Stefan H. Jacobson

Effect of Membrane Permeability on Survival of Hemodialysis Patients

The effect of high-flux hemodialysis membranes on patient survival has not been unequivocally determined. In this prospective, randomized clinical trial, we enrolled 738 incident hemodialysis patients, stratified them by serum albumin < or = 4 and >4 g/dl, and assigned them to either low-flux or high-flux membranes. We followed patients for 3 to 7.5 yr. Kaplan-Meier survival analysis showed no significant difference between high-flux and low-flux membranes, and a Cox proportional hazards model concurred. Patients with serum albumin < or = 4 g/dl had significantly higher survival rates in the high-flux group compared with the low-flux group (P = 0.032). In addition, a secondary analysis revealed that high-flux membranes may significantly improve survival of patients with diabetes. Among those with serum albumin < or = 4 g/dl, slightly different effects among patients with and without diabetes suggested a potential interaction between diabetes status and low serum albumin in the reduction of risk conferred by high-flux membranes. In summary, we did not detect a significant survival benefit with either high-flux or low-flux membranes in the population overall, but the use of high-flux membranes conferred a significant survival benefit among patients with serum albumin < or = 4 g/dl. The apparent survival benefit among patients who have diabetes and are treated with high-flux membranes requires confirmation given the post hoc nature of our analysis.

Uropathogenic Escherichia coli Modulates Immune Responses and Its Curli Fimbriae Interact with the Antimicrobial Peptide LL-37

Bacterial growth in multicellular communities, or biofilms, offers many potential advantages over single-cell growth, including resistance to antimicrobial factors. Here we describe the interaction between the biofilm-promoting components curli fimbriae and cellulose of uropathogenic E. coli and the endogenous antimicrobial defense in the urinary tract. We also demonstrate the impact of this interplay on the pathogenesis of urinary tract infections. Our results suggest that curli and cellulose exhibit differential and complementary functions. Both of these biofilm components were expressed by a high proportion of clinical E. coli isolates. Curli promoted adherence to epithelial cells and resistance against the human antimicrobial peptide LL-37, but also increased the induction of the proinflammatory cytokine IL-8. Cellulose production, on the other hand, reduced immune induction and hence delayed bacterial elimination from the kidneys. Interestingly, LL-37 inhibited curli formation by preventing the polymerization of the major curli subunit, CsgA. Thus, even relatively low concentrations of LL-37 inhibited curli-mediated biofilm formation in vitro. Taken together, our data demonstrate that biofilm components are involved in the pathogenesis of urinary tract infections by E. coli and can be a target of local immune defense mechanisms.

Exercise training in adults with CKD: a systematic review and meta-analysis.

BACKGROUND Whether exercise can affect health outcomes in people with chronic kidney disease (CKD) and what the optimal exercise strategies are for patients with CKD remain uncertain. STUDY DESIGN Systematic review and meta-analysis of randomized controlled trials. SETTING & POPULATION Adults with CKD stages 2-5, dialysis therapy, or a kidney transplant. SELECTION CRITERIA FOR STUDIES Trials evaluating regular exercise training outcomes identified by searches in Cochrane CENTRAL, MEDLINE, EMBASE, CINAHL, Web of Science, BIOSIS, PEDro, AMED, AgeLine, PsycINFO, and KoreaMed, without language restriction. INTERVENTION Regular exercise training for at least 8 weeks. OUTCOMES Vary by study but could include aerobic capacity, muscular functioning, cardiovascular function, walking capacity, and health-related quality of life. Treatment effects were summarized as standardized difference with 95% CIs using random-effects meta-analysis. RESULTS 41 trials (928 participants) comparing exercise training with sham exercise or no exercise were included; overall, improved aerobic capacity, muscular functioning, cardiovascular function, walking capacity, and health-related quality of life were associated with various exercise interventions, although the preponderance of data were for dialysis patients and used aerobic exercise programs. LIMITATIONS Unclear or high risk of bias in 32% of the trials, few trial data concerning resistance training, and limited data for several important outcomes. CONCLUSIONS Regular exercise training generally is associated with improved health outcomes in individuals with CKD. Correctly designed exercise rehabilitation may be an effective part of care for adults with CKD. Future studies should examine longer term outcomes and strategies to translate exercise done in a supervised setting to the home setting for broader applicability.

Increased blood pressure but normal renal function in adult women born preterm

Abstract It has been suggested that children born small for gestational age may develop hypertension and renal dysfunction in adulthood due to impaired fetal kidney development. Very little information on this issue is available on children born preterm. The objective of this study was to investigate the relationship between birth weight, blood pressure, and kidney function in adult subjects who were born preterm or born small for gestational age (SGA). Study design: Subjects (n=50), all women born between 1966 and 1974, were evaluated at a mean age of 26±1.9 years. They were allocated to three groups: (1) born before gestational week 32 (n=15), (2) born full term with birth weight <2600 g (n=18) (SGA), and (3) controls, born full term with appropriate birth weight (n=17). Casual blood pressure, ambulatory 24-h blood pressure (ABPM), glomerular filtration rate (GFR), renal plasma flow (ERPF) and urinary albumin excretion were determined. Results: Preterms had significantly higher casual systolic and mean arterial blood pressure levels compared to controls (123±13 vs 110±7 mmHg, P<0.01, and 87±9 vs 79±6 mmHg, P<0.005, respectively). ABPM was not significantly different between the groups. When the number of systolic recordings >130 mmHg/subject during ABPM was calculated, the preterms had significantly more recordings above this value (P<0.05) as well as a significantly increased area under the curve >130 mmHg and >140 mmHg systolic (P<0.05) compared to the controls. SGA subjects were not significantly different from controls. There were no significant differences in GFR, ERPF or urinary albumin excretion between the three groups. Conclusion: Women born preterm seem to have a disturbance in blood pressure regulation in adulthood, a finding that is not observed for those born small for gestational age. Kidney function in early adulthood seems to be normal in subjects born preterm or small for gestational age.

Long-term prognosis of post-infectious renal scarring in relation to radiological findings in childhood — a 27-year follow-up

In a previous report the long-term prognosis of 30 patients with renal scarring after pyelonephritis in childhood was described. In this study, we have related the extent of renal scarring present in childhood to the conditions in early adulthood. A radiological progression of searring from childhood to adulthood was seen in one-third of the kidneys. The 7 patients with bilateral scarring in childhood had a smaller renal area, lower glomerular filtration rate and higher plasma vasopressin at follow-up than 13 healthy controls. The 20 patients who had unilateral searring in childhood had a smaller renal area, lower glomerular filtration rate, higher diastolic blood pressure and higher plasma renin at follow-up than controls; 4 had hypertension. The most important finding was that children with unilateral disease are at risk of serious long-term complications. Filtration fraction at follow-up was higher in patients with extensive renal scarring in childhood compared with those with a normal renal area or small scars in childhood (r=−0.43,P<0.05). This may indicate glomerular hyperfiltration by remnant glomeruli. This paper emphasizes the potential seriousness of childhood urinary tract infections especially when early infantile infections are overlooked. A follow-up of more than 4 decades may be necessary before the ultimate prognosis can be established, especially in patients with unilateral renal disease. It is advised that most patients with post-infectious renal scars are followed as high-risk patients, and that treatment continuity is established between paediatricians, nephrologists and, when required, obstetricians.

Low Gestational Age Associated with Abnormal Retinal Vascularization and Increased Blood Pressure in Adult Women

The objective was to investigate any possible relationship between functional and structural vascular changes in women with low gestational age and/or low birth weight by analyzing the retinal vascular pattern in women with thoroughly documented blood pressure. Retinal vessel morphology was evaluated by digital image analysis of ocular fundus photographs in 47 subjects, aged 23–30 y. The women were allocated into three groups: 1) those born preterm and appropriate for gestational age (AGA), with a median gestational age at birth of 30 wk and a median birth weight of 1250 g (n = 14); 2) those born small for gestational age (SGA) but full term (median 40 wk), with a median birth weight of 2130 g (n = 17), and 3) those born full term, AGA, and with a median birth weight of 3640 g (n = 16). Women born preterm had significantly higher length index for arterioles compared with the other two groups (median 1.11 and 1.08, respectively, p = 0.005). In addition, the preterm-born women had significantly fewer number of vascular branching points compared with the controls (median 27 and 30, respectively, p = 0.03). The abnormal retinal vascularization observed in ex-preterm women together with an increased casual blood pressure observed in these subjects suggests that being born preterm does have effects on the vascular system that persist into adult life. In addition, it demonstrates that preterm birth seems to affect the vascular system both functionally and structurally, which, in adulthood, could result in a lower threshold for the development of vascular disease.

Biopsy-verified response of severe lupus nephritis to treatment with rituximab (anti-CD20 monoclonal antibody) plus cyclophosphamide after biopsy-documented failure to respond to cyclophosphamide alone

Background: The monoclonal anti-B cell antibody rituximab (Rituxin, Mabthera) may be of benefit in antibody-driven diseases, including systemic lupus erythematosus (SLE) nephritis. Patients and treatment: Two female patients with biopsy-confirmed severe and active SLE nephritis despite treatment with cyclophosphamide (CyX) were given four rituximab infusions plus two additional CyX infusions. Results: Both patients tolerated the treatment well and SLE activity improved. On repeat kidney biopsy after the combined treatment, Patient 1 showed a profound reduction of nephritis activity, and she was maintained on low-dose prednisolone only. A repeat biopsy after 1 year confirmed the sustained reduction of lupus nephritis activity. In Patient 2, rebiopsy after combined treatment also showed a significant reduction in disease activity. Conclusion: These cases provide histopathological documentation of a significant treatment benefit from rituximab plus CyX in two patients refractory to CyX alone. This combination is being explored further as salvage therapy for such CyX-resistant patients.

Recent Changes in Therapeutic Approaches and Association with Outcomes among Patients with Secondary Hyperparathyroidism on Chronic Hemodialysis: The DOPPS Study

BACKGROUND AND OBJECTIVES Elevated parathyroid hormone levels may be associated with adverse clinical outcomes in patients on dialysis. After the introduction of practice guidelines suggesting higher parathyroid hormone targets than those previously recommended, changes in parathyroid hormone levels and treatment regimens over time have not been well documented. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS Using data from the international Dialysis Outcomes and Practice Patterns Study, trends in parathyroid hormone levels and secondary hyperparathyroidism therapies over the past 15 years and the associations between parathyroid hormone and clinical outcomes are reported; 35,655 participants from the Dialysis Outcomes and Practice Patterns Study phases 1-4 (1996-2011) were included. RESULTS Median parathyroid hormone increased from phase 1 to phase 4 in all regions except for Japan, where it remained stable. Prescriptions of intravenous vitamin D analogs and cinacalcet increased and parathyroidectomy rates decreased in all regions over time. Compared with 150-300 pg/ml, in adjusted models, all-cause mortality risk was higher for parathyroid hormone=301-450 (hazard ratio, 1.09; 95% confidence interval, 1.01 to 1.18) and >600 pg/ml (hazard ratio, 1.23; 95% confidence interval, 1.12 to 1.34). Parathyroid hormone >600 pg/ml was also associated with higher risk of cardiovascular mortality as well as all-cause and cardiovascular hospitalizations. In a subgroup analysis of 5387 patients not receiving vitamin D analogs or cinacalcet and with no prior parathyroidectomy, very low parathyroid hormone (<50 pg/ml) was associated with mortality (hazard ratio, 1.25; 95% confidence interval, 1.04 to 1.51). CONCLUSIONS In a large international sample of patients on hemodialysis, parathyroid hormone levels increased in most countries, and secondary hyperparathyroidism treatments changed over time. Very low and very high parathyroid hormone levels were associated with adverse outcomes. In the absence of definitive evidence in support of a specific parathyroid hormone target, there is an urgent need for additional research to inform clinical practice.

Relation between renal function, presentation, use of therapies and in-hospital complications in acute coronary syndrome: data from the SWEDEHEART register.

Abstract.  Szummer K, Lundman P, Jacobson SH, Schön S, Lindbäck J, Stenestrand U, Wallentin L, Jernberg T, for SWEDEHEART. (Karolinska Institute, Karolinska University Hospital, Stockholm; Karolinska Institute, Danderyd Hospital, Danderyd; Ryhov County Hospital, Jönköping; University Hospital, Uppsala and University Hospital, Linköping; Sweden) Relation between renal function, presentation, use of therapies and in‐hospital complications in acute coronary syndrome: data from the SWEDEHEART register. J Intern Med 2010; 268:40–49.

Travel Time to Dialysis as a Predictor of Health-Related Quality of Life, Adherence, and Mortality: The Dialysis Outcomes and Practice Patterns Study (DOPPS)

BACKGROUND Longer travel time to the dialysis unit creates a substantial burden for many patients. This study evaluated the effect of self-reported 1-way travel time to hemodialysis on mortality, health-related quality of life (HR-QOL), adherence, withdrawal from dialysis therapy, hospitalization, and transplantation. STUDY DESIGN Prospective observational cohort. SETTING & PARTICIPANTS Patients enrolled in the Dialysis Outcomes and Practices Patterns Study who completed a patient questionnaire (n = 20,994). PREDICTOR One-way travel time to hemodialysis treatment, categorized as 15 or less, 16 to 30, 31 to 60, and longer than 60 minutes. Covariates included demographics, comorbid conditions, serum albumin level, time on dialysis therapy, and country. OUTCOME & MEASUREMENT HR-QOL was examined by using a linear mixed model. Cox proportional hazards regression was used to examine associations with mortality, withdrawal from dialysis therapy, hospitalization, and transplantation. RESULTS Longer travel time was associated with greater adjusted relative risk (RR) of death (P = 0.05 for overall trend). Adjusted HR-QOL subscales were significantly lower for those with longer travel times compared with those traveling 15 minutes or less. There were no associations of travel time with withdrawal from dialysis therapy (P = 0.6), hospitalization (P = 0.4), or transplantation (P = 0.7). LIMITATIONS The questionnaire nonresponse rate was substantial, and nonresponders were older, with more comorbid conditions. Travel time was assessed by using a single nonvalidated question. CONCLUSIONS Longer travel time is associated significantly with greater mortality risk and decreased HR-QOL. Exploring opportunities to decrease travel time should be incorporated into the dialysis clinical routine.