[Show abstract][Hide abstract] ABSTRACT: Tofacitinib is an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis (RA). During the clinical development programme, increases in mean serum creatinine (SCr) of approximately 0.07 mg/dL and 0.08 mg/dL were observed which plateaued early. This study assessed changes in measured glomerular filtration rate (mGFR) with tofacitinib relative to placebo in patients with active RA.
This was a randomised, placebo-controlled, Phase 1 study ( NCT01484561 ). Patients were aged ≥18 years with active RA. Patients were randomised 2:1 to oral tofacitinib 10 mg twice daily (BID) in Period 1 then placebo BID in Period 2 (tofacitinib → placebo); or oral placebo BID in both Periods (placebo → placebo). Change in mGFR was evaluated by iohexol serum clearance at four time points (run-in, pre-dose in Period 1, Period 1 end, and Period 2 end). The primary endpoint was the change in mGFR from baseline to Period 1 end. Secondary endpoints included: change in mGFR at other time points; change in estimated GFR (eGFR; Cockcroft-Gault equation) and SCr; efficacy; and safety.
148 patients were randomised to tofacitinib → placebo (N = 97) or placebo → placebo (N = 51). Baseline characteristics were similar between groups. A reduction of 8% (90% confidence interval [CI]: 2%, 14%) from baseline in adjusted geometric mean mGFR was observed during tofacitinib treatment in Period 1 vs placebo. During Period 2, mean mGFR returned towards baseline during placebo treatment, and there was no difference between the two treatment groups at the end of the study - ratio (tofacitinib → placebo/placebo → placebo) of adjusted geometric mean fold change of mGFR was 1.04 (90% CI: 0.97, 1.11). Post-hoc analyses, focussed on mGFR variability in placebo → placebo patients, were consistent with this conclusion. At study end, similar results were observed for eGFR and SCr. Clinical efficacy and safety were consistent with prior studies.
Increases in mean SCr and decreases in eGFR in tofacitinib-treated patients with RA may occur in parallel with decreases in mean mGFR; mGFR returned towards baseline after tofacitinib discontinuation, with no significant difference vs placebo, even after post-hoc analyses. Safety monitoring will continue in ongoing and future clinical studies and routine pharmacovigilance.
Clinicaltrials.gov NCT01484561 . Registered 30 November 2011.
[Show abstract][Hide abstract] ABSTRACT: The usefulness of estimated glomerular filtration rate may not be restricted to pre-dialysis patients, since we reported that estimated glomerular filtration rate was well correlated with measured total creatinine clearance in peritoneal dialysis patients. To clarify the clinical usefulness of estimated glomerular filtration rate as a parameter for peritoneal dialysis adequacy, we retrospectively surveyed estimated glomerular filtration rate and total creatinine clearance in peritoneal dialysis patients treated at JA Toride Medical Center.
A total of 114 data sets of estimated glomerular filtration rate and total creatinine clearance from 21 PD patients treated at JA Toride Medical Center were collected from November 2010 to October 2011. The patients consisted of 15 men and six women with an average age of 66.6 ± 12.6 years (46-95 years old). The average number of samples was 5.4 ± 1.5 (2 to 7) per patient.
The collected data showed less correlation of estimated glomerular filtration rate and total creatinine clearance (r. = 0.435) than that of a previous cross-sectional study (r. = 0.836). As reported in pre-dialysis patients, the differences between estimated glomerular filtration rate and total creatinine clearance were correlated with total creatinine excretion in urine and PD effluent (r. = 0.821). The differences were also correlated with normalized protein catabolic rate, which was one of the main determinant factors for total creatinine excretion (r. = 0.636). A similar tendency was apparently observed in one patient with poor compliance to diet therapy and fluctuating dietary intake. From the analysis of these data, serum creatinine seemed to fluctuate less possibly due to compensatory capacity of the residual renal function in small solute clearance.
Consequently, estimated glomerular filtration rate was turned out to be a more stable parameter than total creatinine clearance, which might be a desirable feature in long-term follow-up of peritoneal dialysis patients.
[Show abstract][Hide abstract] ABSTRACT: We congratulate the KDIGO (Kidney Disease: Improving Global Outcomes) work group on their comprehensive work in a broad subject area, and agreed with many of the recommendations in their clinical practice guideline on the evaluation and management of chronic kidney disease. We concur with the KDIGO definitions and classification of kidney disease, and welcome the addition of albuminuria categories at all levels of glomerular filtration rate (GFR) , the terminology of G categories rather than stages to describe level of GFR, the division of former stage 3 into new G categories 3a and 3b, and the addition of the underlying diagnosis. We agree with the use of the heat map to illustrate the relative contributions of low GFR and albuminuria to cardiovascular and renal risk, though we felt that the highest risk category was too broad, including as it does people at quite disparate levels of risk. We add an albuminuria category A4 for nephrotic-range proteinuria, and D and T categories for patients on dialysis or with a functioning renal transplant.We recommend target blood pressure of 140/90 mm Hg regardless of diabetes or proteinuria, and against the combination of angiotensin-receptor blockers with angiotensin-converting enzyme inhibitors. We recommend against routine protein restriction. We concur on individualization of HbA1C targets. We do not agree with routine restriction of sodium to less than 2 g/d, instead suggesting reduction of sodium intake in those with high intake (> 3.3 g/d). We suggest screening for anemia only when GFR < 30 mL/min/1.73 m2. We recognize the absence of evidence on appropriate phosphate targets and methods of achieving them, and do not agree with suggestions in this area. In drug dosing, we agree with the recommendation of using absolute clearance (ie, mL/min), calculated from the patient’s estimated GFR (which is normalized to 1.73 m2) and the patient’s actual anthropomorphic body surface area. We agree with referral to a nephrologist when GFR < 30 mL/min/1.73 m2 (and for many other scenarios), but suggest urine albumin-creatinine ratio > 60 mg/mmol or proteinuria > 1 g/d as the referral threshold for proteinuria.
American Journal of Kidney Diseases 11/2014; 65(2). DOI:10.1053/j.ajkd.2014.10.013 · 5.76 Impact Factor
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