Long-term efficacy and safety of SARS-CoV-2 vaccination in patients with chronic kidney disease, on dialysis or after kidney transplantation: a national prospective observational cohort study.

BACKGROUND: COVID-19 is associated with increased morbidity and mortality in patients with chronic kidney disease (CKD) stages G4-G5, on dialysis or after kidney transplantation (kidney replacement therapy, KRT). SARS-CoV-2 vaccine trials do not elucidate if SARS-CoV-2 vaccination is effective in these patients. Vaccination against other viruses is known to be less effective in kidney patients. Our objective is to assess the efficacy and safety of various types of SARS-CoV-2 vaccinations in patients with CKD stages G4-G5 or on KRT. METHODS: In this national prospective observational cohort study we will follow patients with CKD stages G4-G5 or on KRT (n = 12,000) after SARS-CoV-2 vaccination according to the Dutch vaccination program. Blood will be drawn for antibody response measurements at day 28 and month 6 after completion of vaccination. Patient characteristics and outcomes will be extracted from registration data and questionnaires during 2 years of follow-up. Results will be compared with a control group of non-vaccinated patients. The level of antibody response to vaccination will be assessed in subgroups to predict protection against COVID-19 breakthrough infection. RESULTS: The primary endpoint is efficacy of SARS-CoV-2 vaccination determined as the incidence of COVID-19 after vaccination. Secondary endpoints are the antibody based immune response at 28 days after vaccination, the durability of this response at 6 months after vaccination, mortality and (serious) adverse events. CONCLUSION: This study will fulfil the lack of knowledge on efficacy and safety of SARS-CoV-2 vaccination in patients with CKD stages G4-G5 or on KRT. TRIAL REGISTRATION: The study protocol has been registered in clinicaltrials.gov ( NCT04841785 ). Current knowledge about this subject COVID-19 has devastating impact on patients with CKD stages G4-G5, on dialysis or after kidney transplantation. Effective SARS-CoV-2 vaccination is very important in these vulnerable patient groups. Recent studies on vaccination in these patient groups are small short-term studies with surrogate endpoints. Contribution of this study Assessment of incidence and course of COVID-19 after various types of SARS-CoV-2 vaccination during a two-year follow-up period in not only patients on dialysis or kidney transplant recipients, but also in patients with CKD stages G4-G5. Quantitative analysis of antibody response after SARS-CoV-2 vaccination and its relationship with incidence and course of COVID-19 in patients with CKD stages G4-G5, on dialysis or after kidney transplantation compared with a control group. Monitoring of (serious) adverse events and development of anti-HLA antibodies. Impact on practice or policy Publication of the study design contributes to harmonization of SARS-CoV-2 vaccine study methodology in kidney patients at high-risk for severe COVID-19. Data on efficacy of SARS-CoV-2 vaccination in patients with CKD will provide guidance for future vaccination policy.

Nurse practitioners improve quality of care in chronic kidney disease: two-year results of a randomised study.

BACKGROUND: Chronic kidney disease (CKD) is associated with increased cardiovascular risk. Here we evaluate whether strict implementation of guidelines aimed at multiple targets with the aid of nurse practitioners (NP) improves management in patients with CKD. METHODS: MASTER PLAN is a randomised controlled clinical trial, performed in nine Dutch hospitals. Patients with CKD (estimated glomerular filtration rate (eGFR) 20-70 ml÷min) were randomised to receive NP support (intervention group (IG)) or physician care (control group (CG)). Patients were followed for a median of five years. Presented data are an interim analysis on risk factor control at two-year follow-up. RESULTS: We included 788 patients (532 M, 256 F), (393 CG, 395 IG), mean (±SD ) age 59 (±13) years, eGFR 38 (±15) ml÷min÷1.73m(2), blood pressure (BP) 138 (±21)÷80 (±11) mmHg. At two years 698 patients (352 IG, 346 CG) could be analysed. IG as compared with CG had lower systolic (133 vs 135 mmHg; p= 0.04) and diastolic BP (77 vs 80 mmHg; p=0.007), LDL cholesterol (2.30 vs 2.45 mmol(-l); p= 0.03), and increased use of ACE inhibitors, statins, aspirin and vitamin D. The intervention had no effect on smoking cessation, body weight, physical activity or sodium excretion. CONCLUSION: In both groups, risk factor management improved. However, changes in BP control, lipid management and medication use were more pronounced in IG than in CG. Lifestyle interventions were not effective. Coaching by NPs thus benefits everyday care of CKD patients. Whether these changes translate into improvement in clinical endpoints remains to be established.

Hospital specific factors affect quality of blood pressure treatment in chronic kidney disease.

BACKGROUND: Blood pressure (BP) is the most important modifiable risk factor for cardiovascular (CV) disease and progression of kidney dysfunction in patients with chronic kidney disease. Despite extensive antihypertensive treatment possibilities, adequate control is notoriously hard to achieve. Several determinants have been identified which affect BP control. In the current analysis we evaluated differences in achieved BP and achievement of the BP goal between hospitals and explored possible explanations. METHODS: At baseline, BP was measured in a supine position with an oscillometric device in 788 patients participating in the MASTER PLAN study. We also retrieved the last measured office BP from the patient records. Additional baseline characteristics were derived from the study database. Univariate and multivariate analyses were performed with general linear modelling using hospital as a random factor. RESULTS: In univariate analysis, hospital was a determinant of the level of systolic and diastolic BP at baseline. Adjustment for patient, kidney disease, treatment or hospital characteristics affected the relation. Yet, in a fully adjusted model, differences between centres persisted with a range of 15 mmHg for systolic BP and 11 mmHg for diastolic BP. CONCLUSION: Despite extensive adjustments, a clinically relevant, statistically significant difference between hospitals was found in standardised BP measurements at baseline of a randomised controlled study. We hypothesise that differences in the approach towards BP control exist at the physician level and that these explain the differences between hospitals.

Nephrotic syndrome induced by pamidronate.

Two patients developed nephrotic syndrome and progressive loss of renal function following treatment with i.v. pamidronate. Renal biopsy revealed collapsing focal segmental glomerulosclerosis (FSGS) in both the patients. In one patient, renal function recovered and the nephrotic syndrome disappeared after discontinuation of pamidronate. The second patient became dialysis dependent despite discontinuation of therapy. Nephrotic syndrome due to collapsing FSGS is a serious complication of treatment with bisphosphonates, especially of i.v. pamidronate. Bisphosphonates may also cause renal insufficiency as a result of tubular toxicity. In order to prevent severe nephrotoxicity clinicians should check urinary protein excretion and renal function regularly in patients who receive long-term treatment with i.v. bisphosphonates. In patients with pre-existing renal impairment (estimated GFR below 30 ml/min), bisphosphonates should be used with caution.

Toxicity of contrast media: an update.

Renal toxicity of iodinated radiocontrast media (contrastinduced nephropathy; CIN) is a major cause of acute renal failure in hospitalised patients. Magnetic resonance imaging (MRI) is applied as an alternative technique but the use of gadolinium (Gd) containing contrast media carries the risk of nephrogenic systemic fibrosis (NSF), a potentially lethal disorder that occurs especially in patients with renal failure. In this article we give an update of the literature on toxicity of radiocontrast media and on preventive measures. Risk of nephrotoxicity of iodinated contrast media can be reduced by identification of high-risk patients. In these patients pre- and post-hydration with isotonic saline should be applied. When there is insufficient time to prehydrate, a short infusion protocol with sodium bicarbonate is preferable. There is a lack of evidence to support the use of oral or intravenous N-acetylcysteine or iso-osmolar contrast media. In order to prevent NSF , linear gadolinium chelates should not be used in patients with an estimated glomerular filtration rate (eGFR) of less than 30 ml/min. In patients with eGFR between 10 and 30 ml/min the small chance of NSF with cyclic Gd-containing chelates must be balanced against the high risk of developing CIN, and the morbidity and mortality associated with the start of dialysis. In patients without residual renal function, the small chance of developing NSF after macrocyclic Gd-enhanced MRI imaging may tip the balance to the use of iodine containing contrast media.

[Guideline 'Precautionary measures for contrast media containing iodine']. / Richtlijn 'Voorzorgsmaatregelen bij jodiumhoudende contrastmiddelen'.

Annually, 0.5-1 million injections of contrast media containing iodine are administered in the Netherlands. Almost all contrast media nowadays are low-osmolar and nonionic. Nevertheless, the development ofcontrast-induced nephropathy is still a relevant clinical problem. Through an initiative by the Radiological Society of the Netherlands and with aid of the Dutch Institute for Healthcare Improvement (CBO), a guideline was conceived for the intravascular use of iodine-containing contrast media, based on recent scientific literature. The guideline defines the risk factors for contrast-induced nephropathy. One of the major risk factors is an impaired renal function. It is important to measure the glomerular filtration rate (GFR) in patients with a possible impaired kidney function, preferably by using the 'Modification of diet in renal disease' (MDRD)-study formula. The key measures for avoidance of contrast nephropathy are: limiting the amount of contrast agent used and to assure good hydration, by infusion of sodium chloride 0.9% 12-16 ml/kg body weight, both prior to and after contrast infusion. If time is limited, intravenous administration of sodium bicarbonate is an option. The guideline recommends discontinuation of metformin use from the day of contrast injection, if the GFR < 60 ml/min/1.73 m2, and to restart metformin 2 days following contrast infusion providing the GFR has not significantly deteriorated. Only in the case of previous moderate or severe adverse reactions to contrast media, prophylaxis with corticosteroids and antihistamines is recommended. Iodine allergy or an atopic condition is not a contraindication for the use of iodine-containing contrast media, and no prophylaxis is required. No specific measures are indicated in case of hyperthyroidism, acute pancreatitis, or phaeochromocytoma. Injection of contrast media is not contraindicated in case of pregnancy or lactation.

The gelatin-derived plasma substitute Gelofusine causes low-molecular-weight proteinuria by decreasing tubular protein reabsorption.

PURPOSE: Proteinuria is frequently encountered in patients in the intensive care unit, most likely as a result of renal tubular cell injury. It has been reported that gelatin-derived plasma substitutes contribute to an increase in renal protein excretion. The aim of this study was to investigate the magnitude and the mechanism of the proteinuric effect of Gelofusine, a modified gelatin. MATERIALS AND METHODS: In six healthy male subjects, renal hemodynamics and urinary protein excretion were measured before and after infusion of 330 mL of Gelofusine. RESULTS: Gelofusine had a minor effect on blood pressure, glomerular filtration rate, effective renal plasma flow, and on urinary excretion of immunoglobulin, and albumin. In contrast, there was a major increase in the urinary excretion of the low-molecular-weight proteins beta2-microglobulin (from 0.06 +/- 0.04 to 43.52 +/- 11.75 microg/min; P <.01) and alpha1-microglobulin (from 11 +/- 8 to 72 +/- 24 microg/min; P <.01). The urinary excretion of N-acetyl-beta-D-glucosaminidase (beta-NAG) remained unchanged, suggesting that there was no significant renal tubular cell injury. CONCLUSIONS: When analyzing proteinuria in patients in the intensive care unit it should be considered that Gelofusine increases the urinary excretion of proteins, in particular those of low molecular weight. This effect is most likely due to competitive inhibition of tubular protein reabsorption.

The renal handling of pepsinogen A isozymogens in man.

Pepsinogen A (PGA) isozymogens are low molecular weight proteins that are present in serum and urine. The differences in the molecular structure of PGA-isozymogens involve only 2-4 amino acid substitutions. In a previous study, performed in 13 subjects only, a remarkable difference between the fractional renal clearances of the main PGA-isozymogens (PGA-3, PGA-4 and PGA-5) has been demonstrated. The aim of the present study was to further investigate these differences in fractional clearance between PGA-isozymogens and to determine whether these differences are caused by differences in glomerular sieving. For this purpose the fractional clearances of PGA-isozymogens were measured in 57 subjects. In accordance with the previous study, the median fractional clearance of PGA-5 (13%) was lower than the median fractional clearance of PGA-4 (17%; p < 0.02) and the median fractional clearance of PGA-4 was lower than the median fractional clearance of PGA-3 (26%; p < 0.001). The glomerular sieving coefficients of PGA-isozymogens were measured in 11 subjects during an elective heart catheterization by means of the fractional renal extraction method. No significant difference between the glomerular sieving coefficients of PGA-isozymogens could be demonstrated, being 0.81 for PGA-3, 0.96 for PGA-4 and 0.84 for PGA-5. It is concluded that the differences in renal handling between PGA-isozymogens must be explained by differences in tubular reabsorption. These differences in tubular reabsorption between PGA-isozymogens support the hypothesis that positively charged amino acid residues of proteins are involved in the tubular protein reabsorption.

Renal handling of insulin and C-peptide in patients with non-insulin-dependent diabetes mellitus.

The kidney is responsible for a considerable part of the clearance of insulin and C-peptide. Two routes are thought to be involved in the renal extraction of insulin and C-peptide from the circulation: (1) glomerular filtration, and (2) uptake by tubular cells from peritubular capillaries. The aim of the present study was to investigate these processes in non-insulin-dependent diabetes mellitus (NIDDM). For this purpose we measured the renal extraction of inulin, insulin, and C-peptide in 12 NIDDM patients and 16 control subjects during elective heart catheterization. In addition, a 24-h urine sample was obtained from all subjects to assess the fractional clearance of the peptides. The total renal extraction of both insulin and C-peptide exceeded the amount that was extracted by filtration, confirming the supposition that both peptides are cleared by an additional mechanism, most probably peritubular uptake. The peritubular uptake of insulin in the NIDDM group was not significantly different from that in the control subjects, whereas the insulin extraction over the legs was significantly lower in NIDDM than in the controls. The peritubular uptake of C-peptide was significantly lower in NIDDM, while the fractional clearance of C-peptide was significantly higher. The latter indicates that the reabsorption of C-peptide from the luminal side of the tubular cell is impaired in diabetes mellitus. It is therefore concluded that urinary C-peptide excretion is not a reliable index for insulin production in NIDDM.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenoceptors on blood cells from patients with primary Raynaud's phenomenon.

1. alpha 2-Adrenoceptors on platelet membranes and beta 2-adrenoceptors on lymphocytes were studied in 24 patients with primary Raynaud's phenomenon and in 24 age- and sex-matched control subjects. In two subgroups, a standardized mental arithmetic test and a finger-cooling test were performed. 2. Baseline blood pressure, heart rate and forearm blood flow did not differ between the two groups. 3. Baseline skin microcirculation (laser Doppler flux) was decreased in primary Raynaud's phenomenon (19 +/- 15 arbitrary units) compared with control subjects (33 +/- 14 arbitrary units) (P less than 0.01). 4. Baseline plasma noradrenaline concentration (2.00 +/- 1.44 versus 1.16 +/- 0.36 nmol/l) and alpha 2-adrenoceptor density (301 +/- 119 versus 210 +/- 82 fmol/mg) were increased in patients with primary Raynaud's phenomenon in comparison with the control subjects. The alpha 2-adrenoceptor density/beta 2-adrenoceptor density ratio in patients with primary Raynaud's phenomenon was, with a value of 0.37 +/- 0.04, higher than in the control subjects, where a value of 0.25 +/- 0.02 was measured (P less than 0.001). Plasma adrenaline concentration, beta 2-adrenoceptor density and the antagonist affinity to both receptor subtypes did not differ between both groups under baseline conditions. 5. Whereas during the finger-cooling test no differences were seen in the responses of the parameters measured, the mental arithmetic test induced an increase in laser Doppler flux in patients with primary Raynaud's phenomenon and a decrease in the control group.(ABSTRACT TRUNCATED AT 250 WORDS)

Tubular reabsorption of pepsinogen isozymogens in man studied by the inhibition of tubular protein reabsorption with dibasic amino acids.

1. The fractional clearances of pepsinogen A (PGA), pepsinogen C (PGC) and the main PGA isozymogens, i.e. PGA-3, PGA-4 and PGA-5, were measured in 13 healthy male volunteers before and during blockade of tubular protein reabsorption by intravenous infusion of either L-arginine hydrochloride (n = 8; 0.5 g h-1 kg-1 body weight) or an equimolar amount of L-lysine hydrochloride (n = 5; 0.44 g h-1 kg-1 body weight). Glomerular filtration rate was measured by a radioisotope method. 2. The fractional baseline clearance of PGC (1 +/- 1%) was lower than that of PGA (20 +/- 10%). In addition, the fractional clearance of the PGA isozymogens appeared to be different: the fractional clearance of PGA-5 (7 +/- 3%) was lower than that of PGA-4 (18 +/- 9%), and the fractional clearance of PGA-4 was lower than that of PGA-3 (30 +/- 10%). These differences in fractional clearance between PGA isozymogens decreased during infusion of both arginine and lysine. 3. Pepsinogens are freely filtered proteins. It can therefore be concluded that the differences in fractional clearance between PGA isozymogens imply differences in tubular reabsorption. This is remarkable as PGA isozymogens are proteins with an almost identical amino acid sequence and electric charge. The disappearance of the differences in tubular reabsorption during arginine and lysine infusion suggests that PGA isozymogens differ in affinity for negatively charged binding sites in the tubular cell membrane. In order to explain the low fractional clearance of PGC compared with that of PGA and the less marked effect of arginine or lysine infusion on the fractional clearance of PGC, an additional PGC-specific binding site has to be postulated.

The effect of acute and chronic protein loading on urinary pepsinogen A excretion.

In 8 healthy male volunteers, urinary excretion (UE) and fractional clearance (FC) of pepsinogen A (PGA), beta 2-microglobulin (beta 2-m) and albumin were measured after 6 days high protein diet (HPD; 2.0 g/kg/day) and compared to values obtained after 6 days low protein diet (LPD; 0.5 g/kg/day). In addition, the effect of an acute protein load (APL; 500 g beef) on these variables were measured. Both chronic and acute protein loading induced a rise in glomerular filtration rate (GFR) of about 10% together with a parallel rise in effective renal plasma flow. UE PGA and FC PGA increased both after HPD (UE PGA 1,707 +/- 1,106 ng/min; FC PGA 23 +/- 12%) as compared to LPD (UE PGA 1,200 +/- 987 ng/min, p less than 0.01; FC PGA 18 +/- 12%, p less than 0.05), and after APL (UE PGA 2,276 +/- 1,389 ng/min; FC PGA 26 +/- 16%) as compared to baseline (UE PGA 1,418 +/- 965 ng/min, p less than 0.02; FC PGA 21 +/- 12%, p less than 0.05). UE and FC of beta 2-m and albumin were not affected by protein loading. As PGA is nearly freely filtered, it is concluded that the increase in fractional PGA clearance reflects a decrease in fractional tubular PGA reabsorption. Our results suggest that an increase in fractional protein clearance after protein loading is not necessarily due to an impaired glomerular permselectivity but represents a decreased fractional tubular reabsorption as a result of a GFR-mediated increase in filtered load without a concomitant increase in tubular reabsorption.