.
PMCID: PMC3537641  PMID: 23217151
Endothelin; Endothelin A receptor; Kidney; Nephron; Sodium; Blood pressure
10.  Prevention of sudden cardiac death in patients with chronic kidney disease 
BMC Nephrology  2012;13:162.
Cardiovascular deaths account for about 40% of all deaths of patients with chronic kidney disease (CKD), particularly those on dialysis, while sudden cardiac death (SCD) might be responsible for as many as 60% of SCD in patients undergoing dialysis. Studies have demonstrated a number of factors occurring in hemodialysis (HD) that could lead to cardiac arrhythmias. Patients with CKD undergoing HD are at high risk of ventricular arrhythmia and SCD since changes associated with renal failure and hemodialysis-related disorders overlap. Antiarrhythmic therapy is much more difficult in patients with CKD, but the general principles are similar to those in patients with normal renal function - at first, the cause of arrhythmias should be found and eliminated. Also the choice of therapy is narrowed due to the altered pharmacokinetics of many drugs resulting from renal failure, neurotoxicity of certain drugs and their complex interactions. Cardiac pacing in elderly patients is a common method of treatment. Assessment of patients’ prognosis is important when deciding whether to implant complex devices. There are reports concerning greater risk of surgical complications, which depends also on the extent of the surgical site. The decision concerning implantation of a pacing system in patients with CKD should be made on the basis of individual assessment of the patient.
PMCID: PMC3519551  PMID: 23206758
Arrhythmias; Chronic kidney disease; Renal failure; Sudden cardiac death
11.  The serum vaspin levels are reduced in Japanese chronic hemodialysis patients 
BMC Nephrology  2012;13:163.
Visceral adipose tissue-derived serine proteinase inhibitor (vaspin) is an adipokine identified in genetically obese rats that correlates with insulin resistance and obesity in humans. Recently, we found that 7% of the Japanese population with the minor allele sequence (A) of rs77060950 exhibit higher levels of serum vaspin. We therefore evaluated the serum vaspin levels in Japanese chronic hemodialysis patients.
Healthy Japanese control volunteers (control; n = 95, 49.9±6.91 years) and Japanese patients undergoing hemodialysis therapy (HD; n = 138, 51.4±10.5 years) were enrolled in this study, and serum samples were subjected to the human vaspin RIA system.
The measurement of the serum vaspin levels demonstrated that a fraction of control subjects (n = 5) and HD patients (n = 11) exhibited much higher levels (> 10 ng/ml; VaspinHigh group), while the rest of the population exhibited lower levels (< 3 ng/ml; VaspinLow group). By comparing the patients in the VaspinLow group, the serum vaspin levels were found to be significantly higher in the control subjects (0.87±0.24 ng/ml) than in the HD patients (0.32±0.15 ng/ml) (p < 0.0001). In the stepwise regression analyses, the serum creatinine and triglyceride levels were found to be independently and significantly associated with the vaspin concentrations in all subjects.
The creatinine levels are negatively correlated with the serum vaspin levels and were significantly reduced in the Japanese HD patients in the VaspinLow group.
PMCID: PMC3519721  PMID: 23206815
Adipokine; End-stage renal disease; Hemodialysis
12.  End-stage kidney disease due to haemolytic uraemic syndrome – outcomes in 241 consecutive ANZDATA registry cases 
BMC Nephrology  2012;13:164.
The aim of this study was to investigate the characteristics and outcomes of patients receiving renal replacement therapy for end-stage kidney disease (ESKD) secondary to haemolytic uraemic syndrome (HUS).
The study included all patients with ESKD who commenced renal replacement therapy in Australia and New Zealand between 15/5/1963 and 31/12/2010, using data from the ANZDATA Registry. HUS ESKD patients were compared with matched controls with an alternative primary renal disease using propensity scores based on age, gender and treatment era.
Of the 58422 patients included in the study, 241 (0.4%) had ESKD secondary to HUS. HUS ESKD was independently associated with younger age, female gender and European race. Compared with matched controls, HUS ESKD was not associated with mortality on renal replacement therapy (adjusted hazard ratio [HR] 1.14, 95% CI 0.87-1.50, p = 0.34) or dialysis (HR 1.34, 95% CI 0.93-1.93, p = 0.12), but did independently predict recovery of renal function (HR 54.01, 95% CI 1.45-11.1, p = 0.008). 130 (54%) HUS patients received 166 renal allografts. Overall renal allograft survival rates were significantly lower for patients with HUS ESKD at 1 year (73% vs 91%), 5 years (62% vs 85%) and 10 years (49% vs 73%). HUS ESKD was an independent predictor of renal allograft failure (HR 2.59, 95% CI 1.70-3.95, p < 0.001). Sixteen (12%) HUS patients experienced failure of 22 renal allografts due to recurrent HUS. HUS ESKD was not independently associated with the risk of death following renal transplantation (HR 0.92, 95% CI 0.35-2.44, p = 0.87).
HUS is an uncommon cause of ESKD, which is associated with comparable patient survival on dialysis, an increased probability of renal function recovery, comparable patient survival post-renal transplant and a heightened risk of renal transplant graft failure compared with matched ESKD controls.
PMCID: PMC3544575  PMID: 23206870
Haemolytic uraemic syndrome; Kidney Failure; Chronic; Outcomes; Renal function recovery; Renal transplantation; Thrombotic microangiopathy
13.  Risk factors affecting seroconversion after influenza A/H1N1 vaccination in hemodialysis patients 
BMC Nephrology  2012;13:165.
Hemodialysis (HD) patients have multiple causes of immune dysfunction and poor immune response to influenza vaccination. We investigated the antibody response rate to a pandemic H1N1/2009 influenza vaccination and clinical parameters influencing the induction of antibody responses in HD patients.
A total of 114 HD patients were vaccinated with a monovalent adjuvanted H1N1 inactivated influenza vaccine. Titers of neutralizing antibodies were evaluated by hemagglutination inhibition (HI) assay at pre- and 4 weeks after vaccination. Seroconversion was defined as either a pre-vaccination HI titer < 1:10 and a post vaccination HI titer > 1:40 or a pre-vaccination HI titer ≥ 1:10 and a minimum four-fold rise in post-vaccination HI antibody titer. Seventeen out of 114 HD patients (14.9%) tested positive for antibodies against influenza A/H1N1/2009 before vaccination. The remaining 97 baseline sero-negative patients were included in the analysis.
Only 30 (30.9%) HD patients had seroconversion 4 weeks after vaccination. The elderly patients, those over 65 years of age, showed significantly lower seroconversion rate compared to younger HD patients (20.5% vs. 39.6%, p = 0.042). Furthermore, patients with hemoglobin values less than 10 g/dL had a significantly lower seroconversion rate compared to those with higher hemoglobin values (20.0 vs. 38.6%, p = 0.049). By multivariate logistic regression analysis, only age ≥65 years (OR = 0.336, 95% confidence interval (CI) 0.116-0.971, p = 0.044) and hemoglobin levels <10 g/dL (OR = 0.315, 95% CI 0.106-0.932, p = 0.037) were independently associated with seroconversion after vaccination.
Our data show that HD patients, especially who are elderly with low hemoglobin levels, are at increased risk for lower seroconversion rate after influenza A/H1N1 vaccination. Further studies are needed to improve the efficacy of vaccination in these high risk patients.
PMCID: PMC3560184  PMID: 23206898
Hemodialysis; Pandemic H1N1/2009 influenza; Vaccine; Seroconversion
14.  Juvenile elastic arteries after 28 years of renal replacement therapy in a patient with complete complement C4 deficiency 
BMC Nephrology  2012;13:161.
Complement activation products are present in atherosclerotic plaques. Recently, binding of complement to elastin and collagen in the aortic wall has been demonstrated, suggesting a role of complement in the development aortic stiffness and atherosclerosis. The definitive role of complement in atherosclerosis and arteriosclerosis, however, remains unclear.
Case presentation
We here describe a patient with hereditary complete deficiency of complement C4 suffering from Henoch-Schoenlein purpura and on renal replacement therapy for twenty-eight years. The patient had the full range of risk factors for vascular damage such as hypertension, volume overload, hyperphosphatemia and hyperparathyroidism. Despite that, his carotid artery intima media thickness was below the normal range and his pulse wave velocity was normal. In contrast, the patient’s coronary and peripheral muscular arteries were heavily calcified.
This case supports the hypothesis that complement plays an important role in the development of stiffness of elastic arteries. We speculate that inability to activate complement by the classical or lectin pathways protected the patient from atherosclerosis, arteriosclerosis, stiffening and calcification of the aorta and carotid arteries. Inhibition of complement activation may be a potential target for prophylactic and therapeutic interventions.
PMCID: PMC3536710  PMID: 23199021
Complement; Atherosclerosis; Arteriosclerosis; Renal replacement therapy
15.  Effects of a high-sodium diet on renal tubule Ca2+ transporter and claudin expression in Wistar-Kyoto rats 
BMC Nephrology  2012;13:160.
Urinary Ca2+ excretion increases with dietary NaCl. NaCl-induced calciuria may be associated with hypertension, urinary stone formation and osteoporosis, but its mechanism and long-term effects are not fully understood. This study examined alterations in the expressions of renal Ca2+ transporters, channels and claudins upon salt loading to better understand the mechanism of salt-induced urinary Ca2+ loss.
Eight-week old Wistar-Kyoto rats were fed either 0.3% or 8% NaCl diet for 8 weeks. Renal cortical expressions of Na+/Ca2+ exchanger 1 (NCX1), Ca2+ pump (PCMA1b), Ca2+ channel (TRPV5), calbindin-D28k, and claudins (CLDN-2, -7, -8, -16 and −19) were analyzed by quantitative PCR, western blot and/or immunohistochemistry.
Fractional excretion of Ca2+ increased 6.0 fold with high-salt diet. Renal cortical claudin-2 protein decreased by approximately 20% with decreased immunological staining on tissue sections. Claudin-16 and −19 expressions were not altered. Renal cortical TRPV5, calbindin-D28k and NCX1 expressions increased 1.6, 1.5 and 1.2 fold, respectively.
Chronic high-salt diet decreased claudin-2 protein and increased renal TRPV5, calbindin-D28k, and NCX1. Salt loading is known to reduce the proximal tubular reabsorption of both Na+ and Ca2+. The reduction in claudin-2 protein expression may be partly responsible for the reduced Ca2+ reabsorption in this segment. The concerted upregulation of more distal Ca2+-transporting molecules may be a physiological response to curtail the loss of Ca2+, although the magnitude of compensation does not seem adequate to bring the urinary Ca2+ excretion down to that of the normal-diet group.
PMCID: PMC3538060  PMID: 23199000
Calcium; Sodium chloride; Distal tubule; Na+/Ca2+ exchanger; Ca2+ channel; Claudins
16.  Validation of the Oxford classification of IgA nephropathy for pediatric patients from China 
BMC Nephrology  2012;13:158.
The Oxford classification of IgA nephropathy (IgAN) provides a useful tool for prediction of renal prognosis. However, the application of this classification in children with IgAN needs validation in different patient populations.
A total of 218 children with IgAN from 7 renal centers in China were enrolled. The inclusion criteria was similar to the original Oxford study.
There were 98 patients (45%) with mesangial proliferation (M1), 51 patients (23%) with endocapillary proliferation (E1), 136 patients (62%) with segmental sclerosis/adhesion lesion (S1), 13 patients (6%) with moderate tubulointerstitial fibrosis (T1 26-50% of cortex scarred), and only 2 patients (1%) with severe tubulointerstitial fibrosis (T2, >50% of cortex scarred). During a median follow-up duration of 56 months, 24 children (12.4%) developed ESRD or 50% decline in renal function. In univariate COX analysis, we found that tubular atrophy/interstitial fibrosis (HR 4.3, 95%CI 1.8-10.5, P < 0.001) and segmental glomerulosclerosis (HR 9.2 1.2-68.6, P = 0.03) were significant predictors of renal outcome. However, mesangial hypercellularity, endocapillary proliferation, crescents, and necrosis were not associated with renal prognosis. In the multivariate COX regression model, none of these pathologic lesions were shown to be independent risk factors of unfavorable renal outcome except for tubular atrophy/interstitial fibrosis (HR 2.9, 95%CI 1.0-7.9 P = 0.04).
We confirmed tubular atrophy/interstitial fibrosis was the only feature independently associated with renal outcomes in Chinese children with IgAN.
PMCID: PMC3519602  PMID: 23181565
Glomerulonephritis; IgA nephropathy; Oxford classification; Children; Pediatrics
17.  Paricalcitol reduces oxidative stress and inflammation in hemodialysis patients 
BMC Nephrology  2012;13:159.
Treatment with selective vitamin D receptor activators such as paricalcitol have been shown to exert an anti-inflammatory effect in patients on hemodialysis, in addition to their action on mineral metabolism and independently of parathyroid hormone (PTH) levels. The objective of this study was to evaluate the additional antioxidant capacity of paricalcitol in a clinical setting.
The study included 19 patients with renal disease on hemodialysis, of whom peripheral blood was obtained for analysis at baseline and three months after starting intravenous paricalcitol treatment. The following oxidizing and inflammatory markers were quantified: malondialdehyde (MDA), nitrites and carbonyl groups, indoleamine 2,3-dioxygenase (IDO), tumor necrosis factor alfa (TNF-α), interleukin-6 (IL-6), interleukin-18 (IL-18) and C-reactive protein (CRP). Of the antioxidants and anti-inflammatory markers, superoxide dismutase (SOD), catalase, reduced glutathione (GSH), thioredoxin, and interleukin-10 (IL-10) levels were obtained.
Baseline levels of oxidation markers MDA, nitric oxide and protein carbonyl groups significantly decreased after three months on paricalcitol treatment, while levels of GSH, thioredoxin, catalase and SOD activity significantly increased. After paricalcitol treatment, levels of the inflammatory markers CRP, TNF-α, IL-6 and IL-18 were significantly reduced in serum and the level of anti-inflammatory cytokine IL-10 was increased.
In renal patients undergoing hemodialysis, paricalcitol treatment significantly reduces oxidative stress and inflammation, two well known factors leading to cardiovascular damage.
PMCID: PMC3520723  PMID: 23186077
Oxidative Stress; Immunomodulation; Receptors, Calcitriol; Paricalcitol; 19-nor-1alpha,25-dihydroxyvitamin D2
18.  A multi-centre qualitative study exploring the experiences of UK South Asian and White Diabetic Patients referred for renal care 
BMC Nephrology  2012;13:157.
An exploration of renal complications of diabetes from the patient perspective is important for developing quality care through the diabetic renal disease care pathway.
Newly referred South Asian and White diabetic renal patients over 16 years were recruited from nephrology outpatient clinics in three UK centres - Luton, West London and Leicester – and their experiences of the diabetes and renal care recorded.
A semi-structured qualitative interview was conducted with 48 patients. Interview transcripts were analysed thematically and comparisons made between the White and South Asian groups.
23 South Asian patients and 25 White patients were interviewed. Patient experience of diabetes ranged from a few months to 35 years with a mean time since diagnosis of 12.1 years and 17.1 years for the South Asian and White patients respectively. Confusion emerged as a response to referral shared by both groups. This sense of confusion was associated with reported lack of information at the time of referral, but also before referral. Language barriers exacerbated confusion for South Asian patients.
The diabetic renal patients who have been referred for specialist renal care and found the referral process confusing have poor of awareness of kidney complications of diabetes. Healthcare providers should be more aware of the ongoing information needs of long term diabetics as well as the context of any information exchange including language barriers.
PMCID: PMC3512518  PMID: 23176053
South Asian; Patient experience; Renal complications of diabetes; Access; Care pathway
19.  Characteristics of urinary and serum soluble Klotho protein in patients with different degrees of chronic kidney disease 
BMC Nephrology  2012;13:155.
Klotho is a single-pass transmembrane protein, which appears to be implicated in aging. The purpose of the present study was to characterize the relationship between the soluble Klotho level and renal function in patients with various degrees of chronic kidney disease (CKD).
The levels of soluble Klotho in the serum and urine obtained from one hundred thirty-one CKD patients were determined by a sandwich enzyme-linked immunosorbent assay system.
The amount of urinary excreted Klotho during the 24 hr period ranged from 1.6 to 5178 ng/day (median 427 ng/day; interquartile range [IR] 56.8-1293.1), and the serum Klotho concentration ranged from 163.9 to 2123.7 pg/ml (median 759.7 pg/ml; IR 579.5-1069.1). The estimated glomerular filtration rate (eGFR) was significantly correlated with the log-transformed values of the amount of 24 hr urinary excreted Klotho (r = 0.407, p < 0.01) and the serum Klotho levels (r = 0.232, p < 0.01). However, a stepwise multiple regression analysis identified eGFR to be a variable independently associated only with the log-transformed value of the amount of 24-hr urinary excreted Klotho but not with the log-transformed serum Klotho concentration. Despite the strong correlation between random urine protein-to-creatinine ratio and the 24 hr urinary protein excretion (r = 0.834, p < 0.01), a moderate linear association was observed between the log-transformed value of the amount of 24 hr urinary excreted Klotho and that of the urinary Klotho-to-creatinine ratio (Klotho/Cr) in random urine specimens (r = 0.726, p < 0.01).
The amount of urinary Klotho, rather than the serum Klotho levels, should be linked to the magnitude of the functioning nephrons in CKD patients. The use of random urine Klotho/Cr as a surrogate for the amount of 24-hr urinary excreted Klotho needs to be evaluated more carefully.
PMCID: PMC3519712  PMID: 23176706
Klotho; Chronic kidney disease; Renal function; Urinary protein; Creatinine
20.  Clinician’s use of automated reports of estimated glomerular filtration rate: A qualitative study 
BMC Nephrology  2012;13:154.
There is a growing awareness in primary care of the importance of identifying patients with chronic kidney disease (CKD) so that they can receive appropriate clinical care; one method that has been widely embraced is the use of automated reporting of estimated glomerular filtration rate (eGFR) by clinical laboratories. We undertook a qualitative study to examine how clinicians use eGFR in clinical decision making, patient communication issues, barriers to use of eGFR, and suggestions to improve the clinical usefulness of eGFR reports.
Our study used qualitative methods with structured interviews among primary care clinicians including both physicians and allied health providers, recruited from Kaiser Permanente Northwest, a non-profit health maintenance organization.
We found that clinicians generally held favorable views toward eGFR reporting but did not use eGFR to replace serum creatinine in their clinical decision-making. Clinicians used eGFR as a tool to help identify CKD, educate patients about their kidney function and make treatment decisions. Barriers noted by several clinicians included a desire for greater education regarding care for patients with CKD and tools to facilitate discussion of eGFR findings with patients.
The manner in which clinicians use eGFRs appears to be more complex than previously understood, and our study illustrates some of the efforts that might be usefully undertaken (e.g. specific clinician education) when encouraging further promulgation of eGFR reporting and usage.
PMCID: PMC3537573  PMID: 23173944
Estimated glomerular filtration rate; Qualitative; Serum creatinine
21.  The effects of a selective inhibitor of c-Fos/activator protein-1 on endotoxin-induced acute kidney injury in mice 
BMC Nephrology  2012;13:153.
Sepsis has been identified as the most common cause of acute kidney injury (AKI) in intensive care units. Lipopolysaccharide (LPS) induces the production of several proinflammatory cytokines including tumor necrosis factor (TNF)-alpha, a major pathogenetic factor in septic AKI. c-Fos/activator protein (AP)-1 controls the expression of these cytokines by binding directly to AP-1 motifs in the cytokine promoter regions. T-5224 is a new drug developed by computer-aided drug design that selectively inhibits c-Fos/AP-1 binding to DNA. In this study, we tested whether T-5224 has a potential inhibitory effect against LPS-induced AKI, by suppressing the TNF-alpha inflammatory response and other downstream effectors.
To test this hypothesis, male C57BL/6 mice at 7 weeks old were divided into three groups (control, LPS and T-5224 groups). Mice in the control group received saline intraperitoneally and polyvinylpyrrolidone solution orally. Mice in the LPS group were injected intraperitoneally with a 6 mg/kg dose of LPS and were given polyvinylpyrrolidone solution immediately after LPS injection. In the T-5224 group, mice were administered T-5224 orally at a dose of 300 mg/kg immediately after LPS injection. Serum concentrations of TNF-alpha, interleukin (IL)-1beta, IL-6 and IL-10 were measured by ELISA. Moreover, the expression of intercellular adhesion molecule (ICAM)-1 mRNA in kidney was examined by quantitative real-time RT-PCR. Finally, we evaluated renal histological changes.
LPS injection induced high serum levels of TNF-alpha, IL-1beta and IL-6. However, the administration of T-5224 inhibited the LPS-induced increase in these cytokine levels. The serum levels of IL-10 in the LPS group and T-5224 group were markedly elevated compared with the control group. T-5224 also inhibited LPS-induced ICAM-1 mRNA expression. Furthermore histological studies supported an anti-inflammatory role of T-5224.
In endotoxin-induced AKI, T-5224 inhibited the production of TNF-alpha and other downstream effectors. In contrast, T-5224 did not inhibit IL-10, an anti-inflammatory cytokine. These data support that the use of T-5224 is a promising new treatment for septic kidney injury.
PMCID: PMC3557146  PMID: 23173923
Sepsis; Acute kidney injury; TNF-α; Lipopolysaccharide; Activator protein-1
22.  Comparison of toxin removal outcomes in online hemodiafiltration and intra-dialytic exercise in high-flux hemodialysis: A prospective randomized open-label clinical study protocol 
BMC Nephrology  2012;13:156.
Maintenance hemodialysis (HD) patients universally suffer from excess toxin load. Hemodiafiltration (HDF) has shown its potential in better removal of small as well as large sized toxins, but its efficacy is restricted by inter-compartmental clearance. Intra-dialytic exercise on the other hand is also found to be effective for removal of toxins; the augmented removal is apparently obtained by better perfusion of skeletal muscles and decreased inter-compartmental resistance. The aim of this trial is to compare the toxin removal outcome associated with intra-dialytic exercise in HD and with post-dilution HDF.
The main hypothesis of this study is that intra-dialytic exercise enhances toxin removal by decreasing the inter-compartmental resistance, a major impediment for toxin removal. To compare the HDF and HD with exercise, the toxin rebound for urea, creatinine, phosphate, and β2-microglobulin will be calculated after 2 hours of dialysis. Spent dialysate will also be collected to calculate the removed toxin mass. To quantify the decrease in inter-compartmental resistance, the recently developed regional blood flow model will be employed. The study will be single center, randomized, self-control, open-label prospective clinical research where 15 study subjects will undergo three dialysis protocols (a) high flux HD, (b) post-dilution HDF, (c) high flux HD with exercise. Multiple blood samples during each study session will be collected to estimate the unknown model parameters.
This will be the first study to investigate the exercise induced physiological change(s) responsible for enhanced toxin removal, and compare the toxin removal outcome both for small and middle sized toxins in HD with exercise and HDF. Successful completion of this clinical research will give important insights into exercise effect on factors responsible for enhanced toxin removal. The knowledge will give confidence for implementing, sustaining, and optimizing the exercise in routine dialysis care. We anticipate that toxin removal outcomes from intra-dialytic exercise session will be comparable to that obtained by standalone HDF. These results will encourage clinicians to combine HDF with intra-dialytic exercise for significantly enhanced toxin removal.
Trial registration number, NCT01674153
PMCID: PMC3561063  PMID: 23176731
Hemodialysis; Hemodiafiltration; Intra-dialytic exercise; Toxin removal; Inter-compartmental resistance; Cardiac output; Regional blood flow model; Spent dialysate; Blood temperature
23.  Who should be prioritized for renal transplantation?: Analysis of key stakeholder preferences using discrete choice experiments 
BMC Nephrology  2012;13:152.
Policies for allocating deceased donor kidneys have recently shifted from allocation based on Human Leucocyte Antigen (HLA) tissue matching in the UK and USA. Newer allocation algorithms incorporate waiting time as a primary factor, and in the UK, young adults are also favoured. However, there is little contemporary UK research on the views of stakeholders in the transplant process to inform future allocation policy. This research project aimed to address this issue.
Discrete Choice Experiment (DCE) questionnaires were used to establish priorities for kidney transplantation among different stakeholder groups in the UK. Questionnaires were targeted at patients, carers, donors / relatives of deceased donors, and healthcare professionals. Attributes considered included: waiting time; donor-recipient HLA match; whether a recipient had dependents; diseases affecting life expectancy; and diseases affecting quality of life.
Responses were obtained from 908 patients (including 98 ethnic minorities); 41 carers; 48 donors / relatives of deceased donors; and 113 healthcare professionals. The patient group demonstrated statistically different preferences for every attribute (i.e. significantly different from zero) so implying that changes in given attributes affected preferences, except when prioritizing those with no rather than moderate diseases affecting quality of life. The attributes valued highly related to waiting time, tissue match, prioritizing those with dependents, and prioritizing those with moderate rather than severe diseases affecting life expectancy. Some preferences differed between healthcare professionals and patients, and ethnic minority and non-ethnic minority patients. Only non-ethnic minority patients and healthcare professionals clearly prioritized those with better tissue matches.
Our econometric results are broadly supportive of the 2006 shift in UK transplant policy which emphasized prioritizing the young and long waiters. However, our findings suggest the need for a further review in the light of observed differences in preferences amongst ethnic minorities, and also because those with dependents may be a further priority.
PMCID: PMC3576250  PMID: 23173887
Renal transplant; Allocation; Choice experiment; Stakeholder
24.  Renal AA-amyloidosis in intravenous drug users – a role for HIV-infection? 
BMC Nephrology  2012;13:151.
Chronic renal disease is a serious complication of long-term intravenous drug use (IVDU). Recent reports have postulated a changing pattern of underlying nephropathy over the last decades.
Retrospective investigation including all patients with prior or present IVDU that underwent renal biopsy because of chronic kidney disease between 01.04.2002 and 31.03.2012 in the city of Frankfurt/Main, Germany.
Twenty four patients with IVDU underwent renal biopsy because of progressive chronic kidney disease or proteinuria. Renal AA-amyloidosis was the predominant cause of renal failure in 50% of patients. Membranoproliferative glomerulonephritis (GN) was the second most common cause found in 21%. Patients with AA-amyloidosis were more likely to be HIV infected (67 vs.17%; p=0.036) and tended to have a higher rate of repeated systemic infections (92 vs. 50%; p=0.069). Patients with AA-amyloidosis presented with progressive renal disease and nephrotic-range proteinuria but most patients had no peripheral edema or systemic hypertension. Development of proteinuria preceded the decline of GFR for approximately 1–2 years.
AA-amyloidosis was the predominant cause of progressive renal disease in the last 10 years in patients with IVDU. The highest rate of AA-amyloidosis observed was seen in HIV infected patients with IVDU. We speculate that chronic HIV-infection as well as the associated immunosuppression might promote development of AA-amyloidosis by increasing frequency and duration of infections acquired by IVDU.
PMCID: PMC3519698  PMID: 23171281
AA-amylodosis; IVDU; Chronic kidney disease; HIV
25.  Antiproteinuric effect of add-on paricalcitol in CKD patients under maximal tolerated inhibition of renin-angiotensin system: a prospective observational study 
BMC Nephrology  2012;13:150.
Whether paricalcitol (PCT) reduces proteinuria in the presence of intensified inhibition of Renin-Angiotensin-System (RAS) is poorly studied. We evaluated the antiproteinuric effect of PCT in non-dialysis chronic kidney disease (CKD) patients with proteinuria greater than 0.5 g/24 h persisting despite anti-RAS therapy titrated to minimize proteinuria in the absence of adverse effects.
Forty-eight CKD patients were studied in the first six months of add-on oral PCT (1 mcg/day) and three months after drug withdrawal.
Males were 87.5%, age 63 ± 14 yrs, systolic/diastolic blood pressure (BP) 143 ± 22/78 ± 11 mmHg, eGFR 29.7 ± 14.5 mL/min/1.73 m2, diabetes 40%, and cardiovascular disease 38%. At referral in the center (28 months prior to study baseline), proteinuria was 2.44 (95% CI 1.80-3.04) g/24 h with 6 patients not receiving any anti-RAS and 42 treated with a single agent, at low dosage in most cases. At study baseline, twenty patients were under 2–3 anti-RAS drugs while twenty-eight received 1 agent at full dose and proteinuria resulted to be reduced versus referral to 1.23 g/24 h (95%CI 1.00-1.51). Six months of add-on PCT significantly decreased proteinuria to 0.61 g/24 h (95%CI 0.40-0.93), with levels less than 0.5 g/24 h achieved in 37.5% patients, in the absence of changes of BP and GFR. Proteinuria recovered to basal value after drug withdrawal. The extent of antiproteinuric response to PCT was positively associated with diabetes, eGFR and daily Na excretion (R2 = 0.459, P < 0.0001). PTH decreased from 201 (IQR 92–273) to 83 (IQR 50–189) pg/mL.
In CKD patients, add-on PCT induces a significant reduction of proteinuria that is evident despite intensified anti-RAS therapy and larger in the presence of diabetes, higher GFR and unrestricted salt intake.
PMCID: PMC3511164  PMID: 23167771
Angiotensin converting enzyme inhibitor; Angiotensin II receptor blocker; Renin inhibitor; Paricalcitol; Chronic kidney disease; Proteinuria

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