Hydrochlorothiazide and Prevention of Kidney-Stone Recurrence.

BACKGROUND: Nephrolithiasis is one of the most common conditions affecting the kidney and is characterized by a high risk of recurrence. Thiazide diuretic agents are widely used for prevention of the recurrence of kidney stones, but data regarding the efficacy of such agents as compared with placebo are limited. Furthermore, dose-response data are also limited. METHODS: In this double-blind trial, we randomly assigned patients with recurrent calcium-containing kidney stones to receive hydrochlorothiazide at a dose of 12.5 mg, 25 mg, or 50 mg once daily or placebo once daily. The main objective was to investigate the dose-response effect for the primary end point, a composite of symptomatic or radiologic recurrence of kidney stones. Radiologic recurrence was defined as the appearance of new stones on imaging or the enlargement of preexisting stones that had been observed on the baseline image. Safety was also assessed. RESULTS: In all, 416 patients underwent randomization and were followed for a median of 2.9 years. A primary end-point event occurred in 60 of 102 patients (59%) in the placebo group, in 62 of 105 patients (59%) in the 12.5-mg hydrochlorothiazide group (rate ratio vs. placebo, 1.33; 95% confidence interval [CI], 0.92 to 1.93), in 61 of 108 patients (56%) in the 25-mg group (rate ratio, 1.24; 95% CI, 0.86 to 1.79), and in 49 of 101 patients (49%) in the 50-mg group (rate ratio, 0.92; 95% CI, 0.63 to 1.36). There was no relation between the hydrochlorothiazide dose and the occurrence of a primary end-point event (P = 0.66). Hypokalemia, gout, new-onset diabetes mellitus, skin allergy, and a plasma creatinine level exceeding 150% of the baseline level were more common among patients who received hydrochlorothiazide than among those who received placebo. CONCLUSIONS: Among patients with recurrent kidney stones, the incidence of recurrence did not appear to differ substantially among patients receiving hydrochlorothiazide once daily at a dose of 12.5 mg, 25 mg, or 50 mg or placebo once daily. (Funded by the Swiss National Science Foundation and Inselspital; NOSTONE ClinicalTrials.gov number, NCT03057431.).

Immunogenicity of High-Dose Versus MF59-Adjuvanted Versus Standard Influenza Vaccine in Solid Organ Transplant Recipients: The Swiss/Spanish Trial in Solid Organ Transplantation on Prevention of Influenza (STOP-FLU Trial).

BACKGROUND: The immunogenicity of the standard influenza vaccine is reduced in solid-organ transplant (SOT) recipients, so new vaccination strategies are needed in this population. METHODS: Adult SOT recipients from 9 transplant clinics in Switzerland and Spain were enrolled if they were >3 months after transplantation. Patients were randomized (1:1:1) to a MF59-adjuvanted or a high-dose vaccine (intervention), or a standard vaccine (control), with stratification by organ and time from transplant. The primary outcome was vaccine response rate, defined as a ≥4-fold increase of hemagglutination-inhibition titers to at least 1 vaccine strain at 28 days postvaccination. Secondary outcomes included polymerase chain reaction-confirmed influenza and vaccine reactogenicity. RESULTS: A total of 619 patients were randomized, 616 received the assigned vaccines, and 598 had serum available for analysis of the primary endpoint (standard, n = 198; MF59-adjuvanted, n = 205; high-dose, n = 195 patients). Vaccine response rates were 42% (84/198) in the standard vaccine group, 60% (122/205) in the MF59-adjuvanted vaccine group, and 66% (129/195) in the high-dose vaccine group (difference in intervention vaccines vs standard vaccine, 0.20; 97.5% confidence interval [CI], .12-1); P < .001; difference in high-dose vs standard vaccine, 0.24 [95% CI, .16-1]; P < .001; difference in MF59-adjuvanted vs standard vaccine, 0.17 [97.5% CI, .08-1]; P < .001). Influenza occurred in 6% of the standard, 5% in the MF59-adjuvanted, and 7% in the high-dose vaccine groups. Vaccine-related adverse events occurred more frequently in the intervention vaccine groups, but most of the events were mild. CONCLUSIONS: In SOT recipients, use of an MF59-adjuvanted or a high-dose influenza vaccine was safe and resulted in a higher vaccine response rate. CLINICAL TRIALS REGISTRATION: Clinicaltrials.gov NCT03699839.

Clinical and genetic spectra of autosomal dominant tubulointerstitial kidney disease due to mutations in UMOD and MUC1.

Autosomal dominant tubulointerstitial kidney disease (ADTKD) is an increasingly recognized cause of end-stage kidney disease, primarily due to mutations in UMOD and MUC1. The lack of clinical recognition and the small size of cohorts have slowed the understanding of disease ontology and development of diagnostic algorithms. We analyzed two registries from Europe and the United States to define genetic and clinical characteristics of ADTKD-UMOD and ADTKD-MUC1 and develop a practical score to guide genetic testing. Our study encompassed 726 patients from 585 families with a presumptive diagnosis of ADTKD along with clinical, biochemical, genetic and radiologic data. Collectively, 106 different UMOD mutations were detected in 216/562 (38.4%) of families with ADTKD (303 patients), and 4 different MUC1 mutations in 72/205 (35.1%) of the families that are UMOD-negative (83 patients). The median kidney survival was significantly shorter in patients with ADTKD-MUC1 compared to ADTKD-UMOD (46 vs. 54 years, respectively), whereas the median gout-free survival was dramatically reduced in patients with ADTKD-UMOD compared to ADTKD-MUC1 (30 vs. 67 years, respectively). In contrast to patients with ADTKD-UMOD, patients with ADTKD-MUC1 had normal urinary excretion of uromodulin and distribution of uromodulin in tubular cells. A diagnostic algorithm based on a simple score coupled with urinary uromodulin measurements separated patients with ADTKD-UMOD from those with ADTKD-MUC1 with a sensitivity of 94.1%, a specificity of 74.3% and a positive predictive value of 84.2% for a UMOD mutation. Thus, ADTKD-UMOD is more frequently diagnosed than ADTKD-MUC1, ADTKD subtypes present with distinct clinical features, and a simple score coupled with urine uromodulin measurements may help prioritizing genetic testing.

Cerebral salt wasting in a patient with myeloproliferative neoplasm.

BACKGROUND: Cerebral salt wasting (CSW) is a rare metabolic disorder with severe hyponatremia and volume depletion usually caused by brain injury like trauma, cerebral lesion, tumor or a cerebral hematoma. The renal function is normal with excretion of very high amounts of sodium in the urine. Diagnosis is made by excluding other reasons for hyponatremia, mainly the syndrome of inappropriate antidiuretic hormone secretion (SIADH). CASE PRESENTATION: A 60-year-old patient was admitted to the emergency room with pain in the upper abdomen and visual disturbance two weeks after knee replacement. The patient was confused with severe hematoma at the site of the knee endoprosthesis. Laboratory values showed massive thrombocytosis, leukocytosis, anemia, severe hyponatremia and no evidence of infection. CT scan of the abdomen was inconspicuous. Head MRI showed no ischemia or bleeding, but a mild microangiopathy. A myeloproliferative neoplasm (MPN) was suspected and confirmed by bone marrow biopsy. Cerebral salt wasting syndrome was identified as the cause of severe hyponatremia most likely provoked by cerebral microcirculatory disturbance. The hematoma at the operation site was interpreted as a result of a secondary von Willebrand syndrome (vWS) due to the myeloproliferative neoplasm with massive thrombocytosis. After starting cytoreductive therapy with hydroxycarbamide, thrombocytosis and blood sodium slowly improved along with normalization of his mental condition. CONCLUSION: To the best of our knowledge this is the first description of a patient with CSW most likely caused by a microcirculatory disturbance due to a massive thrombocytosis in the context of a myeloproliferative neoplasm.

Efficacy of standard and low dose hydrochlorothiazide in the recurrence prevention of calcium nephrolithiasis (NOSTONE trial): protocol for a randomized double-blind placebo-controlled trial.

BACKGROUND: Nephrolithiasis is a global healthcare problem with a current lifetime risk of 18.8% in men and 9.4% in women. Given the high cost of medical treatments and surgical interventions as well as the morbidity related to symptomatic stone disease, medical prophylaxis for stone recurrence is an attractive approach. Thiazide diuretics have been the cornerstone of pharmacologic metaphylaxis for more than 40 years. However, evidence for benefits and harms of thiazides in the prevention of calcium containing kidney stones in general remains unclear. In addition, the efficacy of the currently employed low dose thiazide regimens to prevent stone recurrence is not known. METHODS: The NOSTONE trial is an investigator-initiated 3-year prospective, multicenter, double-blind, placebo-controlled trial to assess the efficacy of standard and low dose hydrochlorothiazide treatment in the recurrence prevention of calcium containing kidney stones. We plan to include 416 adult (≥ 18 years) patients with recurrent (≥ 2 stone episodes in the last 10 years) calcium containing kidney stones (containing ≥50% of calcium oxalate, calcium phosphate or a mixture of both). Patients will be randomly allocated to 50 mg or 25 mg or 12.5 mg hydrochlorothiazide or placebo. The primary outcome will be incidence of stone recurrence (a composite of symptomatic or radiologic recurrence). Secondary outcomes will be individual components of the composite primary outcome, safety and tolerability of hydrochlorothiazide treatment, changes in urinary biochemistry elicited by hydrochlorothiazide treatment and impact of baseline disease severity, biochemical abnormalities and stone composition on treatment response. DISCUSSION: The NOSTONE study will provide long-sought information on the efficacy of hydrochlorothiazide in the recurrence prevention of calcium containing kidney stones. Strengths of the study include the randomized, double-blind and placebo-controlled design, the large amount of patients studied, the employment of high sensitivity and high specificity imaging and the exclusive public funding support. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03057431 . Registered on February 20 2017.

[Update on Diabetic Kidney Disease 2018]. / Update diabetische Nephropathie.

Update on Diabetic Kidney Disease 2018 Abstract. The first descriptions of diabetes mellitus are known as "sweet honey urine". Interestingly, the new therapy of diabetic kidney disease, namely SGLT-2-inhibitor, enhances glucosuria, leading to the historical description of sweet urine. This not only leads to a better control of glycemia itself, but it also leads to a better renal prognosis by reducing glomerular hyperfiltration. So far, this effect has been proven for diabetic kidney disease in type 2 diabetic patients. Whether this effect could also lead to a better renal prognosis in other kidney diseases with hyperfiltration (independent of hyperglycemia), is still object of ongoing studies.

The effect of bright light therapy on sleep and circadian rhythms in renal transplant recipients: a pilot randomized, multicentre wait-list controlled trial.

This study assessed the effect and feasibility of morning bright light therapy (BLT) on sleep, circadian rhythms, subjective feelings, depressive symptomatology and cognition in renal transplant recipients (RTx) diagnosed with sleep-wake disturbances (SWD). This pilot randomized multicentre wait-list controlled trial included 30 home-dwelling RTx randomly assigned 1:1 to either 3 weeks of BLT or a wait-list control group. Morning BLT (10 000 lux) was individually scheduled for 30 min daily for 3 weeks. Wrist actimetry (measuring sleep and circadian rhythms), validated instruments (subjective feelings and cognition) and melatonin assay (circadian timing) were used. Data were analysed via a random-intercept regression model. Of 30 RTx recipients (aged 58 ± 15, transplanted 15 ± 6 years ago), 26 completed the study. While BLT had no significant effect on circadian and sleep measures, sleep timing improved significantly. The intervention group showed a significant get-up time phase advance from baseline to intervention (+24 min) [(standardized estimates (SE): -0.23 (-0.42; -0.03)] and a small (+14 min) but significant bedtime phase advance from intervention to follow-up (SE: -0.25 (-0.41; -0.09). Improvement in subjective feelings and depressive symptomatology was observed but was not statistically significant. Bright light therapy showed preliminary indications of a beneficial effect in RTx with sleep-wake disturbances. (ClinicalTrials.gov number: NCT01256983).

Daytime sleepiness in renal transplant recipients is associated with immunosuppressive non-adherence: a cross-sectional, multi-center study.

BACKGROUND: The aims of this study were to determine the prevalence of immunosuppressive non-adherence (NA) in renal transplant patients and describe whether the degree of daytime sleepiness (DS) and depressive symptomatology are associated with immunosuppressive NA. METHODS: Using a cross-sectional design, 926 home-dwelling renal transplant recipients who were transplanted at one of three Swiss transplant centers provided data by self-report. The Basel Assessment of Adherence Scale for immunosuppressive was used to measure the following: taking, timing, and overall NA to immunosuppressive medication. DS was assessed with the Epworth Sleepiness Scale (ESS) (cut-off ≥6 for DS) and the Swiss Transplant Cohort Study DS item (cut-off ≥4 for DS), and depressive symptomatology was assessed with the Depression, Anxiety, and Stress Scale (cut-off>10). An ordinal logistical regression model was applied for statistical analysis. RESULTS: The prevalence of the ESS-DS was 51%. NA for taking, timing, and the median overall NA level assessed by 0-100% visual analog scale (VAS) was 16%, 42%, and 0%, respectively. Based on the multivariate analysis, DS was significantly associated (p < 0.001) with taking (1.08 [1.04-1.13]), timing (1.07 [1.03-1.10]), and overall NA (1.09 [1.05-1.13]). Very similar results were found for the Swiss Transplant Cohort Study DS item. CONCLUSION: DS is associated with immunosuppressive medication NA in renal transplant recipients. Admittedly, the association's strength is limited.

Self-reported sleep disturbances in renal transplant recipients.

BACKGROUND: Poor sleep quality (SQ) and daytime sleepiness (DS) are common in renal transplant (RTx) recipients; however, related data are rare. This study describes the prevalence and frequency of self-reported sleep disturbances in RTx recipients. METHODS: This cross-sectional study included 249 RTx recipients transplanted at three Swiss transplant centers. All had reported poor SQ and / or DS in a previous study. With the Survey of Sleep (SOS) self-report questionnaire, we screened for sleep and health habits, sleep history, main sleep problems and sleep-related disturbances. To determine a basis for preliminary sleep diagnoses according to the International Classification of Sleep Disorders (ICSD), 164 subjects were interviewed (48 in person, 116 via telephone and 85 refused). Descriptive statistics were used to analyze the data and to determine the frequencies and prevalences of specific sleep disorders. RESULTS: The sample had a mean age of 59.1 ± 11.6 years (60.2% male); mean time since Tx was 11.1 ± 7.0 years. The most frequent sleep problem was difficulty staying asleep (49.4%), followed by problems falling asleep (32.1%). The most prevalent sleep disturbance was the need to urinate (62.9%), and 27% reported reduced daytime functionality. Interview data showed that most suffered from the first ICSD category: insomnias. CONCLUSION: Though often disregarded in RTx recipients, sleep is an essential factor of wellbeing. Our findings show high prevalences and incidences of insomnias, with negative impacts on daytime functionality. This indicates a need for further research on the clinical consequences of sleep disturbances and the benefits of insomnia treatment in RTx recipients.

Validation of a single item to assess daytime sleepiness for the Swiss Transplant Cohort Study.

CONTEXT: Daytime sleepiness in kidney transplant recipients has emerged as a potential predictor of impaired adherence to the immunosuppressive medication regimen. Thus there is a need to assess daytime sleepiness in clinical practice and transplant registries. OBJECTIVE: To evaluate the validity of a single-item measure of daytime sleepiness integrated in the Swiss Transplant Cohort Study (STCS), using the American Educational Research Association framework. METHODS: Using a cross-sectional design, we enrolled a convenience sample of 926 home-dwelling kidney transplant recipients (median age, 59.69 years; 25%-75% quartile [Q25-Q75], 50.27-59.69), 63% men; median time since transplant 9.42 years (Q25-Q75, 4.93-15.85). Daytime sleepiness was assessed by using a single item from the STCS and the 8 items of the validated Epworth Sleepiness Scale. Receiver operating characteristic curve analysis was used to determine the cutoff for the STCS daytime sleepiness item against the Epworth Sleepiness Scale score. RESULTS: Based on the receiver operating characteristic curve analysis, a score greater than 4 on the STCS daytime sleepiness item is recommended to detect daytime sleepiness. Content validity was high as all expert reviews were unanimous. Concurrent validity was moderate (Spearman ϱ, 0.531; P< .001) and convergent validity with depression and poor sleep quality although low, was significant (ϱ, 0.235; P<.001 and ϱ, 0.318, P=.002, respectively). For the group difference validity: kidney transplant recipients with moderate, severe, and extremely severe depressive symptom scores had 3.4, 4.3, and 5.9 times higher odds of having daytime sleepiness, respectively, as compared with recipients without depressive symptoms. CONCLUSION: The accumulated evidence provided evidence for the validity of the STCS daytime sleepiness item as a simple screening scale for daytime sleepiness.

[CME: Diagnostic Approach and Management of Thrombotic Microangiopathy]. / CME: Notfallmanagement der thrombotischen Mikroangiopathie.

CME: Diagnostic Approach and Management of Thrombotic Microangiopathy Abstract. Thrombotic microangiopathies (TMA) are characterized by organ thrombosis induced by endothelial injury. They present with thrombocytopenia, hemolytic anemia and schistocytes. In case of an underlying disease-causing TMA, the treatment of the underlying disease is essential. Primary TMAs are divided into thrombotic thrombocytopenic purpura, hemolytic-uremic syndrome and atypical hemolytic-uremic syndrome. Differentiation of these entities is essential, as fast initiation of empiric treatment might be life-saving and disease-modifying treatments for the different entities do exist.

Adherence to, and patient convenience of, prolonged-release tacrolimus in stable kidney and liver transplant recipients after conversion from immediate-release tacrolimus in routine clinical practice in Switzerland.

AIMS OF THE STUDY: Non-adherence to immunosuppressive therapy in patients following solid organ transplantation is associated with an increased risk of transplant rejection and graft loss. A high pill burden can adversely affect patients’ implementation of their treatment regimens and may lead to omitting doses of medication. The aim of this study was to investigate medication implementation adherence in liver and kidney transplant recipients converted from twice-daily, immediate-release tacrolimus to once-daily, prolonged-release tacrolimus. METHODS: This multicentre, non-interventional, observational, 12-month study evaluated implementation adherence in routine practice at five hospitals in Switzerland. Patients attended four clinical visits: at baseline (pre-conversion), and then at week 2, month 6 and month 12 post-conversion. Implementation was defined as consistently taking medication at the correct time and at the correct dose in order to achieve target tacrolimus trough levels. Implementation adherence was evaluated in three ways: using the Basel Assessment of Adherence to Immunosuppressive Medications Scale (BAASIS) interview questionnaire (at baseline and month 12), investigator-rated patient adherence (recorded at all visits), and tacrolimus trough levels (assessed throughout the study; sub-therapeutic levels were predefined by the investigator on an individual patient basis, over-therapeutic levels were defined as tacrolimus trough levels >15 ng/ml). The primary composite endpoint was non-adherence according to the BAASIS at month 12, any post-conversion investigator adherence rating of “poor”, or sub-therapeutic or over-therapeutic tacrolimus trough levels at month 6 or 12. Secondary endpoints included: individual components of the composite non-adherence primary endpoint, tacrolimus pill burden, patient satisfaction, and adverse drug reactions. RESULTS: Seventy-five patients received prolonged-release tacrolimus; 68 patients (46 kidney and 22 liver transplant recipients) completed the study. Of these 68 patients, 24 had missing data for at least one component of the primary endpoint; therefore, data for the primary composite endpoint were evaluable for 44 patients. Most (81.8%; 36/44) patients were non-adherent for the composite endpoint. Sub-therapeutic tacrolimus trough levels outside of the predefined therapeutic range were the largest contributor to the composite endpoint, and were detected in 62.0% (31/50) of patients. Overall non-adherence according to the BAASIS was similar pre-conversion (30.7%) and at 12 months post-conversion (28.3%). Investigators rated adherence as “poor” for two patients. Prolonged-release tacrolimus decreased tacrolimus pill burden in 66.7% of patients. All patients were very satisfied / satisfied with prolonged-release tacrolimus; 75.0% found it easier to remember to take prolonged-release versus immediate-release tacrolimus. Twenty percent of patients reported adverse drug reactions, with infections being the most frequently reported (9.3%). CONCLUSION: Overall, 1-year non-adherence rates were similar following conversion from immediate-release to prolonged-release tacrolimus; however, prolonged-release tacrolimus intake was more convenient. No new safety signals were detected.