Oliver Senn

Sirolimus and Kidney Growth in Autosomal Dominant Polycystic Kidney Disease

BACKGROUND In autosomal dominant polycystic kidney disease (ADPKD), aberrant activation of the mammalian target of rapamycin (mTOR) pathway is associated with progressive kidney enlargement. The drug sirolimus suppresses mTOR signaling. METHODS In this 18-month, open-label, randomized, controlled trial, we sought to determine whether sirolimus halts the growth in kidney volume among patients with ADPKD. We randomly assigned 100 patients between the ages of 18 and 40 years to receive either sirolimus (target dose, 2 mg daily) or standard care. All patients had an estimated creatinine clearance of at least 70 ml per minute. Serial magnetic resonance imaging was performed to measure the volume of polycystic kidneys. The primary outcome was total kidney volume at 18 months on blinded assessment. Secondary outcomes were the glomerular filtration rate and urinary albumin excretion rate at 18 months. RESULTS At randomization, the median total kidney volume was 907 cm3 (interquartile range, 577 to 1330) in the sirolimus group and 1003 cm3 (interquartile range, 574 to 1422) in the control group. The median increase over the 18-month period was 99 cm3 (interquartile range, 43 to 173) in the sirolimus group and 97 cm3 (interquartile range, 37 to 181) in the control group. At 18 months, the median total kidney volume in the sirolimus group was 102% of that in the control group (95% confidence interval, 99 to 105; P=0.26). The glomerular filtration rate did not differ significantly between the two groups; however, the urinary albumin excretion rate was higher in the sirolimus group. CONCLUSIONS In adults with ADPKD and early chronic kidney disease, 18 months of treatment with sirolimus did not halt polycystic kidney growth. (Funded by Wyeth and others; ClinicalTrials.gov number, NCT00346918.)

Effects of Continuous Positive Airway Pressure Therapy Withdrawal in Patients with Obstructive Sleep Apnea

RATIONALE To establish a new approach to investigate the physiological effects of obstructive sleep apnea (OSA), and to evaluate novel treatments, during a period of continuous positive airway pressure (CPAP) withdrawal. OBJECTIVES To determine the effects of CPAP withdrawal. METHODS Forty-one patients with OSA and receiving CPAP were randomized to either CPAP withdrawal (subtherapeutic CPAP), or continued CPAP, for 2 weeks. Polysomnography, sleepiness, psychomotor performance, endothelial function, blood pressure (BP), heart rate (HR), urinary catecholamines, blood markers of systemic inflammation, and metabolism were assessed. MEASUREMENTS AND MAIN RESULTS CPAP withdrawal led to a recurrence of OSA within a few days and a return of subjective sleepiness, but was not associated with significant deterioration of psychomotor performance within 2 weeks. Endothelial function, assessed by flow-mediated dilatation, decreased significantly in the CPAP withdrawal group compared with therapeutic CPAP (mean difference in change, -3.2%; 95% confidence interval [CI], -4.5, -1.9%; P < 0.001). Compared with continuing CPAP, 2 weeks of CPAP withdrawal was associated with a significant increase in morning systolic BP (mean difference in change, +8.5 mm Hg; 95% CI, +1.7, +15.3 mm Hg; P = 0.016), morning diastolic BP (mean difference in change, +6.9 mm Hg; 95% CI, +1.9, +11.9 mm Hg; P = 0.008), and morning HR (mean difference in change, +6.3 bpm, 95% CI, +0.4, +12.2 bpm; P = 0.035). CPAP withdrawal was associated with an increase in urinary catecholamines but did not lead to an increase in markers of systemic inflammation, insulin resistance, or blood lipids. CONCLUSIONS CPAP withdrawal usually leads to a rapid recurrence of OSA, a return of subjective sleepiness, and is associated with impaired endothelial function, increased urinary catecholamines, blood pressure, and heart rate. Thus the proposed study model appears to be suitable to evaluate physiological and therapeutic effects in OSA. Clinical trial registered with www.controlled-trials.com (ISRCTN93153804).

Increases in kidney volume in autosomal dominant polycystic kidney disease can be detected within 6 months

Kidney volume growth is considered the best surrogate marker predicting the decline of renal function in autosomal dominant polycystic kidney disease. To assess the therapeutic benefit of new drugs more rapidly, changes in kidney volume need to be determined over a short time interval. Here we measured renal volume changes by manual segmentation volumetry applied to magnetic resonance imaging scans obtained with an optimized T1-weighted acquisition protocol without gadolinium-based contrast agents. One hundred young patients with autosomal dominant polycystic kidney disease and preserved renal function had a significant increase in total kidney volume by 2.71+/-4.82% in 6 months. Volume measurements were highly reproducible and accurate, as indicated by correlation coefficients of 1.000 for intra-observer and 0.996 for inter-observer agreement, with acceptable within-subject standard deviations. The change in renal volume correlated with baseline total kidney volume in all age subgroups. Total kidney volume positively correlated with male gender, hypertension, albuminuria and a history of macrohematuria but negatively with creatinine clearance. Albuminuria was associated with accelerated volume progression. Our study shows that increases in kidney volume can be reliably measured over a 6 month period in early autosomal dominant polycystic kidney disease using unenhanced magnetic resonance imaging sequences.

Age- and gender-related prevalence of multimorbidity in primary care: the swiss fire project

BackgroundGeneral practitioners often care for patients with several concurrent chronic medical conditions (multimorbidity). Recent data suggest that multimorbidity might be observed more often than isolated diseases in primary care. We explored the age- and gender-related prevalence of multimorbidity and compared these estimates to the prevalence estimates of other common specific diseases found in Swiss primary care.MethodsWe analyzed data from the Swiss FIRE (Family Medicine ICPC Research using Electronic Medical Record) project database, representing a total of 509,656 primary care encounters in 98,152 adult patients between January 1, 2009 and July 31, 2011. For each encounter, medical problems were encoded using the second version of the International Classification of primary Care (ICPC-2). We defined chronic health conditions using 147 pre-specified ICPC-2 codes and defined multimorbidity as 1) two or more chronic health conditions from different ICPC-2 rubrics, 2) two or more chronic health conditions from different ICPC-2 chapters, and 3) two or more medical specialties involved in patient care. We compared the prevalence estimates of multimorbidity defined by the three methodologies with the prevalence estimates of common diseases encountered in primary care.ResultsOverall, the prevalence estimates of multimorbidity were similar for the three different definitions (15% [95%CI 11-18%], 13% [95%CI 10-16%], and 14% [95%CI 11-17%], respectively), and were higher than the prevalence estimates of any specific chronic health condition (hypertension, uncomplicated 9% [95%CI 7-11%], back syndrome with and without radiating pain 6% [95%CI 5-7%], non-insulin dependent diabetes mellitus 3% [95%CI 3-4%]), and degenerative joint disease 3% [95%CI 2%-4%]). The prevalence estimates of multimorbidity rose more than 20-fold with age, from 2% (95%CI 1-2%) in those aged 20–29 years, to 38% (95%CI 31-44%) in those aged 80 or more years. The prevalence estimates of multimorbidity were similar for men and women (15% vs. 14%, p=0.288).ConclusionsIn primary care, prevalence estimates of multimorbidity are higher than those of isolated diseases. Among the elderly, more than one out of three patients suffer from multimorbidity. Management of multimorbidity is a principal concern in this vulnerable patient population.

Effect of ascent protocol on acute mountain sickness and success at Muztagh Ata, 7546 m.

Investigations studying the secretion of EPO (erythropoietin) in response to acute hypoxia have produced mixed results. Further, the errors associated with the various methods used to determine EPO are not well documented. The purpose of the current study was to determine the EPO response of 17 trained male subjects to either an acute bout of normobaric hypoxia (Hy; n = 10) or normoxia (Con; n = 7). A secondary aim was to determine the error associated with the measurement of EPO. After baseline tests, the treatment group (Hy) underwent a single bout of hypoxic exposure (F(I(O(2))) approximately 0.148; 3100 m) consisting of a 90-min rest period followed by a 30-min exercise phase (50% V(O)(2max)). Venous blood samples were drawn pre (0 min) and post (120 min) each test to assess changes in plasma EPO (DeltaEPO). The control (Con) group was subjected to the same general experimental design, but placed in a normoxic environment (F(I(O(2))) approximately 0.2093). The Hy group demonstrated a mean increase in EPO [19.3 (4.4) vs. 24.1 (5.1) mU/mL], p < 0.04, post 120 min of normobaric hypoxia. The calculated technical error of measurement for EPO was 2.1 mU/mL (9.8%). It was concluded that an acute bout of hypoxia, has the capacity to elevate plasma EPO. This study also demonstrates that the increase in EPO accumulation was 2 times greater than the calculated measurement of error.

Acute mountain sickness is related to nocturnal hypoxemia but not to hypoventilation

The purpose of the study was to investigate determinants of acute mountain sickness after rapid ascent to high altitude. A total of 21 climbers were studied ascending from <1,200 m to Capanna Regina Margherita, a hut in the Alps at 4,559 m, within <24 h. During their overnight stay at 4,559 m, breathing patterns and ventilation were recorded by calibrated respiratory inductive plethysmography along with pulse oximetry. In the following morning, acute mountain sickness was assessed. Altogether, 11 mountaineers developed pronounced symptoms of acute mountain sickness (Lake Louise score ≥5) and 10 did not (controls). Compared to controls, subjects with acute mountain sickness had lower nocturnal oxygen saturation (mean±sd 59±13% versus 73±6%), higher minute ventilation (7.94±2.35 versus 6.06±1.34 L·min−1), and greater mean inspiratory flow, a measure of respiratory centre drive (0.29±0.09 versus 0.22±0.05 L·s−1). Periodic respiration was prevalent but not significantly different among the two groups (apnoea/hypopnea index 60.1±34.6 versus 47.1±42.6 events per h). The data suggest that pronounced nocturnal hypoxemia, which was not related to hypoventilation, may have promoted acute mountain sickness. Periodic breathing seems not to play a predominant role in the pathogenesis of acute mountain sickness.

Significant reduction of red blood cell transfusion requirements by changing from a double-unit to a single-unit transfusion policy in patients receiving intensive chemotherapy or stem cell transplantation

Background Traditionally, single-unit red blood cell transfusions were believed to be insufficient to treat anemia, but recent data suggest that they may lead to a safe reduction of transfusion requirements. We tested this hypothesis by changing from a double- to a single-unit red blood cell transfusion policy. Design and Methods We performed a retrospective cohort study in patients with hematologic malignancies receiving intensive chemotherapy or hematopoietic stem cell transplantation. The major end-points were the reduction in the total number of red blood cell units per therapy cycle and per day of aplasia. The study comprised 139 patients who received 272 therapy cycles. Overall 2212 red blood cell units were administered in 1548 transfusions. Results During the periods of the double- and single-unit policies, one red blood cell unit was transfused in 25% and 84% of the cases and the median number of red blood cell units per transfusion was two and one, respectively. Single-unit transfusion led to a 25% reduction of red blood cell usage per therapy cycle and 24% per aplasia day, but was not associated with a higher out-patient transfusion frequency. In multivariate analysis, single-unit transfusion resulted in a reduction of 2.7 red blood cell units per treatment cycle (P=0.001). The pre-transfusion hemoglobin levels were lower during the single-unit period (median 61 g/L versus 64 g/L) and more transfusions were administered to patients with hemoglobin values of 60 gl/L or less (47% versus 26%). There was no evidence of more severe bleeding or more platelet transfusions during the single-unit period and the overall survival was similar in both cohorts. Conclusions Implementing a single-unit transfusion policy saves 25% of red blood cell units and, thereby, reduces the risks associated with allogeneic blood transfusions.

Optimal preprocedural platelet transfusion threshold for central venous catheter insertions in patients with thrombocytopenia

BACKGROUND: Patients with severe thrombocytopenia are at risk for bleeding during insertion of central venous catheters (CVCs). Although most guidelines recommend preprocedural platelet (PLT) transfusions at a threshold of less than 50 × 109/L, there is only weak evidence supporting such recommendations.

What is associated with race performance in male 100-km ultra-marathoners - anthropometry, training or marathon best time?

Abstract We investigated the associations of anthropometry, training, and pre-race experience with race time in 93 recreational male ultra-marathoners (mean age 44.6 years, s = 10.0; body mass 74.0 kg, s = 9.0; height 1.77 m, s = 0.06; body mass index 23.4 kg · m−2, s = 2.0) in a 100-km ultra-marathon using bivariate and multivariate analysis. In the bivariate analysis, body mass index (r = 0.24), the sum of eight skinfolds (r = 0.55), percent body fat (r = 0.57), weekly running hours (r = −0.29), weekly running kilometres (r = −0.49), running speed during training (r = −0.50), and personal best time in a marathon (r = 0.72) were associated with race time. Results of the multiple regression analysis revealed an independent and negative association of weekly running kilometres and average speed in training with race time, as well as a significant positive association between the sum of eight skinfold thicknesses and race time. There was a significant positive association between 100-km race time and personal best time in a marathon. We conclude that both training and anthropometry were independently associated with race performance. These characteristics remained relevant even when controlling for personal best time in a marathon.

Intra- and Inter-Judge Reliabilities in Measuring the Skin-Fold Thicknesses of Ultra Runners under Field Conditions

Inter- and intra-judge reliabilities of skinfold measures were investigated in a sample of 27 men and 11 women ultramarathon runners. Two physicians had agreement higher than 90% in field measurements before an ultramarathon race.