Search

Significant loss of kidney function is not easily identified by serum creatinine (sCr)-based measurements. In the presence of normal sCr, decreased kidney functional reserve (KFR) may identify a significant loss of function. We evaluated KFR in experimental subclinical chronic kidney disease (sCKD) before and after brief ischemia-reperfusion injury (IRI). Using fluorescein isothiocyanate-labeled sinistrin, glomerular filtration rate (GFR) was measured transcutaneously before and after adenine-induced sCKD, and 1 and 2 wk after brief IRI, and compared with urinary kidney damage biomarkers. sCKD reduced stimulated and unstimulated GFR by ∼20% while reducing KFR by 50%. IRI reduced unstimulated GFR for 14 days, but KFR remained relatively unchanged in sCKD and transiently increased in control kidneys at 7 days. sCr increased and creatinine clearance (CrCl) decreased only immediately after IRI; sCr and CrCl correlated poorly with measured GFR except on day 1 after IRI. Heterogeneity in sCr and CrCl resulted from variation in tubular creatinine secretion. The increase in damage biomarker concentrations persisted for up to 14 days after IRI, allowing retrospective detection of sCKD before AKI by urine clusterin/urine kidney injury molecule-1 with an area under the curve of 1.0. sCr and CrCl are unreliable unless sCr is acutely elevated. Measurement of KFR and urine damage biomarker excretion detected sCKD despite normal sCr and CrCl. After IRI, the urine clusterin-to-urine kidney injury molecule-1 ratio may identify prior sCKD. NEW & NOTEWORTHY Early kidney function loss is poorly identified by serum creatinine (sCr)-based measurements. Direct kidney functional reserve (KFR) measurement before kidney injury and elevated urinary biomarkers clusterin and kidney injury molecule-1 detect subclinical chronic kidney disease (sCKD) after kidney injury despite normal range sCr and creatinine clearance. Reliance on sCr masks underlying sCKD. Acute kidney injury risk evaluation requires direct glomerular filtration rate measurement and KFR, whereas kidney damage biomarkers facilitate identification of prior subclinical injury. [ABSTRACT FROM AUTHOR]

Background Kidney functional reserve (KFR), the only clinical kidney stress test, is not routinely measured because the complexity of measurement has limited clinical application. We investigated the utility of plasma cystatin C (CysC) after oral protein loading (PL) to determine KFR in Stages 3 and 4 chronic kidney disease (CKD). Methods Following a 24-h low-protein diet, KFR was measured after oral protein by hourly plasma CysC and compared with simultaneous creatinine clearance (CrCl) and radionuclide 99technetium diethylenetriaminepentaacetatic acid (Tc-99m-DTPA) measured glomerular filtration rate (mGFR) measurement in an observational, single-centre cohort study of adults with CKD Stages 3 and 4. Subjects were followed for 3 years for fast (F) or slow (S) CKD progression, dialysis requirement or death or a combination of major adverse kidney events (MAKEs). Result CysC, CrCl and Tc-99m-DTPA mGFR measurements of KFR in 19 CKD Stage 3 and 21 CKD Stage 4 patients yielded good agreement. KFR was not correlated with baseline kidney function. Eight CKD Stage 3 (42%) and 11 CKD Stage 4 (52%) subjects reached their lowest serum CysC concentration 4 h after PL. CysC KFR and baseline serum creatinine (sCr) predicted death or dialysis or MAKE-F with a respective area under the curve (AUC)  of 0.73 [95% confidence interval (CI) 0.48–0.89] and 0.71 (95% CI 0.51–0.84). Including CysC KFR, age, baseline sCr and nadir CysC predicted a decrease in sCr-estimated GFR >1.2 mL/min/year (MAKE-S) with an AUC of 0.89. Conclusions Serial CysC avoided timed urine collection and radionuclide exposure and yielded equivalent estimates of KFR. Serial CysC may facilitate monitoring of KFR in clinical practice. [ABSTRACT FROM AUTHOR]

The ability to promote three-dimensional (3D) self-organization of induced pluripotent stem cells into complex tissue structures called organoids presents new opportunities for the field of developmental biology. Brain organoids have been used to investigate principles of neurodevelopment and neuropsychiatric disorders and serve as a drug screening and discovery platform. However, brain organoid cultures are currently limited by a lacking ability to precisely control their extracellular environment. Here, this work employs 3D bioprinting to generate a high-throughput, tunable, and reproducible scaffold for controlling organoid development and patterning. Additionally, this approach supports the coculture of organoids and vascular cells in a custom architecture containing interconnected endothelialized channels. Printing fidelity and mechanical assessments confirm that fabricated scaffolds closely match intended design features and exhibit stiffness values reflective of the developing human brain. Using organoid growth, viability, cytoarchitecture, proliferation, and transcriptomic benchmarks, this work finds that organoids cultured within the bioprinted scaffold long-term are healthy and have expected neuroectodermal differentiation. Lastly, this work confirms that the endothelial cells (ECs) in printed channel structures can migrate toward and infiltrate into the embedded organoids. This work demonstrates a tunable 3D culturing platform that can be used to create more complex and accurate models of human brain development and underlying diseases., (© 2024 The Author(s). Advanced Healthcare Materials published by Wiley‐VCH GmbH.)