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Atypical hemolytic uremic syndrome: what is it, how is it diagnosed, and how is it treated?

Sat, 06/29/2013 - 10:02
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Atypical hemolytic uremic syndrome: what is it, how is it diagnosed, and how is it treated?

Hematology Am Soc Hematol Educ Program. 2012;2012:617-25

Authors: Nester CM, Thomas CP

Abstract
Atypical hemolytic uremic syndrome (aHUS) is a rare syndrome of hemolysis, thrombocytopenia, and renal insufficiency. Genetic mutations in the alternate pathway of complement are well recognized as the cause in more than 60% of patients affected by this thrombotic microangiopathy. The identification of aHUS as a disease of the alternate pathway of complement enables directed therapeutic intervention both in the acute and chronic setting and may include one or all of the following: plasma therapy, complement blockade, and liver transplantation. Because aHUS shares many of the presenting characteristics of the other thrombotic microangiopathies, and confirmatory genetic results are not available at the time of presentation, the diagnosis relies heavily on the recognition of a clinical syndrome consistent with the diagnosis in the absence of signs of an alternate cause of thrombotic microangiopathy. Limited understanding of the epidemiology, genetics, and clinical features of aHUS has the potential to delay diagnosis and treatment. To advance our understanding, a more complete characterization of the unique phenotypical features of aHUS is needed. Further studies to identify additional genetic loci for aHUS and more robust biomarkers of both active and quiescent disease are required. Advances in these areas will undoubtedly improve the care of patients with aHUS.

PMID: 23233643 [PubMed - indexed for MEDLINE]

Long-term critical issues in pediatric renal transplant recipients: a single-center experience.

Sat, 06/29/2013 - 10:02
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Long-term critical issues in pediatric renal transplant recipients: a single-center experience.

Transpl Int. 2013 Feb;26(2):154-61

Authors: Harambat J, Ranchin B, Bertholet-Thomas A, Mestrallet G, Bacchetta J, Badet L, Basmaison O, Bouvier R, Demède D, Dubourg L, Floret D, Martin X, Cochat P

Abstract
Data on long-term outcomes after pediatric renal transplantation (Tx) are still limited. We report on a 20-year single-center experience. Medical charts of all consecutive pediatric Tx performed between 1987 and 2007 were reviewed. Data of patients who had been transferred to adult units were extracted from the French databases of renal replacement therapies. Outcomes were assessed using Kaplan-Meier and Cox models. Two hundred forty Tx were performed in 219 children (24.1% pre-emptive and 17.5% living related donor Tx). Median age at Tx was 11.1 years and median follow-up was 10.4 years. Patient survival was 94%, 92%, and 91% at 5, 10, and 15 years post-Tx, respectively. Overall, transplant survival was 92%, 82%, 72%, and 59% at 1, 5, 10, and 15 years post-Tx, respectively. The expected death-censored graft half-life was 20 years. Sixteen patients developed malignancies during follow-up. Median height at 18 years of age was 166 cm in boys and 152 cm in girls with 68% of patients being in the normal range. The proportion of socially disadvantaged young people was higher than in general population. Excellent long-term outcomes can be achieved in pediatric renal Tx, but specific problems such as malignancies, growth, and social outcome remain challenging.

PMID: 23227963 [PubMed - indexed for MEDLINE]

Do drug transporter (ABCB1) SNPs and P-glycoprotein function influence cyclosporine and macrolides exposure in renal transplant patients? Results of the pharmacogenomic substudy within the symphony study.

Sat, 06/29/2013 - 10:02
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Do drug transporter (ABCB1) SNPs and P-glycoprotein function influence cyclosporine and macrolides exposure in renal transplant patients? Results of the pharmacogenomic substudy within the symphony study.

Transpl Int. 2013 Feb;26(2):177-86

Authors: Llaudó I, Colom H, Giménez-Bonafé P, Torras J, Caldés A, Sarrias M, Cruzado JM, Oppenheimer F, Sánchez-Plumed J, Gentil MÁ, Ekberg H, Grinyó JM, Lloberas N

Abstract
The function of the efflux pump P-glycoprotein (Pgp) and ABCB1 single nucleotide polymorphisms (SNPs) should be considered as important tools to deepen knowledge of drug nephrotoxicity and disposition mechanisms. The aim of this study is to investigate the association of C3435T, G2677T, C1236T, and T129C ABCB1 SNPs with Pgp activity and exposure to different immunosuppressive drugs in renal transplant patients. Patients included in the Symphony Pharmacogenomic substudy were genotyped for ABCB1 SNPs. According to the design, patients were randomized into four immunosuppressive regimens: low and standard dose of cyclosporine (n = 30), tacrolimus (n = 13), and sirolimus (n = 23) concomitantly with mycophenolate and steroids. Pgp activity was evaluated in PBMC using the Rhodamine 123 efflux assay. TT carrier patients on C3435T, G2677T, and C1236T SNPs (Pgp-low pumpers) showed lower Pgp activity than noncarriers. Pgp-high pumpers treated with cyclosporine showed lower values of Pgp function than macrolides. There was a negative correlation between cyclosporine AUC and Pgp activity at 3 months. Results did not show any correlation between tacrolimus and sirolimus AUC and Pgp activity at 3 months. We found an important role of the ABCB1 SNPs Pgp function in CD3(+) peripheral blood lymphocytes from renal transplant recipients. Pgp activity was influenced by cyclosporine but not macrolides exposure.

PMID: 23216707 [PubMed - indexed for MEDLINE]

Impact of donor age on long-term outcomes after delayed graft function: 10-year follow-up.

Sat, 06/29/2013 - 10:02
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Impact of donor age on long-term outcomes after delayed graft function: 10-year follow-up.

Transpl Int. 2013 Feb;26(2):162-9

Authors: Lapointe I, Lachance JG, Noël R, Côté I, Caumartin Y, Agharazii M, Houde I, Rousseau-Gagnon M, Kim SJ, De Serres SA

Abstract
Delayed graft function (DGF) has a negative impact on graft survival in donation after brain death (DBD) but not for donation after cardiac death (DCD) kidneys. However, older donor age is associated with graft loss in DCD transplants. We sought to examine the interaction between donor age and DGF in DBD kidneys. This is a single-center, retrospective review of 657 consecutive DBD recipients transplanted between 1990 and 2005. We stratified the cohort by decades of donor age and studied the association between DGF and graft failure using Cox models. The risk of graft loss associated with DGF was not significantly increased for donor age below 60 years (adjusted hazard ratio [aHR] 1.12, 1.51, and 0.90, respectively, for age <40, 41-50 and 51-60 years) but significantly increased after 60 years (aHR 2.67; P = 0.019). Analysis of death-censored graft failure yielded similar results for donor age below 60 years and showed a substantially increased risk with donors above 60 years (aHR 6.98, P = 0.002). This analysis reveals an unexpectedly high impact of older donor age on the association between DGF and renal transplant outcomes. Further research is needed to determine the best use of kidneys from donors above 60 years old, where DGF is expected.

PMID: 23199029 [PubMed - indexed for MEDLINE]

Sirolimus therapy may cause cardiac tamponade.

Sat, 06/29/2013 - 10:02
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Sirolimus therapy may cause cardiac tamponade.

Transpl Int. 2013 Feb;26(2):e4-7

Authors: Bertrand D, Desbuissons G, Pallet N, Debure A, Sartorius A, Anglicheau D, Mamzer MF, Legendre C, Sberro-Soussan R

Abstract
The side-effects associated with the immunosuppressive drug sirolimus are numerous and constitute a major limitation for its use in renal transplantation. In this study, we describe two cases of renal transplant recipients treated with sirolimus who developed pericardial tamponade associated with interstitial pneumonia, proteinuria, microcytic anemia and, in one case, lymphocytic meningitidis. An extensive search for infectious agents was negative, and all symptoms disappeared after sirolimus interruption. Therefore, this case demonstrates for the first time that sirolimus can cause pericardial tamponade as well as lymphocytic meningitidis.

PMID: 23189945 [PubMed - indexed for MEDLINE]

Economic evaluation of different treatment modalities in acute kidney injury.

Sat, 06/29/2013 - 10:02
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Economic evaluation of different treatment modalities in acute kidney injury.

Nephrol Dial Transplant. 2012 Nov;27(11):4095-101

Authors: De Smedt DM, Elseviers MM, Lins RL, Annemans L

Abstract
BACKGROUND: Major controversy exists regarding the preferred treatment option for acute kidney injury (AKI). The purpose of this study was to assess the incremental cost-effectiveness of continuous renal replacement therapy (CRRT) versus intermittent renal replacement therapy (IRRT) and conservative (CONS) AKI treatment in Belgium.
METHODS: An area-under-the-curve model based on survival analysis was used to estimate costs and health outcomes using a 2-year time horizon. Input data were derived from the multi-centre Stuivenberg Hospital Acute Renal Failure 4 study.
RESULTS: Analyses indicated that in-hospital mortality, hospitalization costs and hospital length of stay differed significantly between treatment modes. Follow-up mortality rates and follow-up cost per day showed no significant difference between the treatment modes. Utility values, which improved gradually after admission to the hospital, revealed no significant differences between the three treatment strategies. CONS treatment was associated with a 2-year cost of 33,802€ and 0.54 quality-adjusted life years (QALYs). The CRRT was the most expensive therapy with a cost of 51,365€ leading to 0.57 QALYs. The cost and QALYs associated with IRRT were 43,445€ and 0.50, respectively. One-way sensitivity analyses indicated the 'in-hospital mortality' as the variable with the greatest influence on the results. Probabilistic sensitivity analysis resulted in a significant difference in treatment costs but no significant difference in QALY gain.
CONCLUSIONS: This study has indicated that the most expensive treatment (CRRT) associated with an incremental cost of approximately €7920 generates only a minor non-significant increase in QALYs of 0.07 compared with IRRT. Additionally, the results revealed that the RRTs did not result in a significant increase in QALYs despite their higher cost compared with the CONS treatment. From a health economic perspective, the latter seems to be the preferred treatment strategy.

PMID: 23144072 [PubMed - indexed for MEDLINE]

Screening for chronic kidney disease can be of help to prevent atherosclerotic end-organ damage.

Sat, 06/29/2013 - 10:02
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Screening for chronic kidney disease can be of help to prevent atherosclerotic end-organ damage.

Nephrol Dial Transplant. 2012 Nov;27(11):4046-52

Authors: Özyilmaz A, de Jong PE, Gansevoort RT

Abstract
Atherosclerotic damage to the kidney is one of the most prevalent causes of chronic kidney disease and ultimately kidney failure. It frequently coincides with atherosclerotic damage to the heart, the brain and the lower extremities. In fact, the severity of the damage in the various end organs runs in parallel. As damage to the kidney is easy to measure by monitoring albuminuria and eGFR, and as the early phases of kidney damage frequently precede the alarming symptomatology in the heart, brain and peripheral vasculature, we argue that the nephrologist should consider taking the lead in better organizing early detection and management of CKD. The nephrologist can guide the general practitioner and general health care workers to offer better preventive care to the subjects at risk of progressive atherosclerotic end-organ damage.

PMID: 23144071 [PubMed - indexed for MEDLINE]

Parvalbumin: calcium and magnesium buffering in the distal nephron.

Sat, 06/29/2013 - 10:02
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Parvalbumin: calcium and magnesium buffering in the distal nephron.

Nephrol Dial Transplant. 2012 Nov;27(11):3988-94

Authors: Olinger E, Schwaller B, Loffing J, Gailly P, Devuyst O

Abstract
Parvalbumin (PV) is a classical member of the EF-hand protein superfamily that has been described as a Ca(2+) buffer and Ca(2+) transporter/shuttle protein and may also play an additional role in Mg(2+) handling. PV is exclusively expressed in the early part of the distal convoluted tubule in the human and mouse kidneys. Recent studies in Pvalb knockout mice revealed a role of PV in the distal handling of electrolytes: the lack of PV was associated with a mild salt-losing phenotype with secondary aldosteronism, salt craving and stronger bones compared with controls. A link between the Ca(2+)-buffering capacity of PV and the expression of the thiazide-sensitive Na(+)-Cl(-) cotransporter was established, which could be relevant to the regulation of sodium transport in the distal nephron. Variants in the PVALB gene that encodes PV have been described, but their relevance to kidney function has not been established. PV is also considered a reliable marker of chromophobe carcinoma and oncocytoma, two neoplasms deriving from the distal nephron. The putative role of PV in tumour genesis remains to be investigated.

PMID: 23144069 [PubMed - indexed for MEDLINE]

The enigma of decreased creatinine generation in acute kidney injury.

Sat, 06/29/2013 - 10:02
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The enigma of decreased creatinine generation in acute kidney injury.

Nephrol Dial Transplant. 2012 Nov;27(11):3973-4

Authors: Heimbürger O, Stenvinkel P, Bárány P

PMID: 23144066 [PubMed - indexed for MEDLINE]

The vulnerable man: impact of testosterone deficiency on the uraemic phenotype.

Sat, 06/29/2013 - 10:02
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The vulnerable man: impact of testosterone deficiency on the uraemic phenotype.

Nephrol Dial Transplant. 2012 Nov;27(11):4030-41

Authors: Carrero JJ, Stenvinkel P

Abstract
Testosterone deficiency or hypogonadism is a common finding in men undergoing dialysis, to a great extent a consequence of the failing kidney per se. Testosterone restoration in hypogonadism is common practice among endocrinologists. However, there is currently little awareness of this condition among both uremic patients and nephrologists, and in many cases, testosterone deficiency remains unscreened and untreated. This review article summarizes our current understanding of the role of testosterone deficiency at the crossroad of cardiometabolic complications of patients with chronic kidney disease. Pathways discussed include, among others, the plausible role of testosterone deficiency in the development of anaemia and ESA hyporesponsiveness, muscle catabolism, endothelial dysfunction, cognitive dysfunction, decreased libido, cardiovascular disease and mortality. As there are limited sources to guide decision-making, we also review existing testosterone replacement therapy studies in the context of CKD as well as considerations for side and adverse effects. This review makes a case for consideration of screening and better management of hypogonadism in men undergoing dialysis.

PMID: 22962412 [PubMed - indexed for MEDLINE]

A randomized controlled trial of oral heme iron polypeptide versus oral iron supplementation for the treatment of anaemia in peritoneal dialysis patients: HEMATOCRIT trial.

Sat, 06/29/2013 - 10:02
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A randomized controlled trial of oral heme iron polypeptide versus oral iron supplementation for the treatment of anaemia in peritoneal dialysis patients: HEMATOCRIT trial.

Nephrol Dial Transplant. 2012 Nov;27(11):4146-53

Authors: Barraclough KA, Brown F, Hawley CM, Leary D, Noble E, Campbell SB, Isbel NM, Mudge DW, van Eps CL, Johnson DW

Abstract
BACKGROUND: Preliminary clinical evidence suggests that heme iron polypeptide (HIP) might represent a promising, novel oral iron supplementation strategy in chronic kidney disease. The aim of this multi-centre randomized controlled trial was to determine the ability of HIP administration to augment iron stores in darbepoetin (DPO)-treated patients compared with conventional oral iron supplementation.
METHODS: Adult peritoneal dialysis (PD) patients treated with DPO were randomized 1:1 to receive two capsules daily of either HIP or ferrous sulphate per os for 6 months. The primary outcome measure was transferrin saturation (TSAT). Secondary outcomes comprised serum ferritin, haemoglobin, DPO dose and responsiveness, and adverse events.
RESULTS: Sixty-two patients were randomized to HIP (n = 32) or ferrous sulphate (n = 30). On intention-to-treat analysis, the median (inter-quartile range) TSAT was 22% (16-29) in the HIP group compared with 20% (17-26) in controls (P = 0.65). HIP treatment was not significantly associated with TSAT at 6 months on multivariable analysis (P = 0.95). Similar results were found on per-protocol analysis and subgroup analysis in iron-deficient patients. Serum ferritin levels at 6 months were significantly lower in the HIP group (P = 0.003), while the cost of HIP was 7-fold higher than that of ferrous sulphate. No other differences in secondary outcomes were observed.
CONCLUSIONS: HIP showed no clear safety or efficacy benefit in PD patients compared with conventional oral iron supplements. The reduction in serum ferritin levels and high costs associated with HIP therapy suggest that this agent is unlikely to have a significant role in iron supplementation in PD patients.

PMID: 22962411 [PubMed - indexed for MEDLINE]

Optimizing AVF creation prior to dialysis start: the role of predialysis renal replacement therapy choices.

Sat, 06/29/2013 - 10:02
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Optimizing AVF creation prior to dialysis start: the role of predialysis renal replacement therapy choices.

Nephrol Dial Transplant. 2012 Nov;27(11):4205-10

Authors: Hanko J, Romann A, Taylor P, Copland M, Beaulieu M

Abstract
BACKGROUND: In British Columbia, multidisciplinary predialysis clinics encourage patients to consider independent modalities of renal replacement therapy (RRT) such as peritoneal dialysis (PD) 'first'. Despite up to 50% of patients choosing PD, PD incidence rates are ~30%. We explored the relationship between predialysis RRT choice and arteriovenous fistula (AVF) creation prior to hemodialysis (HD) start with particular focus on the group of patients who despite PD choice actually commence HD, and thus may contribute to 'suboptimal' HD starts without AVF creation.
METHODS: We conducted a retrospective cohort study of all patients starting dialysis between 31 December, 2006 and 31 December 2008 in the province of British Columbia. Inclusion criteria were >3 months predialysis nephrology follow-up, at least one predialysis RRT education session and maintenance on dialysis for a minimum of 3 months (to ensure chronic dialysis). Patients with any prior history of RRT were excluded.
RESULTS: There were 508 patients included in the study: 127 (25%) patients chose HD, 114 (22%) PD, 13 (3%) pre-emptive transplant, 5 (1%) conservative management and 249 (49%) had no documented modality decision. Of those who chose HD, 94% commenced HD. For those who chose PD, 64% commenced PD and 36% HD. In the undecided group, 68% started HD and 32% PD. For those patients who chose PD predialysis, the presence of cardiovascular disease [odds ratio (OR) 2.36, 95% confidence interval (CI) 1.02-5.43] and lower serum albumin levels (OR 0.92, 95% CI 0.86-0.98) were associated with failure to commence PD. Predialysis AVF creation rates were 79% of those who chose and started HD, 39% of those who chose PD but started HD and 50% of those in the undecided group who commenced HD.
CONCLUSIONS: AVF creation rates prior to HD start were lower in those patients with no documented dialysis modality choice and in those who failed to commence PD. Cardiovascular disease and lower serum albumin levels were associated with failure to start PD. Further work to ensure the efficacy of RRT modality choice pathway and to better predict those patients who will fail to commence PD is necessary, so that dialysis start can be 'optimized' with AVF creation in high-risk groups.

PMID: 22962410 [PubMed - indexed for MEDLINE]

Chronic renovascular hypertension is associated with elevated levels of neutrophil gelatinase-associated lipocalin.

Sat, 06/29/2013 - 10:02
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Chronic renovascular hypertension is associated with elevated levels of neutrophil gelatinase-associated lipocalin.

Nephrol Dial Transplant. 2012 Nov;27(11):4153-61

Authors: Eirin A, Gloviczki ML, Tang H, Rule AD, Woollard JR, Lerman A, Textor SC, Lerman LO

Abstract
BACKGROUND: Renovascular hypertension (RVH) is characterized by chronic inflammation of the stenotic kidney and progressive renal dysfunction. Neutrophil gelatinase-associated lipocalin (NGAL), an acute phase protein induced in inflammatory conditions and ischemia, is a novel biomarker for acute kidney injury. We hypothesized that chronic RVH would be associated with increased renal and circulating NGAL levels.
METHODS: We prospectively measured renal vein and inferior vena cava (IVC) levels of NGAL and inflammatory cytokines in essential hypertensive (EH) and RVH patients, during constant sodium intake and anti-hypertensive regimens, and compared them with systemic levels in age-matched normotensive subjects (n = 22 each). In addition, we measured urinary NGAL and kidney injury molecule (KIM)-1 in all patients.
RESULTS: Blood pressure, serum creatinine, estimated glomerular filtration rate (eGFR), lipid panels and medications were similar in RVH and EH. Systemic, stenotic and contralateral renal vein levels of NGAL were all similarly elevated in RVH versus normal hypertension and EH (P < 0.05), as were renal vein levels of inflammatory markers like tumor necrosis factor-α. Furthermore, renal vein NGAL levels inversely correlated with eGFR, and directly with renal vein (but not systemic) levels of inflammatory markers. Urinary levels of NGAL and KIM-1 were elevated in both EH and RVH, as were systemic levels of C-reactive protein.
CONCLUSIONS: Chronic RVH is associated with elevated NGAL levels, likely due to ongoing kidney and systemic inflammation and ischemia. These findings may also imply the occurrence of the inflammation process in chronic RVH, which might contribute to the poorer outcomes of RVH compared with EH patients.

PMID: 22923545 [PubMed - indexed for MEDLINE]

Measurement of free GH and bioactive IGF-I in non-diabetic haemodialysis patients treated with GH for 7 days.

Sat, 06/29/2013 - 10:02
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Measurement of free GH and bioactive IGF-I in non-diabetic haemodialysis patients treated with GH for 7 days.

Nephrol Dial Transplant. 2012 Nov;27(11):4211-8

Authors: Frystyk J, Djurhuus CB, Johansen T, Lange M, Smidt K, Christiansen JS

Abstract
BACKGROUND: End-stage renal failure (ESRF) patients demonstrate augmented growth hormone (GH) secretion, but normal insulin-like growth factor-I (IGF-I) concentrations, indicating a state of GH resistance. To test this hypothesis, we compared the IGF-I response with exogenous GH in haemodialysis patients and healthy controls, with special focus on free GH and bioactive IGF-I.
METHODS: Ultrafiltered free GH and total GH were measured in serum collected hourly for 24 h at baseline and after 7 days of recombinant human (rh) GH (50 µg/kg/day) treatment in 11 non-diabetic haemodialysis patients and 10 matched controls. Serum levels of bioactive IGF-I (determined by cell-based IGF-I receptor activation assay), total IGF-I and the GH-binding protein (GHBP) were assayed twice daily.
RESULTS: At baseline, patients showed elevated total GH (24 ± 5 versus 9 ± 1 µg/L × h, P < 0.02), free GH (21 ± 5 versus 7 ± 1 µg/L × h, P < 0.02), reduced GHBP (1.5 ± 0.3 versus 2.5 ± 0.2 nmol/L, P < 0.01), high-normal total IGF-I (173 ± 18 versus 135 ± 14 µg/L, P = 0.12) and subnormal bioactive IGF-I (2.1 ± 0.3 versus 2.8 ± 0.2 µg/L, P < 0.05) when compared with controls. After 7 days of rhGH treatment, there was a greater GH increase in the non-diabetic haemodialysis patients than in controls (total GH: 293 ± 33 versus 166 ± 13 µg/L × h, P < 0.001; free GH: 284 ± 40 versus 126 ± 15 µg/L × h, P < 0.001). GHB remained unaffected and total IGF-I increased to the same extent in patients and controls (701 ± 87 versus 572 ± 33 µg/L, P = 0.17), whereas bioactive IGF-I tended to be lower in patients (5.37 ± 0.55 versus 6.63 ± 0.25 µg/L, P < 0.10). When adjusting for the actual increments in plasma GH, the ability of exogenous GH to stimulate bioactive IGF-I levels was reduced by ~50% in ESRF (P < 0.02), whereas the response of total IGF-I remained normal (74%; P= 0.18)
CONCLUSIONS: The study demonstrates that ESRF is associated with markedly elevated serum levels of free GH. Furthermore changes in bioactive, but not immunoreactive, IGF-I indicated that the hepatic sensitivity to GH was reduced by 50% in ESRF patients. Clearly, the physiological importance of our observations awaits further studies, but they suggest that changes in total IGF-I may not necessarily reflect changes in the endogenous activity of IGF-I in ESRF patients on GH treatment.

PMID: 22910041 [PubMed - indexed for MEDLINE]

Copeptin: a marker for ADPKD progression?

Sat, 06/29/2013 - 10:02
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Copeptin: a marker for ADPKD progression?

Nephrol Dial Transplant. 2012 Nov;27(11):3985-7

Authors: Fenske W, Wanner C

PMID: 22907952 [PubMed - indexed for MEDLINE]

Growth arrest-specific gene 6 (Gas6) levels are elevated in patients with chronic renal failure.

Sat, 06/29/2013 - 10:02
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Growth arrest-specific gene 6 (Gas6) levels are elevated in patients with chronic renal failure.

Nephrol Dial Transplant. 2012 Nov;27(11):4166-72

Authors: Lee IJ, Hilliard B, Swami A, Madara JC, Rao S, Patel T, Gaughan JP, Lee J, Gadegbeku CA, Choi ET, Cohen PL

Abstract
BACKGROUND: The TAM receptors (tyro3, axl and mer) and their ligands (vitamin K-dependent proteins-Gas6 and Protein S) are crucial modulators of inflammation, which may be relevant in chronic kidney disease (CKD). Gas6 and axl have multiple roles in mediating vascular atherosclerosis and injury, thrombosis and inflammation, yet nothing is known about the Gas6-axl pathway in humans with CKD. Given the prevalence of chronic inflammation and vascular disease in this population, we measured TAM ligands in patients with various levels of renal function.
METHODS: Gas6 and protein S were quantified in the plasma by ELISA in three patient groups: end-stage renal disease on chronic hemodialysis (HD), CKD and normal controls.
RESULTS: Significantly increased levels of Gas6 and protein S were found in CKD patients compared with normal controls (P < 0.01 and <0.001, respectively). In HD patients, Gas6 levels were elevated compared with controls (P < 0.001) and positively associated with low albumin (r = 0.33; P = 0.01), dialysis vintage (r = 0.36; P = 0.008) and IV iron administration (r = 0.33; P = 0.01). The levels of Gas6 rose with CKD stage and were inversely associated with estimated GFR (P < 0.0001).
CONCLUSIONS: Dysregulation of circulating Gas6 is associated with renal disease and inversely proportional to renal function. Low albumin and higher IV iron administration were associated with higher Gas6 levels, suggesting a possible connection between inflammation and oxidative stress mediated by iron. Protein S levels were also elevated in CKD patients, but the relevance of this finding needs to be further investigated.

PMID: 22907951 [PubMed - indexed for MEDLINE]

Resistant hypertension and the neglected antihypertensive: sodium restriction.

Sat, 06/29/2013 - 10:02
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Resistant hypertension and the neglected antihypertensive: sodium restriction.

Nephrol Dial Transplant. 2012 Nov;27(11):4041-5

Authors: Agarwal R

Abstract
Resistant hypertension is defined as blood pressure (BP) that remains above goal (such as 140/90 mmHg or more) in spite of the concurrent use of three antihypertensive agents of different classes. Ideally, one of the three agents should be a diuretic and all agents should be prescribed at optimal dose amounts. Prevalent among 15% of the treated hypertensives, the risk factors for resistant hypertension include older age, chronic kidney disease (CKD), obesity and diabetes mellitus. Causes of resistant hypertension can be classified into four groups: poor adherence, biological-behavioral factors, CKD and secondary causes, and drugs or exogenous substances. However, before labeling the diagnosis of resistant hypertension, it is important to exclude pseudo-resistant hypertension using home BP monitoring in most patients and ambulatory BP monitoring in a few. Before thinking about the next antihypertensive drug, it is important to restrict dietary sodium. Educating the patient on how to interpret the food label and providing feedback by assessing sodium intake with 24 h urine collection are effective sodium restriction strategies. Sodium restriction can lower BP and among patients with proteinuria can even enhance the anti-proteinuric effects of drugs that block the renin-angiotensin system. Sodium restriction is therefore a valuable but a neglected antihypertensive.

PMID: 22899870 [PubMed - indexed for MEDLINE]

Peroxisome proliferator-activated receptor-δ activation ameliorates albuminuria by preventing nephrin loss and restoring podocyte integrity in type 2 diabetes.

Sat, 06/29/2013 - 10:02
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Peroxisome proliferator-activated receptor-δ activation ameliorates albuminuria by preventing nephrin loss and restoring podocyte integrity in type 2 diabetes.

Nephrol Dial Transplant. 2012 Nov;27(11):4069-79

Authors: Lee EY, Kim GT, Hyun M, Kim S, Seok S, Choi R, Lee MY, Chung CH

Abstract
BACKGROUND: Peroxisome proliferator-activated receptor (PPAR)-δ is a ligand-activated transcription factor in regulating gene expression and is believed to play an important role in various kidney diseases including diabetic nephropathy. This study investigated the efficacy of GW610742, a highly specific agonist for PPAR-δ, for the treatment of diabetic nephropathy.
METHODS: Type 2 diabetic Otsuka Long-Evans Tokushima Fatty rats were randomized into an untreated diabetic group (n = 9) and a GW610742-treated diabetic group (n= 9). The GW610742 was administered (10 mg/kg/day) orally for 11 weeks. Long-Evans Tokushima Otsuka rats (n = 9) were used as a non-diabetic control.
RESULTS: Albuminuria was markedly increased and renal PPAR-δ expression was decreased in diabetes. Diabetic albuminuria and renal injury markers, such as glomerular basement membrane thickening, decreased number of slit pores between podocyte foot processes, decreased nephrin expression, increased desmin expression and increased CCL2 expression, were significantly reversed through the treatment with GW610742. PPAR-δ agonist GW610742 markedly increased nephrin expression in cultured podocytes. Nephrin mRNA expression was markedly decreased in response to high glucose in cultured podocytes and effectively prevented by GW610742.
CONCLUSIONS: PPAR-δ activation by GW610742 ameliorates albuminuria by preventing diabetes-induced nephrin loss and restoring podocyte integrity, implying that GW610742 may be a potential therapeutic agent for diabetic nephropathy.

PMID: 22892126 [PubMed - indexed for MEDLINE]

Immunotactoid glomerulopathy: clinicopathologic and proteomic study.

Sat, 06/29/2013 - 10:02
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Immunotactoid glomerulopathy: clinicopathologic and proteomic study.

Nephrol Dial Transplant. 2012 Nov;27(11):4137-46

Authors: Nasr SH, Fidler ME, Cornell LD, Leung N, Cosio FG, Sheikh SS, Amir AA, Vrana JA, Theis JD, Dogan A, Sethi S

Abstract
BACKGROUND: Immunotactoid glomerulopathy (ITG) is a rare glomerular disease. Here, we report the largest clinicopathologic series of ITG and define its proteomic profile.
METHODS: The characteristics of 16 ITG patients who were identified from our pathology archives are provided between 1993 and 2011. We also performed laser microdissection and mass spectrometry (LMD/MS) in three cases.
RESULTS: Presentation included proteinuria (100%), nephrotic syndrome (69%), renal insufficiency (50%) and microhematuria (80%). Hypocomplementemia was present in 46% and a serum M-spike in 63%. Hematologic malignancy was present in 38%, including chronic lymphocytic leukemia in 19%, lymphoplasmacytic lymphoma in 13% and myeloma in 13%. The pattern of glomerular injury was membranoproliferative (56%), membranous (31%) or proliferative (13%) glomerulonephritis. The microtubular deposits were immunoglobulin light chain restricted in 69% and had a mean diameter of 31 nm (range 17-52). During an average of 48 months of follow-up for 12 patients, 50% had remission, 33% had persistent renal dysfunction and 17% progressed to end-stage renal disease. Proteomic analysis by LMD/MS revealed the presence of immunoglobulins, monotypic light chains, complement factors of the classical and terminal pathway and small amount of serum amyloid P-component.
CONCLUSIONS: Hematologic malignancy, particularly lymphoma, is not uncommon in ITG. ITG appears to have a better prognosis than other paraprotein-related renal lesions, with a half of patients expected to recover kidney function with immunosuppressive therapy or chemotherapy. The proteomic profile of ITG is consistent with deposition of monotypic immunoglobulins and activation of the classical and terminal pathway of complement.

PMID: 22872726 [PubMed - indexed for MEDLINE]

Urine podocin:nephrin mRNA ratio (PNR) as a podocyte stress biomarker.

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Urine podocin:nephrin mRNA ratio (PNR) as a podocyte stress biomarker.

Nephrol Dial Transplant. 2012 Nov;27(11):4079-87

Authors: Fukuda A, Wickman LT, Venkatareddy MP, Wang SQ, Chowdhury MA, Wiggins JE, Shedden KA, Wiggins RC

Abstract
BACKGROUND: Proteinuria and/or albuminuria are widely used for noninvasive assessment of kidney diseases. However, proteinuria is a nonspecific marker of diverse forms of kidney injury, physiologic processes and filtration of small proteins of monoclonal and other pathologic processes. The opportunity to develop new glomerular disease biomarkers follows the realization that the degree of podocyte depletion determines the degree of glomerulosclerosis, and if persistent, determines the progression to end-stage kidney disease (ESKD). Podocyte cell lineage-specific mRNAs can be recovered in urine pellets of model systems and in humans. In model systems, progressive glomerular disease is associated with decreased nephrin mRNA steady-state levels compared with podocin mRNA. Thus, the urine podocin:nephrin mRNA ratio (PNR) could serve as a useful progression biomarker. The use of podocyte-specific transcript ratios also circumvents many problems inherent to urine assays.
METHODS: To test this hypothesis, the human diphtheria toxin receptor (hDTR) rat model of progression was used to evaluate potentially useful urine mRNA biomarkers. We compared histologic progression parameters (glomerulosclerosis score, interstitial fibrosis score and percent of podocyte depletion) with clinical biomarkers [serum creatinine, systolic blood pressure (BP), 24-h urine volume, 24-h urine protein excretion and the urine protein:creatinine ratio(PCR)] and with the novel urine mRNA biomarkers.
RESULTS: The PNR correlated with histologic outcome as well or better than routine clinical biomarkers and other urine mRNA biomarkers in the model system with high specificity and sensitivity, and a low coefficient of assay variation.
CONCLUSIONS: We concluded that the PNR, used in combination with proteinuria, will be worth testing for its clinical diagnostic and decision-making utility.

PMID: 22863839 [PubMed - indexed for MEDLINE]

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