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Invasive Fungal Disease in Pediatric Solid Organ Transplant Recipients.

Wed, 10/11/2017 - 15:45

Invasive Fungal Disease in Pediatric Solid Organ Transplant Recipients.

J Pediatric Infect Dis Soc. 2017 Jun 15;:

Authors: Saxena S, Gee J, Klieger S, Kajon A, Petersen H, Zaoutis T, Fisher B

Abstract
Background: Solid organ transplant (SOT) recipients are at risk for invasive fungal disease (IFD). Data on IFD burden in pediatric patients are limited. We aimed to determine the incidence and outcome of IFD in a large cohort of pediatric patients who underwent SOT.
Methods: A single-center cohort of pediatric patients who underwent SOT between 2000 and 2013 was assembled retrospectively. The patients were followed for 180 days after transplant or until death to determine the presence or absence of IFD. The 2008 European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group and the National Institute of Allergy and Infectious Diseases Mycoses Study Group Consensus Group criteria were used to define IFD as proven or probable. The incidence of IFD, all-cause mortality rate, and case-fatality rate at 180 days were calculated.
Results: Among 584 pediatric patients who underwent SOT, 13 patients sustained 14 episodes of IFD (candidiasis, aspergillosis, and mucormycosis). The overall incidence was 2.2% (14.3 IFD events per 100000 patient-days). The IFD rates according to transplant type were 12.5% (1 of 8) (heart/lung), 11.4% (4 of 35) (lung), 4.7% (8 of 172) (liver), 0% (0 of 234) (kidney), and 0% (0 of 135) (heart). Three patients with IFD (2 lung and 1 heart/lung) died, and all these deaths were deemed likely attributable to the IFD; the case-fatality rate was 21.4% (3 of 14).
Conclusions: The overall incidence of IFD in these pediatric SOT recipients was low but varied across transplant type, with heart/lung and lung recipients having the highest IFD rate. Given the attributable case-fatality rate, the risk of death resulting from IFD is potentially high. More data on groups at higher risk, such as lung transplant recipients, are needed to guide targeted antifungal prophylaxis.

PMID: 28992290 [PubMed - as supplied by publisher]

Transcriptomics in kidney biopsy is an untapped resource for precision therapy in nephrology: a systematic review.

Wed, 10/11/2017 - 15:45

Transcriptomics in kidney biopsy is an untapped resource for precision therapy in nephrology: a systematic review.

Nephrol Dial Transplant. 2017 Aug 01;:

Authors: Schena FP, Nistor I, Curci C

Abstract
Background: The diagnosis of glomerular diseases is based on the evaluation of histological lesions in renal tissue by means of light and electronic microscopy, and immunofluorescence technique. Frozen and archival formalin-fixed paraffin-embedded kidney biopsies represent a stored resource for high-throughput technologies. Transcriptomics makes it possible to study the whole gene-expression profile of cells and tissues in a specific period and/or condition. The results, whether considered alone or integrated with other omics data, could help to improve existing knowledge about the pathogenetic mechanisms of glomerulopathies.
Methods: This review describes the molecular analysis of histological lesions obtained by transcriptomics in glomerular diseases, such as minimal change disease, focal and segmental glomerular sclerosis, IgA nephropathy, lupus nephritis and diabetic nephropathy.
Results: Of 716 articles obtained through database searches, 19 relevant articles were considered for the systematic review. Transcriptomics in kidney biopsy from patients with glomerular diseases have generated new insights on a few promising genes, illustrated in each disease section, which may be considered important targets for the care of these diseases.
Conclusions: Transcriptomics is an untapped resource for precision nephrology. Moreover, the integration of transcriptomics and systems pharmacology could predict the best drug combination to revert a pathological condition by targeting disease-specific molecular networks.

PMID: 28992289 [PubMed - as supplied by publisher]

Erlotinib attenuates the progression of chronic kidney disease in rats with remnant kidney.

Wed, 10/11/2017 - 15:45

Erlotinib attenuates the progression of chronic kidney disease in rats with remnant kidney.

Nephrol Dial Transplant. 2017 Sep 07;:

Authors: Yamamoto Y, Iyoda M, Tachibana S, Matsumoto K, Wada Y, Suzuki T, Iseri K, Saito T, Fukuda-Hihara K, Shibata T

Abstract
Background: Increasing evidence indicates that epidermal growth factor receptor (EGFR) has a pathogenic role in renal fibrosis. Currently no effective treatment can completely halt the progression of chronic kidney disease (CKD). This study was undertaken to investigate the renoprotective effects of erlotinib, a tyrosine kinase inhibitor that can block EGFR activity in the progression of CKD and the mechanisms involved.
Methods: Sprague Dawley rats with 5/6 nephrectomy were administered either erlotinib or vehicle from 2 weeks after surgery and for a period of 8 weeks. Blood pressure, proteinuria and serum creatinine were measured periodically. Renal morphological investigations were performed at sacrifice. In vitro , we used normal human mesangial cells (NHMCs) and human proximal tubular cells to investigate the inhibitory effects of erlotinib on renal fibrosis-associated signaling pathways by western blotting.
Results: Erlotinib treatment significantly blunted the progression of CKD as evidenced by reduced levels of serum creatinine, proteinuria and renal cortical profibrogenic genes and scores of glomerulosclerosis and tubulointerstitial damage. Tubulointerstitial macrophage infiltration and multiple pro-inflammatory cytokine gene expression levels were also attenuated by erlotinib treatment. In vitro , heparin-binding epidermal growth factor-like growth factor-induced Akt and extracellular-regulated kinase (ERK) 1/2 activation in normal human mesangial cells and human proximal tubular cells was inhibited by pretreatment with erlotinib.
Conclusions: EGFR blocking by erlotinib protected against renal fibrosis in 5/6 nephrectomized rats via inhibition of Akt and ERK 1/2 signaling pathways, which are associated with renal fibrosis. Erlotinib also has anti-inflammatory properties, which may contribute to its renoprotective effects. Erlotinib represents a potential novel therapeutic strategy for the treatment of CKD.

PMID: 28992288 [PubMed - as supplied by publisher]

Remote ischaemic preconditioning for renal and cardiac protection in adult patients undergoing cardiac surgery with cardiopulmonary bypass: systematic review and meta-analysis of randomized controlled trials.

Wed, 10/11/2017 - 15:45

Remote ischaemic preconditioning for renal and cardiac protection in adult patients undergoing cardiac surgery with cardiopulmonary bypass: systematic review and meta-analysis of randomized controlled trials.

Nephrol Dial Transplant. 2017 Jul 19;:

Authors: Deferrari G, Bonanni A, Bruschi M, Alicino C, Signori A

Abstract
Background: The main aim of this systematic review was to assess whether remote ischaemic preconditioning (RIPC) protects kidneys and the heart in cardiac surgery with cardiopulmonary bypass (CPB) and to investigate a possible role of anaesthetic agents.
Methods: Randomized clinical trials (RCTs) on the effects of RIPC through limb ischaemia in adult patients undergoing cardiac surgery with CPB were searched (1965-October 2016) in PubMed, Cochrane Library and article reference lists. A random effects model on standardized mean difference (SMD) for continuous outcomes and the Peto odds ratio (OR) for dichotomous outcomes were used to meta-analyse data. Subgroup analyses to evaluate the effects of different anaesthetic regimens were pre-planned.
Results: Thirty-three RCTs (5999 participants) were included. In the whole group, RIPC did not significantly reduce the incidence of acute kidney injury (AKI), acute myocardial infarction, atrial fibrillation, mortality or length of intensive care unit (ICU) and hospital stays. On the contrary, RIPC significantly reduced the area under the curve for myocardial injury biomarkers (MIBs) {SMD -0.37 [95% confidence interval (CI) -0.53 to - 0.21]} and the composite endpoint incidence [OR 0.85 (95% CI 0.74-0.97)]. In the volatile anaesthetic group, RIPC significantly reduced AKI incidence [OR 0.57 (95% CI 0.41-0.79)] and marginally reduced ICU stay. Conversely, except for MIBs, RIPC had fewer non-significant effects under propofol with or without volatile anaesthetics.
Conclusions: RIPC did not consistently reduce morbidity and mortality in adults undergoing cardiac surgery with CPB. In the subgroup on volatile anaesthetics only, RIPC markedly and significantly reduced the incidence of AKI and composite endpoint as well as myocardial injury.

PMID: 28992285 [PubMed - as supplied by publisher]

Plasma biomarkers improve prediction of diabetic kidney disease in adults with type 1 diabetes over a 12-year follow-up: CACTI study.

Wed, 10/11/2017 - 15:45

Plasma biomarkers improve prediction of diabetic kidney disease in adults with type 1 diabetes over a 12-year follow-up: CACTI study.

Nephrol Dial Transplant. 2017 Aug 21;:

Authors: Bjornstad P, Pyle L, Cherney DZI, Johnson RJ, Sippl R, Wong R, Rewers M, Snell-Bergeon JK

Abstract
Background: The objective of the study was to determine whether plasma biomarkers of kidney injury improve the prediction of diabetic kidney disease (DKD) in adults with type 1 diabetes (T1D) over a period of 12 years.
Methods: Participants ( n  = 527, 53% females) in the Coronary Artery Calcification in T1D (CACTI) Study were examined during 2002-04, at a mean (± standard deviation) age of 39.6 ± 9.0 years with 24.8 years as the median duration of diabetes. Urine albumin-to-creatinine (ACR) and estimated glomerular filtration rate (eGFR) by CKD-EPI (chronic kidney disease epidemiology collaboration) creatinine were measured at the baseline and after mean follow-up of 12.1 ± 1.5 years. Albuminuria was defined as ACR ≥30 mg/g and impaired GFR as eGFR <60 mL/min/1.73 m 2 . Kidney injury biomarkers (Meso Scale Diagnostics) were measured on stored baseline plasma samples. A principal component analysis (PCA) identified two components: (i) kidney injury molecule-1, calbindin, osteoactivin, trefoil factor 3 and vascular endothelial growth factor; and (ii) β-2 microglobulin, cystatin C, neutrophil gelatinase-associated lipocalin and osteopontin that were used in the multivariable regression analyses.
Results: Component 2 of the PCA was associated with increase in log modulus ACR [β ± standard error (SE): 0.16 ± 0.07, P = 0.02] and eGFR (β ± SE: -2.56 ± 0.97, P = 0.009) over a period of 12 years after adjusting for traditional risk factors (age, sex, HbA1c, low-density lipoprotein cholesterol and systolic blood pressure and baseline eGFR/baseline ACR). Only Component 2 of the PCA was associated with incident-impaired GFR (odds ratio 2.08, 95% confidence interval 1.18-3.67, P = 0.01), adjusting for traditional risk factors. The addition of Component 2 to traditional risk factors significantly improved C-statistics and net-reclassification improvement for incident-impaired GFR (ΔAUC: 0.02 ± 0.01, P = 0.049, and 29% non-events correctly reclassified, P < 0.0001).
Conclusions: Plasma kidney injury biomarkers can help predict development of DKD in T1D.

PMID: 28992280 [PubMed - as supplied by publisher]

Targeting new cellular disease pathways in autosomal dominant polycystic kidney disease.

Wed, 10/11/2017 - 15:45

Targeting new cellular disease pathways in autosomal dominant polycystic kidney disease.

Nephrol Dial Transplant. 2017 Aug 29;:

Authors: Chang MY, C M Ong A

Abstract
Autosomal dominant polycystic kidney disease (ADPKD) is the most common inherited cause of end-stage renal failure. Understanding the molecular and cellular pathogenesis of ADPKD could help to identify new targets for treatment. The classic cellular cystic phenotype includes changes in proliferation, apoptosis, fluid secretion, extracellular matrix and cilia function. Hoever, recent research, suggests that the cellular cystic phenotype could be broader and that changes, such as altered metabolism, autophagy, inflammation, oxidative stress and epigenetic modification, could play important roles in the processes of cyst initiation, cyst growth or disease progression. Here we review these newer cellular pathways, describe evidence for their possible links to cystic pathogenesis or different stages of disease and discuss the options for developing novel treatments.

PMID: 28992279 [PubMed - as supplied by publisher]

White blood cell fractions correlate with lesions of diabetic kidney disease and predict loss of kidney function in Type 2 diabetes.

Wed, 10/11/2017 - 15:45

White blood cell fractions correlate with lesions of diabetic kidney disease and predict loss of kidney function in Type 2 diabetes.

Nephrol Dial Transplant. 2017 Jul 18;:

Authors: Wheelock KM, Saulnier PJ, Tanamas SK, Vijayakumar P, Weil EJ, Looker HC, Hanson RL, Lemley KV, Yee B, Knowler WC, Hadjadj S, Najafian B, Mauer M, Nelson RG

Abstract
Background: Inflammation linked to diabetic kidney disease (DKD) may affect white blood cell (WBC) counts and differentials. We examined the cross-sectional associations of total WBC count and WBC fractions with structural lesions of DKD in 108 Pima Indians with Type 2 diabetes who underwent research kidney biopsies. We also examined the longitudinal association of these WBC variables with renal function loss (RFL) in 941 Europeans with Type 2 diabetes from the SURDIAGENE study.
Methods: Associations of WBC variables with morphometric parameters were assessed by linear regression. RFL was defined as≥40% loss of estimated glomerular filtration rate from baseline. Associations with RFL were evaluated by Cox regression. Hazard ratios (HRs) were reported per standard deviation increment of each WBC variable.
Results: After multivariable adjustment, lymphocyte ( r   = -0.20, P   =   0.043) and eosinophil ( r  =   0.21, P   =   0.032) fractions in the Pima Indians correlated with glomerular basement membrane width. Eosinophil fraction also correlated with glomerular filtration surface density ( r   = -0.21, P   =   0.031). Lymphocyte fraction ( r  =   0.25, P   =   0.013), neutrophil fraction ( r   = -0.23, P   =   0.021) and the neutrophil:lymphocyte ratio ( r   = -0.22, P   =   0.024) correlated with percentage of normally fenestrated endothelial cells. During median follow-up of 4.5 years, 321 SURDIAGENE participants developed RFL. Lower lymphocyte fraction [HR = 0.67, 95% confidence interval (95% CI) 0.60-0.76] and higher neutrophil fraction (HR = 1.35, 95% CI 1.20-1.52), total WBC count (HR = 1.20, 95% CI 1.08-1.35) and neutrophil:lymphocyte ratio (HR = 1.44, 95% CI 1.28-1.62) each predicted RFL in this cohort.
Conclusions: WBC fractions associate with morphometric lesions of DKD and predict RFL in individuals with Type 2 diabetes.

PMID: 28992267 [PubMed - as supplied by publisher]

Glomerular function in relation to circulating adhesion molecules and inflammation markers in a general population.

Wed, 10/11/2017 - 15:45

Glomerular function in relation to circulating adhesion molecules and inflammation markers in a general population.

Nephrol Dial Transplant. 2017 Aug 23;:

Authors: Feng YM, Thijs L, Zhang ZY, Yang WY, Huang QF, Wei FF, Kuznetsova T, Jennings AM, Delles C, Lennox R, Verhamme P, Dominiczak A, Staessen JA

Abstract
Background: Inflammation is a hallmark of chronic kidney disease (CKD) and stimulates glomerular expression of vascular adhesion molecules (VCAMs). We investigated in a general population whether estimated glomerular filtration rate (eGFR) is associated with circulating adhesion molecules, inflammation markers or both.
Methods: We measured serum levels of five adhesion molecules [VCAM-1, intracellular adhesion molecule-1 (ICAM-1), P-selectin, E-selectin and monocyte chemoattractant protein-1 (MCP-1)] and seven inflammation markers [C-reactive protein (CRP), neutrophil gelatinase-associated lipocalin (NGAL), tumour necrosis factor receptor 1 (TNF-R1), TNF-α, interleukin 6 (IL-6), IL-8 and vascular endothelial growth factor] in 1338 randomly recruited people (50.8% women, mean age 51.7 years, eGFR 79.9 mL/min/1.73 m 2 ).
Results: In multivariable-adjusted analyses, eGFR decreased (P ≤ 0.004) with higher VCAM-1 (association size expressed in mL/min/1.73 m 2 for a doubling of the marker, -2.99), MCP-1 (-1.19), NGAL (-1.19), TNF receptor 1 (-2.78), TNF-α (-2.28) and IL-6 (-0.94). The odds ratios of having eGFR <60 versus ≥60 mL/min/1.73 m 2 ( n  = 138 versus 1200) were significant (P ≤ 0.001) for VCAM-1 (1.77), MCP-1 (1.32), NGAL (1.26), TNF-R1 (1.49), TNF-α (1.45) and IL-6 (1.20). Compared with 24-h albuminuria, VCAM-1 increased (P <0.0001) the area under the curve from 0.57 to 0.65, MCP-1 to 0.67 and TNF-R1 to 0.79, but TNF-R1 outperformed both adhesion molecules (P < 0.0001).
Conclusions: In a general population, eGFR is inversely associated with circulating adhesion molecules VCAM-1 and MCP-1 and several inflammation markers, but inflammation markers, in particular TNF-R1 and TNF-α, identify patients with eGFR <60 mL/min/1.73 m 2 more accurately.

PMID: 28992257 [PubMed - as supplied by publisher]

Association of dipstick hematuria with all-cause mortality in the general population: results from the specific health check and guidance program in Japan.

Wed, 10/11/2017 - 15:45

Association of dipstick hematuria with all-cause mortality in the general population: results from the specific health check and guidance program in Japan.

Nephrol Dial Transplant. 2017 Jul 12;:

Authors: Iseki K, Konta T, Asahi K, Yamagata K, Fujimoto S, Tsuruya K, Narita I, Kasahara M, Shibagaki Y, Moriyama T, Kondo M, Iseki C, Watanabe T, Design of the Comprehensive Health Care System for Chronic Kidney Disease (CKD) Based on the Individual Risk Assessment by Specific Health Check

Abstract
Background: Dipstick urine tests are used for general health screening in Japan. The effects of this screening on mortality have not been examined, especially with regard to hematuria.
Methods: Subjects were those who participated in the 2008 Tokutei-Kenshin (nationwide specific health check and guidance program) in six districts in Japan. Using the national database of death certificates from 2008 to 2012, we identified subjects who might have died. We verified the candidates in collaboration with the regional National Health Insurance agency and public health nurses. Data were released to the research team supported by the Ministry of Health, Labor, and Welfare of Japan. Dipstick results of 1+ and higher were defined as hematuria (+). Hazard ratio (HR) [95% confidence interval (CI)] was calculated using the Cox proportional hazard analysis.
Results: Among 112 115 subjects, we identified that 1290 had died by the end of 2012. In hematuria (-) subjects, the crude mortality rates were 1.2% (1.8% in men, 0.7% in women), whereas in hematuria (+) subjects, they were 1.1% (2.9% in men, 0.7% in women). After adjusting for age, body mass index, estimated glomerular filtration rate, proteinuria, comorbid condition (diabetes mellitus, hypertension and dyslipidemia), past history (stroke, heart disease and kidney disease) and lifestyle (smoking, drinking, walking and exercise), the HR (95% CI) for dipstick hematuria (+) in men was 1.464 (1.147-1.846; P = 0.003), whereas that for hematuria (-) was 0.820 (0.617-1.073; P = 0.151).
Conclusions: Dipstick hematuria is significantly associated with mortality in men among Japanese community-based screening participants.

PMID: 28992249 [PubMed - as supplied by publisher]

Treatment by immunoadsorption for recurrent focal segmental glomerulosclerosis after paediatric kidney transplantation: a multicentre French cohort.

Wed, 10/11/2017 - 15:45

Treatment by immunoadsorption for recurrent focal segmental glomerulosclerosis after paediatric kidney transplantation: a multicentre French cohort.

Nephrol Dial Transplant. 2017 Jul 28;:

Authors: Allard L, Kwon T, Krid S, Bacchetta J, Garnier A, Novo R, Deschenes G, Salomon R, Roussey G, Allain-Launay E

Abstract
Background: Primary focal segmental glomerulosclerosis (FSGS) frequently recurs after kidney transplantation (KTx) in children. This can lead to delayed graft loss. As the management of children with recurrent FSGS is not well established, apheresis strategies could be a cornerstone to control the disease. Immunoadsorption (IA) is a recent apheresis therapy. There have been few studies examining IA in this setting. We report the results of IA for management of recurrent FSGS after KTx in children in France.
Methods: We included all children treated with IA for early FSGS recurrence after KTx between January 2011 and June 2014 in France. We excluded genetic forms of FSGS. Patients' characteristics and technical data on IA were retrospectively collected. Recurrence was defined as nephrotic proteinuria during the post-transplantation period. Partial and complete remissions were defined when urine protein:creatinine ratios were less than 0.2 and 0.05 g/mmol, respectively.
Results: Twelve patients, from six paediatric KTx units, presenting with FSGS recurrence between 0 and 21 days after KTx were treated with IA. Ten of 12 children were responders: 2 achieved partial remission and 8 complete remission. The decrease of proteinuria rapidly occurred within the first 10 sessions after initiating IA. After 3 months of IA, two patients maintained remission without IA and eight became IA dependent. No severe side effects were reported.
Conclusions: Our study reports on the efficacy of IA in the recurrence of FSGS after KTx in children. Further prospective controlled studies are required to confirm these results and to optimize the management of FSGS recurrence after paediatric KTx.

PMID: 28992235 [PubMed - as supplied by publisher]

Meta-analysis of cognitive functioning in patients following kidney transplantation.

Wed, 10/11/2017 - 15:45

Meta-analysis of cognitive functioning in patients following kidney transplantation.

Nephrol Dial Transplant. 2017 Sep 07;:

Authors: Joshee P, Wood AG, Wood ER, Grunfeld EA

Abstract
Background: There is mixed evidence regarding the nature of cognitive function in patients who have undergone renal transplantation. The aim of this meta-analysis was to examine which cognitive domains are impacted following kidney transplantation and how performance compares with non-transplanted patients or healthy controls/normative data.
Method: A systematic search was conducted using keywords within three databases (Embase, MEDLINE and PsychINFO), yielding 458 unique studies, 10 of which met the inclusion criteria. Neuropsychological tests were grouped into nine cognitive domains and three separate analyses were undertaken within each domain: (i) within subjects pre- versus post-transplant, (ii) transplanted versus non-transplanted patients and (iii) transplanted versus healthy matched controls and standardized normative data.
Results: Transplanted patients showed moderate to large improvements in the domains of general cognitive status ( g  = 0.526), information and motor speed ( g  = 0.558), spatial reasoning ( g  = 0.376), verbal memory ( g  = 0.759) and visual memory ( g  = 0.690) when compared with their pre-operative scores. Test scores in the same five domains were significantly better in post-transplanted patients when compared with dialysis-dependant or conservatively managed chronic kidney disease patients. However, post-transplanted patients' performance was significantly low compared with that of healthy controls (and standardized normative data) in the domains of executive functioning ( g  = -0.283), verbal fluency ( g  = -0.657) and language ( g  = -0.573).
Conclusions: Two key issues arise from this review. First, domain-specific cognitive improvement occurs in patients after successful transplantation. Nevertheless, transplanted patients still performed significantly below healthy controls in some domains. Second, there are important shortcomings in existing studies; the length of follow-up is typically short and only limited neuropsychological test batteries are employed. These factors are important in order to support the recovery of cognitive function among patients following renal transplant.

PMID: 28992229 [PubMed - as supplied by publisher]

Etiology and renal outcomes of acute tubulointerstitial nephritis: a single-center prospective cohort study in China.

Wed, 10/11/2017 - 15:45

Etiology and renal outcomes of acute tubulointerstitial nephritis: a single-center prospective cohort study in China.

Nephrol Dial Transplant. 2017 Aug 17;:

Authors: Su T, Gu Y, Sun P, Tang J, Wang S, Liu G, Li X, Yang L

Abstract
Background: The aim of this study was to explore the etiology, long-term renal outcomes and affecting factors of acute tubulointerstitial nephritis (ATIN).
Methods: Patients with biopsy-proven ATIN from 1 January 2005 to 31 December 2013 at Peking University First Hospital were enrolled in the study and received scheduled follow-up for at least 24 months. The causes of ATIN were defined at biopsy and reclassified during follow-up. Factors affecting renal recovery at 6 months post-biopsy and estimated glomerular filtration rate (eGFR) at 12 months post-biopsy and at the end of follow-up were analyzed.
Results: A total of 157 ATIN patients were enrolled, with an average follow-up of 48 months (range 24-108 months). A modified etiology spectrum was identified, with a decreased proportion of drug-induced ATIN (D-ATIN, 64% at biopsy to 50% after follow-up) and an increase in autoimmune-related ATIN (22-41%) with late-onset systemic manifestations in patients who had been classified as D-ATIN or ATIN of unknown cause. Recurrent kidney injury was observed in 51% of the patients with tubulointerstitial nephritis and uveitis syndrome (TINU), 53% of those with an autoimmune disease and 8% of those with D-ATIN, resulting in prolonged immunosuppressive treatment. By 12 months, decreased eGFR (<60 mL/min/1.73 m 2 ) was observed in 47% of the patients with D-ATIN, 74% of those with TINU and 57% of those with other autoimmune diseases. In multivariable analysis, female sex, older age, presence of hypertension and recurrent kidney injury were independent risk factors for worse renal outcomes.
Conclusions: Our data demonstrate that autoimmune-related ATIN may present with systemic manifestations after kidney injury and is, therefore, commonly misdiagnosed. Repeated kidney injury is not uncommon in patients with ATIN. Scheduled follow-up is, therefore, critical for defining the exact etiology and proper management of ATIN.

PMID: 28992223 [PubMed - as supplied by publisher]

The diabetes pandemic suggests unmet needs for 'CKD with diabetes' in addition to 'diabetic nephropathy'-implications for pre-clinical research and drug testing.

Wed, 10/11/2017 - 15:45

The diabetes pandemic suggests unmet needs for 'CKD with diabetes' in addition to 'diabetic nephropathy'-implications for pre-clinical research and drug testing.

Nephrol Dial Transplant. 2017 Jul 31;:

Authors: Anguiano Gómez L, Lei Y, Kumar Devarapu S, Anders HJ

Abstract
Curing 'diabetic nephropathy' is considered an unmet medical need of high priority. We propose to question the concept of 'diabetic nephropathy' that implies diabetes as the predominant cause of kidney disease, which may not apply to the majority of type 2 diabetics approaching end-stage kidney disease. With the onset of diabetes, hyperglycaemia/sodium-glucose co-transporter-2-driven glomerular hyperfiltration promotes nephron hypertrophy, which, however, on its own, causes proteinuria not before a decade later, probably because podocyte hypertrophy can usually accommodate an increase in the filtration surface. In contrast, precedent chronic kidney disease (CKD), that is, few nephrons per body mass, e.g. due to poor nephron endowment from birth, obesity, pregnancy, or renal ageing or injury-related nephron loss, usually precedes the onset of type 2 diabetes. This applies in particular in older adults, and each on its own, but especially in combination, further aggravates single nephron hyperfiltration and glomerular hypertrophy. Whenever this additional hyperglycaemia-driven enlargement of the glomerular filtration surface exceeds the capacity of podocytes for hypertrophy, podocytes detachment leads to glomerulosclerosis and nephron loss, i.e. CKD progression. Animal models of 'diabetic nephropathy' based only on hyperglycaemia do not mimic this aspect and therefore poorly predict outcomes of clinical trials usually performed on elderly CKD patients with type 2 diabetes. Thus, we advocate the use of renal mass (nephron) ablation in type 2 diabetic animals to better mimic the pathophysiology of 'CKD with diabetes' in the target patient population and the use of the glomerular filtration rate as a primary endpoint to more reliably predict trial outcomes.

PMID: 28992221 [PubMed - as supplied by publisher]

Metabolic imaging of fatty kidney in diabesity: validation and dietary intervention.

Wed, 10/11/2017 - 15:45

Metabolic imaging of fatty kidney in diabesity: validation and dietary intervention.

Nephrol Dial Transplant. 2017 Sep 15;:

Authors: Jonker JT, de Heer P, Engelse MA, van Rossenberg EH, Klessens CQF, Baelde HJ, Bajema IM, Koopmans SJ, Coelho PG, Streefland TCM, Webb AG, Dekkers IA, Rabelink TJ, Rensen PCN, Lamb HJ, de Vries APJ

Abstract
Background: Obesity and type 2 diabetes have not only been linked to fatty liver, but also to fatty kidney and chronic kidney disease. Since non-invasive tools are lacking to study fatty kidney in clinical studies, we explored agreement between proton magnetic resonance spectroscopy ( 1 H-MRS) and enzymatic assessment of renal triglyceride content (without and with dietary intervention). We further studied the correlation between fatty kidney and fatty liver.
Methods: Triglyceride content in the renal cortex was measured by 1 H-MRS on a 7-Tesla scanner in 27 pigs, among which 15 minipigs had been randomized to a 7-month control diet, cafeteria diet (CAF) or CAF with low-dose streptozocin (CAF-S) to induce insulin-independent diabetes. Renal biopsies were taken from corresponding MRS-voxel locations. Additionally, liver biopsies were taken and triglyceride content in all biopsies was measured by enzymatic assay.
Results: Renal triglyceride content measured by 1 H-MRS and enzymatic assay correlated positively ( r = 0.86, P < 0.0001). Compared with control diet-fed minipigs, renal triglyceride content was higher in CAF-S-fed minipigs (137 ± 51 nmol/mg protein, mean ± standard error of the mean, P < 0.05), but not in CAF-fed minipigs (60 ± 10 nmol/mg protein) compared with controls (40 ± 6 nmol/mg protein). Triglyceride contents in liver and kidney biopsies were strongly correlated ( r = 0.97, P < 0.001).
Conclusions: Non-invasive measurement of renal triglyceride content by 1 H-MRS closely predicts triglyceride content as measured enzymatically in biopsies, and fatty kidney appears to develop parallel to fatty liver. 1 H-MRS may be a valuable tool to explore the role of fatty kidney in obesity and type 2 diabetic nephropathy in humans in vivo .

PMID: 28992141 [PubMed - as supplied by publisher]

Inflammation induces osteoclast differentiation from peripheral mononuclear cells in chronic kidney disease patients: crosstalk between the immune and bone systems.

Wed, 10/11/2017 - 15:45

Inflammation induces osteoclast differentiation from peripheral mononuclear cells in chronic kidney disease patients: crosstalk between the immune and bone systems.

Nephrol Dial Transplant. 2017 Jul 21;:

Authors: Cafiero C, Gigante M, Brunetti G, Simone S, Chaoul N, Oranger A, Ranieri E, Colucci S, Pertosa GB, Grano M, Gesualdo L

Abstract
Background: Inflammation and immune system alterations contribute to bone damage in many pathologies by inducing the differentiation of osteoclasts (OCs), the bone resorbing cells. This link is largely unexplored in chronic kidney disease (CKD) and haemodialysis (HD) patients, in which reduced renal function is accompanied by an increased inflammatory state and skeletal abnormality.
Methods: We used ex vivo culture experiments to investigate the osteoclastogenic potential of peripheral blood mononuclear cells (PBMCs) of CKD and HD patients, focusing on immune cell subsets and inflammatory cytokines such as LIGHT and receptor activator of nuclear factor κB ligand (RANKL).
Results: We observed spontaneous osteoclastogenesis with a significant increase in OC formation and bone resorbing activity in late-stage CKD and HD patients when compared with early-stage CKD patients and healthy donors, likely due to an increased expression of RANKL and LIGHT (homologous to Lymphotoxins exhibiting Inducible expression and competing with herpes simplex virus Glycoprotein D for herpes virus entry mediator [HVEM], a receptor expressed by T lymphocytes) in PBMCs. Specific inhibition of these cytokines in PBMCs isolated from CKD stages 3b-5 and HD patients induced the reduction of OC formation in vitro . The phenotypic characterization of peripheral blood cells revealed a significant increase of OC precursors (CD14 + CD11b + CD51/61 + ) and CD14 + CD16 + monocytes in advanced CKD and HD patients compared with the control group.
Conclusions: Our results suggest that circulating inflammatory monocytes from advanced CKD or HD patients trans differentiate into OCs in vitro and play a relevant role in mineral bone disorders and that LIGHT and RANKL represent new potential therapeutic targets in these settings.

PMID: 28992140 [PubMed - as supplied by publisher]

Concentrations of representative uraemic toxins in a healthy versus non-dialysis chronic kidney disease paediatric population.

Wed, 10/11/2017 - 15:45

Concentrations of representative uraemic toxins in a healthy versus non-dialysis chronic kidney disease paediatric population.

Nephrol Dial Transplant. 2017 Jul 24;:

Authors: Snauwaert E, Van Biesen W, Raes A, Glorieux G, Van Bogaert V, Van Hoeck K, Coppens M, Roels S, Vande Walle J, Eloot S

Abstract
Background: Chronic kidney disease (CKD) in childhood is poorly explained by routine markers (e.g. urea and creatinine) and is better depicted in adults by other uraemic toxins. This study describes concentrations of representative uraemic toxins in non-dialysis CKD versus healthy children.
Methods: In 50 healthy children and 57 children with CKD Stages 1-5 [median estimated glomerular filtration rate 48 (25th-75th percentile 24-71) mL/min/1.73 m 2 ; none on dialysis], serum concentrations of small solutes [symmetric and asymmetric dimethyl-arginine (SDMA and ADMA, respectively)], middle molecules [β2-microglobuline (β2M), complement factor D (CfD)] and protein-bound solutes [ p -cresylglucuronide (pCG), hippuric acid (HA), indole-acetic acid (IAA), indoxyl sulphate (IxS), p -cresyl sulphate (pCS) and 3-carboxy-4-methyl-5-propyl-furanpropionic acid (CMPF)] were measured. Concentrations in the CKD group were expressed as z -score relative to controls and matched for age and gender.
Results: SDMA, CfD, β2M, IxS, pCS, IAA, CMPF and HA concentrations were higher in the overall CKD group compared with controls, ranging from 1.7 standard deviations (SD) for IAA and HA to 11.1 SD for SDMA. SDMA, CfD, β2M, IxS and CMPF in CKD Stages 1-2 with concentrations 4.8, 2.8, 4.5, 1.9 and 1.6 SD higher, respectively. In contrast, pCS, pCG and IAA concentrations were only higher than controls from CKD Stages 3-4 onwards, but only in CKD Stage 5 for ADMA and HA ( z -score 2.6 and 20.2, respectively).
Conclusions: This is the first study to establish reference values for a wide range of uraemic toxins in non-dialysis CKD and healthy children. We observed an accumulation of multiple uraemic toxins, each with a particular retention profile according to the different CKD stages.

PMID: 28992139 [PubMed - as supplied by publisher]

Risk of new-onset diabetes in end-stage renal disease patients undergoing dialysis: analysis from registry data of Taiwan.

Wed, 10/11/2017 - 15:45

Risk of new-onset diabetes in end-stage renal disease patients undergoing dialysis: analysis from registry data of Taiwan.

Nephrol Dial Transplant. 2017 Aug 10;:

Authors: Wang IK, Lin CL, Chen HC, Lin SY, Chang CT, Yen TH, Sung FC

Abstract
Background: This study compared the risk of developing new-onset diabetes between hemodialysis (HD) and peritoneal dialysis (PD) patients. We further investigated the effectiveness of icodextrin in reducing the risk of new-onset diabetes in PD patients.
Methods: From the Taiwan health insurance database, 36 879 incident HD patients and 6382 incident PD patients from 2000 to 2010 were identified as study cohorts. We further selected an additional HD cohort matched by propensity scores (PSs) of PD patients. Incidence rates and hazard ratios (HRs) of new-onset diabetes were assessed among cohorts and between icodextrin users and nonusers by the end of 2011.
Results: For the unmatched cohorts, the incidence of new-onset diabetes was higher in PD patients than in HD patients (9.16 versus 8.18 per 1000 person-years), with an adjusted HR of 1.51 (95% CI 1.30-1.75) for PD patients. For the PS-matched cohorts, the corresponding incidence rates were 9.43 and 5.90 per 1000 person-years, respectively, with an adjusted HR of 1.61 (95% CI 1.32-1.97). Among PD patients, the incidence was lower in icodextrin users than in nonusers (6.22 versus 12.1 per 1000 person-years), with an adjusted HR of 0.66 (95% CI 0.50-0.88) for users.
Conclusions: Our study suggests that PD patients are at a higher risk of developing new-onset diabetes than HD patients. Icodextrin is recommended for PD patients to reduce the risk of new-onset diabetes.

PMID: 28992134 [PubMed - as supplied by publisher]

Can we further enrich autosomal dominant polycystic kidney disease clinical trials for rapidly progressive patients? Application of the PROPKD score in the TEMPO trial.

Wed, 10/11/2017 - 15:45

Can we further enrich autosomal dominant polycystic kidney disease clinical trials for rapidly progressive patients? Application of the PROPKD score in the TEMPO trial.

Nephrol Dial Transplant. 2017 Jul 19;:

Authors: Cornec-Le Gall E, Blais JD, Irazabal MV, Devuyst O, Gansevoort RT, Perrone RD, Chapman AB, Czerwiec FS, Ouyang J, Heyer CM, Senum SR, Le Meur Y, Torres VE, Harris PC

Abstract
Background: The PROPKD score has been proposed to stratify the risk of progression to end-stage renal disease in autosomal dominant polycystic kidney disease (ADPKD) subjects. We aimed to assess its prognostic value in a genotyped subgroup of subjects from the Tolvaptan Phase 3 Efficacy and Safety Study in Autosomal Dominant Polycystic Kidney Disease (TEMPO3/4) trial.
Methods: In the post hoc analysis, PKD1 and PKD2 were screened in 770 subjects and the PROPKD score was calculated in mutation-positive subjects (male: 1 point; hypertension <35 years: 2 points; first urologic event <35 years: 2 points; nontruncating PKD1 mutation: 2 points; truncating PKD1 mutation: 4 points). Subjects were classified into low-risk (LR; 0-3 points), intermediate-risk (IR; 4-6 points) and high-risk (HR; 7-9 points) groups.
Results: The PROPKD score was calculated in 749 subjects (LR = 132, IR = 344 and HR = 273); age was inversely related to risk (LR = 43.6 years, IR = 39.5 years, HR = 36.2 years; P < 0.001). Subjects from the HR group had significantly higher height-adjusted total kidney volume (TKV) and rates of TKV growth. While baseline renal function was similar across all risk groups, the rate of estimated glomerular filtration rate (eGFR) decline significantly increased from LR to HR in the placebo group. Tolvaptan treatment effectiveness to reduce TKV growth was similar in all three risk categories. While tolvaptan significantly slowed eGFR decline in the IR (tolvaptan = -2.34 versus placebo = -3.33 mL/min/1.73 m 2 /year; P = 0.008) and HR groups (tolvaptan = -2.74 versus placebo = -3.94 mL/min/1.73 m 2 /year; P = 0.002), there was no difference in the LR group (tolvaptan = -2.35 versus placebo = -2.50 mL/min/1.73 m 2 /year; P = 0.72). Excluding the LR subjects from the analysis improved the apparent treatment effect of tolvaptan on eGFR decline.
Conclusion: This study confirms the prognostic value of the PROPKD score and suggests that it could reduce costs and enhance endpoint sensitivity by enriching future study populations for rapidly progressing ADPKD subjects.

PMID: 28992127 [PubMed - as supplied by publisher]

Impact of trajectories of abdominal aortic calcification over 2 years on subsequent mortality: a 10-year longitudinal study.

Wed, 10/11/2017 - 15:45

Impact of trajectories of abdominal aortic calcification over 2 years on subsequent mortality: a 10-year longitudinal study.

Nephrol Dial Transplant. 2017 Aug 25;:

Authors: Inoue H, Shimizu S, Watanabe K, Kamiyama Y, Shima H, Nakase A, Ishida H, Kurita N, Fukuma S, Fukuhara S, Yamada Y

Abstract
Background: Although both the presence and progression over time of vascular calcification have been shown to independently predict cardiovascular disease and mortality in chronic dialysis patients, the impact of the pattern of accumulation of abdominal aortic calcification on mortality has not yet been investigated.
Methods: We conducted a longitudinal study at a dialysis hospital in Hokkaido, Japan from 2005 to 2014. An abdominal calcification index (ACI) was generated for 396 patients from their annual abdominal computed tomography (CT) scans. The trajectories of ACIs during the first 2 years were classified using group-based trajectory modeling into four groups; stable (29.0%), slow increase (29.2%), rapid nonlinear increase (24.4%) and advanced with slow increase (17.4%). Incidence rates by group of all-cause mortality during the follow-up period (mean of 4.5 years) were investigated using the Cox proportional hazard model.
Results: Compared with the stable trajectory, both the rapid nonlinear increase and the advanced with slow increase trajectories were associated with an increased risk of death [adjusted hazard ratios (HR) 1.91; 95% confidence interval (CI) 1.02-3.58 and adjusted HR 2.79; 95% CI: 1.44-5.11, respectively]. Sensitivity analyses indicated that ACI trajectories were associated with subsequent mortality, while ACI at individual time points was not.
Conclusions: Chronic hemodialysis patients with a trajectory of longitudinal high or rapid accumulation of vascular calcification over time were at a higher risk of death. Individual trajectories of vascular calcification may be suggested to allow for more accurate mortality risk calculations than one-time assessment.

PMID: 28992124 [PubMed - as supplied by publisher]

Association of serum albumin levels with kidney function decline and incident chronic kidney disease in elders.

Wed, 10/11/2017 - 15:45

Association of serum albumin levels with kidney function decline and incident chronic kidney disease in elders.

Nephrol Dial Transplant. 2017 Aug 23;:

Authors: Lang J, Katz R, Ix JH, Gutierrez OM, Peralta CA, Parikh CR, Satterfield S, Petrovic S, Devarajan P, Bennett M, Fried LF, Cummings SR, Sarnak MJ, Shlipak MG

Abstract
Background: Previous studies in HIV-infected individuals have demonstrated serum albumin to be strongly associated with kidney function decline, independent of urine albumin and inflammatory markers. Lower serum albumin concentrations may be an under-appreciated risk factor for kidney function decline in elders.
Methods: We performed a cohort analysis in the Health Aging and Body Composition Study, a cohort of well-functioning, bi-racial, community-dwelling elders between the age of 70 and 79 years. We examined the associations of serum albumin concentration with longitudinal kidney function decline by estimated glomerular filtration rate (eGFR). Outcomes included linear eGFR decline, rapid kidney function decline defined as >30% decrease in eGFR, defined as a final eGFR <60 mL/min/1.73 m 2 in those with an eGFR >60 mL/min/1.73 m 2 at baseline. Cystatin C-based eGFR was calculated at baseline, Year 3 and Year 10.
Results: Mean age was 74 years, and mean eGFR was 73 mL/min/1.73 m 2 at baseline. The mean rate of eGFR change was 1.81 mL/min/1.73 m 2 per year. After multivariate adjustment, lower serum albumin concentrations were strongly and independently associated with kidney function decline (-0.11 mL/min/1.73 m 2 per year for each standard deviation decrease serum albumin; -0.01 to - 0.20) with no attenuation after adjustment for urine albumin and inflammatory markers (-0.12, -0.03 to - 0.22). When divided into quartiles, serum albumin levels ≤3.80 g/dL were associated with increased odds of rapid kidney function decline (odds ratio 1.59; 1.12-2.26) and increased risk of incident chronic kidney disease (incident rate ratio 1.29; 1.03-1.62) relative to levels >4.21g/dL. Urine albumin to creatinine ratio (ACR) was also significantly and independently associated with kidney function decline (-0.08 mL/min/1.73 m 2 per year for urine ACR >30 mg/g; -0.82 to - 0.13).
Conclusions: Lower serum albumin levels are strongly and independently associated with kidney function decline in elders, independent of clinical risk factors, urine albumin and measured inflammatory markers.

PMID: 28992097 [PubMed - as supplied by publisher]

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