Glomerular Pressure Research Articles

Elucidating the complex interplay between chronic kidney disease and hypertension.

Chronic kidney disease (CKD) and hypertension share a complex relationship, each exacerbating the progression of the other. CKD contributes to hypertension by decreasing renal function, leading to fluid retention and increased plasma volume, whereas hypertension exacerbates CKD by increasing glomerular pressure and causing renal damage. This review examines the intertwined nature of CKD and hypertension, exploring the factors driving hypertension in CKD and how hypertension accelerates CKD progression. It discusses the role of the renin-angiotensin system and inflammatory cytokines in this relationship, as well as the potential of blood pressure management to slow renal decline. While studies suggest that meticulous blood pressure control can help attenuate CKD progression, optimal management strategies remain unclear and require further investigation. This review also evaluates the evidence surrounding strict antihypertensive therapy in patients with CKD, considering both diabetic and non-diabetic cases. It recommends blood pressure targets based on CKD stage and presence of diabetes, emphasizing the importance of individualized treatment approaches. Renin-angiotensin system inhibitors are highlighted as a key pharmacological intervention due to their renal protective effects, particularly in patients with CKD with proteinuria. However, evidence regarding their efficacy in patients with CKD but without proteinuria is inconclusive. This review underscores the need for comprehensive approaches to effectively address the intertwined nature of CKD and hypertension and calls for further research to optimize clinical management strategies in this complex interplay.

Glomerular pressure and tubular oxygen supply: a critical dual target for renal protection.

The primary treatment goal of chronic kidney disease (CKD) is preserving renal function and preventing its progression to end-stage renal disease. Glomerular hypertension and tubular hypoxia are critical risk factors in CKD progression. However, the renal hemodynamics make it difficult to avoid both factors due to the existence of peritubular capillaries that supply oxygen to the renal tubules downstream from the glomerulus through the efferent arteriole. In the treatment strategies for balancing glomerular pressure and tubular oxygen supply, afferent and efferent arterioles of the glomerulus determine glomerular filtration rate and blood flow to the peritubular capillaries. Therefore, sodium-glucose cotransporter 2 inhibitors and angiotensin receptor-neprilysin inhibitors as well as classical renin-angiotensin system inhibitors, which can change the diameter of afferent and/or efferent arterioles, are promising options for balancing this dual target and achieving renal protection. This review focuses on the clinical importance of glomerular pressure and tubular oxygen supply and proposes an effective treatment modality for this dual target.

Heterogeneous afferent arteriolopathy: a key concept for understanding blood pressure-dependent renal damage.

Hypertension, aging, and other factors are associated with arteriosclerosis and arteriolosclerosis, primary morphological features of nephrosclerosis. Although such pathological changes are not invariably linked with renal decline but are prevalent across chronic kidney disease (CKD), understanding kidney damage progression is more pragmatic than precisely diagnosing nephrosclerosis itself. Hyalinosis and medial thickening of the afferent arteriole, along with intimal thickening of small arteries, can disrupt the autoregulatory system, jeopardizing glomerular perfusion pressure given systemic blood pressure (BP) fluctuations. Consequently, such vascular lesions cause glomerular damage by inducing glomerular hypertension and ischemia at the single nephron level. Thus, the interaction between systemic BP and afferent arteriolopathy markedly influences BP-dependent renal damage progression in nephrosclerosis. Both dilated and narrowed types of afferent arteriolopathy coexist throughout the kidney, with varying proportions among patients. Therefore, optimizing antihypertensive therapy to target either glomerular hypertension or ischemia is imperative. In recent years, clinical trials have indicated that combining renin-angiotensin system inhibitors (RASis) and sodium-glucose transporter 2 inhibitors (SGLT2is) is superior to using RASis alone in slowing renal function decline, despite comparable reductions in albuminuria. The superior efficacy of SGLT2is may arise from their beneficial effects on both glomerular hypertension and renal ischemia. A comprehensive understanding of the interaction between systemic BP and heterogeneous afferent arteriolopathy is pivotal for optimizing therapy and mitigating renal decline in patients with CKD of any etiology. Therefore, in this comprehensive review, we explore the role of afferent arteriolopathy in BP-dependent renal damage.

8483 Changes in kidney hemodynamics during gender-affirming hormone therapy in transgender individuals - findings from the KNIGHT pilot study

Abstract Disclosure: S.A. van Eeghen: None. C. Wiepjes: None. L.L. Pyle: None. M. den Heijer: Research Investigator; Self; Kyowa Kirin. Other; Self; Novartis Pharmaceuticals. P. Bjornstad: Advisory Board Member; Self; AstraZeneca, Bayer, Inc., Boehringer Ingelheim, Novo Nordisk, XORTX. Consulting Fee; Self; AstraZeneca, Bayer, Inc., Boehringer Ingelheim, Bristol-Myers Squibb, Eli Lilly & Company, LG Chemistry, Horizon Pharma, Novo Nordisk, Sanofi. Research Investigator; Self; AstraZeneca, Merck, Horizon Pharma. Other; Self; Bayer, Inc. D. van Raalte: Consulting Fee; Self; AstraZeneca, Bayer, Inc., Boehringer Ingelheim, Eli Lilly & Company, Merck, Sanofi, MSD. Research Investigator; Self; AstraZeneca, Boehringer Ingelheim, Eli Lilly & Company, Merck, Sanofi, MSD. N.J. Nokoff: Consulting Fee; Self; Neurocrine Biosciences, Inc, Ionis Pharmaceuticals Inc.. Research Investigator; Self; Neurocrine Biosciences, Inc. Other; Self; World Athletics. Background: Studies in transgender individuals have shown that gender-affirming hormone therapy (GAHT) impacts estimated glomerular filtration rate (eGFR). Masculinizing hormone therapy decreases, while feminizing hormone therapy increases eGFR, based on changes in serum creatinine and cystatin C. These substantial changes suggest an effect of sex hormones on kidney hemodynamics. To investigate this, we studied kidney hemodynamic changes before and after 3 months of gender-affirming hormone therapy (GAHT) in transgender individuals. Methods: This prospective observational pilot study assessed kidney hemodynamics in 23 transgender individuals assigned male at birth receiving feminizing hormone therapy and 21 transgender individuals assigned female at birth receiving masculinizing hormone therapy. Feminizing therapy included transdermal (n=16), sublingual (n=5), or oral estradiol (n=2), in combination with an anti-androgen (n=22); intramuscular triptorelin (n=16), spironolactone (n=5) or finasteride (n=1). Masculinizing therapy involved transdermal (n=17) or injected testosterone (n=4). Measures included glomerular filtration rate (GFR; Iohexol clearance), effective renal plasma flow (ERPF; p-aminohippurate clearance), and renal vascular resistance (RVR; mean arterial pressure/renal blood flow). Glomerular hydraulic pressure (PGLO), and afferent/efferent vascular resistance (RA/RE) were estimated by Gomez equations. Linear mixed models compared baseline and three-month measurements. Results: Individuals undergoing feminizing hormone therapy [median age 21 (IQR 19-29) years, BMI median 22.9 (IQR 18.9-30.7) kg/m²] had increased GFR by 2.8 mL/min per 1.73m² (95% CI, 0.01 to 5.6) and a nonsignificant increase in ERPF (+42 mL/min per 1.73m²; 95% CI, -5 to 90). RVR and RA significantly decreased [RVR: -0.007 mmHg/L/min (95% CI, -0.015 to -0.0003), RA: -294 dyn/s per cm5 (5% CI, -568 to -21)], indicating afferent vasodilation. In contrast, individuals receiving masculinizing therapy (median age median 20 (IQR 18-23) years, BMI median 24.2 (IQR 21.1-27.3) kg/m²) showed a slight, nonsignificant decrease in GFR (-2.1 mL/min per 1.73m²; 95% CI, -4.9 to 0.8), with no changes in other kidney hemodynamic parameters. Conclusions: In this cohort of transgender individuals, GFR increased during feminizing hormone therapy, likely due to afferent vasodilatation, while during masculinizing hormone therapy GFR tended to decrease. These findings suggest an influence of sex hormones on kidney hemodynamics, especially during feminizing hormone therapy. Presentation: 6/3/2024

Perirenal fat and chronic kidney disease in type 2 diabetes: The mediation role of afferent arteriolar resistance

AimPerirenal fat (PRF) is an independent predictor for chronic kidney disease (CKD) in type 2 diabetes mellitus (T2DM) patients. Previous studies speculated that PRF may promote renal dysfunction through affecting renal hemodynamics. To verify this hypothesis, we studied the relationship between PRF and renal hemodynamics in T2DM. Methods91 T2DM patients were included. PRF thickness (PRFT) was measured by magnetic resonance imaging. Glomerular filtration rate (GFR) and effective renal plasma flow (ERPF) were determined by renal dynamic imaging. Renal vascular resistance (RVR), glomerular hydrostatic pressure (PGLO), afferent (RA) and efferent (RE) arteriolar resistance were calculated by Gomez equations. Multiple linear regression was used to determine the relationship between PRFT and renal hemodynamics. Mediation analysis was conducted to estimate the mediation effects of renal hemodynamics on the relationship between PRF and CKD. ResultsAll patients were divided into three groups according to the tertiles of PRFT. Compared with patients in tertile 1, GFR and ERPF were significantly decreased in patients in tertile 3, while RVR and RA were significantly increased. PRFT was negatively correlated with GFR, ERPF and PGLO, and positively correlated with RVR and RA after adjustment for sex, age, visceral adipose tissue and treatments with ACE inhibitors/angiotensin receptor blockers and sodium-glucose cotransporter protein-2 inhibitors. Moreover, RVR and RA mediated the effect of PRF on GFR, with a mediated proportion of 29.1 % and 41.4 % respectively. ConclusionIn T2DM patients, PRF was negatively correlated with GFR, and positively correlated with RA. RA mediated the relationship between PRF and CKD.

Perinatal risk factors of renal outcome in former extremely low birth weight neonates

Former Extremely Low Birthweight (ELBW) neonates suffer from adverse renal and cardiovascular outcomes later in life. Less is known about additional perinatal risk factors for these adverse outcomes which we have investigated in this study. We compared renal outcome between ELBW children and controls, to find perinatal risk factors for poorer renal outcome and to unveil associations between kidney function and blood pressure. This study included 93 former ELBW children and 87 healthy controls with a mean age of 11 years at assessment. We measured cystatin C-based estimated glomerular filtration rate (eGFR) and blood pressure. Blood pressure and eGFR levels were compared between cases and controls. We subsequently investigated perinatal risk factors for adverse outcome amongst ELBW children. ELBW children have significantly higher blood pressure (mean SBP percentile 75thvs. 47th, p <0.001) and lower mean eGFR (94 vs. 107 ml/min/1.73 m2, p = 0.005) compared to the control group. Elevated blood pressure did not correlate with perinatal characteristics and none of them had microalbuminuria. ELBW children with eGFR <90 ml/min/1.73 m2 were ventilated longer (17 vs. 9 days, p = 0.006), more frequently male (OR = 3.33, p = 0.055) and tended to suffer more from intraventricular hemorrhage (40% vs. 15.8%, p = 0.056). There was no association between blood pressure and kidney dysfunction. Conclusions: Understanding risk profiles for unfavorable outcomes may help to identify children at increased risk for kidney dysfunction. Poorer eGFR was associated with longer ventilation, male sex, and intra-ventricular hemorrhage but not with blood pressure. This knowledge can lead to safer neonatal therapeutic regimens for ELBW infants, a more intensive follow-up and earlier treatment initiation for children at highest risk. What is Known:• Extremely Low Birthweight (ELBW) neonates suffer later in life from adverse renal and cardiovascular outcomes.• Perinatal risk factors that further predict the individual risk for adverse outcomes are not well known.What is New:• Poorer eGFR in adolescence was associated with male sex, longer ventilation and intra-ventricular hemorrhage at birth but not with blood pressure.• Former ELBW infants had higher blood pressures compared to controls, but no microalbuminuria.• This knowledge can lead to potential precision medicine, safer neonatal therapeutic regimens for ELBW infants, a more intensive follow-up and earlier treatment initiation for children at highest risk.

Exploration of Gene Therapy for Alport Syndrome.

Alport syndrome is a hereditary disease caused by mutations in the genes encoding the alpha 3, alpha 4, and alpha 5 chains of type IV collagen. It is characterized by hematuria, proteinuria, progressive renal dysfunction, hearing loss, and ocular abnormalities. The main network of type IV collagen in the glomerular basement membrane is composed of α3α4α5 heterotrimer. Mutations in these genes can lead to the replacement of this network by an immature network composed of the α1α1α2 heterotrimer. Unfortunately, this immature network is unable to provide normal physical support, resulting in hematuria, proteinuria, and progressive renal dysfunction. Current treatment options for Alport syndrome include angiotensin-converting enzyme inhibitors and angiotensin receptor blockers, which aim to alleviate glomerular filtration pressure, reduce renal injury, and delay the progression of renal dysfunction. However, the effectiveness of these treatments is limited, highlighting the need for novel therapeutic strategies and medications to improve patient outcomes. Gene therapy, which involves the use of genetic material to prevent or treat diseases, holds promise for the treatment of Alport syndrome. This approach may involve the insertion or deletion of whole genes or gene fragments to restore or disrupt gene function or the editing of endogenous genes to correct genetic mutations and restore functional protein synthesis. Recombinant adeno-associated virus (rAAV) vectors have shown significant progress in kidney gene therapy, with several gene therapy drugs based on these vectors reaching clinical application. Despite the challenges posed by the structural characteristics of the kidney, the development of kidney gene therapy using rAAV vectors is making continuous progress. This article provides a review of the current achievements in gene therapy for Alport syndrome and discusses future research directions in this field.

ASSOCIATION OF SEVERE SLEEP APNOEA IN PRIMARY ALDOSTERONISM

Objective: It is well known that sleep apnoea and primary aldosteronism are related. However, it is unclear whether aldosterone excess contributes to the severity of sleep apnoea. We investigated factors correlated with sleep apnoea in patients with primary aldosteronism: the endocrine system, including aldosterone, cardiac function, renal function, and blood pressure. Design and method: We performed a 3% oxygen saturation index with a pulse oximeter in 50 patients (54% male, 49 ± 7.3 years) diagnosed with primary aldosteronism scheduled for adrenal vein sampling in 2017-2020. 3% oxygen saturation index results were classified as mild (less than 5), moderate (5-15), or severe(15 and above) sleep apnoea. In addition, we compared aldosterone (radioimmunoassay), renin activity, aldosterone/renin activity, brain natriuretic peptide, estimated glomerular filtration rate and blood pressure at the initial visit in the severe group and other groups. Results: The severe group did not have higher aldosterone than the mild (192.7 ± 114.7 vs 238.9 ± 128.8 pg/mL, P=0.640) and moderate (192.7 ± 114.7 vs 187.5 ± 85.5 pg/mL, P=0.995) groups, and the same results were obtained for renin activity and aldosterone/renin activity. In other parameters, estimated glomerular filtration rate was not significantly different between groups, but systolic blood pressure at the initial visit in the severe group was significantly higher than in the mild (175.3±25.7 vs 144.8±18.7 mmHg, P=0.003) and moderate (175.3±25.7 vs 143.0±18.5 mmHg, P=0.003) groups. Similarly, brain natriuretic peptide in the severe group was significantly higher than in the mild (53.5±90.0 vs 12.7±8.3 pg/mL, P=0.020) and moderate (53.5±90.0 vs 10.7±11.2, P=0.014) groups. Conclusions: Our results showed that aldosterone excess did not contribute to the severity of sleep apnoea. However, severe sleep apnoea was significantly associated with elevated systolic blood pressure and brain natriuretic peptide.

Tailored Nutritional Education Program Improves Dietary Compliance and Clinical Outcomes in Chronic Kidney Disease Patients

This study examined the impact of a tailored nutritional education program on dietary compliance and clinical outcomes in chronic kidney disease patients. The study included 440 participants who were randomly divided into an intervention group (n = 220), which received a customized nutritional education program and a control group (n = 220), which received standard treatment without additional dietary supervision. The educational intervention, designed to address key dietary adjustments, was delivered through individual and group sessions, with monthly follow-ups and instructional materials in print and digital formats. Nutrient intake was closely monitored, particularly potassium, phosphate, and protein intake. Clinical outcomes such as serum creatinine levels, glomerular filtration rate, blood pressure, and electrolyte levels were measured at baseline and at six months after the intervention. Dietary compliance was assessed using a validated questionnaire. Results indicated significant improvements in dietary compliance in the intervention group, with notable reductions in potassium and phosphate intake compared to the control group. The intervention group also demonstrated better protein regulation. These changes in nutrient intake were associated with improvements in clinical outcomes, including enhanced glomerular filtration rate, stabilized serum creatinine levels, and improved blood pressure control. These findings suggest that tailored nutritional education programs can significantly enhance dietary adherence and improve clinical outcomes in chronic kidney disease patients, highlighting the importance of personalized dietary interventions in managing chronic conditions.

Clinical implications of primary “occult” vesicoureteral reflux in male children

ObjectivesTo compare characteristics and outcomes of vesicoureteral reflux (VUR) detected solely on isotopic cystography (IC) (“occult” VUR) with voiding cystourethrography (VCUG)-detected VUR.Materials and methodsBetween 2015 and 2020, we retrospectively enrolled all male children first undergoing VCUG and, if negative, IC in the same session. Kidney injury (KI) was defined by abnormal estimated glomerular filtration rate and/or blood pressure and/or proteinuria.ResultsWe enrolled 421 males with a median age of 3 months and a follow-up of 5.3 years. None exhibited KI initially, but 10% of those with VUR developed KI during follow-up. Two hundred and twenty-two patients (52.7%) did not show VUR, 152 (36.1%) had VCUG-diagnosed VUR, and 47 (11.2%) had occult VUR. Therefore, 47/199 patients (23.6%) with VUR had occult VUR. Among these, 34/47 (72.3%) had dilated VUR, and 22/47 (46.8%) exhibited split renal function < 45% and/or scar (scintigraphic damage). Compared to patients with occult VUR, those with VCUG-diagnosed VUR showed a similar prevalence of febrile urinary tract infection (fUTI) before and after VUR diagnostics and KI at the last follow-up but a higher prevalence of dilated VUR, of scintigraphic damage, and underwent surgery more frequently. At multiple logistic regression analysis, patients with VCUG-diagnosed VUR presented an increased risk of fUTI either before or after VUR diagnosis and of KI, while patients with occult VUR presented an increased risk of fUTI before (and among patients with dilated VUR also after) VUR diagnosis and of KI.ConclusionOccult VUR affects 23.6% of male children with VUR with a non-negligible risk of VUR-associated KI and fUTI. IC could select, among males with recurrent fUTIs and negative VCUG, those requiring surgery for a possible dilated occult VUR.Clinical relevance statementVesicoureteral reflux may be overlooked in 25% of boys during VCUG, yet they are at risk of fUTIs and KI. In case of recurrent infections post-negative cystourethrography, IC could detect occult reflux, guiding surgical intervention.

Oligonephronia: another piece in the CKDu jigsaw?

Rates of chronic kidney disease of unknown etiology are high in Aguascalientes, Mexico. Kidneys of adolescents are small by ultrasonography, compatible with oligonephronia, whereas proteinuria and higher estimated glomerular filtration rates and blood pressures among those with relatively higher kidney volumes probably flag relatively greater degrees of compensatory hypertrophy. Glomerulomegaly and podocytopathy, and later segmental glomerulosclerosis in biopsies, suggest a cascade driven by nephron deficiency. Better measures of glomerular number and volume should improve understanding, facilitate risk assessment, and guide interventions.

Effect of Spironolactone on Kidney Function in Kidney Transplant Recipients (the SPIREN trial): A Randomized Placebo-Controlled Clinical Trial.

Long-term kidney allograft survival is hampered by progressive interstitial fibrosis and tubular atrophy. The SPIREN trial tested the hypothesis that the mineralocorticoid receptor antagonist spironolactone stabilizes kidney function and attenuates glomerular barrier injury in kidney transplant patients treated with calcineurin inhibitors. Randomized, placebo-controlled, double blind clinical trial including 188 prevalent kidney transplant patients. Patients were randomized to spironolactone or placebo for three years. Glomerular filtration rate was measured along with proteinuria and kidney fibrosis. The primary endpoint was change in measured glomerular filtration rate. Secondary outcomes were 24h proteinuria, kidney allograft fibrosis and cardiovascular events. Measured glomerular filtration rates, 24h proteinuria and blood pressure were determined yearly. Kidney biopsies were collected at baseline and after two years (n=48). Fibrosis was evaluated by quantitative stereology and classified according to Banff. The groups were comparable at baseline except for slightly older allografts in the spironolactone group. Spironolactone reduced measured glomerular filtration rates (up to -7.6 (95% CI -10.9;-4.3) ml/min compared to placebo) independently of time since transplantation and blood pressure with no impact on the kidney function curve over time and reduced 24h proteinuria after one year. There was no significant effect of spironolactone on the development of interstitial fibrosis. Spironolactone added to standard therapy for three years in kidney transplant patients did not improve kidney function, long-term proteinuria or interstitial fibrosis.

Long-term safety of dietary salt: A 5-year ProspEctive rAndomized bliNded and controlled stUdy in healThy aged cats (PEANUT study).

High-salt diets promote urine dilution and decrease urolithiasis risk. Prospectively evaluate the safety of chronic high dietary salt intake (randomized controlled trial). Twenty research colony neutered, healthy aged cats (11.5 years [10.0-11.6], median [interquartile range]). Healthy cats were randomized to control or high-salt dry diets (sodium: 1.02 ± 0.16 [mean, SD] and 3.26 ± 0.30 g/Mcal metabolizable energy [ME], respectively; chloride: 2.26 ± 0.33 and 5.71 ± 0.28 g/Mcal ME, respectively), fed for up to 60 months. Assessments included CBC, plasma biochemistry, urinalysis, glomerular filtration rate (GFR), blood pressure, renal and cardiac (conventional Doppler and 2-dimensional color tissue Doppler) imaging, annually. Cats that died or were euthanized underwent necropsy. Diet effects over time were evaluated with linear mixed models. Follow-up duration (median [Interquartile range]) was similar between the control (38.7 months [28.6-48.2]) and high-salt group (51.4 months [45.7-59.0]). Diet had no significant effect on changes in GFR, blood pressure, plasma creatinine concentration, end-diastolic left ventricular (LV) wall thicknesses, LV internal diameters, LV systolic function, left atrial size, or systolic and diastolic Doppler variables. One control cat developed hypertension. One high-salt group cat developed persistent azotemia. Serial plasma biochemistry and urine specific gravity suggested early chronic kidney disease in 4 nonazotemic cats (2 per group), consistent with necropsy findings. In healthy aged cats, a commercial veterinary diet containing 3.26 ± 0.30 g/Mcal ME sodium was safe with regard to renal and cardiac function for up to 5 years.

Changes in medical therapy after cardiac resynchronization in patients with heart failure: insights from the U.S. Veterans Affairs healthcare system

Abstract Background Patients with heart failure with reduced ejection fraction (HFrEF) are often not treated with comprehensive guideline directed medical therapy (GDMT) due to hemodynamic and renal limitations. Cardiac resynchronization therapy (CRT) improves hemodynamics in patients with HFrEF and ventricular dyssynchrony. Whether CRT facilitates intensification of GDMT in patients with HFrEF has not been well-studied. Purpose To assess pre-procedure GDMT (B-blocker, ACEI [angiotensin converting enzyme inhibitor]/ARB [angiotensin receptor blocker], ARNI [angiotensin receptor neprilysin inhibitor], MRA [mineralocorticoid receptor antagonist], SGLT2i [sodium-glucose cotransporter-2 inhibitor]) utilization in HFrEF patients who received CRT and to compare changes in GDMT in patients who received CRT with patients who received implantable cardioverter-defibrillator (ICD). Methods Veterans with left ventricular ejection fraction (LVEF) 35% who received CRT or ICD from Feb 22, 2000 – Jul 28, 2022 were identified. Patients with end-stage renal disease were excluded. Changes in GDMT 12-months following device implant were characterized and compared between CRT and ICD recipients. Mixed effects logistic regression models were generated to evaluate associations between receipt of CRT and the composite of therapy initiation, dose increase, or target dose achievement compared with ICD. Models were adjusted for clinical characteristics and pre-implant GDMT utilization. Similar models were developed to evaluate the adjusted associations between CRT and changes in estimated glomerular filtration rate (eGFR) and blood pressure (BP) compared with ICD. Results A total of 2,082 CRT recipients and 7,263 ICD recipients were identified. Pre-procedure heart rate, BP, serum potassium, and eGFR were within normal ranges and similar between groups. Prior to device implant, ACEI/ARB/ARNI were most frequently prescribed (91%), followed by -blockers (88%), MRA (46%), and SGLT2i (33% in post-SGLT2i era). Pre-procedure GDMT was similar between CRT and ICD recipients. At 12 months follow-up, CRT was independently associated with increased odds of therapy initiation, dose increase, or target dose achievement for ACEI/ARB/ARNI, ARNI, B-blockers, and MRA (Figure 1). ICD was associated with a decline in eGFR while CRT was associated with an increase in eGFR (mean [standard deviation]: -0.95 [0.17] vs. +0.6 [0.29]; p&amp;lt;0.01), while no differences were observed in BP or LVEF at 12 months. Conclusions In a large, contemporary cohort of patients with HFrEF, most patients were not prescribed MRA or SGLT2i prior to receiving CRT or ICD despite no apparent renal or blood pressure-related contraindications. CRT is associated with increased odds of the composite of initiation, dose increase, or target dose achievement for ACEI/ARB/ARNI, ARNI, B-blockers, and MRA compared with ICD. GDMT intensification may be mediated by beneficial changes in kidney function in CRT recipients.Figure 1

Modeling the renoprotective mechanisms of SGLT2 inhibition in hypertensive chronic kidney disease.

Sodium-glucose cotransporter (SGLT)-2 inhibitors have recently been approved for chronic kidney disease (CKD) based on their ability to lower proteinuria and slow CKD progression independent of diabetes status. In diabetic renal disease, modulation of tubuloglomerular feedback (TGF) leading to lower intraglomerular pressure has been postulated as one of the mechanisms of renal protection with SGLT2 inhibition; however, this mechanism has not been sufficiently explored in non-diabetic CKD. We hypothesized that SGLT2 inhibition exerts renoprotection in CKD through increasing TGF despite normoglycemia. To test this hypothesis, we used an integrative mathematical model of human physiology, HumMod. Stage 3 CKD conditions were simulated by reducing nephron mass which was associated with hypertension, low glomerular filtration rate (GFR) (55 mL/min), hyperfiltration of remnant nephrons, elevated albuminuria (500 mg/day), and minimal levels of urinary glucose (0.02 mmol/L). SGLT2 inhibition was associated with acute reductions in GFR associated with afferent arteriolar vasoconstriction due to TGF. After 12 months, glomerular pressure, nephron damage, and chronic GFR decline were reduced with SGLT2 inhibition with additional SGLT1 inhibitory effects further enhancing these effects. This model supports the use of SGLT2 inhibitors to reduce hyperfiltration in CKD and mitigate renal disease progression, even in the absence of diabetes.

Soy peptides ameliorate the progression of chronic kidney disease in mice via inhibition of inflammation

For patients with chronic kidney disease (CKD), adequate protein intake is required to cope with proteinuria-induced protein loss, but excessive protein consumption may increase renal pressure and exacerbate kidney injury. In contrast to macromolecular proteins, peptides with high tissue permeability and biological activity can efficiently serve as protein sources without exerting glomerular pressure. To investigate the potential of peptides as nutritional intervention in CKD, we initially optimized CKD mouse model by treating with 75 mg/kg/day adenine for up to 21 days. Subsequently, we confirmed that peptides exhibited higher increase in survival rate of CKD mice compared to proteins, possibly due to their relatively high oligopeptide levels of 64.5%. Additionally, compared to positive control group, the soy peptides replacement feed significantly reduced serum urea nitrogen levels (15.4%, P < 0.05) and notably decreased the cross-sectional area of renal tubules (13.1%, P < 0.05) as observed through HE staining. The findings further indicated that soy peptides ameliorated kidney damage by inhibiting inflammatory factors TNF-α and IL-6 expression. Combined with peptides composition analysis, soy peptides were shown to aid in regulating the acid-base balance in mice with CKD. In summary, this study evidenced that soy peptides are viable protein source for nutritional intervention to ameliorate the progression of CKD.

Retention of Agricultural Workers Participating in a Renal Longitudinal Study

ABSTRACT Objectives The relationship between heat stress, chronic kidney diseases and acute kidney injury has been documented in cross-sectional studies with agricultural workers. However, only a few international studies have assessed renal function in agricultural workers longitudinally. Our research study, Occupational Heat Exposure and Renal Dysfunction (OHEaRD) is the first longitudinal study in the U.S. that monitored renal function in agricultural workers five times over the course of 32-months. The main objectives of this study were to evaluate the rate of retention and identify predictors associated with retention in a longitudinal study with agricultural workers. Methods In January 2020, we enrolled 119 Florida agricultural workers to observe on 5 workdays over 32 months. Retention was defined by the number of follow-up visits that a participant attended, the consistency of visit attendance, and attendance at the last visit. Participants were provided hemoglobin A1C, lipid panel, creatinine measurement, glomerular filtration rate (eGFR), blood pressure, and body mass index results and an incentive gift card were handed out to participants at each visit. Results Four enrollees did not participate on any workday, thus analysis concentrated on the remaining 115 participants. The majority of participants (64%) completed the 32-month study, 78% completed at least 4 visits, and 55% completed all 5 visits. The statistically significant predictors of higher retention among this study were being older in age (p=0.02), Mexican nationality (p=0.004), working in ferneries (p=0.009), more years working in agriculture (p=0.02), and higher total cholesterol (p=0.02). Appreciation for the health tests was associated with greater participation at the final visit (p=0.01). Conclusion Retention in longitudinal studies is crucial to better understand kidney disease among agricultural workers, an understudied population. Participants reported valuing the access to health results, indicating that implementing point-of-care health screenings and providing the health results to each participant is a good retention strategy. There was some evidence that a participant living with or being related to a fellow co-participant could impact retention as they either showed up or missed visits together, suggesting recruiting from the same household may reduce retention.

Reno- and cardioprotective molecular mechanisms of SGLT2 inhibitors beyond glycemic control - from bedside to bench.

Large placebo-controlled clinical trials have shown that sodium-glucose cotransporter-2 inhibitors (SGLT2i) delay the deterioration of renal function and reduce cardiovascular events in a glucose-independent manner, thereby ultimately reducing mortality in patients with chronic kidney disease (CKD) and/or heart failure. These exiting clinical data stimulated preclinical studies aiming to understand the observed clinical effects. In animal models, it was shown that the beneficial effect of SGLT2i on the tubuloglomerular feedback (TGF) improves glomerular pressure and reduces tubular workload by improving renal haemodynamics, which appears to be dependent on salt intake. High salt intake might blunt the SGLT2i effects on the TGF. Beyond the salt-dependent effects of SGLT2i on renal haemodynamics, the beneficial effects of SGLT2i on CKD progression are at least partly mediated by targeting TGF-β1 and or STAT3 and or AMPK signaling pathways affecting macrophage differentiation and polarization as well as inhibiting the activation of inflammatory factors within macrophages. As macrophages are also important cells mediating atherosclerosis and myocardial remodeling after injury, the inhibitory effects of SGLT2i on macrophage differentiation and inflammatory responses may also play a role in stabilizing atherosclerotic plaques and ameliorating myocardial inflammation and fibrosis. Recent studies suggest that SGLT2i may also act directly on the Na+/H+ exchanger and Late-INa in cardiomyocytes thus reducing Na+ and Ca2+ overload-mediated myocardial damage, but studies in this area are limited. In addition, the renal-cardioprotective mechanisms of SGLT2i include systemic effects on the sympathetic nervous system, blood volume, salt excretion and energy metabolic patterns.

COMPARISON OF EFFICACY IN RENOPROTECTION BETWEEN AZILSARTAN AND ENALAPRIL: A RANDOMIZED CONTROLLED TRIAL

Background: Angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin-receptor blockers (ARBs) are reported to improve renal outcomes among patients with hypertension and chronic kidney disease (CKD), but there might be substantial differences in their renoprotective effects. Azilsartan medoxomil is a relatively new available ARB, highly specific angiotensin type 1 receptor and superior in terms of blood pressure reduction, with respect to other ARBs.&#x0D; Methods: The study employed a randomized controlled trial; hypertensive subjects with albuminuria &gt;30 mg/g creatinine at the outpatient clinic, Phramongkutklao Hospital, Bangkok, Thailand were randomly assigned to azilsartan 40-80 mg/day (n=27) or enalapril 10-40 mg/day (n=23) for 24 weeks. The primary outcome was the change in urine albumin creatinine ratio (UACR). UACR, estimated glomerular filtration rate (GFR), blood pressure and serum electrolytes were evaluated at baseline, 12 and 24 weeks.&#x0D; Results: A total of 50 patients with hypertension and albuminuria were recruited. At the end of treatment, systolic blood pressure level was significantly reduced in the azilsartan group compared with the enalapril group (-12.2 mmHg [95%CI -18.9 to -5.5] vs. -1.1 mmHg [95% -7.8 to 5.7], p=0.021). In addition, at 24 weeks, significantly reduced median UACR was observed in the azilsartan group compared with that of the enalapril group (-59.9 mg/g Cr [95% CI -284.6 to -31.0] vs. -40.4 mg/gCr [95% CI -129.4 to 88.3], p=0.026)). No statistically significant difference was found between the two groups in hyperkalemia, estimated GFR, acute kidney injury and serious adverse events.&#x0D; Conclusion: This study demonstrated that azilsartan had superior antihypertensive and albuminuric efficacy compared with the standard dose of enalapril without increasing adverse events.

Renal Oxygen Demand and Nephron Function: Is Glucose a Friend or Foe?

The kidneys and heart work together to balance the body's circulation, and although their physiology is based on strict inter dependence, their performance fulfills different aims. While the heart can rapidly increase its own oxygen consumption to comply with the wide changes in metabolic demand linked to body function, the kidneys physiology are primarily designed to maintain a stable metabolic rate and have a limited capacity to cope with any steep increase in renal metabolism. In the kidneys, glomerular population filters a large amount of blood and the tubular system has been programmed to reabsorb 99% of filtrate by reabsorbing sodium together with other filtered substances, including all glucose molecules. Glucose reabsorption involves the sodium-glucose cotransporters SGLT2 and SGLT1 on the apical membrane in the proximal tubular section; it also enhances bicarbonate formation so as to preserve the acid-base balance. The complex work of reabsorption in the kidney is the main factor in renal oxygen consumption; analysis of the renal glucose transport in disease states provides a better understanding of the renal physiology changes that occur when clinical conditions alter the neurohormonal response leading to an increase in glomerular filtration pressure. In this circumstance, glomerular hyperfiltration occurs, imposing a higher metabolic demand on kidney physiology and causing progressive renal impairment. Albumin urination is the warning signal of renal engagement over exertion and most frequently heralds heart failure development, regardless of disease etiology. The review analyzes the mechanisms linked to renal oxygen consumption, focusing on sodium-glucose management.