Blood pressure monitoring in kidney transplantation: a systematic review on hypertension and target organ damage.

BACKGROUND: Sparse studies show that ambulatory blood pressure monitoring (ABPM) is superior to office BP (oBP) measurements to predict target organ damage and cardiovascular (CV) events in kidney transplant recipients (KTRs). We performed a systematic review aimed at determining the potential associations between BP recordings by different methods and renal and CV outcomes in this population. METHODS: Major medical databases were searched for studies enrolling adult KTRs undergoing 24h ABPM compared to office or home BP measurements. Main outcomes were: associations between different BP recordings and renal and CV outcomes. Additionally, any association between the circadian BP pattern (dipping/non-dipping status) and outcomes was assessed. RESULTS: Twenty-two studies (2078 participants) were reviewed. Amongst 12 studies collecting data on renal endpoints, ten studies found that BP assessed by ABPM was a stronger predictor of renal function decline, assessed by serum creatinine (SCr) and/or creatinine clearance (CrCl) or estimated glomerular filtration rate (eGFR), than traditional office measurements. Twelve studies analyzed the relation between different BP recordings and CV target organ damages and reported robust correlations between echocardiographic abnormalities [i.e. left ventricular mass index (LVM/LVMI)] and 24h ABPM, but not with office BPs. Furthermore, 24h ABPM correlated better than oBP with markers of vascular damage, such as carotid intima-media thickness (IMT), diffuse thickening, and endothelial dysfunction. Additionally, abnormal circadian BP pattern (non-dippers and reverse dippers) identified a group of kidney recipients at risk for kidney function loss and CV abnormalities. CONCLUSIONS: In our systematic review, ABPM reflected target organ damage more closely than oBP in KTRs. Furthermore, altered circadian BP profile associated with renal and CV target organ damages.

Renal denervation for resistant hypertension.

BACKGROUND: Resistant hypertension is highly prevalent among the general hypertensive population and the clinical management of this condition remains problematic. Different approaches, including a more intensified antihypertensive therapy, lifestyle modifications or both, have largely failed to improve patients' outcomes and to reduce cardiovascular and renal risk. As renal sympathetic hyperactivity is a major driver of resistant hypertension, in the last decade renal sympathetic ablation (renal denervation) has been proposed as a possible therapeutic alternative to treat this condition. OBJECTIVES: We sought to evaluate the short- and long-term effects of renal denervation in individuals with resistant hypertension on clinical end points, including fatal and non-fatal cardiovascular events, all-cause mortality, hospital admissions, quality of life, blood pressure control, left ventricular hypertrophy, cardiovascular and metabolic profile and kidney function, as well as the potential adverse events related to the procedure. SEARCH METHODS: For this updated review, the Cochrane Hypertension Information Specialist searched the following databases for randomised controlled trials up to 3 November 2020: Cochrane Hypertension's Specialised Register, CENTRAL (2020, Issue 11), Ovid MEDLINE, and Ovid Embase. The World Health Organization International Clinical Trials Registry Platform (via CENTRAL) and the US National Institutes of Health Ongoing Trials Register ClinicalTrials.gov were searched for ongoing trials. We also contacted authors of relevant papers regarding further published and unpublished work. The searches had no language restrictions. SELECTION CRITERIA: We considered randomised controlled trials (RCTs) that compared renal denervation to standard therapy or sham procedure to treat resistant hypertension, without language restriction. DATA COLLECTION AND ANALYSIS: Two authors independently extracted data and assessed study risk of bias. We summarised treatment effects on available clinical outcomes and adverse events using random-effects meta-analyses. We assessed heterogeneity in estimated treatment effects using Chi² and I² statistics. We calculated summary treatment estimates as a mean difference (MD) or standardised mean difference (SMD) for continuous outcomes, and a risk ratio (RR) for dichotomous outcomes, together with their 95% confidence intervals (CI). Certainty of evidence has been assessed using the GRADE approach. MAIN RESULTS: We found 15 eligible studies (1416 participants). In four studies, renal denervation was compared to sham procedure; in the remaining studies, renal denervation was tested against standard or intensified antihypertensive therapy. Most studies had unclear or high risk of bias for allocation concealment and blinding.  When compared to control, there was low-certainty evidence that renal denervation had little or no effect on the risk of myocardial infarction (4 studies, 742 participants; RR 1.31, 95% CI 0.45 to 3.84), ischaemic stroke (5 studies, 892 participants; RR 0.98, 95% CI 0.33 to 2.95), unstable angina (3 studies, 270 participants; RR 0.51, 95% CI 0.09 to 2.89) or hospitalisation (3 studies, 743 participants; RR 1.24, 95% CI 0.50 to 3.11). Based on moderate-certainty evidence, renal denervation may reduce 24-hour ambulatory blood pressure monitoring (ABPM) systolic BP (9 studies, 1045 participants; MD -5.29 mmHg, 95% CI -10.46 to -0.13), ABPM diastolic BP (8 studies, 1004 participants; MD -3.75 mmHg, 95% CI -7.10 to -0.39) and office diastolic BP (8 studies, 1049 participants; MD -4.61 mmHg, 95% CI -8.23 to -0.99). Conversely, this procedure had little or no effect on office systolic BP (10 studies, 1090 participants; MD -5.92 mmHg, 95% CI -12.94 to 1.10). Moderate-certainty evidence suggested that renal denervation may not reduce serum creatinine (5 studies, 721 participants, MD 0.03 mg/dL, 95% CI -0.06 to 0.13) and may not increase the estimated glomerular filtration rate (eGFR) or creatinine clearance (6 studies, 822 participants; MD -2.56 mL/min, 95% CI -7.53 to 2.42).  AUTHORS' CONCLUSIONS: In patients with resistant hypertension, there is low-certainty evidence that renal denervation does not improve major cardiovascular outomes and renal function. Conversely, moderate-certainty evidence exists that it may improve 24h ABPM and diastolic office-measured BP. Future trials measuring patient-centred instead of surrogate outcomes, with longer follow-up periods, larger sample size and more standardised procedural methods are necessary to clarify the utility of this procedure in this population.

Physical activity in chronic kidney disease and the EXerCise Introduction To Enhance trial.

It is well known from observational studies that sedentary lifestyle and reduced physical activity are common in dialysis and chronic kidney disease (CKD) patients and associate with an increased risk of morbidity and mortality in this patient population. Epidemiological studies indicate that CKD patients undergo physical activity ~9 days/month and 43.9% of dialysis patients report not exercising at all. On the basis of awareness about the strong link between sedentary lifestyle and adverse clinical outcomes, the National Kidney Foundation and Kidney Disease: Improving Global Outcomes have provided specific recommendations for physical activity in patients with kidney disease. Given the fact that CKD is a public health problem and it is still debated which type of exercise should be prescribed in these patients, this review focuses on the most robust evidence accumulated so far on the beneficial effect of various types of physical exercise on clinical outcomes in CKD and dialysis patients. This review does not treat this very important topic in another CKD category of patients, such as kidney-transplanted patients, for whom a special issue should be dedicated.

Comparative effectiveness of different antihypertensive agents in kidney transplantation: a systematic review and meta-analysis.

BACKGROUND: We conducted a systematic review and meta-analysis to compare benefits and harms of different antihypertensive drug classes in kidney transplant recipients, as post-transplant hypertension (HTN) associates with increased cardiovascular (CV) morbidity and mortality. METHODS: The Ovid-MEDLINE, PubMed and CENTRAL databases were searched for randomized controlled trials (RCTs) comparing all main antihypertensive agents versus placebo/no treatment, routine treatment. RESULTS: The search identified 71 RCTs. Calcium channel blockers (CCBs) (26 trials) reduced the risk for graft loss {risk ratio [RR] 0.58 [95% confidence interval (CI) 0.38-0.89]}, increased glomerular filtration rate (GFR) [mean difference (MD) 3.08 mL/min (95% CI 0.38-5.78)] and reduced blood pressure (BP). Angiotensin-converting enzyme inhibitors (ACEIs) (13 trials) reduced the risk for graft loss [RR 0.62 (95% CI 0.40-0.96)] but decreased renal function and increased the risk for hyperkalaemia. Angiotensin receptor blockers (ARBs) (10 trials) did not modify the risk of death, graft loss and non-fatal CV events and increased the risk for hyperkalaemia. When pooling ACEI and ARB data, the risk for graft failure was lower in renin-angiotensin system (RAS) blockade as compared with control treatments. In direct comparison with ACEIs or ARBs (11 trials), CCBs increased GFR [MD 11.07 mL/min (95% CI 6.04-16.09)] and reduced potassium levels but were not more effective in reducing BP. There are few available data on mortality, graft loss and rejection. Very few studies performed comparisons with other active drugs. CONCLUSIONS: CCBs could be the preferred first-step antihypertensive agents in kidney transplant patients, as they improve graft function and reduce graft loss. No definite patient or graft survival benefits were associated with RAS inhibitor use over conventional treatment.

Pulmonary hypertension: a neglected risk condition in renal patients?

Pulmonary hypertension (PH), an acknowledged risk condition at the community level and in patients with heart or lung diseases, is now getting growing attention as a new, potentially modifiable cardiovascular (CV) risk factor also in individuals affected by kidney diseases. PH is highly prevalent in this setting, being about 3 to 6 times more frequent that in the general population and portends a risk excess for mortality, adverse CV outcomes and also worsen graft function in kidney transplant recipients. Several factors might be involved to explain PH in renal patients, including but not limited to volume overload, breath disorders, left heart dysfunction and the presence of highflow artero-venous fistulas. Targeting PH might lead to improved outcomes in renal patients but the lack of specific interventional studies and the need for more accurate evidence adopting standardized ways to assess PH leave the issue open for future research.

Renal biopsy in patients with diabetes: a pooled meta-analysis of 48 studies.

Background: The utility of renal biopsy in patients with diabetes is highly debated. Diabetics with rapidly worsening renal disease are often 'clinically' labelled as having diabetic nephropathy (DN), whereas, in many cases, they are rather developing a non-diabetic renal disease (NDRD) or mixed forms (DN + NDRD). Methods: We performed a systematic search for studies on patients with diabetes with data on the frequency of DN, NDRD and mixed forms, and assessed the positive predictive values (PPVs) and odds ratios (ORs) for such diagnoses by meta-analysing single-study prevalence. Possible factors explaining heterogeneity among the different diagnoses were explored by meta-regression. Results: In the 48 included studies ( n = 4876), the prevalence of DN, NDRD and mixed forms ranged from 6.5 to 94%, 3 to 82.9% and 4 to 45.5% of the overall diagnoses, respectively. IgA nephropathy was the most common NDRD (3-59%). PPVs for DN, NDRD and mixed forms were 50.1% [95% confidence interval (CI): 44.7-55.2], 36.9% (95% CI: 32.3-41.8) and 19.7% (95% CI: 16.3-23.6), respectively. The PPV when combining NDRD and mixed forms was 49.2% (95% CI: 43.8-54.5). Meta-regression identified systolic pressure, HbA1c, diabetes duration and retinopathy as factors explaining heterogeneity for NDRD, creatinine and glomerular filtration rate for mixed forms and only serum creatinine for DN. ORs of DN versus NDRD and mixed forms were 1.71 (95% CI: 1.54-1.91) and 4.1 (95% CI: 3.43-4.80), respectively. Conclusions: NDRD are highly prevalent in patients with diabetes. Clinical judgment alone can lead to wrong diagnoses and delay the establishment of adequate therapies. Risk stratification according to individual factors is needed for selecting patients who might benefit from biopsy.

Renal safety of catheter-based renal denervation: systematic review and meta-analysis.

BACKGROUND: Catheter-based renal denervation (RDN) is a possible treatment to lower blood pressure. The invasive nature of RDN and the use of contrast agents raise concerns about potential consequent kidney damage. Our objective was to determine the change in renal function after RDN by performing a systematic review on hypertensive patients treated with RDN. METHODS: A systematic search was performed in the Embase and MEDLINE databases to identify studies reporting on the effects of catheter-based RDN on renal outcome. Studies published between January 2009 and May 2016, irrespective of study design, device used or indication for treatment were included. We performed random effects meta-analyses on the change in estimated glomerular filtration rate (eGFR), serum creatinine, serum cystatin C and albumin:creatinine ratio after RDN. We only extracted and meta-analysed data from patients treated with RDN. RESULTS: From 1034 citations, 52 studies (38 cohort studies, 4 non-randomized comparative studies and 10 randomized controlled trials) reporting on 56 RDN cohorts were included in meta-analyses and another 14 studies in a qualitative review. Of these 56 cohorts, 48 were specifically eligible for determining the change in eGFR after RDN, totaling 2381 patients. There was no statistically significant change in eGFR after a mean follow-up time of 9.1 ± 7.0 months [0.64 mL/min/1.73 m 2 (95% confidence interval -0.47 to 1.76), P = 0.26]. The pooled mean change in serum creatinine and the results of the qualitative review further supported these findings. CONCLUSIONS: Based on meta-analyses of 52 studies and a qualitative review of an additional 14 studies, reporting on 2898 patients in total, we conclude that renal function does not significantly change up to at least 9 months after RDN.

Renal denervation for resistant hypertension.

BACKGROUND: Resistant hypertension is highly prevalent among the general hypertensive population and the clinical management of this condition remains problematic. Different approaches, including a more intensified antihypertensive therapy, lifestyle modifications, or both, have largely failed to improve patients' outcomes and to reduce cardiovascular and renal risk. As renal sympathetic hyperactivity is a major driver of resistant hypertension, renal sympathetic ablation (renal denervation) has been recently proposed as a possible therapeutic alternative to treat this condition. OBJECTIVES: We sought to evaluate the short- and long-term effects of renal denervation in individuals with resistant hypertension on clinical end points, including fatal and non-fatal cardiovascular events, all-cause mortality, hospital admissions, quality of life, blood pressure control, left ventricular hypertrophy, cardiovascular and metabolic profile, and kidney function, as well as the potential adverse events related to the procedure. SEARCH METHODS: We searched the following databases to 17 February 2016 using relevant search terms: the Cochrane Hypertension Group Specialised Register, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE and ClinicalTrials.gov SELECTION CRITERIA: We considered randomised controlled trials (RCTs) that compared renal denervation to standard therapy or sham procedure to treat resistant hypertension, without language restriction. DATA COLLECTION AND ANALYSIS: Two authors independently extracted data and assessed study risks of bias. We summarised treatment effects on available clinical outcomes and adverse events using random-effects meta-analyses. We assessed heterogeneity in estimated treatment effects using Chi² and I² statistics. We calculated summary treatment estimates as a mean difference (MD) or standardised mean difference (SMD) for continuous outcomes, and a risk ratio (RR) for dichotomous outcomes, together with their 95% confidence intervals (CI). MAIN RESULTS: We found 12 eligible studies (1149 participants). In four studies, renal denervation was compared to sham procedure; one study compared a proximal ablation to a complete renal artery denervation; in the remaining, renal denervation was tested against standard or intensified antihypertensive therapy.None of the included trials was designed to look at hard clinical end points as primary outcomes.When compared to control, there was low quality evidence that renal denervation did not reduce the risk of myocardial infarction (4 studies, 742 participants; RR 1.31, 95% CI 0.45 to 3.84), ischaemic stroke (4 studies, 823 participants; RR 1.15, 95% CI 0.36 to 3.72), or unstable angina (2 studies, 201 participants; RR 0.63, 95% CI 0.08 to 5.06), and moderate quality evidence that it had no effect on 24-hour ambulatory blood pressure monitoring (ABPM) systolic BP (5 studies, 797 participants; MD 0.28 mmHg, 95% CI -3.74 to 4.29), diastolic BP (4 studies, 756 participants; MD 0.93 mmHg, 95% CI -4.50 to 6.36), office measured systolic BP (6 studies, 886 participants; MD -4.08 mmHg, 95% CI -15.26 to 7.11), or diastolic BP (5 studies, 845 participants; MD -1.30 mmHg, 95% CI -7.30 to 4.69). Furthermore, low quality evidence suggested that this procedure produced no effect on either serum creatinine (3 studies, 736 participants, MD 0.01 mg/dL; 95% CI -0.12 to 0.14), estimated glomerular filtration rate (eGFR), or creatinine clearance (4 studies, 837 participants; MD -2.09 mL/min, 95% CI -8.12 to 3.95). Based on low-quality evidence, renal denervation significantly increased bradycardia episodes compared to control (3 studies, 220 participants; RR 6.63, 95% CI 1.19 to 36.84), while the risk of other adverse events was comparable or not assessable.Data were sparse or absent for all cause mortality, hospitalisation, fatal cardiovascular events, quality of life, atrial fibrillation episodes, left ventricular hypertrophy, sleep apnoea severity, need for renal replacement therapy, and metabolic profile.The quality of the evidence was low for cardiovascular outcomes and adverse events and moderate for lack of effect on blood pressure and renal function. AUTHORS' CONCLUSIONS: In patients with resistant hypertension, there is low quality evidence that renal denervation does not change major cardiovascular events, and renal function. There was moderate quality evidence that it does not change blood pressure and and low quality evidence that it caused an increaseof bradycardia episodes. Future trials measuring patient-centred instead of surrogate outcomes, with longer follow-up periods, larger sample size and more standardized procedural methods are necessary to clarify the utility of this procedure in this population.

Xanthine Oxidase Inhibitors for Improving Renal Function in Chronic Kidney Disease Patients: An Updated Systematic Review and Meta-Analysis.

BACKGROUND: Accruing evidence suggests that Xanthine Oxidase inhibitors (XOis) may bring direct renal benefits, besides those related to their hypo-uricemic effect. We hence aimed at performing a systematic review of randomized controlled trials (RCTs) to verify if treatment with XOis may improve renal outcomes in individuals with chronic kidney disease (CKD). METHODS: Ovid-MEDLINE, PubMed and CENTRAL databases were searched for RCTs comparing any XOi to standard therapy or placebo. The primary endpoint of interest was progression to End-Stage Kidney Disease (ESKD); secondary endpoints were changes in serum creatinine, glomerular filtration rate (eGFR), proteinuria and albuminuria. RESULTS: XOis treatment significantly reduced the risk of ESKD compared to the control (3 studies, 204 pts; RR = 0.42; 95% CI, 0.22, 0.80) and also improved eGFR in data pooled from RCTs with long follow-up times (>3 mo.) (4 studies, 357 pts; mean difference (MD) 6.82 mL/min/1.73 m²; 95% CI, 3.50, 10.15) and high methodological quality (blind design) (3 studies, 400 pts; MD 2.61 mL/min/1.73 m²; 95% CI, 0.23, 4.99). Conversely, no definite effects were apparently noticed on serum creatinine, proteinuria and albuminuria. CONCLUSIONS: XOis may represent a promising tool for retarding disease progression in CKD patients. Future trials are awaited to confirm the generalizability of these findings to the whole CKD population.

Insulin resistance in chronic kidney disease: a systematic review.

Insulin resistance (IR) is an early metabolic alteration in chronic kidney disease (CKD) patients, being apparent when the glomerular filtration rate is still within the normal range and becoming almost universal in those who reach the end stage of kidney failure. The skeletal muscle represents the primary site of IR in CKD, and alterations at sites beyond the insulin receptor are recognized as the main defect underlying IR in this condition. Estimates of IR based on fasting insulin concentration are easier and faster but may not be adequate in patients with CKD because renal insufficiency reduces insulin catabolism. The hyperinsulinemic euglycemic clamp is the gold standard for the assessment of insulin sensitivity because this technique allows a direct measure of skeletal muscle sensitivity to insulin. The etiology of IR in CKD is multifactorial in nature and may be secondary to disturbances that are prominent in renal diseases, including physical inactivity, chronic inflammation, oxidative stress, vitamin D deficiency, metabolic acidosis, anemia, adipokine derangement, and altered gut microbiome. IR contributes to the progression of renal disease by worsening renal hemodynamics by various mechanisms, including activation of the sympathetic nervous system, sodium retention, and downregulation of the natriuretic peptide system. IR has been solidly associated with intermediate mechanisms leading to cardiovascular (CV) disease in CKD including left ventricular hypertrophy, vascular dysfunction, and atherosclerosis. However, it remains unclear whether IR is an independent predictor of mortality and CV complications in CKD. Because IR is a modifiable risk factor and its reduction may lower CV morbidity and mortality, unveiling the molecular mechanisms responsible for the pathogenesis of CKD-related insulin resistance is of importance for the identification of novel therapeutic targets aimed at reducing the high CV risk of this condition.

Renal Biopsy in 2015--From Epidemiology to Evidence-Based Indications.

BACKGROUND: Although the number of patients reaching end-stage kidney disease without a biopsy-proven diagnosis is increasing, the utility of renal biopsy is still an object of debate. We analyzed epidemiological data and the main indications for renal biopsy with a systematic, evidence-based review at current literature. SUMMARY: There is a high discrepancy observed in biopsy rates and in the epidemiology of glomerular diseases worldwide, related to the different time frame of the analyzed reports, lack of data collection, the different reference source population and the heterogeneity of indications. The evidence-based analysis of indications showed that renal biopsy should be crucial in adults with nephrotic syndrome or urinary abnormalities as coexistent hematuria and proteinuria and in corticosteroid resistant-children with severe proteinuria. The knowledge of renal histology can change the clinical management in patients with acute kidney injury significantly, after the exclusion of pre-renal or obstructive causes of kidney damage. Scarce evidence indicates that renal biopsy can be useful in patients with advanced chronic kidney disease and its use should always be considered after weighing the benefits and potential risks. Renal biopsy should be crucial in patients with renal involvement due to systemic disease. In patients with diabetes with atypical features, renal biopsy may be fundamental to diagnose an unexpected parenchymal disease mislabeled as diabetic nephropathy. Finally, in elderly patients, the indications and the risks are not different from those in the general population. KEY MESSAGE: Renal biopsy still remains a concrete approach for managing a substantial percentage of renal diseases.

High versus low dialysate sodium concentration in chronic haemodialysis patients: a systematic review of 23 studies.

BACKGROUND: It is the object of debate whether a low or high dialysate sodium concentration (DNa(+)) should be advocated in chronic haemodialysis patients. In this paper, we aimed at evaluating benefits and harms of different DNa(+) prescriptions through a systematic review of the available literature. METHODS: MEDLINE and CENTRAL databases were searched for studies comparing low or high DNa(+) prescriptions. Outcomes of interest were mortality, blood pressure (BP), interdialytic weight gain (IDWG), plasma sodium, hospitalizations, use of anti-hypertensive agents and intradialytic complications. RESULTS: Twenty-three studies (76 635 subjects) were reviewed. There was high heterogeneity in the number of patients analysed, overall study quality, duration of follow-up, DNa(+) and even in the definition of 'high' or 'low' DNa(+). The only three studies looking at mortality were observational. The risk of death was related to the plasma-DNa(+) gradient, but was also shown to be confounded by indication from the dialysate sodium prescription itself. BP was not markedly affected by high or low DNa(+). Patients treated with higher DNa(+) had overall higher IDWG when compared with those with lower DNa(+). Three studies reported a significant increase in intra-dialytic hypotensive episodes in patients receiving low DNa(+). Data on hospitalizations and use of anti-hypertensive agents were sparse and inconclusive. CONCLUSIONS: There is currently no definite evidence proving the superiority of a low or high uniform DNa(+) on hard or surrogate endpoints in maintenance haemodialysis patients. Future trials adequately powered to evaluate the impact of different DNa(+) on mortality or other patient-centred outcomes are needed.

Effect of pentoxifylline on renal outcomes in chronic kidney disease patients: A systematic review and meta-analysis.

Chronic kidney disease (CKD) represents an important health problem worldwide and the search for new therapeutic approaches for retarding CKD progression is a timely issue. Recent evidence suggest that the anti-inflammatory and hemorrheologic drug Pentoxifylline (PTX), may produce favorable effects on kidney function. We conducted a systematic review and meta-analysis of randomized controlled trials (RCTs) to ascertain whether PTX derivatives, alone or in combination to other treatments, may be useful in slowing down disease progression in patients with diabetic or non-diabetic CKD. We found 26 studies (1518 subjects) matching our search criteria. Information on the effects of PTX on hard renal outcomes (doubling of serum creatinine or need for chronic dialysis) were lacking in all the reviewed trials. Conversely, PTX was effective in reducing proteinuria compared to control, a benefit that was more evident in patients with type-1 diabetes mellitus, higher proteinuria at baseline and early renal impairment. An improvement in renal function (eGFR/creatinine clearance) was observed particularly in patients with more advanced CKD stage and in studies with longer follow-up. Conversely, cumulative analyses did not reveal any evident reduction in urinary albumin excretion, even in diabetic patients. The use of PTX was relatively safe as most trials recorded only minor gastrointestinal adverse effects. Although these findings point at some reno-protective effects of PTX, there is no conclusive evidence proving the usefulness of this agent for improving renal outcomes in subjects with chronic kidney disease of various etiology. Future trials adequately powered and designed on hard clinical end-points are needed.

Good-quality research in rare diseases: trials and tribulations.

Despite the fact that rare diseases affecting the kidney are not as uncommon as generally believed, proper clinical guidelines for guiding therapeutic management are scarce or absent owing to the overall lack of reliable scientific evidence. Although the randomized controlled trial (RCT) is the best study design for dealing with questions of intervention, RCTs under low-prevalence conditions are extremely challenging because of the limited number of patients, the variable phenotypic expression, and the long course of these disorders. In this brief review, we aimed to summarize the main alternative methods to traditional RCTs designed with the intent of minimizing the number of subjects needed for recruitment or maximizing the statistical efficiency of study analyses. Most of these approaches have not yet been extensively employed, may denote crucial limitations to wide applicability, or still lack proper validation in the field of rare diseases. Nevertheless, the growing number of proposed strategies is indicative of the perceived necessity by the scientific community to fill the quality gap between clinical guidelines for common and rare pathological conditions.

CHF6001 II: a novel phosphodiesterase 4 inhibitor, suitable for topical pulmonary administration--in vivo preclinical pharmacology profile defines a potent anti-inflammatory compound with a wide therapeutic window.

CHF6001 [(S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(3-(cyclopropylmethoxy)-4-(methylsulfonamido)benzoyloxy)ethyl)pyridine 1-oxide] is a novel phosphodiesterase 4 (PDE4) inhibitor designed for use in pulmonary diseases by inhaled administration. Intratracheal administration of CHF6001 to ovalbumin-sensitized Brown-Norway rats suppressed the antigen-induced decline of lung functions (ED50 = 0.1 µmol/kg) and antigen-induced eosinophilia (ED50 = 0.03 µmol/kg) when administered (0.09 µmol/kg) up to 24 hours before antigen challenge, in agreement with CHF6001-sustained lung concentrations up to 72 hours after intratracheal treatment (mean residence time 26 hours). Intranasal, once daily administration of CHF6001 inhibited neutrophil infiltration observed after 11 days of tobacco smoke exposure in mice, both upon prophylactic (0.15-0.45 µmol/kg per day) or interventional (0.045-0.45 µmol/kg per day) treatment. CHF6001 was ineffective in reversing ketamine/xylazine-induced anesthesia (a surrogate of emesis in rat) up to 5 µmol/kg administered intratracheally, a dose 50- to 150-fold higher than anti-inflammatory ED50 observed in rats. When given topically to ferrets, no emesis and nausea were evident up to 10 to 20 µmol/kg, respectively, whereas the PDE4 inhibitor GSK-256066 (6-[3-(dimethylcarbamoyl)phenyl]sulfonyl-4-(3-methoxyanilino)-8-methylquinoline-3-carboxamide) induced nausea at 1 µmol/kg intratracheally. A 14-day inhalation toxicology study in rats showed a no-observed-adverse-effect level dose of 4.4 µmol/kg per day for CHF6001, lower than the 0.015 µmol/kg per day for GSK-256066. CHF6001 was found effective and extremely well tolerated upon topical administration in relevant animal models, and may represent a step forward in PDE4 inhibition for the treatment of asthma and chronic obstructive respiratory disease.

A genetic marker of uric acid level, carotid atherosclerosis, and arterial stiffness: a family-based study.

BACKGROUND: Hyperuricemia associates with atherosclerosis complications, but it is uncertain whether this relationship is causal in nature. The urate transporter GLUT9 (encoded by the SLC2A9 gene) is a major genetic determinant of serum uric acid level in humans. Because polymorphisms are distributed randomly at mating (Mendelian randomization), studies based on GLUT9 polymorphisms may provide unconfounded assessment of the nature of the link between uric acid and atherosclerosis. STUDY DESIGN: Cross-sectional study. SETTING & PARTICIPANTS: Family-based study including 449 individuals in 107 families in a genetically homogeneous population in Southern Italy. FACTOR: Serum uric acid level, rs734553 allele, and age. OUTCOME: Ultrasound biomarkers of atherosclerosis (intima-media thickness [IMT] and internal diameter) and pulse wave velocity (PWV). RESULTS: Serum uric acid level was dose-dependently associated with the T allele of rs734553, a polymorphism in SLC2A9 (P=8×10(-6)). Serum uric acid level was a strong modifier of the relationship between age and IMT in fully adjusted analyses (ß=0.33; P=0.01), whereas no such relationship was found for internal diameter (ß=-0.15; P=0.3) or PWV (ß=0.10; P=0.6). The T allele coherently associated with carotid IMT, internal diameter, and PWV and emerged as an even stronger modifier of the age-IMT and age-internal diameter relationships in both crude and fully adjusted (ß=0.40 [P<0.001] and ß=0.48 [P=0.003], respectively) analyses. LIMITATIONS: This is a hypothesis-generating study. CONCLUSIONS: Results in this family-based study implicate uric acid as an important modifier of the age-dependent risk for atherosclerosis. Trials testing uric acid-lowering interventions are needed to prove this hypothesis.

Integrating children with psychiatric disorders in the classroom: a systematic review.

BACKGROUND: The school setting may be the optimal context for early screening of and intervention on child mental health problems, because of its large reach and intertwinement with various participants (child, teacher, parent, other community services). But this setting also exposes children to the risk of stigma, peer rejection and social exclusion. This systematic literature review investigates the efficacy of mental health interventions addressed to children and adolescents in school settings, and it evaluates which programs explicitly take into account social inclusion indicators. METHOD: Only randomized controlled trials conducted on clinical populations of students and carried out in school settings were selected: 27 studies overall. Most studies applied group Cognitive Behavioural Therapy or Interpersonal Psychotherapy. RESULTS: Findings were suggestive of the effectiveness of school-based intervention programs in reducing symptoms of most mental disorders. Some evidence was found about the idea that effective studies on clinical populations may promote the social inclusion of children with an ongoing mental disorder and avoid the risk of being highly stigmatized. CONCLUSION: School programs are still needed that implement standardized models with verifiable and evidence-based practices involving the whole school community.

Sleep apnoea syndrome prevalence in chronic kidney disease and end-stage kidney disease patients: a systematic review and meta-analysis.

Background: Several studies have examined the frequency of sleep apnoea (SA) in patients with chronic kidney disease (CKD), reporting different prevalence rates. Our systematic review and meta-analysis aimed to define the clinical penetrance of SA in CKD and end-stage kidney disease (ESKD) patients. Methods: Ovid-MEDLINE and PubMed databases were explored up to 5 June 2023 to identify studies providing SA prevalence in CKD and ESKD patients assessed by different diagnostic methods, either sleep questionnaires or respiration monitoring equipment [such as polysomnography (PSG), type III portable monitors or other diagnostic tools]. Single-study data were pooled using the random-effects model. The Chi2 and Cochrane-I2 tests were used to assess the presence of heterogeneity, which was explored performing sensitivity and/or subgroup analyses. Results: A cumulative analysis from 32 single-study data revealed a prevalence of SA of 57% [95% confidence interval (CI) 42%-71%] in the CKD population, whereas a prevalence of 49% (95% CI 47%-52%) was found pooling data from 91 studies in ESKD individuals. The prevalence of SA using instrumental sleep monitoring devices, including classical PSG and type III portable sleep monitors, was 62% (95% CI 52%-72%) and 56% (95% CI 42%-69%) in CKD and ESKD populations, respectively. Sleep questionnaires revealed a prevalence of 33% (95% CI 16%-49%) and 39% (95% CI 30%-49%). Conclusions: SA is commonly seen in both non-dialysis CKD and ESKD patients. Sleep-related questionnaires underestimated the presence of SA in this population. This emphasizes the need to use objective diagnostic tools to identify such a syndrome in kidney disease.

A follow-up on patients with severe mental disorders in Sardinia after two changes in regional policies: poor resources still correlate with poor outcomes.

BACKGROUND: This survey followed a cohort of patients with chronic psychosis recruited from five catchment areas (DSMs) of the Sardinian community mental health services. The objective was to examine whether the amount of resources in the different sites may be a determinant of the outcomes. METHODS: Naturalistic follow-up study on 309 consecutive users with diagnosis of schizophrenic disorder, schizoaffective disorder, bipolar affective disorder with psychotic symptoms (DSM-IV TR) of five Sardinian community mental health services. Mental state and clinical symptoms along with functioning were assessed using semi-structured clinical interviews (ANTAS), Clinical Global Impression Severity Scale (CGI-S), Global Assessment of Functioning Scale (GAF) and Health of the Nation Outcome Scales (HONOS). Assessments were conducted at the beginning of the study and after one year. RESULTS: The proportion of professionals working in all DSMs participating in the study was found lower than the national Italian standard (0.7 vs. 1.0 per 1,500 inhabitants). Follow-up revealed significant differences between DSMs in the improvement of the Honos scores (F = 5.932, p = 0.000). These differences correlate with the improvement of resources in terms of number of professionals during, and one year prior, to the trial. CONCLUSIONS: The study shows that mental health services provided in the public sector in Sardinia are still very resource-poor, at least in terms of human resources. Our findings suggest that mental health service resources influence outcomes as regards the social functioning of users. We urge policy makers to take these observations into account when planning future services.