SIGNIFICANCE STATEMENT: Reliable prediction tools are needed to personalize treatment in ANCA-associated GN. More than 1500 patients were collated in an international longitudinal study to revise the ANCA kidney risk score. The score showed satisfactory performance, mimicking the original study (Harrell's C=0.779). In the development cohort of 959 patients, no additional parameters aiding the tool were detected, but replacing the GFR with creatinine identified an additional cutoff. The parameter interstitial fibrosis and tubular atrophy was modified to allow wider access, risk points were reweighted, and a fourth risk group was created, improving predictive ability (C=0.831). In the validation, the new model performed similarly well with excellent calibration and discrimination ( n =480, C=0.821). The revised score optimizes prognostication for clinical practice and trials. BACKGROUND: Reliable prediction tools are needed to personalize treatment in ANCA-associated GN. A retrospective international longitudinal cohort was collated to revise the ANCA renal risk score. METHODS: The primary end point was ESKD with patients censored at last follow-up. Cox proportional hazards were used to reweight risk factors. Kaplan-Meier curves, Harrell's C statistic, receiver operating characteristics, and calibration plots were used to assess model performance. RESULTS: Of 1591 patients, 1439 were included in the final analyses, 2:1 randomly allocated per center to development and validation cohorts (52% male, median age 64 years). In the development cohort ( n =959), the ANCA renal risk score was validated and calibrated, and parameters were reinvestigated modifying interstitial fibrosis and tubular atrophy allowing semiquantitative reporting. An additional cutoff for kidney function (K) was identified, and serum creatinine replaced GFR (K0: <250 μ mol/L=0, K1: 250-450 μ mol/L=4, K2: >450 μ mol/L=11 points). The risk points for the percentage of normal glomeruli (N) and interstitial fibrosis and tubular atrophy (T) were reweighted (N0: >25%=0, N1: 10%-25%=4, N2: <10%=7, T0: none/mild or <25%=0, T1: ≥ mild-moderate or ≥25%=3 points), and four risk groups created: low (0-4 points), moderate (5-11), high (12-18), and very high (21). Discrimination was C=0.831, and the 3-year kidney survival was 96%, 79%, 54%, and 19%, respectively. The revised score performed similarly well in the validation cohort with excellent calibration and discrimination ( n =480, C=0.821). CONCLUSIONS: The updated score optimizes clinicopathologic prognostication for clinical practice and trials.
- MeSH
- ANCA-asociované vaskulitidy * diagnóza MeSH
- atrofie MeSH
- fibróza MeSH
- kreatinin MeSH
- ledviny MeSH
- lidé středního věku MeSH
- lidé MeSH
- longitudinální studie MeSH
- protilátky proti cytoplazmě neutrofilů * MeSH
- retrospektivní studie MeSH
- rizikové faktory MeSH
- Check Tag
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
OBJECTIVES: Rituximab is being increasingly prescribed for the treatment of autoimmune glomerular diseases. While it is highly effective for some diseases, the response is less predictable for others, which may be due to differing requirements in terms of the dosing according to the disease type and variations concerning exposure to the drug. METHODS: We compiled novel rituximab dosing schedules according to pharmacokinetic analysis of data gathered from rituximab treated patients in a tertiary referral nephrology centre between May 2020 and June 2023. The population-pharmacokinetic analysis was based on the rituximab dosing, the patients' characteristics, rituximab levels and anti-rituximab antibodies. RESULTS: The analysis, which was based on data from 185 patients, clearly highlighted differing rituximab dosing requirements for patients with ANCA associated vasculitis and minimal change disease compared to those with membranous nephropathy, focal-segmental glomerulosclerosis and lupus nephritis. This corresponded to the good treatment response of the first two diseases and the unreliable efficacy for the others. The model predicts the rituximab pharmacokinetics with high degree of accuracy when body weight, proteinuria, type of glomerulonephritis, treatment length and anti-rituximab antibodies formation are used as covariates. We proposed a dosing schedule with shortened dosing intervals for difficult-to-treat diagnoses with high proteinuria. CONCLUSION: In order to ensure reliable and comparable exposure of rituximab with respect to the full range of glomerular diseases, the dosing schedule should be adjusted for membranous nephropathy, focal-segmental glomerulosclerosis and lupus nephritis. This is largely, but not solely, due to the enhanced level of unselective proteinuria in these diseases.
- MeSH
- biologické modely MeSH
- dospělí MeSH
- glomerulonefritida farmakoterapie MeSH
- lidé středního věku MeSH
- lidé MeSH
- membranózní glomerulonefritida farmakoterapie MeSH
- mladý dospělý MeSH
- rituximab * farmakokinetika aplikace a dávkování terapeutické užití MeSH
- rozvrh dávkování léků MeSH
- senioři MeSH
- výsledek terapie MeSH
- vztah mezi dávkou a účinkem léčiva MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mladý dospělý MeSH
- mužské pohlaví MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
PURPOSE OF REVIEW: Chronic kidney disease (CKD) is associated with a significantly increased risk of cardiovascular disease (CVD). This review summarizes known risk factors, pathophysiological mechanisms, and current therapeutic possibilities, focusing on lipid-lowering therapy in CKD. RECENT FINDINGS: Novel data on lipid-lowering therapy in CKD mainly stem from clinical trials and clinical studies. In addition to traditional CVD risk factors, patients with CKD often present with non-traditional risk factors that include, e.g., anemia, proteinuria, or calcium-phosphate imbalance. Dyslipidemia remains an important contributing CVD risk factor in CKD, although the mechanisms involved differ from the general population. While statins are the most commonly used lipid-lowering therapy in CKD patients, some statins may require dose reduction. Importantly, statins showed diminished beneficial effect on cardiovascular events in patients with severe CKD and hypercholesterolemia despite high CVD risk and effective reduction of LDL cholesterol. Ezetimibe enables the reduction of the dose of statins and their putative toxicity and, in combination with statins, reduces CVD endpoints in CKD patients. The use of novel drugs such as PCSK9 inhibitors is safe in CKD, but their potential to reduce cardiovascular events in CKD needs to be elucidated in future studies.
- MeSH
- anticholesteremika * terapeutické užití MeSH
- chronická renální insuficience * komplikace epidemiologie MeSH
- kardiovaskulární nemoci * epidemiologie etiologie prevence a kontrola MeSH
- LDL-cholesterol MeSH
- lidé MeSH
- proproteinkonvertasa subtilisin/kexin typu 9 MeSH
- rizikové faktory kardiovaskulárních chorob MeSH
- rizikové faktory MeSH
- statiny * terapeutické užití MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- přehledy MeSH
- Publikační typ
- abstrakt z konference MeSH
- Publikační typ
- abstrakt z konference MeSH
BACKGROUND: Amikacin monotherapy is recommended for urinary tract infection (UTI) treatment with multi-resistant pathogens. Even though amikacin efficacy in the treatment of UTIs is dependent on its urinary concentration, there are no robust data proving that sufficiently high urinary concentration is reached in patients with reduced glomerular filtration rate (GFR). METHODS: A prospective study to monitor amikacin penetration into urine of 70 patients [40 males, median (interquartile range) age 70 (65-79) years] with different levels of glomerular filtration decline, including patients treated by dialysis, was conducted. The bactericidal efficacy of amikacin in urine samples has been evaluated. RESULTS: Patients with estimated GFR (eGFR) <30 mL/min had significantly lower median amikacin urinary concentration than patients with eGFR >30 mL/min (89.75 vs 186.0 mg/L, P < .0001; 200.5 vs 830.0 mg/L, P < .0001; and 126.0 vs 408.0 mg/L, P < .0001 for minimal, maximal and minimal together with maximal concentrations, respectively). The amount of amikacin eliminated in the first 10-13 h after dose administration was dependent on eGFR (r2 = 0.6144, P < .0001). The urinary concentration of amikacin in patients treated by dialysis was indirectly proportional to pH of urine. The plasma concentrations of amikacin did not correlate with urinary levels in patients in either of the GFR categories. Microbiological evaluation showed that the critical urinary concentration for efficacy of amikacin during UTI monotherapy in patients treated by dialysis is 100 mg/L. We found that 4 out of 11 patients treated by dialysis did not reach this level during the treatment. CONCLUSION: Systemic administration of amikacin monotherapy in patients treated by dialysis is questionable as the concentrations of amikacin in their urine are often below the threshold of effectivity. Amikacin plasma concentrations are not a major determinant of amikacin concentration in urine, therefore pulse dosing is neither necessary nor safe in patients treated by dialysis, and may cause undesirable toxicity.
- Publikační typ
- časopisecké články MeSH
Heart failure (HF) is life-threatening disease due to electro-mechanical dysfunction associated with hemodynamic overload, while alterations of extracellular matrix (ECM) along with perturbed connexin-43 (Cx43) might be key factors involved. We aimed to explore a dual impact of pressure, and volume overload due to aorto-caval fistula (ACF) on Cx43 and ECM as well as effect of renin-angiotensin blockade. Hypertensive Ren-2 transgenic rats (TGR) and normotensive Hannover Sprague-Dawley rats (HSD) that underwent ACF were treated for 15-weeks with trandolapril or losartan. Blood serum and heart tissue samples of the right (RV) and left ventricles (LV) were used for analyses. ACF-HF increased RV, LV and lung mass in HSD and to lesser extent in TGR, while treatment attenuated it and normalized serum ANP, BNP-45 and TBARS. Cx43 protein and its ser368 variant along with PKCε were lower in TGR vs HSD and suppressed in both rat strains due to ACF but prevented more by trandolapril. Pro-hypertrophic PKCδ, collagen I and hydroxyproline were elevated in TGR and increased due to ACF in both rat strains. While SMAD2/3 and MMP2 levels were lower in TGR vs HSD and reduced due to ACF in both strains. Findings point out the strain-related differences in response to volume overload. Disorders of Cx43 and ECM signalling may contribute not only to HF but also to the formation of arrhythmogenic substrate. There is benefit of treatment with trandolapril and losartan indicating their pleiotropic anti-arrhythmic potential. It may provide novel input to therapy.
- MeSH
- extracelulární matrix MeSH
- hypertenze * MeSH
- konexin 43 genetika MeSH
- krevní tlak MeSH
- krysa rodu rattus MeSH
- losartan farmakologie MeSH
- píštěle * MeSH
- potkani Sprague-Dawley MeSH
- potkani transgenní MeSH
- renin MeSH
- srdeční selhání * MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
The extracellular matrix (ECM) is a highly dynamic structure controlling the proper functioning of heart muscle. ECM remodeling with enhanced collagen deposition due to hemodynamic overload impairs cardiomyocyte adhesion and electrical coupling that contributes to cardiac mechanical dysfunction and arrhythmias. We aimed to explore ECM and connexin-43 (Cx43) signaling pathways in hemodynamically overloaded rat heart as well as the possible implication of angiotensin (1-7) (Ang (1-7)) to prevent/attenuate adverse myocardial remodeling. Male 8-week-old, normotensive Hannover Spraque-Dawley rats (HSD), hypertensive (mRen-2)27 transgenic rats (TGR) and Ang (1-7) transgenic rats (TGR(A1-7)3292) underwent aortocaval fistula (ACF) to produce volume overload. Five weeks later, biometric and heart tissue analyses were performed. Cardiac hypertrophy in response to volume overload was significantly less pronounced in TGR(A1-7)3292 compared to HSD rats. Moreover, a marker of fibrosis hydroxyproline was increased in both ventricles of volume-overloaded TGR while it was reduced in the Ang (1-7) right heart ventricle. The protein level and activity of MMP-2 were reduced in both ventricles of volume-overloaded TGR/TGR(A1-7)3292 compared to HSD. SMAD2/3 protein levels were decreased in the right ventricle of TGR(A1-7)3292 compared to HSD/TGR in response to volume overload. In parallel, Cx43 and pCx43 implicated in electrical coupling were increased in TGR(A1-7)3292 versus HSD/TGR. It can be concluded that Ang (1-7) exhibits cardio-protective and anti-fibrotic potential in conditions of cardiac volume overload.
The specific B-cell depleting anti-CD20 monoclonal antibody rituximab (RTX) is effective in terms of the treatment of various immune-mediated glomerulopathies. The administration of RTX has been shown to be reliable and highly effective particularly in patients with ANCA-associated vasculitis, which is manifested predominantly with non-nephrotic proteinuria. Stable long-term B-cell depletion is usually readily attained in such patients using standard dosing regimens. However, in patients with nephrotic syndrome and non-selective proteinuria, the RTX pharmacokinetics is altered profoundly and RTX does not maintain high enough levels for a sufficiently long period, which may render RTX treatment ineffective. Since complement-derived cytotoxicity is one of the important modes of action of RTX, hypocomplementemia, frequently associated with systemic lupus erythematodes, may act to hamper the efficacy of RTX in the treatment of patients with lupus nephritis. This review provides a description of RTX pharmacokinetics and pharmacodynamics in several selected glomerulopathies, as well as the impact of proteinuria, anti-drug antibodies and other clinical variables on the clearance and volume of distribution of RTX. The impact of plasmapheresis and peritoneal dialysis on the clearance of RTX is also discussed in the paper. A review is provided of the potential association between pharmacokinetic and pharmacodynamic alterations in various kidney-affecting glomerular diseases, the sustainability of B-cell depletion and the clinical efficacy of RTX, with proposals for potential dosing implications. The role of therapeutic drug monitoring in treatment tailoring is also discussed, and various previously tested RTX dosing schedules are compared in terms of their clinical and laboratory treatment responses. Since alternative anti-CD20 molecules may prove effective in RTX unresponsive patients, their pharmacokinetics, pharmacodynamics and current role in the treatment of glomerulopathies are also mentioned.
- MeSH
- antigeny CD20 * MeSH
- lidé MeSH
- monoklonální protilátky MeSH
- nemoci ledvin * MeSH
- proteinurie MeSH
- rituximab terapeutické užití MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- přehledy MeSH
