Causal relationship between basal metabolic rate and kidney function: a bidirectional two-sample mendelian randomization study.

Background: The relationship between basal metabolic rate (BMR) and Chronic kidney disease (CKD) remains unclear and controversial. In this study, we investigated the causal role of BMR in renal injury, and inversely, whether altered renal function causes changes in BMR. Methods: In this two-sample mendelian randomization (MR) study, Genetic data were accessed from published genome-wide association studies (GWAS) for BMR ((n = 454,874) and indices of renal function, i.e. estimated glomerular filtration rate (eGFR) based on creatinine (n =1, 004, 040), CKD (n=480, 698), and blood urea nitrogen (BUN) (n =852, 678) in European. The inverse variance weighted (IVW) random-effects MR method serves as the main analysis, accompanied by several sensitivity MR analyses. We also performed a reverse MR to explore the causal effects of the above indices of renal function on the BMR. Results: We found that genetically predicted BMR was negatively related to eGFR, (ß= -0.032, P = 4.95*10-12). Similar results were obtained using the MR-Egger (ß= -0.040, P = 0.002), weighted median (ß= -0.04, P= 5.35×10-11) and weighted mode method (ß= -0.05, P=9.92×10-7). Higher BMR had a causal effect on an increased risk of CKD (OR =1.36, 95% CI = 1.11-1.66, P =0.003). In reverse MR, lower eGFR was related to higher BMR (ß= -0.64, P = 2.32×10-6, IVW analysis). Bidirectional MR supports no causal association was observed between BMR and BUN. Sensitivity analyses confirmed these findings, indicating the robustness of the results. Conclusion: Genetically predicted high BMR is associated with impaired kidney function. Conversely, genetically predicted decreased eGFR is associated with higher BMR.

Association of BKV viremia and nephropathy with adverse alloimmune outcomes in kidney transplant recipients.

BACKGROUND: Immunosuppression reduction for BK polyoma virus (BKV) must be balanced against risk of adverse alloimmune outcomes. We sought to characterize risk of alloimmune events after BKV within context of HLA-DR/DQ molecular mismatch (mMM) risk score. METHODS: This single-center study evaluated 460 kidney transplant patients on tacrolimus-mycophenolate-prednisone from 2010-2021. BKV status was classified at 6-months post-transplant as "BKV" or "no BKV" in landmark analysis. Primary outcome was T-cell mediated rejection (TCMR). Secondary outcomes included all-cause graft failure (ACGF), death-censored graft failure (DCGF), de novo donor specific antibody (dnDSA), and antibody-mediated rejection (ABMR). Predictors of outcomes were assessed in Cox proportional hazards models including BKV status and alloimmune risk defined by recipient age and molecular mismatch (RAMM) groups. RESULTS: At 6-months post-transplant, 72 patients had BKV and 388 had no BKV. TCMR occurred in 86 recipients, including 27.8% with BKV and 17% with no BKV (p = .05). TCMR risk was increased in recipients with BKV (HR 1.90, (95% CI 1.14, 3.17); p = .01) and high vs. low-risk RAMM group risk (HR 2.26 (95% CI 1.02, 4.98); p = .02) in multivariable analyses; but not HLA serological MM in sensitivity analysis. Recipients with BKV experienced increased dnDSA in univariable analysis, and there was no association with ABMR, DCGF, or ACGF. CONCLUSIONS: Recipients with BKV had increased risk of TCMR independent of induction immunosuppression and conventional alloimmune risk measures. Recipients with high-risk RAMM experienced increased TCMR risk. Future studies on optimizing immunosuppression for BKV should explore nuanced risk stratification and may consider novel measures of alloimmune risk.

Impact of hyperparathyroidism on allograft histology and function after kidney transplantation: Rethinking its causal role in graft dysfunction.

INTRODUCTION: The causal relationship between hyperparathyroidism and kidney graft dysfunction remains inconclusive. Applying Bradford-Hill's temporality and consistency causation principles, we assessed the effect of parathyroid hormone (iPTH) on graft histology and eGFR trajectory on kidney transplant recipients (KTRs) with normal time-zero graft biopsies. METHODS: Retrospective cohort study evaluating the effect of hyperparathyroidism on interstitial fibrosis and tubular atrophy (IF/TA) development in 1232 graft biopsies. Pre-transplant hyperparathyroidism was categorized by KDIGO or KDOQI criteria, and post-transplant hyperparathyroidism by iPTH >1× and >2× the URL 1 year after transplantation. RESULTS: We included 325 KTRs (56% female, age 38 ± 13 years, follow-up 4.2 years [IQR: 2.7-5.8]). Based on pre-transplant iPTH levels, 26% and 66% exceeded the KDIGO and KDOQI targets, respectively. There were no significant differences in the development of >25% IF/TA between KTRs with pre-transplant iPTH levels above and within target range according to KDIGO (53% vs. 62%, P = .16, HR.94 [95% CI:.67-1.32]) and KDOQI (60% vs. 60%, P = 1.0, HR 1.19 [95% CI:.88-1.60]) criteria. Similarly, there were no differences when using 1 year post-transplant iPTH cut-offs > 88 pg/mL (58% vs. 64%, P = .33) and > 176 pg/mL (55% vs. 62%, P = .19). After adjusting for confounders, no significant differences were observed in eGFR trajectories among the iPTH strata. CONCLUSION: In young KTRs who received a healthy graft, no association was found between increased pre- and post-transplant iPTH levels and graft dysfunction, as assessed histologically and through eGFR trajectory. The concept of hyperparathyroidism as a risk factor for graft dysfunction in recipients at low risk requires reevaluation.

Impact of delayed listing after initiating kidney transplant evaluation on transplant outcomes.

OBJECTIVE: Longer end-stage renal disease time has been associated with inferior kidney transplant outcomes. However, the contribution of transplant evaluation is uncertain. We explored the relationship between time from evaluation to listing (ELT) and transplant outcomes. METHODS: This retrospective study included 2535 adult kidney transplants from 2000 to 2015. Kaplan-Meier survival curves, log-rank tests, and Cox regression models were used to compare transplant outcomes. RESULTS: Patient survival for both deceased donor (DD) recipients (p < .001) and living donor (LD) recipients (p < .0001) was significantly higher when ELT was less than 3 months. The risks of ELT appeared to be mediated by other risks in DD recipients, as adjusted models showed no associated risk of graft loss or death in DD recipients. For LD recipients, ELT remained a risk factor for patient death after covariate adjustment. Each month of ELT was associated with an increased risk of death (HR = 1.021, p = .04) but not graft loss in LD recipients in adjusted models. CONCLUSIONS: Kidney transplant recipients with longer ELT times had higher rates of death after transplant, and ELT was independently associated with an increased risk of death for LD recipients. Investigations on the impact of pretransplant evaluation on post-transplant outcomes can inform transplant policy and practice.

Efficacy of Flexible Ureteroscopy Lithotripsy and Percutaneous Nephrolithotomy in the Treatment of Patients with Kidney Stones and Their Impact on Inflammatory Response and Renal Function.

BACKGROUND: Kidney stones are one of the most common benign diseases in urology. As technology updates and iterates, more minimally invasive and laparoscopic surgeries with higher safety performance appear. This paper explores the effectiveness of retrograde intrarenal surgery (RIRS) and percutaneous nephrolithotomy (PCNL) in treating kidney stones, focusing on their effects on inflammatory responses and renal function. METHODS: We conducted a retrospective analysis of 200 patients with kidney stones treated in our hospital between June 2019 and June 2023. 100 patients who underwent RIRS were included in the RIRS group. Another 100 patients who underwent PCNL treatment were included in the PCNL group. The intraoperative blood loss, operation duration, and hospitalization time of the two groups of patients were recorded and compared. The enzyme-linked immunosorbent assay (ELISA) was used to detect the levels of inflammatory factors in the serum of the two groups of patients: [serum amyloid A (SAA), interleukin-6 (IL-6) and high-sensitivity C-reactive protein (CRP)] and renal function index [blood urea nitrogen (BUN), creatinine (Scr) and serum cystatin (Cys-c)]. The two groups of patients were recorded separately: Postoperative complications and stone-free rate. RESULTS: Operation duration was longer for the RIRS group than the PCNL group, which exhibited significantly less intraoperative blood loss and shorter hospital stays (p < 0.05). Before surgery, there was no statistically significant difference in the serum levels of SAA, IL-6, and CRP between the two groups of patients (p > 0.05). On the first day after surgery, the serum SAA levels in both groups were lower than before surgery, IL-6 and CRP levels were higher than before surgery, and the serum levels of SAA, IL-6, and CRP in the RIRS group were significantly lower than those in the PCNL group. The difference was statistically significant (p < 0.05). Before surgery, there was no statistically significant difference in the serum BUN, Scr, and Cys-c levels between the two groups of patients (p > 0.05). On the first day after surgery, the serum BUN, Scr, and Cys-c levels of the two groups of patients were significantly higher than those before surgery. The serum BUN, Scr, and Cys-c levels of the RIRS group were significantly lower than those of the PCNL group, and the difference was statistically significant (p < 0.05). Both surgical methods have sound stone-clearing effects regarding long-term stone clearance rates 1 month and 3 months after surgery (p > 0.05). PCNL had a better stone clearance rate on the 2nd postoperative day (p < 0.05). The incidence of postoperative complications in the RIRS group was significantly lower than that in the PCNL group, and the difference was statistically significant (p < 0.05). CONCLUSION: For kidney stones ≤2 cm, PCNL showed higher stone clearance rates on the second postoperative day. However, RIRS and PCNL demonstrated adequate long-term stone clearance at 1 and 3 months post-surgery. Both surgical methods are safe and effective, and RIRS is safer than PCNL. Compared with PCNL, RIRS is a new method of kidney stone operation, which has less trauma to the patient's body and fewer complications after the operation, speeding up the recovery process of the patient.

Application of the European Kidney Function Consortium Equation to Estimate Glomerular Filtration Rate: A Comparison Study of the CKiD and CKD-EPI Equations Using the Korea National Health and Nutrition Examination Survey (KNHANES 2008-2021).

Background and Objectives: The European Kidney Function Consortium (EKFC) equation has been newly proposed for estimating glomerular filtration rate (eGFR) across the spectrum of age. We compared the EKFC equation with the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equations in a large-scale Korean population. Materials and Methods: Using the representative Korean health examination data, the Korea National Health and Nutrition Examination Survey (KNHANES 2008-2021), the records of 91,928 subjects (including 9917 children) were analyzed. We compared the EKFC equation with CKiD, CKD-EPI 2009, and CKD-EPI 2021 equations and investigated their agreement across GFR categories. Results: In the total population, the CKD-EPI 2021 equation yielded the highest eGFR value, followed by the CKD-EPI 2009 and EKFC equations. In children, the distribution of eGFR differed significantly between the EKFC and CKiD equations (p < 0.001), with a wider range of eGFR values found with the CKiD equation. Each equation showed weak or moderate agreement on the frequency of the GFR category (κ = 0.54 between EKFC and CKD-EPI 2021; κ = 0.77 between EKFC and CKD-EPI 2009). The eGFR values found by the EKFC equation showed high or very high correlations with those by the CKiD, CKD-EPI 2009, and CKD-EPI 2021 equations (r = 0.85, 0.97, and 0.97, respectively). As eGFR values increased, bigger differences were observed between equations. Conclusions: This large-scale study demonstrates that the EKFC equation would be applicable across the entire age spectrum in Asian populations. It also underscores that national kidney health would be highly affected by an eGFR equation being implemented. Additional investigation and more caution would be warranted for the transition of eGFR equations.

Evaluation of differential renal function in children - a comparative study between magnetic resonance urography and dynamic renal scintigraphy.

BACKGROUND: Urinary system anomalies, both congenital and acquired, constitute a relatively common clinical problem in children. The main role of diagnostic imaging is to determine early diagnosis and support therapeutic decisions to prevent the development of chronic renal disease. The aim of this study was to evaluate the utility of magnetic resonance urography (MRU) in assessment of urinary system in children, by comparing differential renal function calculated using MRU with dynamic renal scintigraphy (DRS). MATERIALS AND METHODS: The study group consisted of 46 patients aged 1 week to 17 years (median 7 (0.5; 13) years, 17 (37%) girls, 29 (63%) boys), who underwent dynamic renal scintigraphy due to various clinical reasons. All participants underwent MRU, which was used to measure differential renal function. Functional analysis was performed using dedicated external software (CHOP-fMRU and pMRI without prior knowledge of DRS results. MRU results acquired using pMRI were assessed for inter and intraobserver agreement. RESULTS: Statistical analysis of the results showed excellent agreement between MRU and DRS in measuring differential renal function with Pearson correlation coefficient 0.987 for CHOP-fMRU and 0.971 for pMRI, p < 0.001. Interclass correlation coefficient (ICC) for these programs was 0.987 (95% CI 0.976-0.993) and 0.969 (95% CI 0.945-0.983) respectively, p < 0.001. The Bland-Altman 95% limits of agreement for CHOP-fMRU results vs. DRS was - 6.29-5.50 p.p. and for pMRI results vs. DRS - 9.15-9.63 p.p. The differential renal function measurements calculated in pMRI showed excellent intraobserver and interobserver agreement with ICC 0.996 (95% CI 0.994-0.998) and 0.992 (95% CI 0.986-0.996) respectively, p < 0.001. CONCLUSIONS: The study showed no significant differences between magnetic resonance urography and dynamic renal scintigraphy in calculating differential renal function. It indicates high utility of MRU in the evaluation of urinary system in children.

Assessment of epidemiology and outcomes of adult patients with kidney-limited thrombotic microangiopathies.

Thrombotic microangiopathies (TMA) are usually associated with hematological features (RH-TMA). The epidemiology of TMA limited to kidneys (RL-TMA) is unclear Therefore, patients with TMA and native kidney biopsies were identified during 2009-2022 in 20 French hospitals and results evaluated. RL-TMA was present in 341/757 (45%) patients and associated with lower creatinine levels (median 184 vs 346 µmol/L) than RH-TMA. RL-TMA resulted from virtually all identified causes, more frequently from anti-VEGF treatment and hematological malignancies but less frequently from shigatoxin-associated hemolytic uremic syndrome (HUS), systemic sclerosis, gemcitabine and bacterial infection, and even less frequently when three or more causes/triggers were combined (RL-TMA: 5%; RH-TMA: 12%). RL-TMA was associated with significantly lower major cardiovascular events (10% vs 20%), kidney replacement therapy (23% vs 43%) and death (12% vs 20%) than RH-TMA during follow-up (median 28 months). Atypical HUS (aHUS) was found in 326 patients (RL-TMA: 43%, RH-TMA: 44%). Among the 69 patients with proven complement-mediated aHUS, eculizumab (anti-C5 therapy) was used in 43 (62%) (RL-TMA: 35%; RH-TMA: 71%). Among the 257 other patients with aHUS, including 51% with RL-TMA, eculizumab was used in 29 but with unclear effects of this treatment. Thus, RL-TMA represents a very high proportion of patients with TMA and results from virtually all known causes of TMA and includes 25% of patients with complement-mediated aHUS. Adverse outcomes of RL-TMA are lower compared to RH-TMA but remain significant. Anti-C5 therapy was rarely used in RL-TMA, even in proven complement-mediated aHUS, and its effects remain to be assessed.

A fully automatic deep learning-based method for segmenting regions of interest and predicting renal function in pediatric dynamic renal scintigraphy.

OBJECTIVE: Accurate delineation of renal regions of interest (ROIs) is critical for the assessment of renal function in pediatric dynamic renal scintigraphy (DRS). The purpose of this study was to develop and evaluate a deep learning (DL) model that can fully automatically delineate renal ROIs and calculate renal function in pediatric 99mTechnetium-ethylenedicysteine (99mTc-EC) DRS. METHODS: This study retrospectively analyzed 1,283 pediatric DRS data at a single center from January to December 2018. These patients were divided into training set (n = 1027), validation set (n = 128), and testing set (n = 128). A fully automatic segmentation of ROIs (FASR) model was developed and evaluated. The pixel values of the automatically segmented ROIs were calculated to predict renal blood perfusion rate (BPR) and differential renal function (DRF). Precision, recall rate, intersection over union (IOU), and Dice similarity coefficient (DSC) were used to evaluate the performance of FASR model. Intraclass correlation (ICC) and Pearson correlation analysis were used to compare the consistency of automatic and manual method in assessing the renal function parameters in the testing set. RESULTS: The FASR model achieved a precision of 0.88, recall rate of 0.94, IOU of 0.83, and DSC of 0.91. In the testing set, the r values of BPR and DRF calculated by the two methods were 0.94 (P < 0.01) and 0.97 (P < 0.01), and the ICCs (95% confidence interval CI) were 0.94 (0.90-0.96) and 0.94 (0.91-0.96). CONCLUSION: We propose a reliable and stable DL model that can fully automatically segment ROIs and accurately predict renal function in pediatric 99mTc-EC DRS.

Development of a physiologically based pharmacokinetic model for levetiracetam in patients with renal impairment to guide dose adjustment based on steady-state peak/trough concentrations.

Levetiracetam may cause acute renal failure and myoclonic encephalopathy at high plasma levels, particularly in patients with renal impairment. The aim of this study was to develop a physiologically based pharmacokinetic (PBPK) model to predict levetiracetam pharmacokinetics in Chinese adults with epilepsy and renal impairment and define appropriate levetiracetam dosing regimen.PBPK models for healthy subjects and epilepsy patients with renal impairment were developed, validated, and adapted. Furthermore, we predicted the steady-state trough and peak concentrations of levetiracetam in patients with renal impairment using the final PBPK model, thereby recommending appropriate levetiracetam dosing regimens for different renal function stages. The predicted maximum plasma concentration (Cmax), time to maximum concentration (Tmax), area under the plasma concentration-time curve (AUC) were in agreement (0.8 ≤ fold error ≤ 1.2) with the observed, and the fold error of the trough concentrations in end-stage renal disease (ESRD) was 0.77 - 1.22. The prediction simulations indicated that the recommended doses of 1000, 750, 500, and 500 mg twice daily for epilepsy patients with mild, moderate, severe renal impairment, and ESRD, respectively, were sufficient to achieve the target plasma concentration of levetiracetam.

Motion-compensated image reconstruction for improved kidney function assessment using dynamic contrast-enhanced MRI.

Accurately measuring renal function is crucial for pediatric patients with kidney conditions. Traditional methods have limitations, but dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) provides a safe and efficient approach for detailed anatomical evaluation and renal function assessment. However, motion artifacts during DCE-MRI can degrade image quality and introduce misalignments, leading to unreliable results. This study introduces a motion-compensated reconstruction technique for DCE-MRI data acquired using golden-angle radial sampling. Our proposed method achieves three key objectives: (1) identifying and removing corrupted data (outliers) using a Gaussian process model fitting with a k -space center navigator, (2) efficiently clustering the data into motion phases and performing interphase registration, and (3) utilizing a novel formulation of motion-compensated radial reconstruction. We applied the proposed motion correction (MoCo) method to DCE-MRI data affected by varying degrees of motion, including both respiratory and bulk motion. We compared the outcomes with those obtained from the conventional radial reconstruction. Our evaluation encompassed assessing the quality of images, concentration curves, and tracer kinetic model fitting, and estimating renal function. The proposed MoCo reconstruction improved the temporal signal-to-noise ratio for all subjects, with a 21.8% increase on average, while total variation values of the aorta, right, and left kidney concentration were improved for each subject, with 32.5%, 41.3%, and 42.9% increases on average, respectively. Furthermore, evaluation of tracer kinetic model fitting indicated that the median standard deviation of the estimated filtration rate ( σ F T ), mean normalized root-mean-squared error (nRMSE), and chi-square goodness-of-fit of tracer kinetic model fit were decreased from 0.10 to 0.04, 0.27 to 0.24, and, 0.43 to 0.27, respectively. The proposed MoCo technique enabled more reliable renal function assessment and improved image quality for detailed anatomical evaluation in the case of bulk and respiratory motion during the acquisition of DCE-MRI.

Interaction between cold ischemia time and Kidney Donor Profile Index on postrenal transplant outcomes.

We analyzed whether there is an interaction between the Kidney Donor Profile Index (KDPI) and cold ischemia time (CIT) in recipients of deceased donor kidney transplant (KTs). Adults who underwent KTs in the United States between 2014 and 2020 were included and divided into 3 KDPI groups (≤20%, 21%-85%, >85%) and 4 CIT strata (<12, 12-17.9, 18-23.9, ≥24 hours). Multivariate analyses were used to test the interaction between KDPI and CIT for the following outcomes: primary graft nonfunction (PGNF), delayed graft function (DGF), estimated glomerular filtration rate (eGFR) at 6 and 12 months, patient survival, graft survival, and death-censored graft survival (DCGS). A total of 69,490 recipients were analyzed: 18,241 (26.3%) received a graft with KDPI ≤20%, 46,953 (67.6%) with KDPI 21%-85%, and 4,296 (6.2%) with KDPI >85%. Increasing KDPI and CIT were associated with worse post-KT outcomes. Contrary to our hypothesis, howerver, the interaction between KDPI and CIT was statistically significant only for PGNF and DGF and eGFR at 6 months. Paradoxically, the negative coefficient of the interaction suggested that increasing duration of CIT was more detrimental for low and intermediate-KDPI organs relative to high-KDPI grafts. Conversely, for mortality, graft survival, and DCGS, we found that the interaction between CIT and KDPI was not statistically significant. We conclude that, high KDPI and prolonged CIT are independent risk factors for inferior outcomes after KT. Their interaction, however, is statistically significant only for the short-term outcomes and more pronounced on low and intermediate-KDPI grafts than high-KDPI kidneys.

Impact of humanized vancomycin infusion on kidney function and kidney injury in a translational rat model.

Allometric dose scaling aims to create isometric exposures between animals and humans and is often employed in preclinical pharmacokinetic/pharmacodynamic models. Bolus-administration with allometric scaling is the most simple and commonly used strategy in pre-clinical kidney injury studies; however, it is possible to humanize drug exposures. Currently, it is unknown if dose-matched, bolus-administration with allometric scaling results in similar outcomes compared to humanized infusions in the vancomycin induced kidney injury model. We utilized a preclinical Sprague-Dawley rat model to compare traditional allometrically-scaled, dose-matched, bolus-administration of vancomycin to an infusion-pump controlled, humanized infusion scheme to assess for differences in iohexol-measured kidney function and urinary kidney injury biomarkers. Following 24 h of vancomycin administration, rats in the humanized infusion group had equivalent area under the curve exposures to animals in the dose-matched bolus group (93.7 mg·h/L [IQR 90.2-97.2] vs. 99.5 mg·h/L [IQR 95.1-104.0], P = 0.07). No significant differences in iohexol-measured kidney function nor meaningful differences in urinary kidney injury biomarkers, kidney injury molecule-1, clusterin, and osteopontin, were detected. Administration of intravenous vancomycin as either a humanized infusion or dose-matched bolus resulted in similar vancomycin exposures. No differences in iohexol-measured GFR nor meaningful differences in urinary kidney injury biomarkers were observed among male Sprague-Dawley rats.

Diabetic Kidney Disease Without Albuminuria: A New Entity in Diabetic Nephropathy.

Non-albuminuric diabetic kidney disease (NA-DKD) is characterized by progressive loss of kidney function with an annual loss of estimated glomerular filtration rate (eGFR) more than 3 mL/ min/ 1.73m2 per year. NA-DKD is also associated with the late manifestation of diabetic kidney disease, characterized by reduced eGFR (< 60 mL/min/ 1.73m2), in the absence of albuminuria (urine albumin-to-creatinine ratio [UACR] less than 30 mg/g. The typical glomerular changes seen in diabetic nephropathy are less frequently observed in normoalbuminuric patients, while they predominantly show mesangial expansion and tubulointerstitial and vascular changes. The prevalence of NA-DKD has been increasing during the past decade, with a wide range of prevalence in different studies. It seems that patients with NA-DKD are more likely to be female and have better metabolic profile including a lower Hb A1c, lower triglyceride, lower cholesterol, lower BMI and systolic blood pressure, and lower rate of retinopathy. Compared to patients with albuminuria, those with NA-DKD show a lower risk for progression to end-stage kidney disease (ESKD), or rapid decline in eGFR. They also have increased risks of death and hospitalization for heart failure compared with non-DKD diabetic patients, but a lower risk in comparison with albuminuric DKD, regardless of GFR. There is no effective treatment for this phenotype of the disease, but limited data support the use of SGLT2 inhibitors to slow chronic kidney disease progression along with appropriate metabolic risk factor control. More clinical research and pathologic studies are needed for a better understanding of the phenotype, prevention, and treatment methods of the disease.  DOI: 10.52547/ijkd.7966.

Phase 2 Trial of Cemdisiran in Adult Patients with IgA Nephropathy: A Randomized Controlled Trial.

BACKGROUND: IgA nephropathy is the most common primary GN. Clinical features of IgA nephropathy include proteinuria, which is the strongest known surrogate of progression to kidney failure. Complement pathway activation is a critical driver of inflammation and tissue injury in IgA nephropathy. Cemdisiran is an investigational RNA interference therapeutic that suppresses hepatic production of complement component 5 (C5), thereby potentially reducing proteinuria in IgA nephropathy. We evaluated the efficacy and safety of cemdisiran in adult patients with IgA nephropathy at high risk of kidney disease progression. METHODS: In this phase 2, 36-week, double-blind study, adult patients with IgA nephropathy and urine protein ≥1 g/24 hours were randomized (2:1) to subcutaneous cemdisiran 600 mg or placebo every 4 weeks in combination with the standard of care. The primary end point was percentage change from baseline at week 32 in urine protein-to-creatinine ratio (UPCR) measured by 24-hour urine collection. Additional end points included change from baseline in UPCR measured by spot urine, serum C5 level, and safety assessments. RESULTS: Thirty-one patients were randomized (cemdisiran, N =22; placebo, N =9). Cemdisiran-treated patients had a placebo-adjusted geometric mean change in 24-hour UPCR of -37.4% (cemdisiran-adjusted geometric mean ratio to baseline [SEM], 0.69 [0.10]) at week 32. Spot UPCR was consistent with 24-hour UPCR placebo-adjusted change of -45.8% (cemdisiran-adjusted geometric mean ratio to baseline [SEM], 0.73 [0.11]). Mean (SD) change in serum C5 level from baseline at week 32 was -98.7% (1.2) with cemdisiran and 25.2% (57.7) with placebo. Over 36 weeks, most adverse events were mild or moderate and transient; the most common adverse event after cemdisiran treatment was injection-site reaction (41%). CONCLUSIONS: These findings indicate that treatment with cemdisiran resulted in a reduction of proteinuria at week 32 and was well tolerated.

Can non-renal clearance and/or bioavailability of drugs be assessed reliably in renal impairment studies with oral drug administration?

OBJECTIVE: The causes for the variable susceptibility of renal clearance (CLr) and bioavailability (F) of drugs in renal impairment are still unknown. We investigated whether the impact of chronic kidney disease (CKD) on non-renal clearance (CLnr) or F can be appraised when drug administration is by the oral route only in dedicated renal impairment studies (DRIS), as is routinely done when developing drugs intended for oral use. MATERIALS AND METHODS: A literature search on DRIS administering drugs orally only or orally and intravenously was conducted. Seven drugs administered orally only with notable CLnr and 2 drugs administered by the oral and intravenous routes with negligible CLnr were identified. Regressions of oral clearance (CL/F), normalized by absolute bioavailability in healthy subjects (F1), on CLr were performed for the drugs with notable non-renal elimination to determine the impact of CKD on CLnr. Regressions of CL/F and CL on CLr were conducted for the drugs with negligible CLnr to determine F. RESULTS: Excessive variability in CL/F and CLr precluded evaluation of CLnr for 1 drug with notable CLnr and F1 < 0.01. A categorization based on the susceptibility of CLnr to CKD appeared possible for the 6 drugs with notable non-renal elimination if the parameters of the F1 normalized regressions of CL/F on CLr are taken at face value, i.e., if equality of F and F1 is assumed. However, the true relationship between F and F1 in subjects with varying renal function is unknowable for drugs with significant CLnr when administered orally only. F of drugs with significant CLnr may be altered by a reduced activity of uptake-transporters and/or enzymes so that in renal impaired subjects both absorption and first pass metabolism of intact drug may be reduced relative to healthy subjects, making it impossible to predict whether F in the former or latter population is greater. Bioavailability of drugs with negligible CLnr may depend primarily on the integrity of uptake-transporters so that F in healthy subjects is expected to be greater than in renal impaired subjects. Apparently accurate estimates of F for drugs with negligible CLnr may be obtained from DRIS with oral administration by using the reciprocal of the slope of the regressions. CONCLUSION: A reliable assessment of the impact of CKD on CLnr for drugs with significant non-renal elimination requires information after oral and intravenous administration in the same DRIS study. However, apparently accurate estimates of F for drugs with negligible non-renal elimination may be obtained in DRIS with oral drug administration only, but validation of the proposed method with other drugs exhibiting negligible non-renal elimination and variable F1 is required.

Screening, identifying, and treating chronic kidney disease: why, who, when, how, and what?

1 in 7 American adults have chronic kidney disease (CKD); a disease that increases risk for CKD progression, cardiovascular events, and mortality. Currently, the US Preventative Services Task Force does not have a screening recommendation, though evidence suggests that screening can prevent progression and is cost-effective. Populations at risk for CKD, such as those with hypertension, diabetes, and age greater than 50 years should be targeted for screening. CKD is diagnosed and risk stratified with estimated glomerular filtration rate utilizing serum creatinine and measuring urine albumin-to-creatinine ratio. Once identified, CKD is staged according to C-G-A classification, and managed with lifestyle modification, interdisciplinary care and the recently expanding repertoire of pharmacotherapy which includes angiotensin converting enzyme inhibitors or angiotensin-II receptor blockers, sodium-glucose-cotransporter-2 inhibitors, and mineralocorticorticoid receptor antagonists. In this paper, we present the why, who, when, how, and what of CKD screening.