Actual Glomerular Filtration Rate Research Articles

#968 Impact of the presence of acute kidney injury at the time of renal biopsy on long-term prognosis of IgA nephropathy

Abstract Background and Aims IgA nephropathy is the most common primary glomerular disease and an important cause of end-stage renal disease. Factors such as decreased renal function, persistent proteinuria, hypertension, and older age predict a poor prognosis in IgA nephropathy. Current international prediction tools for IgA nephropathy determine prognosis based on renal function using estimated glomerular filtration rate (eGFR) at the time of kidney biopsy. However, we observed differences in prognosis between patients with and without concurrent acute kidney injury (AKI) at the time of kidney biopsy. Therefore, we aimed to investigate whether renal function at the time of renal biopsy is a suitable indicator for assessing the long-term prognosis of patients with IgA nephropathy with AKI. Method We retrospectively analyzed a total of 185 patients who were diagnosed with IgA nephropathy between 2009 and 2016 at the Gyeongsang National University Hospital. Clinical data, including pathological, demographic, and laboratory findings of patients, were used. We divided the patients into two groups based on the progression rate of kidney function per year, ‘Progression’ or ‘Non-progression group’. AKI was defined according to the KDIGO Clinical Practice Guidelines. Results Among a total of 185 patients, 113 showed a sustained decline in eGFR of more than 1 ml/min/1.73 m2 per year. The mean eGFR level of the non-progression group was significantly lower than that of the progression group (p = 0.027). The percentage of patients with AKI in the non-progression group was 25%, which was higher than that in the progression group (p < 0.001). The two groups had no significant differences in comorbid disease, medications at kidney biopsy, and treatment. In sub-analysis, the mean eGFR at kidney biopsy was significantly lower than that in the non-AKI group (p < 0.001). The mean estimated risk, calculated by the international prediction tool, was significantly lower in the AKI group. On the other hand, the mean rate of actual GFR decline per year was higher in the non-AKI group (p < 0.001). Conclusion We confirmed a discrepancy between the predicted prognosis and the actual decline in GFR, particularly in the AKI group. We found that AKI at the time of renal biopsy was a good long-term prognostic factor. There is a need to conduct further research to confirm whether this is due to early detection of AKI and early active treatment.

#501 Evaluation of the accuracy of serum creatinine-based GFR calculations across the different levels of renal function among Filipinos

Abstract Background and Aims Chronic kidney disease (CKD) is a worldwide health concern which continues to increase in prevalence. Early studies have evaluated kidney function by measuring serum creatinine (sCr) and/or the estimated glomerular filtration rate (eGFR). To date, there are limited studies that correlate nuclear GFR scans and eGFR by equations that include the Cockroft-Gault (CG), Modification of Diet in Renal Disease (MDRD), and Chronic Kidney Disease Epidemiology Collaboration equation (CKD-EPI) 2021 in Asians, specifically in a Filipino population. This study aims to compare the accuracy of GFR scan results and GFR estimated from the formulas across different levels of kidney functions, age groups, gender, and co-morbidities among a Filipino subset. Method A cross-sectional study was done among 2986 patients who underwent Nuclear GFR scan in a single kidney center. Results obtained were compared to estimated GFR results. Weighted Kappa and Bland-Altman Analyses were used to test for agreement between the measured and estimated GFR results. Results Absolute GFR values derived from the three equations demonstrated moderate reliability with results from nuclear scan when intraclass correlation coefficients were calculated with CKD-EPI 2021 being the highest. When further categorized into GFR levels, there was substantial level of agreement between each equation and GFR scan, with all weighted kappa coefficients being at least 0.700 with CG having the highest result (Table 1). Furthermore, when subgroup analysis was done according to age group, gender, and comorbidities, CG was found to be the most accurate per category (Table 2). Conclusion CKD-EPI 2021 was the most accurate in the actual GFR values however we cannot fully eliminate the utility of CG due to its categorical accuracy and in monitoring the deterioration of renal function.

Comparing Estimated and Measured Glomerular Filtration Rate in Children with Posterior Urethral Valve.

Posterior urethral valve (PUV) is obstructive uropathy that may lead to chronic kidney disease (CKD) and end-stage renal disease (ESRD) in children. Glomerular filtration rate (GFR) measurement remains the gold standard for renal function measurement. However, due to its less availability and cumbersome, it is not commonly used, and GFR is estimated utilizing various endogenous filtration markers. This study includes pediatric patients with PUV. We aimed to compare the measured GFR (mGFR) with various creatinine-based estimated GFR methods (eGFR). A single-center retrospective study included 62 treated cases of PUV, postvalve fulguration. The mGFR measured by 99mTc-diethylenetriaminepentaacetate in vitro method and compared with eight eGFR (Schwartz, Cockcroft-Gault [CG], Counahan-Barratt [CB], CKD Epidemiology Collaboration [CKD-EPI], full-age spectrum [FAS] age, FAS height (FAS Ht), Schwartz-Lyon [SL], and Ht independent). Patients were subdivided into different CKD grades and compared with various eGFR. PUV is a common cause of CKD in children and needs special consideration as there is growth retardation associated with it. It decreases creatinine production and thus fallacies in eGFR measurement. There is a requisite to identify and closely monitor the subset of patients with baseline decreased renal function and therefore at risk of developing ESRD. A total of 62 patients were included. Mean age and serum creatinine levels were 8.02 ± 5.53 years and 1.15 ± 0.95 mg/dl (range: 0.4-4.5), respectively. The mean mGFR was 61.6 ± 31.80 mL/min/1.73 m2 and a positive variable correlation was 0.46-0.77 between mGFR and eGFR. Based on mGFR, there were 14 (22.6%), 21 (33.8%), 13 (20.9%), 9 (14.5%), and 5 (8.1%) patients in Grades I-V, respectively. The correct classification of the CKD grades was noted in 25 (40.3%), 16 (25.8%), 32 (51.6%), 16 (25.8%), 25 (40.3%), 27 (43.5%), 26 (41.9%), and 28 (45.2%) patients by Schwartz, CG, CB, CKD-EPI, FAS age, FAS Ht, SL, and Ht-independent equation. The eGFR overestimates GFR at the lower level and underestimates at higher levels. Our results confirm the considerable limitations of various creatinine-based clearance methods for estimating actual GFR. The creatinine clearance-based eGFR should not replace the measurement of the GFR. An initial measure of the mGFR followed by serial follow-up with the eGFR equation may be done. The most accurate eGFR equations are CB for Grade II, SL or Ht independent for Grade III, FAS age for Grade IV, and SL for Grade V CKD.

POS-230 COMPARISON OF MEASURED GLOMERULAR FILTRATION RATE BY PLASMA IOHEXOL CLEARANCE WITH EXISTING EQUATIONS OF ESTIMATING GLOMERULAR FILTRATION RATE IN INDIAN SUBJECTS

Glomerular filtration rate (GFR) is a basis of diagnosis and severity of renal diseases. Currently used estimating GFR equations are ethnicity- specific and have not been validated in Indian population. We evaluated the performance of the existing eGFR equations for assessment of GFR in Indians using plasma clearance of Iohexol method. We measured GFR in 208 subjects who were being evaluated as healthy prospective kidney donors (HPKDs) or diagnosed as chronic kidney disease (CKD). The demographic details, anthropometric measurements and clinical data were recorded and baseline blood sample was collected. 3-5ml Iohexol was intravenously injected and blood sampling was done at 60, 120, 180 and 240 mins. The Iohexol were analysed using UHPLC. Serum creatinine was measured by Jaffe’s kinetic Assays and serum Cystatin C using ELISA kit. The GFR was measured by plasma disappearance rate of Iohexol. The dietary protein intake was measured using 24-hour diet recall method. The precision and accuracy of estimating GFR equations was calculated against measured GFR. The bias was expressed as mean difference between measured GFR and estimated GFR and precision was expressed as 95% confidence interval of bias. The accuracy (P30) was calculated as number of subjects with eGFR within ±30% of mGFR. Study participants with mean age 48.4±11.1 years included 130 CKD patients and 78 prospective renal donors. 52% were male and half of the total subjects were vegetarian. The average daily protein intake was 49.9±14.0 g/day. The mean mGFR was 49.0±25.0 ml/min/1.73m2. The mean estimated GFR was 64.6±36.1 ml/min/1.73m2, 46.9±22.2 ml/min/1.73m2and 64.1±40.7 ml/min/1.73m2by CKD-EPIcr, CKD-EPIcys and MDRD, respectively. Barring CKD-EPIcys equation, a significant difference was observed between mGFR and other two eGFR equations (CKD-EPIcr: p<0.001 and MDRD: p<0.001). The mean bias was -15.6±22.4 ml/min/1.73m2(95% CI: -18.6 to -12.5), 2.1±16.8 ml/min/1.73m2(95% CI: -0.1 to 4.4) and -15.1±26.4 ml/min/1.73m2 (95% CI: -18.7 to -11.8) for CKD-EPIcr, CKD-EPIcys and MDRD equations. The P30 was 46.2% for CKD-EPIcr, 57.7% for CKD-EPIcys and 45.2% for MDRD equation. When data were stratified by CKD and HPKD groups, the mean mGFR was 35.1±14.4 ml/min/1.73m2 in CKD and 72.3±21.4 in HPKD. 32% of HPKDs had measured GFR <60ml/min/1.73m2. The mean bias for CKD-EPICr, CKD-EPICys and MDRD were -5.6±14.4 ml/min/1.73m2 (95%CI: -8.1 to -3.1), 1.6±12.9 ml/min/1.73m2 (95%CI: -0.62to 3.9) and -3.2 ± 14.5 ml/min/1.73m2 (95%CI: -5.7 to -0.6) in CKD patients and it was -32.2±23.6 ml/min/1.73m2(95% CI: -37.4 to -26.8), 3.0±21.9 ml/min/1.73m2 (95% CI: -1.9 to 7.9) and -35.0±29.9 ml/min/1.73m2 (95% CI: -41.7 to -28.3 in HPKD. In CKD group, P30 for CKD-EPIcr, CKD-EPICys and MDRD was 53.8%, 51.5% and 55.3% whereas it was 33.3%, 67.9% and 28.2% in HPKDs. Creatinine-based eGFR equations overestimated GFR. However, eGFR by CKD-EPIcys was close to mGFR; exhibited lowest bias and highest accuracy. The accuracy of eGFR equations against mGFR in Indians will become clear in future study in healthy general population to assess the actual GFR.

Abstract 3015: Tucatinib inhibits creatinine and metformin renal tubule secretion but has no effect on renal function (GFR)

Abstract Background: Tucatinib (TUC) is a potent, highly selective investigational HER2 tyrosine kinase inhibitor in development for treatment of patients with HER2+ metastatic breast cancer (MBC). In HER2CLIMB (H2C), a pivotal study of patients with HER2+ MBC, a modest transient, reversible increase in serum creatinine (SCr) levels was observed in patients who received TUC. Similarly, in a study with healthy volunteers, SCr increased after 300 mg BID TUC and returned to baseline levels after TUC discontinuation. Clinically, SCr is used as a biomarker for glomerular filtration rate (GFR) and is routinely measured to monitor for potential renal injury. However, SCr renal elimination also depends on the kidney transporters OCT2 (uptake), MATE1 (efflux) and MATE2-K (efflux). Inhibition of OCT2 and MATE1/2-K has been associated with SCr increases in the absence of kidney damage (e.g., abemaciclib). In vitro assessments and a clinical study were performed to assess the impact of TUC on OCT2 and MATE1/2-K-mediated transport. Methods: Inhibition of OCT2, MATE1, and MATE2-K-mediated transport by TUC was estimated in transfected MDCK-II cells using creatinine and metformin (MF), a sensitive OCT2 and MATE1/2-K substrate used to quantify transport inhibition in vivo, as probe substrates. Subsequently, a single-arm drug-drug interaction study was performed in 17 healthy volunteers to evaluate the effects of TUC on MF PK. MF (850 mg, PO) was administered in the absence and presence of TUC (300 mg BID, PO). Iohexol was administered to calculate actual GFR (aGFR) in the absence and presence of TUC. Plasma (iohexol, MF and TUC) and urine (MF) samples were collected for PK analysis; drug concentrations were measured using validated LC-MS/MS methods. Serum and urine creatinine levels were also measured. Results: In MDCK II cells, TUC inhibited creatinine transport by OCT2 (IC50 = 0.107 µM) and MATE1 (IC50 = 0.086 µM) and MF transport by MATE1 (IC50 = 0.340 µM) and MATE2-K (IC50 = 0.135 µM), but not by OCT2 (IC50 = 14.7 µM). Using these IC50 values, physiologically-based pharmacokinetic (PBPK) model simulations predicted a 1.16 to 1.35-fold increase of MF exposure in the presence of TUC. Consistent with the PBPK prediction, in healthy volunteers MF exposure (AUCinf) increased ~1.4-fold and renal clearance decreased from 29.99 L/h to 17.64 L/h in the presence of TUC with no effect on MF Cmax. Iohexol clearance was unaffected in the presence of TUC indicating no change in aGFR. SCr increased in the presence of TUC and returned to baseline 8 days after TUC discontinuation. Conclusions: Together, these data demonstrate that the observed SCr increase in clinical studies with TUC is due to inhibition of tubular secretion of creatinine via OCT2 and MATE1 and not due to an effect on kidney function. An alternative, non-creatinine-based measure of renal function should be considered for tucatinib. Citation Format: Ariel R. Topletz-Erickson, Anthony Lee, JoAl Mayor, Evelyn Rustia, Layth Abdulrasool, Luke Walker, Christopher J. Endres. Tucatinib inhibits creatinine and metformin renal tubule secretion but has no effect on renal function (GFR) [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3015.

Analysis of carboplatin dosing in patients with a glomerular filtration rate greater than 125 mL/min: To cap or not to cap? A retrospective analysis and review.

The use of the Calvert formula to calculate carboplatin doses allows clinicians to achieve the appropriate carboplatin area under the concentration (AUC) curve. Thrombocytopenia is the dose limiting toxicity of carboplatin and optimizing AUC minimizes the risk of thrombocytopenia. Carboplatin clearance directly correlates with glomerular filtration rate (GFR) and, therefore, an accurate estimation of the renal function is needed. The Calvert formula was designed using the GFR measured by 51Cr-EDTA; however, many clinicians substitute estimated creatinine clearance (CrCl) as calculated by the Cockcroft-Gault (C-G) equation. The potential for overestimating AUC occurs when clinicians substitute actual weight in obese patients or use a low serum creatinine when calculating C-G estimated CrCl. In 2010, the National Cancer Institute recommended the GFR value within the Calvert formula should not exceed 125 mL/min, thereby capping the carboplatin dose. However, there are studies demonstrating that certain patients' actual GFR values do exceed 125 mL/min. Therefore, capping the carboplatin dose in these patients may lead to underestimating the carboplatin AUC. A single-center, retrospective study was performed to evaluate the change in platelet count pre- and post-carboplatin exposure in patients with C-G estimated CrCl greater than 125 mL/min receiving capped versus uncapped carboplatin doses. A review of carboplatin dosing strategies is also presented. This study indicated there was a larger mean difference in pre- and post-platelet count in patients receiving uncapped carboplatin compared to patients receiving capped carboplatin with no differences in toxicities. Dose capping this patient population will likely lead to a lower AUC rather than the intended AUC target, which could ultimately lead to substandard outcomes.

25. Royal free hospital cirrhosis GFR is not better than creatinine-based equations in predicting mortality and need for renal replacement therapy

Background and Aims: Acute kidney injury (AKI) among cirrhotic patients carries poor prognosis. Various eGFR equations tend to over-estimate GFR in cirrhotics. Royal Free Hospital has developed new model for GFR assessment, which is supposedly close to measured GFR. We aim to evaluate the performance of various GFR equations, to predict the in-hospital mortality and requirement of Renal replacement therapy (RRT). Methods: From April 2017 to March 2018, consecutive cirrhotic patients with AKI admitted in ICU were included. Patients with CKD and ACLF were excluded. e- GFR was calculated using CKD-EPI, MDRD-4, MDRD-6 equations and Royal Free Hospital cirrhosis GFR (RFHC GFR) equation. In-hospital mortality and requirement of RRT was evaluated using ROC curve. Results: 120 patients [88.2% male, mean age 48.5 years ± 10.7 (SD)] with mean CTP score 10.84 ± 1.84 and mean MELD 27.8 ± 7.4 were included. There were 80.3%, 17.1% and 2.6% of patients in AKIN Stage I, Stage II and Stage III respectively. In-hospital mortality was 36.6%. 56.8% among non-survival group and 1.3% among survival group underwent RRT. Mean eGFR by RFHC GFR (18.36 ± 7.18 ml/min/1.73m2) was significantly lower than CKD-EPI (42.68 ± 18.88), MDRD4 (39.97 ± 16 .17) and MDRD6 (31.36 ± 13.64). AUROC failed to show significant differences among various equation in predicting the in-hospital mortality (CKD-EPI: 60.0%, MDRD4: 60.4%, MDRD6: 61.3%, RFHC GFR: 59.6%; p > 0.05) and requirement of RRT (CKD-EPI: 66.3%, MDRD4: 67.2%, MDRD6: 67.8%, RFHC GFR: 65.5%). Conclusions: Though the Royal free hospital cirrhosis GFR equation might be lowest and closest to the actual GFR, none of the equations failed to show superiority over other in predicting the in-hospital mortality and requirement of RRT among critically ill cirrhotic patients with AKI. The authors have none to declare.

The Case | Labile creatinine levels in a patient with breast cancer

The Case | Labile creatinine levels in a patient with breast cancer

Validation of 3D volumetric-based renal function prediction calculator for nephron sparing surgery.

To evaluate a recently published volume-based renal function prediction calculator intended to be used in small renal mass surgical counseling. Retrospective data collection included three-dimensional calculation of renal mass and parenchyma of patients who have undergone extirpative therapy. The predicted glomerular filtration rate (GFR) was calculated using the online calculator. The predicted GFR was compared with the actual 6-month GFR. The Pearson correlation coefficient, paired t test and root-mean-square error (RMSE) are utilized for statistical analysis. After institutional review board approval, three institutions provided data for analysis. After patients with renal mass size >300cc, renal size >400cc or preoperative CKD ≥stage 3 had been excluded, we retrospectively analyzed data from 136 patients. The median mass volume was 22.2cc (IQR 7-49). In multiple linear regression analysis, the most significant variables predicting postoperative GFR were partial versus radical nephrectomy and preoperative GFR with an overall R2 of .68 (F=26.13, P<.001). The predicted GFR was 75.4mL/min/1.73m2 compared to an actual GFR of 70.7mL/min/1.73m2 (P<.001, paired t test). The predicted GFR was highly correlated with the actual postoperative GFR at 6months (Pearson correlation, r=.65, P<.001). RMSE of the validation cohort was 16.87. The predictive tool to determine renal function benefit of nephron sparing surgery compared to radical nephrectomy online calculator effectively predicts GFR and could potentially be used to help urologists and patients discuss renal function prior to extirpative renal surgery.

Rationale and clinical utility of the darunavir-cobicistat combination in the treatment of HIV/AIDS.

This article is to provide an update overview of cobicistat (COBI)-boosted darunavir in response to its recent approval by the US Food and Drug Administration, and inclusion as an alternative first-line regime in the 2015 treatment guidelines in the US. COBI is a relatively new non-antiretroviral cytochrome P450 3A inhibitor or pharmacoenhancer. The rationale behind COBI development was to provide an alternative to ritonavir (RTV) as a protease inhibitor pharmacoenhancer, due to associated adverse events with short- and long-term RTV use, such as gastrointestinal intolerability, drug–drug interactions, insulin resistance, lipodystrophy, and hyperlipidemia. Although in vitro studies suggest that COBI may result in a lower incidence of undesired drug–drug interactions and lipid-associated disorders than RTV, not all Phase III studies have well addressed these issues, and the data are limited. However, Phase III studies have demonstrated tolerability, noninferiority, and bioequivalence of COBI compared to RTV. Two main advantages of COBI over RTV-containing regimes have been noted as follows: 1) COBI has no anti-HIV activity; therefore, resistance to COBI as a booster in addition to protease inhibitor resistance is of little concern, allowing for COBI-containing regimes in future. 2) COBI’s solubility and dissolution rate allow for co-formulated/fixed-dose combination products. Nonetheless, prior to initiating COBI-containing treatment regimens, the following should be considered: 1) COBI may increase serum creatinine levels and reduce estimated glomerular filtration rate (GFR) without affecting actual GFR; 2) potential drug–drug interaction data are insufficient, warranting caution when initiating COBI in conjunction with concomitant medication or in individuals with multiple comorbidities; 3) food plays a pivotal role in boosting darunavir exposure, warranting caution and patient education on the importance of taking COBI-containing regimens with appropriate amounts of food; and 4) data on the success of COBI-containing regimens in treatment-experienced patients are limited.

Efficacy, safety, and patient acceptability of elvitegravir/cobicistat/emtricitabine/tenofovir in the treatment of HIV/AIDS.

The fixed-dose combination (FDC) elvitegravir/cobicistat/emtricitabine/tenofovir (EVG/c/FTC/TDF) is a once-daily, single-tablet regimen containing an integrase strand transfer inhibitor and a pharmacoenhancer (cobicistat) associated with two nucleos(t)ide reverse transcriptase inhibitors. It is approved as the preferred regimen and as the first-line combined antiretroviral therapy in treatment-naïve patients with HIV infection. Two large trials, 102-Study and 103-Study, demonstrated that EVG/c/FTC/TDF was not inferior to efavirenz/FTC/TDF and ritonavir-boosted atazanavir in association with FTC/TDF, in terms of virological suppression and immunological reconstitution through week 144. Also, simplification arms containing EVG/c/FTC/TDF reached noninferiority in comparison with a nonnucleoside reverse transcriptase inhibitor, or a protease inhibitor, or a raltegravir-based regimen. Furthermore, EVG/c/FTC/TDF exhibited an excellent tolerability profile, with a safer lipid profile, and despite the indication of its use in subjects with an estimated creatinine clearance >70 mL/min, recent data demonstrated that EVG/c/FTC/TDF determined a reduction in estimated glomerular filtration rate (GFR) but not a reduction of actual GFR. Moreover, in a cohort of naïve patients with pretreatment mild-to-moderate renal impairment, GFR decrease was noted as early at week 2, after which it generally stabilized and was nonprogressive through week 48. The FDC’s efficacy and good tolerability enable EVG/c/FTC/TDF to meet the patients’ needs, improving adherence and quality of life, which are among the most important factors affecting the therapeutic efficacy of an antiretroviral regimen. This paper describes the evidence making EVG/c/FTC/TDF a new therapeutic opportunity for different HIV-infected patients.

Intravenous fenoldopam for early acute kidney injury after liver transplantation.

Acute kidney injury remains a serious complication after orthotopic liver transplantation. To date, several 'renal-protective' agents have been explored in this setting but with conflicting and disappointing results. Therefore, our aim is to evaluate the effects of fenoldopam in liver transplant patients with an established renal injury. In this prospective study, intravenous fenoldopam 0.1 µg/kg/min was administered to consecutive liver transplant patients with postoperative (within 7 days from surgery) stage 2 acute kidney injury (AKI) according to the Acute Kidney Injury Network classification. Actual glomerular filtration rate (GFR; calculated by the iohexol plasma clearance), serum creatinine (SCr) and cystatin C (SCyC) were used to assess the effect of the medication on the patients. During the study, 295 patients underwent liver transplant. Fifty-one patients (17.6%) met the inclusion criteria and the data from 48 patients were analysed. SCr and SCyC levels decreased (p < 0.001 after 48 h; p < 0.0001 after 72 h) and GFR increased (p < 0.001 after 24 h; p < 0.0001 after 72 h). When compared to a cohort of comparable patients with AKI from our historical series, the patients in the present study showed better SCr and SCyC levels. It was not necessary to discontinue the infusion of fenoldopam in any patient because of the occurrence of adverse events potentially attributable to it. We showed that fenoldopam was capable of improving some renal function parameters in postoperative liver transplantation patients with on-going AKI. This preliminary study now sets the stage for a multicenter, randomized, placebo-controlled trial in order to provide definite evidence.

Switching from ritonavir to cobicistat in HIV patients with renal impairment who are virologically suppressed on a protease inhibitor.

IntroductionCobicistat (COBI) is a pharmacoenhancer and one of the components of ECF/TDF (elvitegravir/cobicistat/emtricitabine/tenofovir DF), which is approved in treatment-naïve HIV patients with creatinine clearance (CrCl) ≥70 mL/min. Study 118 assessed the renal safety of COBI-containing regimens in HIV patients with mild to moderate renal impairment.Material and MethodsPhase 3, open label study in HIV-1-infected patients with CrCl 50–89 mL/min who are virologically suppressed on a stable regimen containing ritonavir (RTV)-boosted atazanavir (ATV) or darunavir (DRV). Patients switched RTV to COBI, while keeping the rest of their regimen unchanged. We present the 96-week (Wk) data.ResultsSeventy-three patients were enrolled. Mean age was 54 years; male 82%; white 77%; hypertension 38%; diabetes 18%; baseline proteinuria (≥trace) 51%; median CrCl 71 mL/min (range: 42–98). At Wk 96, 89% maintained virologic suppression (95% CI 77.4–95.8%). No emergent resistance developed. Reductions in CrCl (median [IQR]) were observed as early as Wk 2, after which they were nonprogressive through Wk 96 (Wk 48: −3.8 [−9–0.8]; Wk 96: −5.0 [−13.0–0.1]). Changes in CrCl by baseline CrCl (<70 vs ≥70) at Wk 96 were: −3.1 [−5.1–0.5] vs −7.6 [−15.2 to −3.6], respectively. Cystatin C-based eGFR remained stable through Wk 96 (median [IQR]: −2.8 [−7.4–8.9 mL/min/1.73 m2). Actual GFR assessment using CLiohexol (n=14) was unaffected over 24 Wks (median at baseline: 82.5, median changes from baseline at Wks 2, 4, and 24: 1.6, 7.0, −4.1 mL/min, respectively). Three renal discontinuations occurred (two worsening CrCl and one proteinuria/hematuria); none had proximal renal tubulopathy [PRT]. No patient had laboratory evidence of PRT (>1 confirmed renal laboratory abnormalities [increase in serum Cr≥0.4 mg/dL, ≥2-grade increase in proteinuria,≥1-grade increase in normoglycemic glycosuria or hypophosphatemia]).ConclusionsIn HIV-infected patients with CrCl 50–89 mL/min, on ATV- or DRV-based regimen switching to COBI from RTV, demonstrated that COBI was well tolerated with no cases of PRT through 96 Wks. The renal safety profile of COBI in patients with mild to moderate renal impairment was consistent with the long-term data in patients without renal impairment (CrCl≥70 mL/min) from the phase 3 studies of COBI-containing regimens.

Antiretrovirals and the kidney in current clinical practice: renal pharmacokinetics, alterations of renal function and renal toxicity.

Assessment of renal function in HIV-positive patients is of increasing importance in the context of ageing and associated comorbidities. Exposure to nephrotoxic medications is widespread, and several commonly used antiretroviral drugs have nephrotoxic potential. Moreover, specific antiretrovirals inhibit renal tubular transporters resulting in the potential for drug-drug interactions as well as increases in serum creatinine concentrations, which affect estimates of glomerular filtration rate in the absence of changes in actual glomerular filtration rate. This review explores the effects of antiretroviral therapy on the kidney and offers an understanding of mechanisms that lead to apparent and real changes in renal function.

Cost-Effectiveness of Tolvaptan in Autosomal Dominant Polycystic Kidney Disease

Letters21 January 2014Cost-Effectiveness of Tolvaptan in Autosomal Dominant Polycystic Kidney DiseaseJames Lineen, MB BCh, MSc and David M.J. Naimark, MD, MSc, on behalf of the Sunnybrook Nephrology Journal ClubJames Lineen, MB BCh, MScFrom Sunnybrook Health Sciences Centre and Institute of Health Policy, Management, and Evaluation, University of Toronto, Toronto, Ontario, Canada.Search for more papers by this author and David M.J. Naimark, MD, MScFrom Sunnybrook Health Sciences Centre and Institute of Health Policy, Management, and Evaluation, University of Toronto, Toronto, Ontario, Canada.Search for more papers by this author, on behalf of the Sunnybrook Nephrology Journal ClubSearch for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/L14-5001-5 SectionsAboutFull TextPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail TO THE EDITOR:Erickson and colleagues (1) have published an elegant Markov-based cost-effectiveness analysis that extends the results of the TEMPO (Tolvaptan Efficacy and Safety in Management of Autosomal Dominant Polycystic Kidney Disease and Its Outcomes) trial (2) of tolvaptan for the treatment of adult autosomal dominant polycystic kidney disease (ADPKD). The authors indicate that a key input parameter was the change in estimated glomerular filtration rate (eGFR) in patients who would or would not receive chronic tolvaptan therapy. In fact, the parameter that was modeled was the change in the actual GFR. However, because the eGFR is a nonlinear ...

Modulating kidney transplant interstitial fibrosis and tubular atrophy: is the RAAS an important target?

In follow-up to a recently published randomized controlled clinical trial, Issa et al. provide evidence that systemic activity and physiological responsiveness of the renin aldosterone angiotensin system (RAAS) are well within normal limits in most kidney recipients during the first 5 years post-transplant. Implications of the results include the need to better understand intra-renal RAAS activity in transplanted kidneys and to identify patients in which the graft-protective effects of RAAS blockade are most relevant.

Cobicistat: A Review of Its Use as a Pharmacokinetic Enhancer of Atazanavir and Darunavir in Patients with HIV-1 Infection

Cobicistat (Tybost™) is a mechanism-based inhibitor of cytochrome P450 (CYP) 3A enzymes that is indicated in the EU as a pharmacokinetic enhancer (i.e. booster) of the HIV-1 protease inhibitors (PIs) atazanavir and darunavir in adults. Cobicistat has a lower potential for off-target drug interactions than the standard boosting agent ritonavir, due to its more selective inhibition of CYP3A and lower likelihood for enzymatic induction, and is devoid of anti-HIV activity. When used to boost darunavir or atazanavir in healthy volunteers, oral cobicistat 150 mg once daily provided bioequivalent PI exposure to that seen with oral ritonavir 100 mg once daily (i.e. low-dose ritonavir). Moreover, in treatment-naïve adults infected with HIV-1 participating in a large, double-blind, phase III trial, an atazanavir-based antiretroviral regimen boosted with cobicistat 150 mg once daily provided a high rate of virological suppression after 48 weeks of therapy that was noninferior to that seen with low-dose ritonavir boosting. Cobicistat was generally well tolerated in this study, with a tolerability profile similar to that of ritonavir. Cobicistat may increase serum creatinine levels (possibly via inhibition of proximal renal tubular cell transporters) and thus reduce estimated glomerular filtration rate (GFR), although it does not appear to affect actual GFR. The drug is more soluble than ritonavir, making coformulation easier, and fixed-dose formulations combining cobicistat with darunavir and atazanavir are in development. Thus, cobicistat is an emerging alternative to ritonavir for the pharmacokinetic enhancement of PIs in adults with HIV-1 infection.

Cystatin C – More than a filtration marker?

A reduced glomerular filtration rate (GFR) is a strong indepen-dent predictor of all-cause and cardiovascular mortality, and isconsidered by many to confer a cardiovascular risk roughly equiv-alent to that of a previous myocardial infarction [1,2]. In routineclinical practice, direct measurement of actual GFR is impracticaland is estimated based on the circulating concentration of anendogenous marker, usually creatinine. Since the original obser-vation bySimonsenet al. in 1985 [3], of a strong inverse correlationbetween serum cystatin C concentration and GFR, interest in thisprotein as an alternative to creatinine-based estimates of GFR(eGFR

FRI0394 Efficacy and safety of canakinumab in gouty arthritis patients with chronic kidney disease stage ≥3

BackgroundMajority of gouty arthritis (GA) patients (pts) have comorbidities. Chronic kidney disease (CKD) can limit treatment options due to intolerance and contraindications to available therapies. Canakinumab, a fully human monoclonal...

GFR Estimating Equations

The application of serum creatinine and cystatin C in patients with CKD has been limited to using estimated glomerular filtration rate (eGFR). Criteria for choosing the best GFR estimating equation are 1) accuracy in estimating measured GFR, 2) optimal discrimination of clinical outcomes, and 3) association with CKD risk factors and outcomes similar to that of measured GFR. Notably, these criteria are often not in agreement; and while the last criterion is the most important, it has been widely overlooked. The primary problem with eGFR is that the non-GFR determinants of serum creatinine and cystatin C, as well as their surrogates (age, sex, and race), associate with CKD risk factors and outcomes. This leads to a distorted understanding of CKD, though eGFR based on serum creatinine appears to be less biased than eGFR based on cystatin C. Because of this problem, the use of eGFR should be limited to settings where knowing actual GFR is relevant and eGFR is more informative about GFR than serum creatinine or cystatin C alone. Such settings include staging CKD severity by GFR and dosing medications cleared by glomerular filtration. Alternatively, the diagnosis of CKD, the longitudinal progression of CKD, and prognostic models for CKD are settings where serum creatinine and cystatin C can be better applied and interpreted without eGFR.