A funnel plot is a graphical method to evaluate health‐care quality by comparing hospital performances on certain outcomes. So far, in nephrology, this method has been applied to clinical outcomes ...like mortality and complications. However, patient‐reported outcomes (PROs; eg, health‐related quality of life HRQOL) are becoming increasingly important and should be incorporated into this quality assessment. Using funnel plots has several advantages, including clearly visualized precision, detection of volume‐effects, discouragement of ranking hospitals and easy interpretation of results. However, without sufficient knowledge of underlying methods, it is easy to stumble into pitfalls, such as overinterpretation of standardized scores, incorrect direct comparisons of hospitals and assuming a hospital to be in‐control (ie, to perform as expected) based on underpowered comparisons. Furthermore, application of funnel plots to PROs is accompanied by additional challenges related to the multidimensional nature of PROs and difficulties with measuring PROs. Before using funnel plots for PROs, high and consistent response rates, adequate case mix correction and high‐quality PRO measures are required. In this article, we aim to provide insight into the use and interpretation of funnel plots by presenting an overview of the basic principles, pitfalls and considerations when applied to PROs, using examples from Dutch routine dialysis care.
SUMMARY AT A GLANCE
The statistical review provides insights into the use and interpretation of funnel plots by presenting an overview of the basic principles, pitfalls and considerations when applied to patient‐reported outcomes using examples from Dutch routine dialysis care.
Aims We examined the effect of the renin inhibitor, aliskiren, on renal blood flow (RBF) in patients with heart failure with reduced ejection fraction (HFREF) and decreased glomerular filtration rate ...(GFR). Renal blood flow is the main determinant of GFR in HFREF patients. Both reduced GFR and RBF are associated with increased mortality. Aliskiren can provide additional renin-angiotensin-aldosterone system inhibition and increases RBF in healthy individuals. Methods and results Patients with left ventricular ejection fraction ≤45% and estimated GFR 30 to 75 mL/min per 1.73 m2 on optimal medical therapy were randomized 2:1 to receive aliskiren 300 mg once daily or placebo. Renal blood flow and GFR were measured using radioactive-labeled125 I-iothalamate and131 I-hippuran at baseline and 26 weeks. After 41 patients were included, the trial was halted based on an interim safety analysis showing futility. Mean age was 68 ± 9 years, 82% male, GFR (49 ± 16 mL/min per 1.73 m2 ), RBF (294 ± 77 mL/min per 1.73 m2 ), and NT-proBNP 999 (435-2040) pg/mL. There was a nonsignificant change in RBF after 26 weeks in the aliskiren group compared with placebo (−7.1 ± 30 vs +14 ± 54 mL/min per 1.73 m2 ; P = .16). However, GFR decreased significantly in the aliskiren group compared with placebo (−2.8 ± 6.0 vs +4.4 ± 9.6 mL/min per 1.73 m2 ; P = .01) as did filtration fraction (−2.2 ± 3.3 vs +1.1 ± 3.1%; P = .01). There were no significant differences in plasma aldosterone, NT-proBNP, urinary tubular markers, or adverse events. Plasma renin activity was markedly reduced in the aliskiren group versus placebo throughout the treatment phase ( P = .007). Conclusions Adding aliskiren on top of optimal HFREF medical therapy did not improve RBF and was associated with a reduction of GFR and filtration fraction.
Orthostatic hypotension is a common clinical problem, but the underlying mechanisms have not been fully delineated.
We describe 2 families, with 4 patients in total, experiencing severe ...life-threatening orthostatic hypotension because of a novel cause.
As in dopamine β-hydroxylase deficiency, concentrations of norepinephrine and epinephrine in the patients were low. Plasma dopamine β-hydroxylase activity, however, was normal, and the
gene had no mutations. Molecular genetic analysis was performed to determine the underlying genetic cause. Homozygosity mapping and exome and Sanger sequencing revealed pathogenic homozygous mutations in the gene encoding cytochrome b561 (
); a missense variant c.262G>A, p.Gly88Arg in exon 3 in the Dutch family and a nonsense mutation (c.131G>A, p.Trp44*) in exon 2 in the American family. Expression of
was investigated using RNA from different human adult and fetal tissues, transcription of RNA into cDNA, and real-time quantitative polymerase chain reaction. The
gene was found to be expressed in many human tissues, in particular the brain. The CYB561 protein defect leads to a shortage of ascorbate inside the catecholamine secretory vesicles leading to a functional dopamine β-hydroxylase deficiency. The concentration of the catecholamines and downstream metabolites was measured in brain and adrenal tissue of 6
knockout mice (reporter-tagged deletion allele post-Cre, genetic background C57BL/6NTac). The concentration of norepinephrine and normetanephrine was decreased in whole-brain homogenates of the
mice compared with wild-type mice (
<0.01), and the concentration of normetanephrine and metanephrine was decreased in adrenal glands (
<0.01), recapitulating the clinical phenotype. The patients responded favorably to treatment with l-dihydroxyphenylserine, which can be converted directly to norepinephrine.
This study is the first to implicate cytochrome b561 in disease by showing that pathogenic mutations in
cause an as yet unknown disease in neurotransmitter metabolism causing orthostatic hypotension.
Background.
Kidney transplant recipients (KTRs) are still at risk of severe COVID-19 disease after SARS‑CoV‑2 vaccination, especially when they have limited antibody formation. Our aim was to ...understand the factors that may limit their humoral response.
Methods.
Our data are derived from KTRs who were enrolled in the Dutch Renal Patients COVID-19 Vaccination consortium, using a discovery cohort and 2 external validation cohorts. Included in the discovery (N = 1804) and first validation (N = 288) cohorts were participants who received 2 doses of the mRNA-1273 vaccine. The second validation cohort consisted of KTRs who subsequently received a third dose of any SARS-CoV-2 vaccine (N = 1401). All participants had no history of SARS-CoV-2 infection. A multivariable logistic prediction model was built using stepwise backward regression analysis with nonseroconversion as the outcome.
Results.
The discovery cohort comprised 836 (46.3%) KTRs, the first validation cohort 124 (43.1%) KTRs, and the second validation cohort 358 (25.6%) KTRs who did not seroconvert. In the final multivariable model‚ 12 factors remained predictive for nonseroconversion: use of mycophenolate mofetil/mycophenolic acid (MMF/MPA); chronic lung disease, heart failure, and diabetes; increased age; shorter time after transplantation; lower body mass index; lower kidney function; no alcohol consumption; ≥2 transplantations; and no use of mammalian target of rapamycin inhibitors or calcineurin inhibitors. The area under the curve was 0.77 (95% confidence interval CI, 0.74-0.79) in the discovery cohort after adjustment for optimism, 0.81 (95% CI, 0.76-0.86) in the first validation cohort, and 0.67 (95% CI, 0.64-0.71) in the second validation cohort. The strongest predictor was the use of MMF/MPA, with a dose-dependent unfavorable effect, which remained after 3 vaccinations.
Conclusions.
In a large sample of KTRs, we identify a selection of KTRs at high risk of nonseroconversion after SARS-CoV-2 vaccination. Modulation of MMF/MPA treatment before vaccination may help to optimize vaccine response in these KTRs. This model contributes to future considerations on alternative vaccination strategies.
Aldosterone is elevated in chronic kidney disease (CKD) and may be involved in hypertension. Surprisingly, the determinants of the plasma aldosterone concentration (PAC) and its role in hypertension ...are not well studied in CKD. Therefore, we studied the determinants of aldosterone and its association with blood pressure in CKD patients. We also studied this during renin-angiotensin-aldosterone system inhibition (RAASi) to establish clinical relevance, as RAASi is the treatment of choice in CKD with albuminuria.
We performed a post-hoc analysis on data from a randomized controlled double blind cross-over trial in non-diabetic CKD patients (n = 33, creatinine clearance (CrCl) 85 (75-95) ml/min, proteinuria 3.2 (2.5-4.0) g/day). Patients were treated with losartan 100 mg (ARB), and ARB + hydrochlorothiazide 25 mg (HCT), during both a regular (200 ± 10 mmol Na
/day) and low (89 ± 8 mmol Na
/day) dietary sodium intake, in 6-week study periods. PAC data at the end of each study period were analyzed. The association between PAC and blood pressure was analyzed continuously, and according to PAC above or below the median.
Lower CrCl was correlated with higher PAC during placebo as well as during ARB (β = -1.213, P = 0.008 and β = -1.090, P = 0.010). Higher PAC was not explained by high renin, illustrated by a comparable association between CrCl and the aldosterone-to-renin ratio. The association between lower CrCl and higher PAC was also found in a second study with single RAASi with ACE inhibition (ACEi; lisinopril 40 mg/day), and dual RAASi (lisinopril 40 mg/day + valsartan 320 mg/day). Higher PAC was associated with a higher systolic blood pressure (P = 0.010) during different study periods. Only during maximal treatment with ARB + HCT + dietary sodium restriction, blood pressure was no longer different in subjects with a PAC above and below the median.
In CKD patients with a standardized regular sodium intake, worse renal function is associated with a higher aldosterone, untreated and during RAASi with either ARB, ACEi, or both. Furthermore, higher aldosterone is associated with higher blood pressure, which can be treated with the combination of RAASi, HCT and dietary sodium restriction. The first study was performed before it was standard to register trials and the study was not retrospectively registered. The second study was registered in the Netherlands Trial Register on the 5th of May 2006 (NTR675).
Renal impairment (RI) in patients with multiple myeloma (MM) is associated with poor prognosis. In this population-based cohort study, we assessed the effects of renal response, evaluated according ...to the IMWG-criteria, on overall survival (OS) in patients with newly diagnosed MM with RI at presentation. All included patients were diagnosed between January 2005 and January 2014 with MM and RI in Friesland, a province of the Netherlands. Of the 131 included patients, 61% achieved renal response. Using a time-varying exposure Cox model, no difference in OS between renal response and non-response was observed (HR = 1.08, 95% CI = 0.67-1.74, p = .76). In multivariable analysis, baseline eGFR <30 ml/min (HR = 1.71), age >70 yrs (HR = 1.77), hypercalcemia (HR = 2.73), lambda Bence-Jones (HR= 1.76), and initial treatment regimen (HR = 0.89 for thalidomide, HR = 1.95 in treatment regimens without novel agents and HR = 3.60 for no chemotherapy, all vs. bortezomib) were associated with decreased OS. In conclusion, achieving renal response was not associated with improved OS.
Chronic kidney disease (CKD) is associated with a higher prevalence of depression, neuropathic pain and insomnia. These conditions are often treated pharmaceutically. In this study we aimed to ...determine the prevalence of chronic antidepressant use among CKD patients with and without kidney replacement therapy (KRT).
By using the Dutch health claims database, we were able to determine the prevalence, type and dosage of chronic antidepressant prescriptions in patients with CKD Stage G4/G5 without KRT (
= 14 905), patients on dialysis (
= 3872) and patients living on a functioning graft (
= 8796) and compared these to age-, sex- and socio-economic status (SES)-matched controls from the general population.
Our data show that the prevalence of chronic antidepressant prescription is 5.6%, 5.3% and 4.2% in CKD Stage G4/G5, dialysis and kidney transplant patients, respectively, which is significantly higher than in matched controls. Although our data revealed more prescriptions in female patients and in the age category 45-64 years, our data did not show any association between antidepressant prescriptions and SES. Selective serotonin reuptake inhibitors were the most prescribed drugs in all patient groups and controls. Tricyclic antidepressants were more often used in patients compared with controls.
This nationwide analysis revealed that chronic antidepressant prescription in the Netherlands is higher in CKD patients with and without KRT than in controls, higher in middle-aged patients and women, unrelated to socio-economic status and lower than chronic use reported in other countries.
Abstract
Graft function and patient survival are traditionally the most used parameters to assess the objective benefits of kidney transplantation. Monitoring graft function, along with therapeutic ...drug concentrations and transplant complications, comprises the essence of outpatient management in kidney transplant recipients (KTRs). However, the patient’s perspective is not always included in this process. Patients’ perspectives on their health after kidney transplantation, albeit subjective, are increasingly acknowledged as valuable healthcare outcomes and should be considered in order to provide patient-centred healthcare. Such outcomes are known as patient-reported outcomes (PROs; e.g. health-related quality of life and symptom burden) and are captured using PRO measures (PROMs). So far, PROMs have not been routinely used in clinical care for KTRs. In this review we will introduce PROMs and their potential application and value in the field of kidney transplantation, describe commonly used PROMs in KTRs and discuss structural PROMs implementation into kidney transplantation care.
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