Surrogate measures of glomerular filtration rate (GFR) continue to serve as pivotal determinants of the incidence, severity, and management of acute kidney injury (AKI), as well as the primary reference point underpinning knowledge of its pathophysiology. However, several clinically important deficits in aspects of renal excretory function during AKI other than GFR decline, including acid-base regulation, electrolyte and water balance, and urinary concentrating capacity, can evade detection when diagnostic criteria are built around purely GFR-based assessments. The use of putative markers of tubular injury to detect \"sub-clinical\" AKI has been proposed to expand the definition and diagnostic criteria for AKI, but their diagnostic performance is curtailed by ambiguity with respect to their biological meaning and context specificity. Efforts to devise new holistic assessments of overall renal functional compromise in AKI would foster the capacity to better personalize patient care by replacing biomarker threshold-based diagnostic criteria with a shift to assessment of compromise along a pathophysiological continuum. The term AKI refers to a syndrome of sudden renal deterioration, the severity of which is classified by precise diagnostic criteria that have unquestionable utility in patient management as well as blatant limitations. Particularly, the absence of an explicit pathophysiological definition of AKI curtails further scientific development and clinical handling, entrapping the field within its present narrow GFR-based view. A refreshed approach based on a more holistic consideration of renal functional impairment in AKI as the basis for a new diagnostic concept that reaches beyond the boundaries imposed by the current GFR threshold-based classification of AKI, capturing broader aspects of pathogenesis, could enhance AKI prevention strategies and improve AKI patient outcome and prognosis.

UNASSIGNED: Juxtaglomerular apparatus (JGA)-mediated homeostatic mechanism links to how sodium-glucose cotransporter 2 inhibitors (SGLT2is) slow progression of chronic kidney disease (CKD) and may link to how tolvaptan slows renal function decline in autosomal dominant polycystic kidney disease (ADPKD).
UNASSIGNED: JGA-mediated homeostatic mechanism has been hypothesized based on investigations of tubuloglomerular feedback and renin-angiotensin system. We reviewed clinical trials of SGLT2is and tolvaptan to assess the relationship between this mechanism and these drugs.
UNASSIGNED: When sodium load to macula densa (MD) increases, MD increases adenosine production, constricting afferent arteriole (Af-art) and protecting glomeruli. Concurrently, MD signaling suppresses renin secretion, increases urinary sodium excretion, and counterbalances reduced sodium filtration. However, when there is marked increase in sodium load per-nephron, as in advanced CKD, MD adenosine production increases, relaxing Af-art and maintaining sodium homeostasis at the expense of glomeruli. The beneficial effects of tolvaptan on renal function in ADPKD may also depend on the JGA-mediated homeostatic mechanisms since tolvaptan inhibits sodium reabsorption in the thick ascending limb.The JGA-mediated homeostatic mechanism regulates Af-arts, constricting to relaxing according to homeostatic needs. Understanding this mechanism may contribute to the development of pharmacotherapeutic compounds and better care for patients with CKD.

Podocytes, specialized postmitotic cells, are central players in various kidney-related diseases. Zebrafish have become a valuable model system for studying podocyte biology because they are genetically easy to manipulate, transparent, and their glomerular structure is similar to that of mammals. This review provides an overview of the knowledge of podocyte biology in zebrafish larvae, with particular focus on their essential contribution to understanding the mechanisms that underlie kidney diseases as well as supporting drug development. In addition, special attention is given to advances in live-imaging techniques allowing the observation of dynamic processes, including podocyte motility, podocyte process behavior, and glomerulus maturation. The review further addresses the functional aspects of podocytes in zebrafish larvae. This includes topics such as glomerular filtration, ultrastructural analyses, and evaluation of podocyte response to nephrotoxic insults. Studies presented in this context have provided important insights into the maintenance and resistance of the glomerular filtration barrier in zebrafish larvae and explored the potential transferability of these findings to mammals such as mice, rats, and most importantly, humans. The recent ability to identify potential therapeutic targets represents a promising new way to identify drugs that could effectively treat podocyte-associated glomerulopathies in humans. In summary, this review gives an overview about the importance of zebrafish as a model for podocyte-related disease and targeted drug development. It also highlights the key role of advanced imaging techniques in transparent zebrafish larvae, improving our understanding of glomerular diseases and the significant potential for translation of these findings to humans.

Background: Glomerular hyperfiltration (GH) is an important mechanism in the development of albuminuria in hypertension. The Munich Wistar Frömter (MWF) rat is a non-diabetic model of chronic kidney disease (CKD) with GH due to inherited low nephron number resulting in spontaneous albuminuria and podocyte injury. In MWF rats, we identified prostaglandin (PG) E2 (PGE2) signaling as a potential causative mechanism of albuminuria in GH. Method: For evaluation of the renal PGE2 metabolic pathway, time-course lipidomic analysis of PGE2 and its downstream metabolites 15-keto-PGE2 and 13-14-dihydro-15-keto-PGE2 was conducted in urine, plasma and kidney tissues of MWF rats and albuminuria-resistant spontaneously hypertensive rats (SHR) by liquid chromatography electrospray ionization tandem mass spectrometry (LC/ESI-MS/MS). Results: Lipidomic analysis revealed no dysregulation of plasma PGs over the time course of albuminuria development, while glomerular levels of PGE2 and 15-keto-PGE2 were significantly elevated in MWF compared to albuminuria-resistant SHR. Overall, averaged PGE2 levels in glomeruli were up to ×150 higher than the corresponding 15-keto-PGE2 levels. Glomerular metabolic ratios of 15-hydroxyprostaglandin dehydrogenase (15-PGDH) were significantly lower, while metabolic ratios of prostaglandin reductases (PTGRs) were significantly higher in MWF rats with manifested albuminuria compared to SHR, respectively. Conclusion: Our data reveal glomerular dysregulation of the PGE2 metabolism in the development of albuminuria in GH, resulting at least partly from reduced PGE2 degradation. This study provides first insights into dynamic changes of the PGE2 pathway that support a role of glomerular PGE2 metabolism and signaling for early albuminuria manifestation in GH.

BACKGROUND: We aimed to evaluate the prognostic impact of renal insufficiency and fluctuation of glomerular filtration observed during hospitalization for heart failure (HF).
METHODS: We followed 3,639 patients hospitalized for acute HF and assessed the mortality risk associated with moderate or severe renal insufficiency, either permanent or transient.
RESULTS: After adjustment, severe renal failure defined as estimated glomerular filtration (eGFR) <30 mL/min indicates ≈60% increase in 5-year mortality risk. Similar risk also had patients with only transient decline of eGFR to this range. In contrast, we did not observe any apparent mortality risk attributable to mild/moderate renal insufficiency (eGFR 30-59.9 mL/min), regardless of whether it was transient or permanent.
CONCLUSIONS: Even transient severe renal failure during hospitalization indicates poor long-term prognosis of patients with manifested HF. In contrast, only moderate renal insufficiency observed during hospitalization has no additive long-term mortality impact.

OBJECTIVE: To evaluate the prevalence of stroke among chronic kidney disease (CKD) patients in Taif, Saudi Arabia.
METHODS: A multicentric retrospective study was carried out from May 2021 to August 2022 on 4 dialysis centers in Taif, Saudi Arabia. With a total of 1857 CKD patients (aged ≥18 years old) participated in this study. Data were collected by reviewing patients\' files.
RESULTS: Approximately 98.3% of the participants had severely decreased glomerular filtration rate. Approximately 49.1% of them were on dialysis; the majority of them (87.2%) underwent hemodialysis. The prevalence of stroke in these CKD patients was 8.3%. Ischemic stroke was the most frequently reported issue (81.2%). Ischemic stroke was comparatively more frequently observed in peritoneal dialysis patients (12.1%); whereas hemorrhagic stroke was more on hemodialysis patients with statistically significant association (p=0.029). However, there was no significant association between the prevalence of stroke and stages of CKD.
CONCLUSIONS: The prevalence of stroke in our cohort was 8.3%, and the majority of cases were ischemic strokes. Furthermore, ischemic strokes were more frequent in peritoneal dialysis patients, whereas hemorrhagic strokes occurred more frequently in hemodialysis patients with a statistically significant association.

Atrial fibrillation (AF) and renal insufficiency often coexist and are increasingly prevalent with advancing age. Both the risk of thromboembolic events and bleeding propensity are higher in patients with AF and impaired renal function versus those with good renal health. Direct oral anticoagulants (DOACs) are being increasingly preferred over vitamin K antagonists (VKAs) in the treatment of patients with AF and impaired renal function as VKAs may accelerate progression of chronic kidney disease. DOACs, however, are eliminated by the kidneys to varying degrees, and their dosages must be adapted in accordance with renal function. Since creatinine clearance (CrCl) monitoring is recommended in patients with AF receiving DOAC therapy, CrCl must be routinely monitored in patients at the start and during the course of anticoagulation to avoid deviation from Summary of Product Characteristics dosage specifications. This review article provides an overview of current knowledge on the selection and dose of DOACs including apixaban, dabigatran, edoxaban and rivaroxaban in AF patients at different stages of renal insufficiency, with a special focus on elderly patients with comorbidities and receiving multiple medications. The groups discussed in this review include patients with varying levels of CrCl including hyperfiltration or CrCl > 90 ml/min, CrCl < 90-50 ml/min, CrCl < 50-30 ml/min, CrCl < 30-15 ml/min and end-stage renal disease or on dialysis.

There is a growing body of evidence that the equations used to estimate the glomerular filtration rate (GFR) are not suitable in critically ill patients, a population whose GFR fluctuates continuously. Glomerular filtration is usually estimated by measuring urine creatinine clearance (CrCl) at various time points. The aim of our study was to evaluate the performance of the most widely used GFR calculators in the subpopulation of critically ill patients admitted for severe trauma, and to compare the results against determinations of CrCl in urine collected over a 4-h period (4h-CrCl).
Observational study in patients hospitalized for severe trauma. We measured the 4h-CrCl and estimated GFR using the Cockcroft-Gault, modified Jelliffe, MDRD, t-MDRD, and CKD-EPI equations, adjusting the results for body surface area (BSA) (ml/min/1.73m2). Data were analysed using R version 4.0.4.
A total of 85 patients were included. Median age was 51 years, and 68 were men (78.82%). The mean BSA-adjusted 4h-CrCl (4h-ClCr/1.73m2) was 84.5 ml/min/1.73m2. We found that GFR estimated using the t-MDRD equation correlated significantly with 4h-CrCl/1.73m2. The Cockcroft-Gault equation correlated significantly with 4h-CrCl/1.73m2 when GFR was greater than 130ml/min/m2.
In ICU patients, glomerular filtration can be reliably estimated by determining urine CrCl, but GFR calculators are not accurate in this population.

Recent events have made it apparent that the creatinine based estimating equations for glomerular filtration have their flaws. Some flaws have been known for some time; others have prompted radical modification of the equations themselves. These issues persist in part owing to the behaviour of the creatinine molecule itself, particularly in acute and critical illness. There are significant implications for patient treatment decisions, including drug and fluid therapies and choice of imaging modality (contrast vs. non-contrast CT scan for example). An alternative biomarker, Cystatin C, has been used with some success both alone and in combination with creatinine to help improve the accuracy of particular estimating equations. Problems remain in certain circumstances and costs may limit the more widespread use of the alternative assay. This review will explore both the historical and more recent evidence for glomerular filtration estimation, including options to directly measure glomerular filtration (rather than estimate), perhaps the holy grail for both Biochemistry and Nephrology.

With the constant need for technique improvement for ensuring correct diagnoses and precise treatment, imaging examinations that use contrast media have become unavoidable and indispensable. However, the long-term effects of contrast media on renal function remain unclear in populations with advanced renal failure. This study aimed to examine the relationship between contrast media exposure and long-term trends in renal function in patients with renal failure.
This retrospective cohort study included patients with a definitive diagnosis of chronic kidney disease who visited medical institutions in Japan between April 2012 and December 2020. The cohort was divided into contrast agent therapy and non-contrast agent therapy groups. The assessment indices were the number of contrast exposures and renal function decline. Renal function decline was calculated based on observed chronic kidney disease stage trends and glomerular filtration rate correspondence tables sourced from various guidelines. A stratified analysis focusing on changes in renal function while accounting for the acceleration of chronic kidney disease progression was also performed.
After adjusting for patient background with propensity score matching, 333 patients each were included in both groups. The observation period was 5.3 ± 2.1 and 4.9 ± 2.2 years per case in the contrast-enhanced and non-contrast-enhanced groups, respectively. The baseline estimated glomerular filtration rate at the beginning of the observation period was 55.2 ± 17.8 mL/min/1.73 m2 in the contrast-enhanced groups (P = 0.65). Although only slightly different in both groups, the glomerular filtration rate change was 1.1 ± 3.3 mL/min/1.73 m2/year in the contrast agent therapy group and tended to be higher with contrast media exposure. Stratified analysis showed that the annual glomerular filtration rate changes in patients with more contrast media exposures and altered renal function were 7.9 ± 7.1 mL/min/1.73 m2/year and 4.7 ± 3.6 mL/min/1.73 m2/year in the contrast agent therapy and non-contrast agent therapy groups, respectively (1.69 times, P < 0.05).
We were able to identify a clinical trend of successful measures for preventing adverse renal outcomes associated with contrast media exposure. However, increased frequency of contrast media exposure has a long-term effect on renal function in patients with altered it. Appropriate treatment choices related to contrast media may control chronic kidney disease.