Improved patient survival with simultaneous pancreas and kidney transplantation in recipients with diabetic end-stage renal disease

Aims/hypothesis

We aimed to determine whether simultaneous pancreas and kidney (SPK) transplantation would improve patient and kidney graft survival in diabetic end-stage renal disease (ESRD) compared with kidney transplantation alone (KTA).

Methods

Follow-up data were retrieved for all 630 patients with diabetic ESRD who had received SPK or KTA at our centre from 1983 to the end of 2010. Recipients younger than 55 years of age received either an SPK (n?=?222) or, if available, a single live donor kidney (LDK; n?=?171). Older recipients and recipients with greater comorbidity received a single deceased donor kidney (DDK; n?=?237). Survival was analysed by the Kaplan–Meier method and in multivariate Cox regression analysis adjusting for recipient and donor characteristics.

Results

Patient survival was superior in SPK compared with both LDK and DDK recipients in univariate analysis. Follow-up time (mean?±?SD) after transplantation was 7.1?±?5.7 years. Median actuarial patient survival was 14.0 years for SPK, 11.5 years for LDK and 6.7 years for DDK recipients. In multivariate analyses including recipient age, sex, treatment modality, time on dialysis and era, SPK transplantation was protective for all-cause mortality compared with both LDK (p?=?0.02) and DDK (p?=?0.029) transplantation. After the year 2000, overall patient survival improved compared with previous years (HR 0.40, 95% CI 0.30, 0.55; p?<?0.001). Pancreas graft survival also improved after 2000, with a 5 year graft survival rate of 78% vs 61% in previous years (1988–1999).

Conclusions/interpretation

Recipients of SPK transplants have superior patient survival compared with both LDK and DDK recipients, with improved results seen over the last decade.     

Agreement between cystatin-C and creatinine based eGFR estimates after a 12-month exercise intervention in patients with chronic kidney disease

Background

Estimation of GFR (eGFR) using formulae based on serum creatinine concentrations are commonly used to assess kidney function. Physical exercise can increase creatinine turnover and lean mass; therefore, this method may not be suitable for use in exercising individuals. Cystatin-C based eGFR formulae may be a more accurate measure of kidney function when examining the impact of exercise on kidney function. The aim of this study was to assess the agreement of four creatinine and cystatin-C based estimates of GFR before and after a 12-month exercise intervention.

Methods

One hundred forty-two participants with stage 3–4 chronic kidney disease (CKD) (eGFR 25–60?mL/min/1.73?m²) were included. Subjects were randomised to either a Control group (standard nephrological care [n?=?68]) or a Lifestyle Intervention group (12?months of primarily aerobic based exercise training [n?=?74]). Four eGFR formulae were compared at baseline and after 12?months: 1) MDRDcr, 2) CKD-EPIcr, 3) CKD-EPIcys and 4) CKD-EPIcr-cys.

Results

Control participants were aged 63.5[9.4] years, 60.3% were male, 42.2% had diabetes, and had an eGFR of 40.5?±?8.9?ml/min/1.73m². Lifestyle Intervention participants were aged 60.5[14.2] years, 59.5% were male, 43.8% had diabetes, and had an eGFR of 38.9?±?8.5?ml/min/1.73m². There were no significant baseline differences between the two groups. Lean mass (r?=?0.319, p?<?0.01) and grip strength (r?=?0.391, p?<?0.001) were associated with serum creatinine at baseline. However, there were no significant correlations between cystatin-C and the same measures. The Lifestyle Intervention resulted in significant improvements in exercise capacity (+?1.9?±?1.8 METs, p?<?0.001). There were no changes in lean mass in both Control and Lifestyle Intervention groups during the 12?months. CKD-EPIcys was considerably lower in both groups at both baseline and 12?months than CKD-EPIcr (Control?=???10.5?±?9.1 and???13.1?±?11.8, and Lifestyle Intervention?=???7.9?±?8.6 and???8.4?±?12.3?ml/min/1.73?m²), CKD-EPIcr-cys (Control?=???3.6?±?3.7 and???4.5?±?4.5, and Lifestyle Intervention?=???3.6?±?3.7 and???2.5?±?5.5?ml/min/1.73?m²) and MDRDcr (Control?=???9.3?±?8.4 and???12.0?±?10.7, Lifestyle Intervention?=???6.4?±?8.4 and???6.9?±?11.2?ml/min/1.73?m²).

Conclusions

In CKD patients participating in a primarily aerobic based exercise training, without improvements in lean mass, cystatin-C and creatinine based eGFR provided similar estimates of kidney function at both baseline and after 12?months of exercise training.

Trial registration

The trial was registered at www.anzctr.org.au (Registration Number ANZCTR12608000337370) on the 17/07/2008 (retrospectively registered).

     

Vasopressin-related copeptin is a novel predictor of early endothelial dysfunction in patients with adult polycystic kidney disease

Background

In this study, we examined the relative usefulness of serum copeptin levels as a surrogate marker of vasopressin (AVP) in adult polycystic kidney disease (ADPKD) by correlating it with baseline and longitudinal changes in markers of both renal function and common CVD manifestations (hypertensive vascular disease, atherosclerosis and endothelial dysfunction) that accompany the progression of this disease.

Methods

We studied a cohort of young and otherwise healthy ADPKD patients (n?=?235) and measured cardiovascular function using flow-mediation dilatation (FMD), carotid intima media thickness (cIMT) and pulse wave velocity (PWV), as well as serum copeptin (commercial ELISA, a stable marker of AVP activity). The same analyses were carried out at baseline and after 3 years of follow-up.

Results

At baseline, median eGFR was 69 mL/min./1.73 m², mean FMD 6.9?±?0.9%, cIMT 0.7?±?0.1 mm, and PWV 8.1?±?1.2 m/s. At follow-up, equivalent values were 65 (44–75) mL/min./1.73 m², 5.8?±?0.9%, 0.8?±?0.1 mm. and 8.2?±?1.3 m/s. with all changes statistically significant. Plasma copeptin also rose from 0.62?±?0.12 to 0.94?±?0.19 ng/mL and this change correlated with ΔeGFR (-0.33, p?<?0.001), ΔFMD (0.599, p?<?0.001), ΔcIMT (0.562, p?<?0.001) and ΔPWV (0.27, p?<?0.001) also after linear regression modeling to correct for confounders. Finally, ROC analysis was done for a high baseline copeptin with ΔeGFR [cut-off:≤59], ΔFMD [cut-off: ≤7.08], ΔcIMT [cut-off:>0.76], and ΔPWV [cut-off:≤7.80].

Conclusions

Vascular dysfunction as reflected by FMD and cIMT, but not PWV or an altered cardiac geometry, precede most other signs of disease in ADPKD but is predicted by elevated levels of the circulating AVP-marker copeptin.

     

Low dose of mycophenolate mofetil is enough in desensitized kidney transplantation using rituximab

Background

Rituximab is widely used in kidney transplantation. However, it is not clear whether the conventional doses of maintenance immunosuppressant in rituximab-treated kidney transplantation (KT) are appropriate. In our previous study, decreasing mycophenolate mofetil (MMF) dose due to infection did not increase the incidence of rejection or graft failure. Based on these experiences, we developed a new protocol with a lower dose of MMF and studied its clinical outcomes in rituximab-treated KT.

Methods

We enrolled all patients who underwent ABO-incompatible or human leukocyte antigen (HLA)-sensitized living donor KT with the new immunosuppressant protocol after preconditioning with rituximab, but without splenectomy from November 2011 to May 2013. Seventy-two patients (group 1) were consecutively enrolled in this study and followed until November 2013. Patients from our previous study served as control groups. Sixty-seven patients received KT using rituximab with a conventional dose of MMF (group 2), and 87 patients received ABO compatible KT without need for rituximab (group 3). Clinical outcomes, including rejection, infection, and graft survival, were compared between the groups. The χ ² test and Fisher’s exact test were used for categorical variables, the Student’s t-test and Mann-Whitney U test were used for continuous variables, and a log-rank test was used for mortality analysis.

Results

Doses of postoperative MMF (g/day) were lower in group 1 than in the other groups (1.03?±?0.19, 1.48?±?0.34 and 1.48?±?0.32 g/day at 1 week, p?<?0.001). Infectious complications occurred more often in groups with conventional MMF doses (group 2 and 3) than in group 1 (16.7 vs. 37.3 %, p?=?0.007 and 16.7 vs. 34.5 %, p?=?0.012, respectively). Notably, group 1 showed a lower incidence of cytomegalovirus infection than group 2. However, reduction in MMF dose did not increase the incidence of acute rejection (4.2, 4.5 and 10.3 %). Only one graft failure occurred in group 2 due to vessel kinking after operation. There were no significant differences in the incidence of malignancy and mortality between groups.

Conclusions

A low MMF dose reduces infection without increasing rejection or graft loss and it may be appropriate to reduce the dose of MMF for rituximab-treated KT patients.

     

Cardiac autonomic neuropathy predicts renal function decline in patients with type 2 diabetes: a cohort study

Aims/hypothesis

The aim of this work was to assess the impact of cardiac autonomic neuropathy (CAN) on the development and progression of chronic kidney disease (CKD) in patients with type 2 diabetes.

Methods

We conducted a cohort study in adults with type 2 diabetes. Patients with end-stage renal disease were excluded. CKD was defined as the presence of albuminuria (albumin/creatinine ratio GFR >?3.4 mg/mmol) or an estimated (eGFR) <?60 ml min^?1 1.73 m^?2. CKD progression was based on repeated eGFR measurements and/or the development of albuminuria. CAN was assessed using heart rate variability.

Results

Two hundred and four patients were included in the analysis. At baseline, the prevalence of CKD and CAN was 40% and 42%, respectively. Patients with CAN had lower eGFR and higher prevalence of albuminuria and CKD. Spectral analysis variables were independently associated with eGFR, albuminuria and CKD at baseline. After a follow-up of 2.5 years, eGFR declined to a greater extent in patients with CAN than in those without CAN (?9.0?±?17.8% vs ?3.3?±?10.3%, p?=?0.009). After adjustment for baseline eGFR and baseline differences, CAN remained an independent predictor of eGFR decline over the follow-up period (β?=??3.5, p?=?0.03). Spectral analysis variables were also independent predictors of eGFR decline.

Conclusions/interpretation

CAN was independently associated with CKD, albuminuria and eGFR in patients with type 2 diabetes. In addition, CAN was an independent predictor of the decline in eGFR over the follow-up period. CAN could be used to identify patients with type 2 diabetes who are at increased risk of rapid decline in eGFR, so that preventative therapies might be intensified.     

An adult-based insulin resistance genetic risk score associates with insulin resistance,metabolic traits and altered fat distribution in Danish children and adolescents who are overweight or obese

Aims/hypothesis

A genetic risk score (GRS) consisting of 53 insulin resistance variants (GRS₅₃) was recently demonstrated to associate with insulin resistance in adults. We speculated that the GRS₅₃ might already associate with insulin resistance during childhood, and we therefore aimed to investigate this in populations of Danish children and adolescents. Furthermore, we aimed to address whether the GRS associates with components of the metabolic syndrome and altered body composition in children and adolescents.

Methods

We examined a total of 689 children and adolescents who were overweight or obese and 675 children and adolescents from a population-based study. Anthropometric data, dual-energy x-ray absorptiometry scans, BP, fasting plasma glucose, fasting serum insulin and fasting plasma lipid measurements were obtained, and HOMA-IR was calculated. The GRS₅₃ was examined for association with metabolic traits in children by linear regressions using an additive genetic model.

Results

In overweight/obese children and adolescents, the GRS₅₃ associated with higher HOMA-IR (β?=?0.109?±?0.050 (SE); p?=?2.73?×?10^?2), fasting plasma glucose (β?=?0.010?±?0.005 mmol/l; p?=?2.51?×?10^?2) and systolic BP SD score (β?=?0.026?±?0.012; p?=?3.32?×?10^?2) as well as lower HDL-cholesterol (β?=??0.008?±?0.003 mmol/l; p?=?1.23?×?10^?3), total fat-mass percentage (β?=??0.143?±?0.054%; p?=?9.15?×?10^?3) and fat-mass percentage in the legs (β?=??0.197?±?0.055%; p?=?4.09?×?10^?4). In the population-based sample of children, the GRS₅₃ only associated with lower HDL-cholesterol concentrations (β?=??0.007?±?0.003 mmol/l; p?=?1.79?×?10^?2).

Conclusions/interpretation

An adult-based GRS comprising 53 insulin resistance susceptibility SNPs associates with insulin resistance, markers of the metabolic syndrome and altered fat distribution in a sample of Danish children and adolescents who were overweight or obese.

     

Side-to-end vs. straight stapled colorectal anastomosis after low anterior resection: results of randomized clinical trial

Aim

The aim of this study is to compare surgical, functional, physiologic outcomes and QOL after low anterior resection (LAR) with andside-to-end or straight colorectal anastomosis.

Method

Between 2012 and 2015, 86 patients with mid and low rectal tumors were enrolled into randomized trial. Wexner score, number of defecations, use of antidiarrheal medicine or laxatives, enemas, pads, episodes of nocturnal incontinence, and urgency were recorded. The Fecal Incontinence Quality of Life (FIQL) scale was used for assessment of QOL. Anal manometry and volumetric examination were performed.

Results

Six patients were excluded from the study. There was no mortality. The morbidity rate was 6 (14.6 %) for side-to-end vs. 8 (20.0 %) for straight anastomosis (p?=?0.57). The median Wexner score was 5 vs. 6 (p?=?0.033), 4 vs. 5 (p?=?0.006), and 2 vs. 3 (p?=?0.1) at 1, 3, and 6 months after stoma reversal, respectively. Side-to-end anastomosis resulted in a fewer mean numbers of bowel movements per day at the same check points of follow-up: 5.8?±?0.14 vs. 6.4?±?0.15 (p?=?0.006), 3.7?±?0.1 vs. 4.2?±?0.1 (p?=?0.003), and 2.5?±?0.1 vs. 3.0?±?0.10 (p?=?0.0002), correspondingly. Maximal tolerated volume was higher for side-to-end anastomosis at 3 and 6 months of follow-up: 152.0 vs. 137.8 cm³ (p?=?0.002) and 180.5 vs. 167.0 cm³ (p?=?0.006), respectively. Better FIQL score was found at 1 and 3 months in the side-to-end group.

Conclusion

Better functional outcomes and QOL were observed in a short period after stoma closure, but at 6 months of follow-up, the only benefit of side-to-end anastomosis was a lower number of bowel movements.

     

Copeptin, a surrogate marker for arginine vasopressin, is associated with declining glomerular filtration in patients with diabetes mellitus (ZODIAC-33)

Aim/hypothesis

Arginine vasopressin (AVP), the hormone important for maintaining fluid balance, has been shown to cause kidney damage in rodent models of diabetes. We investigated the potential role of AVP in the natural course of kidney function decline in diabetes in an epidemiological study.

Methods

Plasma copeptin, a surrogate for AVP, was measured in baseline samples from patients with type 2 diabetes treated in primary care and included in the Zwolle Outpatient Diabetes project Integrating Available Care (ZODIAC) cohort.

Results

Samples from 1,328 patients were available; 349 were analysed separately because they used renin–angiotensin–aldosterone system inhibition (RAASi), which influences albumin/creatinine ratio (ACR) and estimated (e)GFR. In the other 979 patients (46% men, age 68 years [58–75], ACR 1.8 mg/mmol [0.9–5.7], eGFR 67?±?14 ml min^?1 1.73 m^?2) baseline copeptin (5.3 pmol/l [3.2–9.5]) was significantly associated with log _e [ACR] and eGFR, even after adjustment for sex, age and risk factors for kidney function decline (standardised [std] β 0.13, p?<?0.001, std β ?0.20, p?<?0.001 respectively). Follow-up data were available for 756 patients (6.5 years [4.1–9.6]). Baseline copeptin was associated with increase in ACR (std β 0.09, p?=?0.02), but lost significance after adjustment (std β 0.07, p?=?0.08). Copeptin was associated with a decrease in eGFR after adjustment (std β ?0.09, p?=?0.03). The strength of the association of copeptin with change in eGFR was stronger than that of established risk factors for kidney function decline (e.g. BMI, HbA_1c). In patients who used RAASi there was a significant association between baseline copeptin and ACR and eGFR, but not with change in ACR and eGFR.

Conclusions/interpretation

In patients with diabetes not using RAASi a higher baseline copeptin concentration is significantly associated with higher baseline ACR and lower eGFR values and with a decline in eGFR during follow-up. This last association is independent of, and stronger than, most traditional risk factors for kidney function decline.     

<Emphasis Type="Italic">Vegf-A</Emphasis> mRNA transfection as a novel approach to improve mouse and human islet graft revascularisation

Aims/hypothesis

The initial avascular period following islet transplantation seriously compromises graft function and survival. Enhancing graft revascularisation to improve engraftment has been attempted through virus-based delivery of angiogenic triggers, but risks associated with viral vectors have hampered clinical translation. In vitro transcribed mRNA transfection circumvents these risks and may be used for improving islet engraftment.

Methods

Mouse and human pancreatic islet cells were transfected with mRNA encoding the angiogenic growth factor vascular endothelial growth factor A (VEGF-A) before transplantation under the kidney capsule in mice.

Results

At day 7 post transplantation, revascularisation of grafts transfected with Vegf-A (also known as Vegfa) mRNA was significantly higher compared with non-transfected or Gfp mRNA-transfected controls in mouse islet grafts (2.11- and 1.87-fold, respectively) (vessel area/graft area, mean?±?SEM: 0.118?±?0.01 [n?=?3] in Vegf-A mRNA transfected group (VEGF) vs 0.056?±?0.01 [n?=?3] in no RNA [p?<?0.05] vs 0.063?±?0.02 [n?=?4] in Gfp mRNA transfected group (GFP) [p?<?0.05]); EndoC-bH3 grafts (2.85- and 2.48-fold. respectively) (0.085?±?0.02 [n?=?4] in VEGF vs 0.030?±?0.004 [n?=?4] in no RNA [p?<?0.05] vs 0.034?±?0.01 [n?=?5] in GFP [p?<?0.05]); and human islet grafts (3.17- and 3.80-fold, respectively) (0.048?±?0.013 [n?=?3] in VEGF vs 0.015?±?0.0051 [n?=?4] in no RNA [p?<?0.01] vs 0.013?±?0.0046 [n?=?4] in GFP [p?<?0.01]). At day 30 post transplantation, human islet grafts maintained a vascularisation benefit (1.70- and 1.82-fold, respectively) (0.049?±?0.0042 [n?=?8] in VEGF vs 0.029?±?0.0052 [n?=?5] in no RNA [p?<?0.05] vs 0.027?±?0.0056 [n?=?4] in GFP [p?<?0.05]) and a higher beta cell volume (1.64- and 2.26-fold, respectively) (0.0292?±?0.0032 μl [n?=?7] in VEGF vs 0.0178?±?0.0021 μl [n?=?5] in no RNA [p?<?0.01] vs 0.0129?±?0.0012 μl [n?=?4] in GFP [p?<?0.001]).

Conclusions/interpretation

Vegf-A mRNA transfection before transplantation provides a promising and safe strategy to improve engraftment of islets and other cell-based implants.

     

Association of plasma somatostatin with disease severity and progression in patients with autosomal dominant polycystic kidney disease

Background

Somatostatin (SST) inhibits intracellular cyclic adenosine monophosphate (cAMP) production and thus may modify cyst formation in autosomal dominant polycystic kidney disease (ADPKD). We investigated whether endogenous plasma SST concentration is associated with disease severity and progression in patients with ADPKD, and whether plasma SST concentrations change during treatment with a vasopressin V2 receptor antagonist or SST analogue.

Methods

In this observational study, fasting concentrations of SST were measured in 127 ADPKD patients (diagnosed upon the revised Ravine criteria) by ELISA. cAMP was measured in 24?h urine by Radio Immuno Assay. Kidney function was measured (mGFR) as ¹²⁵I-iothalamate clearance, and total kidney volume was measured by MRI volumetry and adjusted for height (htTKV). Disease progression was expressed as annual change in mGFR and htTKV. Additionally, baseline versus follow-up SST concentrations were compared in ADPKD patients during vasopressin V2 receptor antagonist (tolvaptan) (n?=?27) or SST analogue (lanreotide) treatment (n?=?25).

Results

In 127 ADPKD patients, 41?±?11?years, 44% female, eGFR 73?±?32?ml/min/1.73m², mGFR 75?±?32?ml/min/1.73m² and htTKV 826 (521–1297) ml/m, SST concentration was 48.5 (34.3–77.8) pg/ml. At baseline, SST was associated with urinary cAMP, mGFR and htTKV (p?=?0.02, p?=?0.004 and p?=?0.02, respectively), but these associations lost significance after adjustment for age and sex or protein intake (p?=?0.09, p?=?0.06 and p?=?0.15 respectively). Baseline SST was not associated with annual change in mGFR, or htTKV during follow-up (st. β?=???0.02, p?=?0.87 and st. β?=???0.07, p?=?0.54 respectively). During treatment with tolvaptan SST levels remained stable 38.2 (23.8–70.7) pg/mL vs. 39.8 (31.2–58.5) pg/mL, p?=?0.85), whereas SST levels decreased significantly during treatment with lanreotide (42.5 (33.2–55.0) pg/ml vs. 29.3 (24.8–37.6), p?=?0.008).

Conclusions

Fasting plasma SST concentration is not associated with disease severity or progression in patients with ADPKD. Treatment with lanreotide caused a decrease in SST concentration. These data suggest that plasma SST cannot be used as a biomarker to assess prognosis in ADPKD, but leave the possibility open that change in SST concentration during lanreotide treatment may reflect therapy efficacy.

     

Glucocorticoid treatment impairs microvascular function in healthy men in association with its adverse effects on glucose metabolism and blood pressure: a randomised controlled trial

Aims/hypothesis

Glucocorticoids (GCs) are widely used anti-inflammatory agents that frequently induce side effects, including insulin resistance, diabetes and hypertension. Here, we investigated the contribution of microvascular dysfunction to the development of these adverse effects in healthy men.

Methods

In a randomised, placebo-controlled, dose–response intervention study, 32 healthy normoglycaemic men (age: 21?±?2 years; BMI: 21.9?±?1.7 kg/m²) were allocated to receive prednisolone 30 mg once daily (n?=?12), prednisolone 7.5 mg once daily (n?=?12) or placebo (n?=?8) for 2 weeks using block randomisation. A central office performed the treatment allocation, and medication was dispersed by the hospital pharmacy that was also blinded. Treatment allocation was kept in concealed envelopes. Participants, study personnel conducting the measures and assessing the outcome were blinded to group assignment. The study was conducted at a university hospital. Primary endpoint was prednisolone-induced changes in microvascular function, which was assessed by capillary microscopy. Insulin sensitivity was determined by hyperinsulinaemic–euglycaemic clamp and postprandial glycaemic excursions by standardised meal tests.

Results

Compared with placebo, prednisolone 7.5 mg and 30 mg decreased insulin-stimulated capillary recruitment by 9?±?4% and 17?±?3%, respectively (p?<?0.01). In addition, prednisolone 7.5 mg and 30 mg reduced insulin sensitivity (M value) by ?11.4?±?4.5 μmol kg^?1 min^?1 and ?25.1?±?4.1 μmol kg^?1 min^?1 (p?<?0.001) and increased postprandial glucose levels by 11?±?5% and 27?±?9% (p?<?0.001), respectively. Only high-dose prednisolone increased systolic blood pressure (6?±?1.2 mmHg, p?=?0.006). Prednisolone-induced changes in insulin-stimulated capillary recruitment were associated with insulin sensitivity (r?=?+0.76; p?<?0.001), postprandial glucose concentrations (r?=??0.52; p?<?0.03) and systolic blood pressure (r?=??0.62; p?<?0.001). Prednisolone increased resistin concentrations, which were negatively related to insulin-stimulated capillary recruitment (r?=??0.40; p?=?0.03). No effects were noted on adiponectin and leptin concentrations. Prednisolone treatment was well tolerated; none of the participants left the study.

Conclusions/interpretation

Prednisolone-induced impairment of insulin-stimulated capillary recruitment was paralleled by insulin resistance, increased postprandial glucose levels, hypertension and increased circulating resistin concentrations in healthy men. We propose that GC-induced impairments of microvascular function may contribute to the adverse effects of GC treatment on glucose metabolism and blood pressure.

Trial registration

isrctn.org ISRTCN 78149983

Funding

The study was funded by the Dutch Top Institute Pharma T1-106.     

Urinary mitochondrial DNA level as a biomarker of tissue injury in non-diabetic chronic kidney diseases

Background

Urinary mitochondrial DNA (mtDNA) fragment level has been proposed as a biomarker of chronic kidney disease (CKD). In this study, we determine the relation between urinary mtDNA level and rate of renal function deterioration in non-diabetic CKD.

Methods

We recruited 102 non-diabetic CKD patients (43 with kidney biopsy that showed non-specific nephrosclerosis). Urinary mtDNA level was measured and compared to baseline clinical and pathological parameters. The patients were followed 48.3?±?31.8?months for renal events (need of dialysis or over 30% reduction in estimated glomerular filtration rate [eGFR]).

Results

The median urinary mtDNA level was 1519.42 (inter-quartile range 511.81–3073.03) million copy/mmol creatinine. There were significant correlations between urinary mtDNA level and baseline eGFR (r?=?0.429, p?<?0.001), proteinuria (r?=?0.368, p?<?0.001), severity of glomerulosclerosis (r?=???0.537, p?<?0.001), and tubulointerstitial fibrosis (r?=???0.374, p?=?0.014). The overall rate of eGFR decline was ??2.18?±?5.94?ml/min/1.73m² per year. There was no significant correlation between the rate of eGFR decline and urinary mtDNA level. By univariate analysis, urinary mtDNA level predicts dialysis-free survival, but the result became insignificant after adjusting for clinical and histological confounding factors.

Conclusion

Urinary mtDNA levels have no significant association with the rate of renal function decline in non-diabetic CKD, although the levels correlate with baseline renal function, proteinuria, and the severity of histological damage. Urinary mtDNA level may be a surrogate marker of permanent renal damage in non-diabetic CKD.

     

Hemodynamic impact of percutaneous left atrial appendage closure in patients with paroxysmal atrial fibrillation

Purpose

Percutaneous left atrial appendage (LAA) closure has become a valid alternative to anticoagulation therapy for the prevention of thromboembolic events in patients with atrial fibrillation (AF). However, scarce data exist on the impact of LAA closure on left atrial and ventricular function. We sought to assess the acute hemodynamic changes associated with percutaneous LAA closure in patients with paroxysmal AF.

Methods

The study population consisted of 31 patients (mean age 73?±?10 years; 49% women) with paroxysmal AF who underwent successful percutaneous LAA closure. All patients were in sinus rhythm and underwent 2D transthoracic echocardiography at baseline and the day after the procedure. A subset of 14 patients underwent preprocedural cardiac computed tomography (CT) with 3D LA and LAA reconstruction.

Results

Left ventricular systolic function parameters and LA volumetric indexes remained unchanged after the procedure. No significant changes in left ventricular stroke volume (72.4?±?16.0 vs. 73.3?±?15.7 mL, p?=?0.55) or LA stroke volume (total 15.6?±?4.2 vs. 14.6?±?4.2 mL, p?=?0.21; passive 9.0?±?2.8 vs. 8.3?±?2.6 mL, p?=?0.31; active 10.3?±?5.6 vs. 10.0?±?6.4 mL, p?=?0.72) occurred following LAA closure. Mean ratio of LAA to LA volume by 3D CT was 10.2?±?2.3%. No correlation was found between LAA/LA ratio and changes in LA stroke volume (r?=?0.35, p?=?0.22) or left ventricular stroke volume (r?=?0.28, p?=?0.33).

Conclusions

The LAA accounts for about 10% of the total LA volume, but percutaneous LAA closure did not translate into any significant changes in LA and left ventricular function.

     

Genetics correlates with lung function and nocturnal ventilation in myotonic dystrophy

Background

Dystrophia myotonica (DM) is the most frequent adult-onset muscular dystrophy. Type 1 is caused by the cytosine–thymine–guanine (CTG) repeat expansion in the DM protein kinase gene. Respiratory muscle weakness and altered central ventilatory control lead to hypercapnia and lung volume restriction.

Purpose

This study aims to review the respiratory involvement in DM patients and study its relation with genetics.

Methods

Retrospective study of patients with DM referred for respiratory assessment was made. Noninvasive ventilation (NIV) was considered to daytime hypercapnia or symptoms of nocturnal hypoventilation.

Results

Forty-two consecutive patients (37.9?±?13.6 years) were evaluated. Mean CTG length was 642.8?±?439.2 repeats. In the first evaluation, mean forced vital capacity (FVC) was 74.4?±?20.2 %, maximal expiratory pressure (MEP) 35?±?16 %, maximal inspiratory pressure 52?±?23 %, peak cough flow (PCF) 327.3?±?97.7 L/min, arterial pressure of oxygen 79.7?±?11.3 mmHg, arterial pressure of carbon dioxide 45.5?±?6.2 mmHg, overnight minimal peripheral oxygen saturation (SpO₂) 79.6?±?11.6 %, and apnea–hypopnea index 13.9?±?9.9. CTG length was found to be related with MEP (r?=??0.67; p?=?0.001) and SpO₂ (r?=??0.37; p?=?0.039). NIV was started in 25 patients. Ventilated patients had lower FVC (2.19 to 3.21 L; p?<?0.001) and PCF (285.3 to 388.5 L/min; p?=?0.003) and more CTG repeats (826.6 to 388.5 repeats; p?=?0.02). NIV compliance was poor in seven patients (28 %) and related with hypercapnia (r?=?0.87; p?=?0.002) and inspiratory positive airway pressure setting (r?=?0.65; p?=?0.009). Ventilation improved symptoms and nocturnal hypoventilation. Comparing the first and last evaluations, only PCF was significantly lower (275.0 to 310.8 L/min; p?=?0.019).

Conclusions

Ventilatory insufficiency is very common in patients with DM and CTG length may be useful to predict it. Prolonged NIV improves symptoms, nocturnal hypoventilation and maintains daily blood gases. Routine evaluation of PCF should not be forgotten and assisted coughing training provided.     

Fibrosis and electrophysiological characteristics of the atrial appendage in patients with atrial fibrillation and structural heart disease

Purpose

This study was conducted to investigate the degree of fibrosis in atrial appendages of patients with and without atrial fibrillation (AF) undergoing cardiac surgery. In addition, we hypothesized that areas of atrial fibrosis can be identified by electrogram fractionation and low voltage for potential ablation therapy.

Methods

Interstitial fibrosis from right (RAA) and/or left atrial appendages (LAA) was studied in patients with sinus rhythm (SR, n?=?8), paroxysmal (n?=?21), and persistent AF (n?=?20) undergoing coronary artery bypass and/or aortic or mitral valve surgery. Atrial fibrosis quantification was performed with Masson trichrome staining. Intraoperative bipolar epicardial electrophysiological measurements were performed to correlate fibrosis to electrogram fractionation, voltage, and AF cycle length.

Results

The average degree of fibrosis was 11.2?±?7.2 % in the LAA and 22.8?±?7.6 % in the RAA (p?<?0.001). Fibrosis was not significantly higher in paroxysmal AF patients compared to SR subjects (18.2?±?8.7 versus 20.7?±?5.3 %). Persistent AF patients had a higher degree of LAA and RAA fibrosis compared to paroxysmal AF patients (LAA 14.6?±?8.7 versus 8.6?±?4.7 %, p?=?0.02, and RAA 28.2?±?7.9 versus 18.2?±?8.7 %, respectively, p?=?0.04). The left atrial end diastolic volume index was higher in persistent AF patients compared to SR controls (38.3?±?16.4 and 28?±?11 ml/m², respectively, p?=?0.04). No correlation between atrial fibrosis and electrogram fractionation or voltage was found.

Conclusion

Patients with structural heart disease undergoing cardiac surgery have more fibrosis in the RAA than in the LAA. Furthermore, RAA fibrosis is increased in persistent AF but not paroxysmal AF patients compared to control subjects. Electrogram fractionation and low voltage did not provide accurate identification of the fibrotic substrate.     

Incidence,predictors, and clinical course of atrial tachyarrhythmias in patients with pulmonary hypertension

Background

The prevalence and predictors of atrial tachyarrhythmias (ATa) in patients with pulmonary hypertension (PH) is less well understood.

Methods

We performed a retrospective study including 311 patients with PH, confirmed by right heart catheterization in our center between 2007 and 2011. Baseline characteristics, clinical, echocardiographic, and hemodynamic data were collected and compared between patients with and without ATa.

Results

The mean age was 61?±?13 years with 64 % females. The mean pulmonary artery pressure (mPAP) was 46?±?20 mmHg, mean left ventricular ejection fraction (LVEF) was 55?±?13 %, and mean pulmonary capillary wedge pressure (PCWP) was 19?±?9 mmHg. Of the 311 patients with PH, 121 (39 %) patients had ATa. Patients with ATa were older (p?p?=?0.03), diabetes (p?=?0.015), coronary artery disease (p?p?p?=?0.001), impaired LVEF (p?=?0.02), and left atrial enlargement (p?p?=?0.022). In multivariate analysis using Cox-proportional hazard model, the independent predictors of mortality were age (HR 1.05; p?=?0.003), coronary artery disease (HR 2.34; p?=?0.047), LVEF (HR 0.793; p?=?0.023), and mPAP (HR 1.023; p?=?0.003).

Conclusion

ATa are common in patients with PH. Left heart disease, left atrial enlargement, and elevated PCWP but not right atrial enlargement or mPAP predict the occurrence of ATa in patients with PH.     

Obstructive sleep apnea is associated with interdialytic weight gain and increased long-term cardiovascular events in hemodialysis patients

Background

Obstructive sleep apnea (OSA) is common in hemodialysis (HD) patients. The reasons for the high prevalence and whether OSA is associated with vascular impairment, end-organ damage, and prognosis are not completely clear.

Methods

We evaluated patients with low cardiovascular risk on HD, not treated by CPAP. Laboratory tests, sleep questionnaires (Berlin and Epworth) and polysonography studies, echocardiography, and markers of arterial stiffness and atherosclerosis were performed. After the initial evaluation, patients were followed up until cardiovascular events, renal transplantation, or death.

Results

Fifty-five patients (49% male, 50?±?9 years, body mass index 24.7?±?4.5 kg/m²) were included. OSA (apnea-hypopnea index ≥?5 events/h) occurred in 73% of the patients. The proportion of patients with interdialytic weight gain >?2 kg was higher in patients with OSA than those without OSA (96 vs. 55%; p?=?0.002). Left ventricular (LV) posterior wall thickness (10.0?±?1.9 vs. 11.3?±?1.8 mm; p?=?0.04) and LV diastolic diameter (48?±?5 vs. 53?±?5 mm; p?=?0.003) were higher in patients with OSA than in patients without OSA, respectively. Sleep questionnaires did not predict OSA. No significant differences were found in pulse wave velocity, carotid intima-media thickness, and ankle-brachial index between the groups. Multivariate analysis showed that interdialytic weight gain >?2 kg and LV diastolic diameter were independently associated with OSA. On follow-up (median 45 months), OSA was found to be associated with a higher incidence of cardiovascular (CV) events (28 vs. 7%, log-rank?=?0.042).

Conclusions

OSA was associated with increased risk of CV events. Significant (>?2 kg) interdialytic weight gain was independently associated with OSA.

     

Does bariatric surgery change olfactory perception? Results of the early postoperative course

Purpose

Changes of food preference toward foods with low caloric density have been demonstrated after bariatric surgery and may contribute to sustained body weight loss. It has been hypothesized that olfactory perception as an integral part of food selection might be altered after bariatric surgery.

Methods

Sniffin’ Sticks® were used to investigate the olfactory perception of morbidly obese patients undergoing either Roux-en-Y gastric bypass (RYGB, n?=?15) or sleeve gastrectomy (SG, n?=?15) before 1, 6, 12, and 24 weeks after surgery. Obese patients without surgical intervention served as controls (CG, n?=?12). Results are presented using the testing odor threshold, discrimination, and identification score (TDI; higher scores indicate better olfactory perception). Body weight loss was recorded.

Results

Initial BMI of the SG group (56.04?±?7.096 kg m^?2) was higher compared to the BMI of the RYGB (48.71?±?6.49 kg m^?2) and CG (50.35?±?6.78 kg m^?2); p?=?0.011. Body weight loss among the surgical groups was not different (p?=?0.011) while controls did not lose weight. Mean baseline TDI scores were significantly lower in the SG group 27.1?±?3.9 vs. 32.6?±?3.6 (RYGB) and 32.1?±?5.3 (CG), respectively, whereas there were after 24 weeks no changes in RYGB and CG patients; the TDI score in the SG group increased significantly to 31.1?±?3.5 (p?<?0.01).

Conclusions

Our data suggest that a substantial body weight loss per se does not affect olfactory perception. However, our results point towards improved olfactory perception after sleeve gastrectomy but not Roux-en-Y gastric bypass.     

Common variant in the HMGA2 gene increases susceptibility to nephropathy in patients with type 2 diabetes

Aims/hypothesis

Type 2 diabetes is a chronic metabolic disorder associated with devastating microvascular complications. Genome-wide association studies have identified more than 60 genetic variants associated with type 2 diabetes and/or glucose and insulin traits, but their role in the progression of diabetes is not established. The aim of this study was to explore whether these variants were also associated with the development of nephropathy in patients with type 2 diabetes.

Methods

We studied 28 genetic variants in 2,229 patients with type 2 diabetes from the local Malmö Scania Diabetes Registry (SDR) published during 2007–2010. Diabetic nephropathy (DN) was defined as micro- or macroalbuminuria and/or end-stage renal disease. Estimated glomerular filtration rate (eGFR) was assessed using the MDRD-4 formula. Replication genotyping of rs1531343 was performed in diabetic (Steno type 2 diabetes [n?=?345], Genetics of Diabetes Audit and Research in Tayside Scotland [Go-DARTS] [n?=?784]) and non-diabetic (Malmö Preventive Project [n?=?2,523], Botnia study [n?=?2,247]) cohorts.

Results

In the SDR, HMGA2 single-nucleotide polymorphism rs1531343 was associated with DN (OR 1.50, 95% CI 1.20, 1.87, p?=?0.00035). In the combined analysis totalling 3,358 patients with type 2 diabetes (n?=?1,233 cases, n?=?2,125 controls), carriers of the C-allele had a 1.45-fold increased risk of developing nephropathy (95% CI 1.20, 1.75, p?=?0.00010). Furthermore, the risk C-allele was associated with lower eGFR in patients with type 2 diabetes (n?=?2,499, β?±?SEM, ?3.7?±?1.2 ml/min, p?=?0.002) and also in non-diabetic individuals (n?=?17,602, β?±?SEM, ?0.008?±?0.003 ml/min (log _e ), p?=?0.006).

Conclusions/interpretation

These data demonstrate that the HMGA2 variant seems to be associated with increased risk of developing nephropathy in patients with type 2 diabetes and lower eGFR in both diabetic and non-diabetic individuals and could thus be a common denominator in the pathogenesis of type 2 diabetes and kidney complications.     

Effects of calcium–vitamin D co-supplementation on glycaemic control,inflammation and oxidative stress in gestational diabetes: a randomised placebo-controlled trial

Aims/hypothesis

This study was designed to assess the effects of calcium and vitamin D supplementation on the metabolic status of pregnant women with gestational diabetes mellitus (GDM).

Methods

This randomised placebo-controlled trial was performed at maternity clinics affiliated to Kashan University of Medical Sciences, Kashan, Iran. Participants were 56 women with GDM at 24–28 weeks’ gestation (18 to 40 years of age). Subjects were randomly assigned to receive calcium plus vitamin D supplements or placebo. All study participants were blinded to group assignment. Individuals in the calcium–vitamin D group (n?=?28) received 1,000 mg calcium per day and a 50,000 U vitamin D₃ pearl twice during the study (at study baseline and on day 21 of the intervention), and those in the placebo group (n?=?28) received two placebos at the mentioned times. Fasting blood samples were taken at study baseline and after 6 weeks of intervention.

Results

The study was completed by 51 participants (calcium–vitamin D n?=?25, placebo n?=?26). However, as the analysis was based on an intention-to-treat approach, all 56 women with GDM (28 in each group) were included in the final analysis. After the administration of calcium plus vitamin D supplements, we observed a significant reduction in fasting plasma glucose (?0.89?±?0.69 vs +0.26?±?0.92 mmol/l, p?p?=?0.02) and HOMA-IR (?0.91?±?1.18 vs +0.63?±?2.01, p?=?0.001) and a significant increase in QUICKI (+0.02?±?0.03 vs ?0.002?±?0.02, p?=?0.003) compared with placebo. In addition, a significant reduction in serum LDL-cholesterol (?0.23?±?0.79 vs +0.26?±?0.74 mmol/l, p?=?0.02) and total cholesterol: HDL-cholesterol ratio (?0.49?±?1.09 vs +0.18?±?0.37, p?=?0.003) and a significant elevation in HDL-cholesterol levels (+0.15?±?0.25 vs ?0.02?±?0.24 mmol/l, p?=?0.01) was seen after intervention in the calcium–vitamin D group compared with placebo. In addition, calcium plus vitamin D supplementation resulted in a significant increase in GSH (+51.14?±?131.64 vs ?47.27?±?203.63 μmol/l, p?=?0.03) and prevented a rise in MDA levels (+0.06?±?0.66 vs +0.93?±?2.00 μmol/l, p?=?0.03) compared with placebo.

Conclusions/interpretation

Calcium plus vitamin D supplementation in women with GDM had beneficial effects on their metabolic profile.

Trial registration

www.irct.ir IRCT201311205623N11

Funding

The study was supported by a grant (no. 92110) from Kashan University of Medical Sciences.