Despite the high costs of treatment of people with kidney disease and associated comorbid conditions, the amount of reliable information available to guide the care of such patients is very limited. ...Some treatments have been assessed in randomized trials, but most such trials have been too small to detect treatment effects of a magnitude that would be realistic to achieve with a single intervention. Therefore, KDIGO convened an international, multidisciplinary controversies conference titled “Challenges in the Conduct of Clinical Trials in Nephrology” to identify the key barriers to conducting trials in patients with kidney disease. The conference began with plenary talks focusing on the key areas of discussion that included appropriate trial design (covering identification and evaluation of kidney and nonkidney disease outcomes) and sensible trial execution (with particular emphasis on streamlining both design and conduct). Break out group discussions followed in which the key areas of agreement and remaining controversy were identified. Here we summarize the main findings from the conference and set out a range of potential solutions. If followed, these solutions could ensure future trials among people with kidney disease are sufficiently robust to provide reliable answers and are not constrained by inappropriate complexities in design or conduct.
Aim
In short‐term studies, hormonal contraceptives (HC) have been suggested to induce a rise in blood pressure (BP) and urinary albumin excretion (UAE), while the effect of HC in renal function (GFR) ...is still under debate. Data on long‐term and withdrawal effects of HC use on these outcomes are, however, not available. We therefore studied whether the start and cessation of HC induce changes in BP, UAE and GFR.
Methods
We used data from the PREVEND Study, a prospective cohort of subjects aged 28–75 years. Eligible were women aged ≤ 45 years with complete clinical and pharmacy data on baseline and follow‐up screening (4 years later). Multivariate regression analysis was used to estimate the effects of HC on BP, UAE and GFR in those who started (n = 73), stopped (n = 117) or continued (n = 183) with those who never used HC (n = 286) as the reference group.
Results
BP increased among starters and fell in stoppers. These changes compared with never‐users were statistically significant, even after adjustment for relevant variables. UAE increased by 14.2% in starters (P = 0.074) and fell by 10.6% in stoppers (P = 0.021), while GFR fell by 6.3% in starters (P < 0.001) and did not change in stoppers. The effects of stopping HC on UAE and GFR were significantly different compared with changes among never‐users, even after adjustment for other variables (P = 0.023 and 0.036, respectively).
Conclusions
The start of HC was independently associated with worsening of BP, UAE and GFR, while stopping HC use resulted in an improvement. These data suggest that long‐term HC use (aged 28–45 years) may be deleterious from the cardiovascular and renal point of view, but stopping may result in correction of these effects.
Background. Incidence of dialysis in elderly patients in the Netherlands is low compared to other countries. This study aims to assess the impact of patients' age and comorbidity on the likelihood of ...referral and acceptance of patients for dialysis and whether this is affected by physician characteristics. Methods. A vignette study was performed among 209 primary care physicians, 162 non-nephrology specialists and 20 nephrologists working in the north of the Netherlands. Physicians were offered six vignettes concerning case-reports of patients with end-stage renal disease (ESRD) and varying comorbidities or circumstances and asked about the likelihood of referral/acceptance of the patient in the given circumstances. Results. The likelihood of referral within groups of physicians varied widely, especially within the group of primary care physicians and non-nephrology specialists, but was not affected by characteristics of physicians. The likelihood of referral or acceptance of patients for dialysis depended on the patient's age, and type and severity of comorbidity. In general, primary care physicians and non-nephrology specialists were less likely to refer than nephrologists were to accept. Differences within and between groups of physicians were larger for 80- than for 65-year-old patients, and for patients with less severe shortness of breath and cognitive impairments and more severe diabetes and social impairments. Hardly any differences were found for patients with cancer. Conclusion. Patients' age and comorbidities affect the likelihood of referral. Differences between groups of physicians suggest that there is insufficient agreement on the extent to which these factors should affect the referral/acceptance of patients for dialysis. These findings underline the need for more research into circumstances under which patients might benefit from dialysis. Guidelines should be developed to improve the referral of elderly and less healthy patients.
Elevated concentrations of albumin in the urine, albuminuria, are a hallmark of diabetic kidney disease and are associated with an increased risk for end-stage renal disease and cardiovascular ...events. To gain insight into the pathophysiological mechanisms underlying albuminuria, we conducted meta-analyses of genome-wide association studies and independent replication in up to 5,825 individuals of European ancestry with diabetes and up to 46,061 without diabetes, followed by functional studies. Known associations of variants in CUBN, encoding cubilin, with the urinary albumin-to-creatinine ratio (UACR) were confirmed in the overall sample (P = 2.4 × 10(-10)). Gene-by-diabetes interactions were detected and confirmed for variants in HS6ST1 and near RAB38/CTSC. Single nucleotide polymorphisms at these loci demonstrated a genetic effect on UACR in individuals with but not without diabetes. The change in the average UACR per minor allele was 21% for HS6ST1 (P = 6.3 × 10(-7)) and 13% for RAB38/CTSC (P = 5.8 × 10(-7)). Experiments using streptozotocin-induced diabetic Rab38 knockout and control rats showed higher urinary albumin concentrations and reduced amounts of megalin and cubilin at the proximal tubule cell surface in Rab38 knockout versus control rats. Relative expression of RAB38 was higher in tubuli of patients with diabetic kidney disease compared with control subjects. The loci identified here confirm known pathways and highlight novel pathways influencing albuminuria.
Autosomal dominant polycystic kidney disease (ADPKD) is characterized by progressive cyst formation in both kidneys and loss of renal function, eventually leading to a need for kidney replacement ...therapy. There are limited therapeutic management options.
To examine the effect of the somatostatin analogue lanreotide on the rate of kidney function loss in patients with later-stage ADPKD.
An open-label randomized clinical trial with blinded end point assessment that included 309 patients with ADPKD from July 2012 to March 2015 at 4 nephrology outpatient clinics in the Netherlands. Eligible patients were 18 to 60 years of age and had an estimated glomerular filtration rate (eGFR) of 30 to 60 mL/min/1.73 m2. Follow-up of the 2.5-year trial ended in August 2017.
Patients were randomized to receive either lanreotide (120 mg subcutaneously once every 4 weeks) in addition to standard care (n = 153) or standard care only (target blood pressure <140/90 mm Hg; n = 152).
Primary outcome was annual change in eGFR assessed as slope through eGFR values during the 2.5-year treatment phase. Secondary outcomes included change in eGFR before vs after treatment, incidence of worsening kidney function (start of dialysis or 30% decrease in eGFR), change in total kidney volume and change in quality of life (range: 1 not bothered to 5 extremely bothered).
Among the 309 patients who were randomized (mean SD age, 48.4 7.3 years; 53.4% women), 261 (85.6%) completed the trial. Annual rate of eGFR decline for the lanreotide vs the control group was -3.53 vs -3.46 mL/min/1.73 m2 per year (difference, -0.08 95% CI, -0.71 to 0.56; P = .81). There were no significant differences for incidence of worsening kidney function (hazard ratio, 0.87 95% CI, 0.49 to 1.52; P = .87), change in eGFR (-3.58 vs -3.45; difference, -0.13 mL/min/1.73 m2 per year 95% CI, -1.76 to 1.50; P = .88), and change in quality of life (0.05 vs 0.07; difference, -0.03 units per year 95% CI, -0.13 to 0.08; P = .67). The rate of growth in total kidney volume was lower in the lanreotide group than the control group (4.15% vs 5.56%; difference, -1.33% per year 95% CI, -2.41% to -0.24%; P = .02). Adverse events in the lanreotide vs control group included injection site discomfort (32% vs 0.7%), injection site papule (5.9% vs 0%), loose stools (91% vs 6.6%), abdominal discomfort (79% vs 20%), and hepatic cyst infections (5.2% vs 0%).
Among patients with later-stage autosomal dominant polycystic kidney disease, treatment with lanreotide compared with standard care did not slow the decline in kidney function over 2.5 years of follow-up. These findings do not support the use of lanreotide for treatment of later-stage autosomal dominant polycystic kidney disease.
ClinicalTrials.gov Identifier: NCT01616927.
The immune response to COVID-19 vaccination is inferior in kidney transplant recipients (KTRs) and to a lesser extent in patients on dialysis or with chronic kidney disease (CKD). We assessed the ...immune response 6 months after mRNA-1273 vaccination in kidney patients and compared this to controls.
A total of 152 participants with CKD stages G4/5 (eGFR <30 mL/min/1.73 m2), 145 participants on dialysis, 267 KTRs, and 181 controls were included. SARS-CoV-2 Spike S1 specific IgG antibodies were measured using fluorescent bead-based multiplex-immunoassay, neutralizing antibodies to ancestral, Delta, and Omicron (BA.1) variants by plaque reduction, and T-cell responses by interferon-γ release assay.
At 6 months after vaccination, S1-specific antibodies were detected in 100% of controls, 98.7% of CKD G4/5 patients, 95.1% of dialysis patients, and 56.6% of KTRs. These figures were comparable to the response rates at 28 days, but antibody levels waned significantly. Neutralization of the ancestral and Delta variants was detected in most participants, whereas neutralization of Omicron was mostly absent. S-specific T-cell responses were detected at 6 months in 75.0% of controls, 69.4% of CKD G4/5 patients, 52.6% of dialysis patients, and 12.9% of KTRs. T-cell responses at 6 months were significantly lower than responses at 28 days.
Although seropositivity rates at 6 months were comparable to rates at 28 days after vaccination, significantly decreased antibody levels and T-cell responses were observed. The combination of low antibody levels, reduced T-cell responses, and absent neutralization of the newly emerging variants indicates the need for additional boosts or alternative vaccination strategies in KTRs.
NCT04741386.
Trends in the incidence of treated end-stage renal failure in The Netherlands: Hope for the future? This study shows that in The Netherlands there is a changing pattern in incidence of renal ...replacement therapy over time when adjusted for age and sex. There has been an almost linear increase in crude incidence rates during four decades. However, unlike the situation elsewhere in the Western world, a flattening of the curve has been observed during the last six years. The growing incidence of end-stage renal disease (ESRD) due to especially hypertensive renovascular disease and diabetes mellitus type 2 has been neutralized by a decrease in ESRD due to glomerulonephritis, urologic interstitial nephritis, and diabetes mellitus type 1. The latter observations suggest that renoprotective interventions can be successful on a population level, and thus, provide hope for the future. To battle the increase in ESRD due to atherosclerosis and diabetes mellitus type 2–related renal disease, it is important that screening programs are being developed that enable us to identify in an early phase patients at risk for development of ESRD who may benefit from preventive strategies. Population screening for albuminuria will be helpful in this respect.
As patients with impaired kidney function are at increased risk not only for progressive renal function loss, but also for cardiovascular disease, it is of importance to have accurate techniques to ...screen patients for the presence of an impaired kidney function.
Glomerular filtration rate can in mass screenings best be evaluated using a formula based upon a serum creatinine measurement and anthropometric parameters. The Cockcroft-Gault and Modification of Diet in Renal Disease (MDRD) formulas are mostly used. Both are easy to use, but have their limitations. Interpreting the results of such glomerular filtration rate estimates requires a good knowledge of these limitations. Urinary albumin excretion can best be measured from 24 h urine collections. As these collections are difficult to perform, however, an early morning spot urine sample for the measurement of urinary albumin concentration can be applied as preselection for screening purposes.
Mass screening for early kidney function impairment, expressed by an impaired glomerular filtration rate or elevated urinary albumin excretion, may help to detect patients at increased cardiac and renal risk. This can best be done using formulas to estimate glomerular filtration rate and by measuring urinary albumin loss.
PDF
