Age- and time-dependent increases in incident anti-glomerular basement membrane disease: a nationwide cohort study.

Background: Epidemiologic assessments of anti-glomerular basement membrane (GBM) disease have been challenging due to its rare occurrence. We examined changes in the incidence and outcomes from 1998 to 2018 using nationwide healthcare registries. Methods: All patients with incident anti-GBM disease were identified using the International Classification of Diseases, 10th Revision code DM31.0A. Controls were matched 4:1 on birthyear and sex using exposure density sampling. Log link regression adjusted for time, age and sex was applied to model survival. Results: We identified 97 patients with incident anti-GBM disease, corresponding to an incidence of 0.91 cases/million/year [standard deviation (SD) 0.6]. The incidence increased over time [1998-2004: 0.50 (SD 0.2), 2005-2011: 0.80 (SD 0.4), 2012-2018: 1.4 (SD 0.5); P = .02] and with age [0.76 (SD 0.4), 1.5 (SD 1.04) and 4.9 (SD 2.6) for patients <45, 45-75 and >75 years]. The median age was 56 years (interquartile range 46) and 51.6% were female. Dialysis was required in 58.4%, 61.9% and 62.9% of patients at day 30, 180 and 360, respectively. The 1-year kidney survival probability was 0.38 (SD 0.05) and exhibited time-dependent changes [1998-2004: 0.47 (SD 0.13), 2005-2011: 0.16 (SD 0.07), 2012-2018: 0.46 (SD 0.07); P = .035]. The 5-year mortality was 26.8% and mortality remained stable over time (P = .228). The risk of death was greater than that of the matched background population {absolute risk ratio [ARR] 5.27 [confidence interval (CI) 2.45-11.3], P < .001}, however, it was comparable to that of patients with anti-neutrophil cytoplasmic antibody-associated vasculitis (AAV) requiring renal dialysis at presentation [ARR 0.82 (CI 0.48-1.41), P = .50]. Conclusion: The incidence of anti-GBM disease increased over time, possibly related to temporal demographic changes. Mortality remained high and was comparable with an age- and sex-matched cohort of dialysis-dependent AAV patients.

A life-changing process when living with chronic kidney disease: A qualitative study.

BACKGROUND: Patients with chronic kidney disease and their family members experience a number of lifestyle changes caused by the illness. The value of advance care planning includes understanding health status and options for future care, communication between close family members, and identification of wishes and preferences for care and treatment in relation to family and everyday life. OBJECTIVE: Explore how patients with chronic kidney disease and their families experience everyday life and how they experience having to make choices about treatment. DESIGN: An explorative study using a qualitative method with a phenomenological-hermeneutic approach. PARTICIPANTS: Twelve patients with chronic kidney disease without kidney replacement therapy who were considering their treatment options and eight family members. APPROACH: Individual semistructured interviews with a narrative approach were conducted between August 2021 and March 2022. The data were analysed using Ricoeur's interpretation theory on three levels: naïve reading, structural analysis and critical interpretation and discussion. FINDINGS: One main theme was generated: Family dynamics in a life-changing process. From this, three subthemes were derived: Living in an ordinary life placed in a waiting position, The dilemma of readiness to share and Feelings of being left alone. CONCLUSION: There are changes in family roles and in identity and a desire to maintain the known and ordinary life. Living with chronic kidney disease as a part of daily life is managed differently in the family, which can lead to feelings such as sadness, frustration and loss of shared life and resilience.

Advance care planning to patients with chronic kidney disease and their families: An intervention development study.

AIM: To develop an advance care planning intervention based on the needs of patients with chronic kidney disease, families and healthcare professionals. BACKGROUND: Patients with chronic kidney disease and their families request early advance care planning that continues throughout their illness trajectory. Healthcare professionals experience barriers to initiating advance care planning. Involvement of stakeholders in development of health interventions is important, to identify priorities, understand the problem and find solutions. METHOD: The development was inspired by the Medical Research Council's framework, and codesign was applied. One future workshop and one design workshop were conducted with the consumers. The process was iterative, and data were analysed using the action research spiral. The Guidance for reporting intervention development studies in healthcare (GUIDED) was used. RESULTS: Five areas were considered significant to an advance care planning intervention; a biopsychosocial approach, early palliative care, a family-focused approach, early and continuous advance care planning and a consumer-centred approach. Based on these, a conversation process with healthcare professionals was designed to give patients and families the opportunity to share values, preferences and wishes for treatment and their family and everyday life. CONCLUSION: Codesign facilitated a collaborative process that allowed the consumers to have a significant impact on the design of an advance care planning intervention. A conversation process concerning everyday life, illness and treatment was designed for patients and families. The intervention included an advance care planning tool to guide the healthcare professionals. PRACTICE IMPLICATIONS: The intervention has the intention to improve the communication between healthcare professionals, patients and families. The study provides important knowledge about the significance of giving the patients and their families support in sharing their values, preferences and wishes for treatment and everyday life, thus, to improve care and treatment in their illness trajectory. IMPACT: What problem did the study address Patients with chronic kidney disease and their families strongly request early initiation of advance care planning that continues throughout the illness trajectory. Healthcare professionals experience barriers to the initiation of the advance care planning and request a more systematic approach. What were the main findings Development of a conversation process about everyday life, illness and treatment for patients diagnosed with chronic kidney disease and families, including an advance care planning tool to guide the healthcare professionals. Where and on whom will the research have an impact The study contributes an advance care planning intervention to patients in the early stages of chronic kidney disease and their families. We believe that the intervention could be included during consultations with healthcare professionals in other stages of chronic kidney disease as well as other chronic disease. REPORTING METHOD: To strengthen the reporting of the development of the advance care planning intervention, we used the Guidance for reporting intervention development studies in healthcare (GUIDED). PATIENT OR PUBLIC CONTRIBUTION: The development of the intervention in this study was a collaborative process between patients, families, healthcare professionals and representatives from the Danish Kidney Association, the department's user council and the research team.

Advance care planning in chronic kidney disease: A national Danish survey of knowledge and attitudes among clinicians.

INTRODUCTION: Patients with chronic kidney disease and their families strongly request advance care planning. They want it to start early-before treatment decisions are made-and to be an ongoing process during their illness trajectory. Previous international studies show that health care professionals find there to be significant barriers that impact the extent of involvement in advance care planning. AIM: To identify Danish nephrology health care professionals' knowledge and attitudes to advance care planning and the status of current advance care planning practice in Denmark. METHOD: An anonymous, cross-sectional survey was administrated online. The questionnaire was developed in Australia and translated and culturally adapted into Danish. Health care professionals were recruited via email lists. In descriptive statistics and multiple ordinal regression, the influence of the respondents' attributes on the extent of involvement in advance care planning was explored, along with the involvement of family, and skills, comfort, barriers and facilitators in relation to advance care planning. RESULTS: The 207 respondents comprised nephrologists (23%), other physicians (8%), nurses (62%) and other HCPs (7%), of whom 27% had participated in advance care planning training. In total, 66% indicated that they lacked access to material about advance care planning for patients with chronic kidney disease and 46% indicated that the conversations were performed ad hoc. A total of 47% reported that advance care planning was performed well at their workplace. Reported barriers were time, lack of experience and procedure. Training in advance care planning could facilitate the involvement. Nurses were less likely to feel skilled and comfortable in engaging advance care planning, while those with more than 10 years of experience were more likely to feel skilled and comfortable. CONCLUSION: Training in advance care planning with patients with chronic kidney disease and their families on both a theoretical and clinical level is important to ensure comfort among health care professionals and to facilitate the extent of involvement. A systematic chronic kidney disease-specific approach is significant, in order to guide the conversations and ensure that advance care planning is conducted to a set standard.

Patients' with chronic kidney disease and their relatives' perspectives on advance care planning: A meta-ethnography.

INTRODUCTION: Advance care planning is a process that supports adults of any age and stage of illness in understanding and sharing their values, life goals, and preferences regarding medical care. Chronic kidney disease is a progressive and lifelong disease. Close relatives often represent patients' most important support. Advance care planning is recommended to be a continuous part of a person's ongoing treatment and is not solely related to end-of-life care. However, no studies have focused on advanced care planning for patients with chronic kidney disease earlier than the onset of a terminal illness. AIM: The aim is to describe experiences of and perspectives on advance care planning among patients with chronic kidney disease and their close relatives. METHODS: We conducted a meta-ethnography of studies that used individual, dyad, and focus group interviews. We searched five electronic databases: PubMed, Cinahl, Embase, PsycINFO, and Scopus and reference lists of relevant articles. RESULTS: Seven articles were included. Participants had a need for advance care planning to make shared decisions about treatment and everyday life. The responsibility for initiating advance care planning lay with the healthcare professionals. Differences between advance care planning goals among patients, relatives, and healthcare professionals complicated the advance care planning process. A focus on day-to-day care at the expense of focusing on advance care planning gave an impression of a lack of competencies and interest. For some patients, the involvement of relatives was of significant value; however, it could be associated with burden and pressure. CONCLUSION: Patients with chronic kidney disease and their families have a need for early advance care planning before dialysis or transplantation is initiated, so as to facilitate shared decision-making related to treatment options and everyday life. It is important that patients, their relatives, and healthcare professionals share the same advance care planning goals, to get sufficient discussions and thus, achieve clarity about prognosis, medical care, and the illness trajectory.

Increasing incidence and improved survival in ANCA-associated vasculitis-a Danish nationwide study.

BACKGROUND: Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) carries a high risk of morbidity and mortality, with outcomes modified by treatment and an incidence that may be increasing. We examined temporal changes in incidence and mortality during 2000-15 using nationwide healthcare registries. METHODS: Patients with incident AAV were identified using International Classification of Diseases Version 10 (ICD10) codes and grouped according to inclusion year (Period 1: 2000-04, Period 2: 2005-09, Period 3: 2010-15). Log link cumulative incidence regression adjusted for age, sex, renal function, cardiovascular disease, diabetes, hypertension and advanced disease severity were used to model survival. RESULTS: We identified 1631 patients (52% male), corresponding to an incidence of 18.5 persons/million/year (Period 1: 15.1, Period 2: 18.5, Period 3: 21.4). The slope of incident serologic ANCA testing was steeper than that of AAV (P = 0.002). Mean [standard deviation (SD)] age was 60.2 (16.7) years and mean (SD) follow-up was 6.8 (4.7) years. A total of 571 (35%) patients died (5-year mortality of 22.1%), with an absolute risk ratio (ARR) for Periods 2 and 3 compared with Period 1 of 0.80 [confidence interval (CI) 0.65-0.98, P = 0.031] and 0.39 (CI 0.31-0.50, P < 0.001). About 274 patients developed end-stage renal disease (ESRD) [16.8% (Period 1: 23.3%, Period 2: 17.6%, Period 3: 12.5%)], with ARR decreasing over time: Period 2 0.61 (CI 0.42-0.87, P = 0.007) and Period 3 0.57 (CI 0.39-0.83, P = 0.003). The overall risk of death associated with ESRD or chronic kidney disease was 1.74 (CI 1.29-2.37, P < 0.001) and 1.58 (CI 1.21-2.07, P < 0.001). CONCLUSIONS: Incidence of ANCA testing and AAV diagnosis increased over the test period. Falls over time in mortality and ESRD risk may relate to earlier diagnosis and changes in treatment practice.

Real-world costs of autosomal dominant polycystic kidney disease in the Nordics.

BACKGROUND: There is limited real-world data on the economic burden of patients with autosomal dominant polycystic kidney disease (ADPKD). The objective of this study was to estimate the annual direct and indirect costs of patients with ADPKD by severity of the disease: chronic kidney disease (CKD) stages 1-3; CKD stages 4-5; transplant recipients; and maintenance dialysis patients. METHODS: A retrospective study of ADPKD patients was undertaken April-December 2014 in Denmark, Finland, Norway and Sweden. Data on medical resource utilisation were extracted from medical charts and patients were asked to complete a self-administered questionnaire. RESULTS: A total of 266 patients were contacted, 243 (91%) of whom provided consent to participate in the study. Results showed that the economic burden of ADPKD was substantial at all levels of the disease. Lost wages due to reduced productivity were large in absolute terms across all disease strata. Mean total annual costs were highest in dialysis patients, driven by maintenance dialysis care, while the use of immunosuppressants was the main cost component for transplant care. Costs were twice as high in patients with CKD stages 4-5 compared to CKD stages 1-3. CONCLUSIONS: Costs associated with ADPKD are significant and the progression of the disease is associated with an increased frequency and intensity of medical resource utilisation. Interventions that can slow the progression of the disease have the potential to lead to substantial reductions in costs for the treatment of ADPKD.

Health-related quality of life across all stages of autosomal dominant polycystic kidney disease.

BACKGROUND: A limited number of studies have assessed health-related quality of life (HRQoL) in autosomal dominant polycystic kidney disease (ADPKD). Results to date have been conflicting and studies have generally focused on patients with later stages of the disease. This study aimed to assess HRQoL in ADPKD across all stages of the disease, from patients with early chronic kidney disease (CKD) to patients with end-stage renal disease. METHODS: A study involving cross-sectional patient-reported outcomes and retrospective clinical data was undertaken April-December 2014 in Denmark, Finland, Norway and Sweden. Patients were enrolled into four mutually exclusive stages of the disease: CKD stages 1-3; CKD stages 4-5; transplant recipients; and dialysis patients. RESULTS: Overall HRQoL was generally highest in patients with CKD stages 1-3, followed by transplant recipients, patients with CKD stages 4-5 and patients on dialysis. Progressive disease predominately had an impact on physical health, whereas mental health showed less variation between stages of the disease. A substantial loss in quality of life was observed as patients progressed to CKD stages 4-5. CONCLUSIONS: Later stages of ADPKD are associated with reduced physical health. The value of early treatment interventions that can delay progression of the disease should be considered.

A novel mutation affecting the arginine-137 residue of AVPR2 in dizygous twins leads to nephrogenic diabetes insipidus and attenuated urine exosome aquaporin-2.

Mutations in the vasopressin V2 receptor gene AVPR2 may cause X-linked nephrogenic diabetes insipidus by defective apical insertion of aquaporin-2 in the renal collecting duct principal cell. Substitution mutations with exchange of arginine at codon 137 can cause nephrogenic syndrome of inappropriate antidiuresis or congenital X-linked nephrogenic diabetes insipidus. We present a novel mutation in codon 137 within AVPR2 with substitution of glycine for arginine in male dizygotic twins. Nephrogenic diabetes insipidus was demonstrated by water deprivation test and resistance to vasopressin administration. While a similar urine exosome release rate was shown between probands and controls by western blotting for the marker ALIX, there was a selective decrease in exosome aquaporin-2 versus aquaporin-1 protein in probands compared to controls.

Danish guidelines for lipid-lowering treatment in patients with chronic renal failure.

Measurement of lipid profile in adults with CKD 1-5: We recommend measuring the lipid profile (T cholesterol, LDL cholesterol, HDL cholesterol and triglycerides) in all adults with newly diagnosed CKD 1-5 (including patients in renal replacement therapy). Monitoring of lipid profile in adults with CKD 1-5: In many cases it is not necessary to regularly monitor the lipid profile. Patients ≥ 50 years with CKD 1-5 ND: We recommend that these patients be treated with a statin (CKD 1-2, evidence level B), and in CKD patients in stages 3-5 ND that a statin or the combination statin/ezetimibe be used (evidence level A). Patients aged 18-49 years with CKD 1-5 ND: We suggest treating these patients with a statin if they also have one or more of the following conditions (evidence level A): known CVD, DM, Prior ischaemic stroke, Estimated 10-year risk of coronary death or non-fatal AMI > 10 % or risk of fatal cardiovascular disease > 5% (SCORE). Patients with CKD stage 5D: We suggest that these patients not be given a statin or started on statin/ezetimibe treatment (evidence level A). Patients who start dialysis and are already being treated with a statin or statin/ezetimibe: We suggest that treatment be continued (evidence level C). Adult kidney transplanted patients: We suggest that these patients be treated with a statin (evidence level B).

Management of an acute outbreak of diarrhoea-associated haemolytic uraemic syndrome with early plasma exchange in adults from southern Denmark: an observational study.

BACKGROUND: Diarrhoea-associated haemolytic uraemic syndrome in adults is a life-threatening, but rare multisystem disorder that is characterised by acute haemolytic anaemia, thrombocytopenia, and renal insufficiency. We aimed to assess the success of management of this disorder with plasma exchange therapy. METHODS: Patients diagnosed with diarrhoea-associated haemolytic uraemic syndrome in southern Denmark were treated with daily plasma exchange by centrifugation and substitution with fresh frozen plasma. Stool culture and serological testing was done to identify the cause of disease, and the success of management with plasma exchange therapy was assessed from change in platelet count, glomerular filtration rate, and lactate dehydrogenase. FINDINGS: During May 25-28, 2011, five patients with a median age of 62 years (range 44-70) presented with diarrhoea-associated haemolytic uraemic syndrome, which was caused by an unusual Shiga-toxin-producing Escherichia coli serotype O104:H4. Strains of E coli showed a high resistance to third-generation cephalosporins because the strains had extended-spectrum ß lactamases. After plasma exchange, median platelet count and glomerular filtration rate increased, median lactate dehydrogenase concentration decreased, and neurological status improved. The time interval from onset of bloody diarrhoea to start of plasma exchange had an inverse correlation with reduction of lactate dehydrogenase concentrations by plasma exchange (p=0.02). All patients were discharged with normal neurological status at 7 days (range 5-8) after starting plasma exchange. INTERPRETATION: Early plasma exchange might ameliorate the course of diarrhoea-associated haemolytic uraemic syndrome in adults. However, this finding should be verified in randomised controlled trials FUNDING: None.

Clinical implications of converting stable haemodialysis patients from subcutaneous to intravenous administration of darbepoetin alfa.

BACKGROUND: The erythropoiesis-stimulating protein darbepoetin alfa (Aranesp) can be given intravenously (i.v.) or subcutaneously (s.c.). Despite a s.c. bioavailability of only 37%, darbepoetin alfa i.v. or s.c. dose requirements were comparable in previous studies designed to evaluate other aspects of anaemia treatment. The present study was designed to compare i.v. vs s.c. dose requirements. METHODS: A single-centre open-label, prospective and randomized crossover study was undertaken in 71 stable haemodialysis patients. After a run-in period randomized to a 20 week study treatment with either s.c. or i.v. darbepoetin alfa, the patients were crossed over to the other treatment modality for another 20 week study period. The unit dose of weekly darbepoetin alfa was adjusted to maintain each patient's haemoglobin within a target range of -0.8 to +0.8 mmol/l of the individual baseline haemoglobin and between 6.8 and 8.5 mmol/l throughout the study period. The primary endpoint was the mean dose of darbepoetin alfa necessary to maintain the haemoglobin level in the defined range. RESULTS: Data from 58 patients were available for analysis. Haemoglobin concentrations were maintained effectively in subjects, regardless of whether they received darbepoetin alfa i.v. or s.c.. The overall mean difference in haemoglobin levels during s.c. or i.v. was 0.052 mmol/l (95% confidence interval: -0.132 to 0.236 mmol/l). The difference had no statistical or clinical significance. The population mean darbepoetin alfa dose during i.v. treatment was 32.1 microg/week, compared with a mean value for s.c. treatment of 34.1 microg/week. A paired two-tailed ratio t-test showed that P = 0.036, indicating a 95% probability of a mean dose reduction between 1.2% and 28% by i.v. treatment instead of s.c.. CONCLUSIONS: Renal anaemia of stable haemodialysis patients can be treated with darbepoetin alfa more effectively by the i.v. as compared with the s.c. route.

Prolonged aPTT after kidney transplantation due to transient lupus anticoagulants.

BACKGROUND: After kidney transplantation, a renal biopsy may be needed to elucidate the reasons for lack of graft function. If the activated partial thromboplastin time (aPTT) is prolonged, the biopsy will often be postponed, as increased risk of bleeding must be expected. However, aPTT prolongation is not always due to lack of coagulation factors, but can be due to the presence of lupus anticoagulants (LAs). Clinical observations in our department indicated that a large proportion of recently kidney-transplanted patients developed prolonged aPTT values without clinical complications. METHODS: A prospective study of patients receiving a kidney transplant in 2004 was conducted to investigate the frequency and cause of prolongation of the aPTT. RESULTS: Twenty-seven patients were included in the study; none had prolonged aPTT or LAs before the transplantation. In the post-transplantation period, 19 patients (70.4%) had a significantly prolonged aPTT. Further investigation showed that for all 19 patients, prolongation was due to acquired antibodies: 13 had developed LAs and six had developed unspecific antibodies. The acquired antibodies were transient and did not affect clinical outcome. CONCLUSIONS: This is the first study investigating prolonged aPTT in the post-transplantation period. All patients with prolonged aPTT had acquired transient antibodies, i.e. LA or 'LA-like'. If a renal biopsy was requested, 70.4% of the transplanted patients would presumably have their biopsy postponed due to prolonged aPTT, but as LAs do not increase the risk of bleeding, such a delay would be unnecessary. Immediate LA investigation is therefore recommended if a recently transplanted patient requiring surgical procedures has a prolonged aPTT.

Impaired glomerular and tubular function as a short-term effect of sirolimus treatment in the rat.

AIMS: To investigate acute and short-term effects of sirolimus (SRL) on glomerulo-tubular function, blood pressure (BP), and renal morphology in the rat. METHODS: Male Sprague-Dawley rats, weighing initially 140-180 g were treated with SRL in three series: SRL 0.2, 0.4, or 0.8 mg/kg/day intraperitoneally for up to 28 days after skin allo-transplantation from Lewis donors (to establish a dosage with significant immunosuppressive effect). SRL 0.4 mg/kg intravenously (acute effects). SRL 0.4 mg/kg/day intraperitoneally for 7 days (short-term effects). Inulin, lithium (C(Li)) and sodium clearance, and intra-arterial BP were measured in conscious catheterized rats. Morphological kidney studies were completed after post-mortem fixation. RESULTS: Maximum immunosuppressive effect was achieved with SRL 0.4 mg/kg/day. SRL acutely increased GFR and C(Li), whereas fractional proximal reabsorption (PFR) declined. In the short-term study SRL had opposite effects on GFR and C(Li), unaffected proximal tubular reabsorption and PFR, raised BP, diminished food consumption, and slower increase in body weight. Morphological changes were non-specific. CONCLUSION: In a dosage giving maximum immunosuppressive effect, SRL revealed acute effects on glomerular and proximal tubular function thus indicating increased outflow from the proximal tubules whereas one week of SRL treatment produced a change resembling the known nephrotoxic effects of the calcineurine inhibitors.

The resistance of delayed xenograft rejection to alpha(1,3)-galactosyltransferase gene inactivation and CD4 depletion in a mouse-to-rat model.

Critical to the prevention of xenograft loss is the prevention of delayed xenograft rejection (DXR), due to its resistance to conventional immunosuppression. The role of the carbohydrate galactose-alpha1,3-galactose (alpha1,3Gal) has been a matter of great debate and it has been proposed that the reaction between alpha1,3Gal epitopes on donor endothelial cells and recipient anti-alpha1,3Gal antibodies (Abs) may damage the graft during DXR. Recipient anti-alpha1,3Gal Abs are produced by CD4-dependent B cells. To test the above-mentioned hypothesis, hearts from alpha1,3Gal-free mice (GT-Ko mice), generated by alpha1,3-galacto-syltransferase gene disruption, were transplanted to anti-alpha1,3Gal antibody-free Lew/Mol rats. This model consists of an alpha1,3Gal/alpha1,3Gal-antibody-free environment, eliminating a possible influence of this specific system on DXR. A subgroup of recipients were furthermore CD4 depleted in order to inhibit CD4-dependent B-cell antibody production. Rejected hearts were evaluated by light- and immunofluorescence microscopy. Treatment effects on recipient T-cell subsets and cytokine expression were analyzed by flow cytometry, while antibody production was measured by ELISA. All recipients developed DXR with no differences among the groups. DXR was related to thrombosis with IgG and IgM desposition in vessel walls, as well as macrophage and granulocyte accumulation in the myocardium. No complement C3, CD4 cells or NK cells were found. Flow cytometric analysis confirmed peripheral blood CD4 depletion and IFN-gamma suppression in CD4 Ab-treated recipients. Finally, ELISA showed that specific anti-alpha1,3Gal Ab production was absent. However, Ab(s) against an unidentified Galalpha 1 were found among recipients. In our model, DXR is resistant to alpha1,3-galactosyltransferase gene inactivation and CD4 depletion. However, other Galalpha 1 epitopes and antibodies may play a role during DXR. Further studies are needed to elucidate the precise pathways leading to DXR.

Importance of hyperglycemia on the primary function of allogeneic islet transplants.

BACKGROUND: Hyperglycemia has been shown to influence primary function of islet isografts. In this study, we investigated the influence of hyperglycemia on primary function of allogeneic islets transplanted into spontaneously diabetic recipients (NOD) or streptozotocin-induced diabetic mice (BALB/c). METHODS: Mice with moderate, severe, or very severe hyperglycemia underwent transplantation with a marginal number of islets (350 into BALB/c mice and 700 into NOD mice). To prevent the alloimmune response, we used blockade of CD28:B7 and CD40L:CD40 costimulatory signaling pathways to determine the effect of hyperglycemia alone. Blood glucose levels of the mice were monitored after transplantation, and the grafts were assessed morphologically. RESULTS: Transplantation of allogeneic islets into moderately hyperglycemic BALB/c mice or severely diabetic NOD mice normalized the blood glucose levels in all mice within 3 days after transplantation, demonstrating the primary function of the graft. However, primary nonfunction was observed in all animals when islet transplantation was performed into severely diabetic BALB/c mice or very severely diabetic NOD mice. When mice were treated with costimulation blockade, reversal of diabetes was observed in severely diabetic BALB/c mice 15 days after transplantation, showing that the islets could adapt to the environment and function. However, transplantation of islets into NOD mice with very severe diabetes treated with costimulation blockade did not reverse diabetes, showing that even in the absence of alloimmune responses and given an adaptation period, the islets could not function. CONCLUSIONS: This study demonstrates that severe hyperglycemia impairs islet allograft function in BALB/c and NOD mice and that successful islet allotransplantation depends on the degree of hyperglycemia in the recipient.

Clinical experience with a new bicarbonate (25 mmol/L)/lactate (10 mmol/L) peritoneal dialysis solution.

OBJECTIVE: Physiological bicarbonate/lactate-based solutions may correct acidosis in a better way than standard lactate-based solutions. In this study, a new 25 mmol/L bicarbonate/10 mmol/L lactate peritoneal dialysis (PD) solution was compared with a standard 35 mmolL lactate solution. DESIGN: This was a prospective open label study. All patients had a 2-week baseline period using the standard lactate solution, followed by 8 weeks on the bicarbonate/ lactate solution and 2 weeks on the lactate-based solution. SETTING: Four Danish and four Spanish nephrology centers. PATIENTS: 40 well-dialyzed (creatinine clearance > 55 L/week/1.73 m2 body surface area) patients on continuous ambulatory PD. INTERVENTIONS: Blood samples were taken for biochemistry (including venous blood gases) at week -2, day 1, weeks 2, 4, and 8, and at follow-up. A physical examination, a peritoneal equilibration test (PET), and quality of life (K/DQOL), ultrafiltration, and adequacy assessments were performed at baseline and at week 8. Vital signs and other safety parameters were followed at each visit. Extraneal (Baxter Healthcare, Castlebar, Ireland) was used by all patients for the long dwell. MAIN OUTCOME MEASURE: Effect on the venous plasma bicarbonate level. RESULTS: Venous plasma bicarbonate levels rose from 24.4 mmol/L when patients were on the pure lactate to 26.1 mmol/L when using the bicarbonate/lactate solution (p < 0.001). When patients were using the bicarbonate/ lactate solution, 66% of values were maintained within the venous normal range of 24-30 mmol/L, versus 46.2% when patients were on the pure lactate solution (p < 0.001). There were no adverse findings with respect to clinical symptoms, vital signs, or physical examination. The PET and adequacy, ultrafiltration, and K/DQOL assessment results were unchanged. CONCLUSIONS: The new 25 mmol/L bicarbonate/ 10 mmol/L lactate solution provided better correction of acidosis than an equivalent 35 mmol/L standard lactate solution, without any safety issues.