Renal histology in diabetic nephropathy predicts progression to end-stage kidney disease but not the rate of renal function decline.

BACKGROUND: While histopathologic changes correlate with functional impairment in cross-sectional studies of diabetic nephropathy (DN), whether these findings predict future rate of kidney function loss remains uncertain. We thus sought to examine the relationship between kidney histopathology, incidence of end-stage kidney disease (ESKD), and rate of estimated glomerular filtration rate (eGFR) loss in DN. METHODS: In this longitudinal cohort study, we studied 50 adults diagnosed with biopsy-proven DN. We analyzed the histopathologic parameters of each patient's kidney biopsy, as defined by the Renal Pathology Society classification system for DN, and tracked all available eGFR measurements post-biopsy. We additionally collected baseline clinical parameters (at the time of biopsy), including eGFR, albumin-to-creatinine ratio (ACR), and hemoglobin A1c. Multivariable linear regression was used to assess the relationship between histologic and clinical parameters at the time of the biopsy and eGFR slope. Kaplan-Meier curves and Cox regression were used to evaluate the association between histologic and clinical parameters and ESKD incidence. RESULTS: Progression to ESKD was associated with worsening interstitial fibrosis score (p = 0.05), lower baseline eGFR (p = 0.02), higher ACR (p = 0.001), and faster eGFR decline (p < 0.001). The rate of eGFR decline did not associate with any histologic parameter. Baseline ACR was the only studied variable correlating with eGFR slope (rho = - 0.41). CONCLUSIONS: Renal histology predicts ultimate progression to ESKD, but not the rate of progression. Future work is required to identify novel predictors of rapid functional decline in patients with diabetic nephropathy.

Clinical aspects of magnesium physiology in patients on dialysis.

Magnesium balance is infrequently discussed in the dialysis population, and the clinical consequences of derangements in magnesium homeostasis are incompletely understood. There is an association between hypomagnesemia and adverse outcomes including increases in cardiovascular disease and mortality, while elevated magnesium levels have also been linked with complications such as osteomalacia. In this review, we discuss the features of magnesium physiology relevant to dialysis patients and provide an updated summary of the literature linking magnesium derangements with bone disease, cardiovascular disease, sudden cardiac death, and mortality.

"Biocompatible" Neutral pH Low-GDP Peritoneal Dialysis Solutions: Much Ado About Nothing?

Adverse outcomes in peritoneal dialysis (PD), including PD related infections, the loss of residual kidney function (RKF), and longitudinal, deleterious changes in peritoneal membrane function continue to limit the long-term success of PD therapy. The observation that these deleterious changes occur upon exposure to conventional glucose-based PD solutions fuels the search for a more biocompatible PD solution. The development of a novel PD solution with a neutral pH, and lower in glucose degradation products (GDPs) compared to its conventional predecessors has been labeled a "biocompatible" solution. While considerable evidence in support of these novel solutions' biocompatibility has emerged from cell culture and animal studies, the clinical benefits as compared to conventional PD solutions are less clear. Neutral pH low GDP (NpHLGDP) PD solutions appear to be effective in reducing infusion pain, but their effects on other clinical endpoints including peritoneal membrane function, preservation of RKF, PD-related infections, and technique and patient survival are less clear. The literature is limited by studies characterized by relatively few patients, short follow-up time, heterogeneity with regards to the novel PD solution type under study, and the different patient populations under study. Nonetheless, the search for a more biocompatible PD solution continues with emerging data on promising non glucose-based solutions.

The relationship between proton pump inhibitor use and serum magnesium concentration among hemodialysis patients: a cross-sectional study.

BACKGROUND: Observational data suggest that serum magnesium (Mg) concentration is inversely related to vascular calcification and hyperparathyroidism among patients with end-stage renal disease (ESRD). In recent years, there have been several case reports of hypomagnesemia due to use of proton-pump inhibitors (PPI), with the hypomagnesemia attributed to inappropriate gastrointestinal (GI) Mg loss. We hypothesized that the tendency to GI Mg loss is more common than is currently reported. Since patients with ESRD have little to no renal Mg loss to affect serum Mg concentration, dialysis patients are an interesting population in whom to study the relationship between PPI use and serum Mg levels. METHODS: Using a single-center cross-sectional design, we studied 155 prevalent hemodialysis (HD) patients. Serum Mg concentration for each patient was determined based on the mean of 3 consecutive serum Mg levels drawn at 6 week intervals. PPI use at the time of the blood tests was documented. The relationship between PPI use and Mg concentration was determined in unadjusted analyses, as well as after adjustment for age, gender, race, cause of ESRD, diabetes, time on HD and dialysate Mg concentration. RESULTS: 55 % of patients were on PPIs at the time of the study. The majority of patients (62 %) used a dialysate Mg (in mmol/L) of 0.5, and the remainder (38 %) used a dialysate Mg of 0.375. Serum Mg levels were significantly lower among PPI users vs. non-users (0.93 vs. 1.02 mmol/L, p < 0.001). This finding persisted after stratifying for dialysate Mg concentration, and after multivariable adjustment (p < 0.001). In addition, more PPI users vs. non-users had a Mg level < 1 mmol/L (79 % vs. 43 %) and a Mg level < 0.8 mmol/L (16 % vs. 4 %). There was a non-significant trend toward increased time on PPI being associated with lower serum Mg levels (p = 0.067). CONCLUSION: Among HD patients, PPI users have lower serum Mg levels as compared with non-users. Further research is required to determine whether the magnitude of change in Mg levels among PPI users is associated with adverse outcomes.

Dual Role of Caspase 8 in Adipocyte Apoptosis and Metabolic Inflammation.

Caspases are cysteine-aspartic proteases that were initially discovered to play a role in apoptosis. However, caspase 8, in particular, also has additional nonapoptotic roles, such as in inflammation. Adipocyte cell death and inflammation are hypothesized to be initiating pathogenic factors in type 2 diabetes. Here, we examined the pleiotropic role of caspase 8 in adipocytes and obesity-associated insulin resistance. Caspase 8 expression was increased in adipocytes from mice and humans with obesity and insulin resistance. Treatment of 3T3-L1 adipocytes with caspase 8 inhibitor Z-IETD-FMK decreased both death receptor-mediated signaling and targets of nuclear factor κ-light-chain-enhancer of activated B (NF-κB) signaling. We generated novel adipose tissue and adipocyte-specific caspase 8 knockout mice (aP2Casp8-/- and adipoqCasp8-/-). Both males and females had improved glucose tolerance in the setting of high-fat diet (HFD) feeding. Knockout mice also gained less weight on HFD, with decreased adiposity, adipocyte size, and hepatic steatosis. These mice had decreased adipose tissue inflammation and decreased activation of canonical and noncanonical NF-κB signaling. Furthermore, they demonstrated increased energy expenditure, core body temperature, and UCP1 expression. Adipocyte-specific activation of Ikbkb or housing mice at thermoneutrality attenuated improvements in glucose tolerance. These data demonstrate an important role for caspase 8 in mediating adipocyte cell death and inflammation to regulate glucose and energy homeostasis. ARTICLE HIGHLIGHTS: Caspase 8 is increased in adipocytes from mice and humans with obesity and insulin resistance. Knockdown of caspase 8 in adipocytes protects mice from glucose intolerance and weight gain on a high-fat diet. Knockdown of caspase 8 decreases Fas signaling, as well as canonical and noncanonical nuclear factor κ-light-chain-enhancer of activated B (NF-κB) signaling in adipose tissue. Improved glucose tolerance occurs via reduced activation of NF-κB signaling and via induction of UCP1 in adipocytes.

Disruption of adipocyte YAP improves glucose homeostasis in mice and decreases adipose tissue fibrosis.

OBJECTIVE: Adipose tissue is a very dynamic metabolic organ that plays an essential role in regulating whole-body glucose homeostasis. Dysfunctional adipose tissue hypertrophy with obesity is associated with fibrosis and type 2 diabetes. Yes-associated protein 1 (YAP) is a transcription cofactor important in the Hippo signaling pathway. However, the role of YAP in adipose tissue and glucose homeostasis is unknown. METHODS: To study the role of YAP with metabolic stress, we assessed how increased weight and insulin resistance impact YAP in humans and mouse models. To further investigate the in vivo role of YAP specifically in adipose tissue and glucose homeostasis, we developed adipose tissue-specific YAP knockout mice and placed them on either chow or high fat diet (HFD) for 12-14 weeks. To further study the direct role of YAP in adipocytes we used 3T3-L1 cells. RESULTS: We found that YAP protein levels increase in adipose tissue from humans with type 2 diabetes and mouse models of diet-induced obesity and insulin resistance. This suggests that YAP signaling may contribute to adipocyte dysfunction and insulin resistance under metabolic stress conditions. On an HFD, adipose tissue YAP knockout mice had improved glucose tolerance compared to littermate controls. Perigonadal fat pad weight was also decreased in knockout animals, with smaller adipocyte size. Adipose tissue fibrosis and gene expression associated with fibrosis was decreased in vivo and in vitro in 3T3-L1 cells treated with a YAP inhibitor or siRNA. CONCLUSIONS: We show that YAP is increased in adipose tissue with weight gain and insulin resistance. Disruption of YAP in adipocytes prevents glucose intolerance and adipose tissue fibrosis, suggesting that YAP plays an important role in regulating adipose tissue and glucose homeostasis with metabolic stress.

Myofibroblast YAP/TAZ activation is a key step in organ fibrogenesis.

Fibrotic diseases account for nearly half of all deaths in the developed world. Despite its importance, the pathogenesis of fibrosis remains poorly understood. Recently, the two mechanosensitive transcription cofactors YAP and TAZ have emerged as important profibrotic regulators in multiple murine tissues. Despite this growing recognition, a number of important questions remain unanswered, including which cell types require YAP/TAZ activation for fibrosis to occur and the time course of this activation. Here, we present a detailed analysis of the role that myofibroblast YAP and TAZ play in organ fibrosis and the kinetics of their activation. Using analyses of cells, as well as multiple murine and human tissues, we demonstrated that myofibroblast YAP and TAZ were activated early after organ injury and that this activation was sustained. We further demonstrated the critical importance of myofibroblast YAP/TAZ in driving progressive scarring in the kidney, lung, and liver, using multiple transgenic models in which YAP and TAZ were either deleted or hyperactivated. Taken together, these data establish the importance of early injury-induced myofibroblast YAP and TAZ activation as a key event driving fibrosis in multiple organs. This information should help guide the development of new antifibrotic YAP/TAZ inhibition strategies.

NUAK1 promotes organ fibrosis via YAP and TGF-ß/SMAD signaling.

Fibrosis is a central pathway that drives progression of multiple chronic diseases, yet few safe and effective clinical antifibrotic therapies exist. In most fibrotic disorders, transforming growth factor-ß (TGF-ß)-driven scarring is an important pathologic feature and a key contributor to disease progression. Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ) are two closely related transcription cofactors that are important for coordinating fibrogenesis after organ injury, but how they are activated in response to tissue injury has, so far, remained unclear. Here, we describe NUAK family kinase 1 (NUAK1) as a TGF-ß-inducible profibrotic kinase that is up-regulated in multiple fibrotic organs in mice and humans. Mechanistically, we show that TGF-ß induces a rapid increase in NUAK1 in fibroblasts. NUAK1, in turn, can promote profibrotic YAP and TGF-ß/SMAD signaling, ultimately leading to organ scarring. Moreover, activated YAP and TAZ can induce further NUAK1 expression, creating a profibrotic positive feedback loop that enables persistent fibrosis. Using mouse models of kidney, lung, and liver fibrosis, we demonstrate that this fibrogenic signaling loop can be interrupted via fibroblast-specific loss of NUAK1 expression, leading to marked attenuation of fibrosis. Pharmacologic NUAK1 inhibition also reduced scarring, either when initiated immediately after injury or when initiated after fibrosis was already established. Together, our data suggest that NUAK1 plays a critical, previously unrecognized role in fibrogenesis and represents an attractive target for strategies that aim to slow fibrotic disease progression.

Overexpression of the Severe Acute Respiratory Syndrome Coronavirus-2 Receptor, Angiotensin-Converting Enzyme 2, in Diabetic Kidney Disease: Implications for Kidney Injury in Novel Coronavirus Disease 2019.

OBJECTIVES: Diabetes is associated with adverse outcomes, including death, after coronavirus disease 19 (COVID-19) infection. Beyond the lungs, Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2), the etiologic agent of the COVID-19 pandemic, can infect a range of other tissues, including the kidney, potentially contributing to acute kidney injury in those with severe disease. We hypothesized that the renal abundance of angiotensin-converting enzyme (ACE) 2, the cell surface receptor for SARS-CoV-2, may be modulated by diabetes and agents that block the renin-angiotensin-aldosterone system (RAAS). METHODS: The expression of ACE 2 was examined in 49 archival kidney biopsies from patients with diabetic kidney disease and from 12 healthy, potential living allograft donors using next-generation sequencing technology (RNA Seq). RESULTS: Mean ACE 2 messenger RNA was increased approximately 2-fold in diabetes when compared with healthy control subjects (mean ± SD, 13.2±7.9 vs 7.7±3.6 reads per million reads, respectively; p=0.001). No difference in transcript abundance was noted between recipients and nonrecipients of agents that block the RAAS (12.2±6.7 vs 16.2±10.7 reads per million reads, respectively; p=0.25). CONCLUSIONS: Increased ACE 2 messenger RNA in the diabetic kidney may increase the risk and/or severity of kidney infection with SARS-CoV-2 in the setting of COVID-19 disease. Further studies are needed to ascertain whether this diabetes-related overexpression is generalizable to other tissues, most notably the lungs.

Islet-Resident Endocrine Progenitors: A New Hope for Beta Cell PROCReation?

The existence of an endocrine progenitor in the adult mouse pancreas has been controversial. Recently in Cell, Wang et al. (2020) use the cell-surface marker Procr to define a population of cells within the adult islet of Langerhans that is capable of generating all endocrine cells and is amenable to in vitro expansion.

Roadblocks and Opportunities to the Implementation of Novel Therapies for Acute Kidney Injury: A Narrative Review.

BACKGROUND: Acute kidney injury (AKI) is a complex and heterogeneous clinical syndrome with limited effective treatment options. Therefore, a coherent research structure considering AKI pathophysiology, treatment, translation, and implementation is critical to advancing patient care in this area. PURPOSE OF REVIEW: In this narrative review, we discuss novel therapies for AKI from their journey from bench to bedside to population and focus on roadblocks and opportunities to their successful implementation. SOURCES OF INFORMATION: Peer-reviewed articles, opinion pieces from research leaders and research funding agencies, and clinical and research expertise. METHODS: This narrative review details the challenges of translation of preclinical studies in AKI and highlights trending research areas and innovative designs in the field. Key developments in preclinical research, clinical trials, and knowledge translation are discussed. Furthermore, this article discusses the current need to involve patients in clinical research and the barriers and opportunities for effective knowledge translation. KEY FINDINGS: Preclinical studies have largely been unsuccessful in generating novel therapies for AKI, due both to the complexity and heterogeneity of the disease, as well as the limitations of commonly available preclinical models of AKI. The emergence of kidney organoid technology may be an opportunity to reverse this trend. However, the roadblocks encountered at the bench have not precluded researchers from running well-designed and impactful clinical trials, and the field of renal replacement therapy in AKI is highlighted as an area that has been particularly active. Meanwhile, knowledge translation initiatives are bolstered by the presence of large administrative databases to permit ongoing monitoring of clinical practices and outcomes, with research output from such evaluations having the potential to directly impact patient care and inform the generation of meaningful clinical practice guidelines. LIMITATIONS: There are limited objective data examining the process of knowledge creation and translation in AKI, and as such the opinions and research areas of the authors are significantly drawn upon in the discussion. IMPLICATIONS: The use of an organized knowledge-to-action framework involving multiple stakeholders, especially patient partners, is critical to translating basic research findings to improvements in patient care in AKI, an area where effective treatment options are lacking.

CONTEXTE: L'insuffisance rénale aigüe (IRA) est un syndrome clinique complexe et hétérogène pour lequel les options de traitement efficaces sont limitées. Ainsi, une structure de recherche cohérente, tenant compte de la physiopathologie et du traitement de l'IRA, de même que de la transposition et de l'application des résultats de recherche, est essentielle à l'avancement des soins aux patients. JUSTIFICATION: Dans cette revue narrative, nous discutons des nouveaux traitements de l'IRA, et du parcours que ces derniers empruntent du laboratoire au chevet des patients, et jusqu'à la population générale, en se concentrant sur les obstacles et les facilitateurs qui influencent la réussite de leur application. SOURCES: Des articles révisés par les pairs, des avis d'éminents chercheurs et d'organismes de financement de la recherche, de même que l'expertise clinique et de recherche des auteurs. MÉTHODOLOGIE: Cette revue narrative expose les défis de la transposition des études précliniques en IRA, et met en lumière les nouveaux axes de recherche et les modèles novateurs dans le domaine. La discussion porte également sur les principaux développements en recherche préclinique, en essais cliniques et en transfert des connaissances. Enfin, cet article aborde la nécessité d'impliquer les patients en recherche clinique, de même que les obstacles et possibilités pour une transfert efficace de connaissances. PRINCIPAUX RÉSULTATS: Les études précliniques ont en grande partie échoué à proposer de nouveaux traitements à l'IRA en raison de la complexité et de l'hétérogénéité de la maladie, mais également des limites inhérentes aux modèles précliniques communément utilisés. Une tendance qui pourrait s'inverser grâce à l'émergence de la technologie des organoïdes rénaux. Les difficultés rencontrées au laboratoire n'ont toutefois pas empêché les chercheurs de mener des essais cliniques significatifs et bien conçus; la recherche sur les thérapies de remplacement rénal est d'ailleurs un domaine de recherche particulièrement actif. Parallèlement, les initiatives visant le transfert des connaissances sont appuyées par d'importantes bases de données administratives qui permettent un suivi constant des pratiques et des résultats cliniques; les résultats des recherches issues de ces évaluations pourraient avoir une incidence directe sur les soins aux patients et l'élaboration de lignes directrices pertinentes en matière de pratique clinique. LIMITES: Il existe peu de données objectives examinant la création et le transfert de connaissances en IRA. À ce titre, les opinions et domaines de recherche des auteurs sont largement pris en compte dans la discussion. CONCLUSION: Un cadre de recherche « du savoir à l'action ¼ impliquant plusieurs intervenants, surtout des patients partenaires, est essentiel à l'application des découvertes de la recherche fondamentale et à l'amélioration des soins aux patients atteints d'IRA; un domaine où les options de traitement efficaces font défaut.

A new, easily generated mouse model of diabetic kidney fibrosis.

Our understanding of diabetic kidney disease pathogenesis has been hampered by the lack of easily generated pre-clinical animal models that faithfully recapitulate critical features of human disease. While most standard animal models develop manifestations of early stage diabetic injury such as hyperfiltration and mesangial matrix expansion, only a select few develop key late stage features such as interstitial fibrosis and reduced glomerular filtration rate. An underlying theme in these late stage disease models has been the addition of renin-angiotensin system hyperactivation, an important contributor to human disease pathogenesis. Widespread use of these models has been limited, however, as they are either labour intensive to generate, or have been developed in the rat, preventing the use of the many powerful genetic tools developed for mice. Here we describe the Akita+/- Ren+/- mouse, a new, easily generated murine model of diabetic kidney disease that develops many features of late stage human injury, including not only hyperglycemia, hypertension, and albuminuria, but also reduced glomerular filtration rate, glomerulosclerosis, and interstitial fibrosis.