Adenine crosses the biomarker bridge: from 'omics to treatment in diabetic kidney disease.

Enabling the early detection and prevention of diabetic kidney damage has potential to substantially reduce the global burden of kidney failure. There is a critical need for identification of mechanistic biomarkers that can predict progression and serve as therapeutic targets. In this issue of the JCI, Sharma and colleagues used an integrated multiomics approach to identify the metabolite adenine as a noninvasive biomarker of progression in early diabetic kidney disease (DKD). The highest tertile of urine adenine/creatinine ratio (UAdCR) was associated with higher risk for end-stage kidney disease and mortality across independent cohorts, including participants with early DKD without macroalbuminuria. Spatial metabolomics, single-cell transcriptomics, and experimental studies localized adenine to regions of tubular pathology and implicated the mTOR pathway in adenine-mediated tissue fibrosis. Inhibition of endogenous adenine production was protective in a diabetic model. These findings exemplify the potential for multiomics to uncover mechanistic biomarkers and targeted therapies in DKD.

Associations Between Albuminuria and Mortality Among US Adults by Demographic and Comorbidity Factors.

Background Albuminuria is a known marker of mortality risk. Whether the association between albuminuria and mortality differs by demographic and comorbidity factors remains unclear. Therefore, we sought to determine whether albuminuria is differentially associated with mortality. Methods and Results This study included 49 640 participants from the National Health and Nutrition Examination Survey (1999-2018). All-cause mortality through 2019 was linked from the National Death Index. Multivariable-adjusted Poisson regression models were used to determine whether levels of urine albumin-to-creatinine ratio (ACR) were associated with mortality. Models were adjusted for demographic, socioeconomic, behavioral, and clinical factors. Mean age in the population was 46 years, with 51.3% female, and 30.3% with an ACR ≥10 mg/g. Over a median follow-up of 9.5 years, 6813 deaths occurred. Compared with ACR <10, ACR ≥300 was associated with increased risk of mortality by 132% overall (95% CI, 2.01-2.68), 124% among men (95% CI, 1.84-2.73), 158% among women (95% CI, 2.14-3.11), 130% among non-Hispanic White adults (95% CI: 1.89-2.79), 135% among non-Hispanic Black adults (95% CI, 1.82-3.04), and 114% among Hispanic adults (95% CI, 1.55-2.94). Compared with ACR <10, ACR ≥300 was associated with increased risk of mortality by 148% among individuals with neither hypertension nor hypercholesterolemia (95% CI, 1.69-3.64), 128% among individuals with hypertension alone (95% CI, 1.86-2.79), and 166% among individuals with both hypertension and hypercholesterolemia (95% CI, 2.18-3.26). Conclusions We found strong associations between albuminuria and mortality risk, even at mildly increased levels of albuminuria. Associations persisted across categories of sex, race or ethnicity, and comorbid conditions, with subtle differences.

Management of Lupus Nephritis: New Treatments and Updated Guidelines.

Management of lupus nephritis has evolved considerably over the past years. Here, we provide a comprehensive review of clinical trials that form the basis for the Kidney Disease: Improving Global Outcomes and EULAR/ERA-EDTA updated guidelines and present day trials that will change the landscape of lupus nephritis therapy in years to come. In addition, we highlight the issues related to cost of therapy, resistant disease, and downstream adverse effects of specific therapies.

Identification of Glomerular and Plasma Apolipoprotein M as Novel Biomarkers in Glomerular Disease.

Introduction: Dysregulation of sphingolipid and cholesterol metabolism contributes to the pathogenesis of glomerular diseases (GDs). Apolipoprotein M (ApoM) promotes cholesterol efflux and modulates the bioactive sphingolipid sphingosine-1-phosphate (S1P). Glomerular ApoM expression is decreased in patients with focal segmental glomerulosclerosis (FSGS). We hypothesized that glomerular ApoM deficiency occurs in GD and that ApoM expression and plasma ApoM correlate with outcomes. Methods: Patients with GD from the Nephrotic Syndrome Study Network (NEPTUNE) were studied. We compared glomerular mRNA expression of ApoM (gApoM), sphingosine kinase 1 (SPHK1), and S1P receptors 1 to 5 (S1PR1-5) in patients (n = 84) and controls (n = 6). We used correlation analyses to determine associations between gApoM, baseline plasma ApoM (pApoM), and urine ApoM (uApoM/Cr). We used linear regression to determine whether gApoM, pApoM, and uApoM/Cr were associated with baseline estimated glomerular filtration rate (eGFR) and proteinuria. Using Cox models, we determined whether gApoM, pApoM, and uApoM/Cr were associated with complete remission (CR) and the composite of end-stage kidney disease (ESKD) or ≥40% eGFR decline. Results: gApoM was reduced (P < 0.01) and SPHK1 and S1PR1 to 5 expression was increased (P < 0.05) in patients versus controls, consistent with ApoM/S1P pathway modulation. gApoM positively correlated with pApoM in the overall cohort (r = 0.34, P < 0.01) and in the FSGS (r = 0.48, P < 0.05) and minimal change disease (MCD) (r = 0.75, P < 0.05) subgroups. Every unit decrease in gApoM and pApoM (log2) was associated with a 9.77 ml/min per 1.73 m2 (95% confidence interval [CI]: 3.96-15.57) and 13.26 ml/min per 1.73 m2 (95% CI: 3.57-22.96) lower baseline eGFR, respectively (P < 0.01). From Cox models adjusted for age, sex, or race, pApoM was a significant predictor of CR (hazard ratio [HR]: 1.85; 95% CI: 1.06-3.23). Conclusions: pApoM is a potential noninvasive biomarker of gApoM deficiency and strongly associates with clinical outcomes in GD.

Retrospective analysis of the impact of severe obesity on kidney transplant outcomes.

BACKGROUND: The prevalence of obesity among kidney transplant recipients is rising. We sought to determine the association between recipient body mass index (BMI) and post-transplant complications. METHODS: Single-center, retrospective cohort study of all adult kidney transplant recipients from 2004 to 2020. Recipients were stratified into four BMI categories: normal-weight (BMI 18.5-24.9 kg/m2, n = 1020), overweight (BMI 25-29.9 kg/m2, n = 1002), moderately obese (BMI 30-34.9 kg/m2, n = 510) and severely-to-morbidly obese (BMI ≥35 kg/m2, n = 274). Logistic regression was used to estimate the association between BMI category and surgical site infections (SSIs). RESULTS: Recipients with BMI ≥35 kg/m2 had significantly higher rates of SSIs (P < .0001) compared with recipients in all other categories. On multivariable analysis, recipients with BMI ≥35 kg/m2 had increased odds of SSIs compared with normal-weight recipients [odds ratio (OR) 3.34, 95% confidence interval (CI) 1.55-7.22, P = .022). On multivariable and Kaplan-Meier analyses, no BMI groups demonstrated increased odds for death-censored graft failure. CONCLUSION: Severe obesity in kidney transplant recipients is associated with increased SSIs, but not kidney allograft failure.

Novel Therapies for Alport Syndrome.

Alport syndrome (AS) is a hereditary kidney disease associated with proteinuria, hematuria and progressive kidney failure. It is characterized by a defective glomerular basement membrane caused by mutations in type IV collagen genes COL4A3/A4/A5 which result in defective type IV collagen α3, α4, or α5 chains, respectively. Alport syndrome has three different patterns of inheritance: X-linked, autosomal and digenic. In a study of CKD of unknown etiology type IV collagen gene mutations accounted for the majority of the cases of hereditary glomerulopathies which suggests that AS is often underrecognized. The natural history and prognosis in patients with AS is variable and is determined by genetics and environmental factors. At present, no preventive or curative therapies exist for AS. Current treatment includes the use of renin-angiotensin-aldosterone system inhibitors which slow progression of kidney disease and prolong life expectancy. Ramipril was found in retrospective studies to delay the onset of ESKD and was recently demonstrated to be safe and effective in children and adolescents, supporting that early initiation of Renin Angiotensin Aldosterone System (RAAS) blockade is very important. Mineralocorticoid receptor blockers might be favorable for patients who develop "aldosterone breakthrough." While the DAPA-CKD trial suggests a beneficial effect of SGLT2 inhibitors in CKD of non-metabolic origin, only a handful of patients had Alport in this cohort, and therefore conclusions can't be extrapolated for the treatment of AS with SGLT2 inhibitors. Advances in our understanding on the pathogenesis of Alport syndrome has culminated in the development of innovative therapeutic approaches that are currently under investigation. We will provide a brief overview of novel therapeutic targets to prevent progression of kidney disease in AS. Our review will include bardoxolone methyl, an oral NRf2 activator; lademirsen, an anti-miRNA-21 molecule; sparsentan, dual endothelin type A receptor (ETAR) and angiotensin 1 receptor inhibitor; atrasentan, oral selective ETAR inhibitor; lipid-modifying agents, including cholesterol efflux transporter ATP-binding cassette A1 (ABCA1) inducers, discoidin domain receptor 1 (DDR1) inhibitors and osteopontin blocking agents; the antimalarial drug hydroxychloroquine; the antiglycemic drug metformin and the active vitamin D analog paricalcitol. Future genomic therapeutic strategies such as chaperone therapy, genome editing and stem cell therapy will also be discussed.

Associations of sodium and potassium intake with chronic kidney disease in a prospective cohort study: findings from the Hispanic Community Health Study/Study of Latinos, 2008-2017.

BACKGROUND: According to dietary recommendations, reduction of sodium intake has potential to reduce Chronic Kidney Disease (CKD) risk; however the role of dietary potassium and the sodium -to- potassium ratio in the development of CKD is unclear. METHODS: We studied 9778 participants of the Hispanic Community Health Study/Study of Latinos (HCHS/SOL) from four US urban communities. Participants were aged 18-74 yrs., free from CKD at baseline in 2008-2011 and re-examined between 2014 and - 2017. Dietary intake of sodium, potassium and the ratio of dietary sodium -to- potassium were measured from two baseline 24-h dietary recalls. Incident CKD was defined as: 1) estimated glomerular filtration rate (eGFR) decline of 1 unit per year and eGFR < 60 ml/min/1.73m2 or 2) albumin to creatinine ratio ≥ 30 mg/g at the follow-up visit. We used multivariable survey weighted Poisson regression to estimate adjusted incident rates of incident CKD. RESULTS: At baseline, mean age was 41 years. Average follow up time was 6.2 years. From fully adjusted Poisson regression analyses, self-reported sodium intake was not associated with incident CKD. However, for each 500 mg decrement in potassium intake, there was an 11% increase risk of incident CKD (IRR = 1.11, 95% CI = 1.00, 1.24). Additionally, every 1 M ratio increment of sodium -to -potassium ratio was associated with a 21% increased risk of incident CKD (IRR = 1.21, 95% CI = 1.02, 1.45), p < 0.05). CONCLUSIONS: We conclude that diets low in potassium and high in sodium are associated with increased risk of developing chronic kidney disease among healthy US Hispanic/Latino adults.

Sphingosine-1-Phosphate Metabolism and Signaling in Kidney Diseases.

In the past few decades, sphingolipids and sphingolipid metabolites have gained attention because of their essential role in the pathogenesis and progression of kidney diseases. Studies in models of experimental and clinical nephropathies have described accumulation of sphingolipids and sphingolipid metabolites, and it has become clear that the intracellular sphingolipid composition of renal cells is an important determinant of renal function. Proper function of the glomerular filtration barrier depends heavily on the integrity of lipid rafts, which include sphingolipids as key components. In addition to contributing to the structural integrity of membranes, sphingolipid metabolites, such as sphingosine-1-phosphate (S1P), play important roles as second messengers regulating biologic processes, such as cell growth, differentiation, migration, and apoptosis. This review will focus on the role of S1P in renal cells and how aberrant extracellular and intracellular S1P signaling contributes to the pathogenesis and progression of kidney diseases.

Role of Sphingolipid Signaling in Glomerular Diseases: Focus on DKD and FSGS.

Sphingolipids are well-recognized as major players in the pathogenesis of many human diseases, including chronic kidney disease. The kidney is a very sensitive organ to alterations in sphingolipid metabolism. The critical issues to be addressed in this review relate to the role of sphingolipids and enzymes involved in sphingolipid metabolism in the pathogenesis of glomerular diseases with a special focus on podocytes, a key cellular component of the glomerular filtration barrier. Among several sphingolipids, we will highlight the role of ceramide, sphingosine, sphingosine-1-phosphate and ceramide-1-phosphate. Additionally, we will summarize the current knowledge with regard to the use of sphingolipids as therapeutic agents for the treatment of podocyte injury in kidney disease.

Sterol-O-acyltransferase-1 has a role in kidney disease associated with diabetes and Alport syndrome.

Defective cholesterol metabolism primarily linked to reduced ATP-binding cassette transporter A1 (ABCA1) expression is closely associated with the pathogenesis and progression of kidney diseases, including diabetic kidney disease and Alport Syndrome. However, whether the accumulation of free or esterified cholesterol contributes to progression in kidney disease remains unclear. Here, we demonstrate that inhibition of sterol-O-acyltransferase-1 (SOAT1), the enzyme at the endoplasmic reticulum that converts free cholesterol to cholesterol esters, which are then stored in lipid droplets, effectively reduced cholesterol ester and lipid droplet formation in human podocytes. Furthermore, we found that inhibition of SOAT1 in podocytes reduced lipotoxicity-mediated podocyte injury in diabetic kidney disease and Alport Syndrome in association with increased ABCA1 expression and ABCA1-mediated cholesterol efflux. In vivo, Soat1 deficient mice did not develop albuminuria or mesangial expansion at 10-12 months of age. However, Soat1 deficiency/inhibition in experimental models of diabetic kidney disease and Alport Syndrome reduced cholesterol ester content in kidney cortices and protected from disease progression. Thus, targeting SOAT1-mediated cholesterol metabolism may represent a new therapeutic strategy to treat kidney disease in patients with diabetic kidney disease and Alport Syndrome, like that suggested for Alzheimer's disease and cancer treatments.

Aldosterone blockade in chronic kidney disease.

Although blockade of the renin-angiotensin-aldosterone system with angiotensin-converting enzyme inhibitors or angiotensin-receptor blockers has become standard therapy for chronic kidney disease (CKD), renewed interest in the role of aldosterone in mediating the injuries and progressive insults of CKD has highlighted the potential role of treatments targeting the mineralocorticoid receptor (MR). Although salt restriction is an important component of mitigating the profibrotic effects of MR activation, a growing body of literature has shown that MR antagonists, spironolactone and eplerenone, can reduce proteinuria and blood pressure in patients at all stages of CKD. These agents carry a risk of hyperkalemia, but this risk likely can be predicted based on baseline renal function and mitigated using dietary modifications and adjustments of concomitant medications. Data on hard outcomes, such as progression to end-stage renal disease and overall mortality, still are lacking in patients with CKD.

Definition, identification and treatment of resistant hypertension in chronic kidney disease patients.

Resistant hypertension, the inability to achieve goal blood pressure despite the use of three or more appropriately dosed antihypertensive drugs (including a diuretic), remains a common clinical problem, especially in patients with chronic kidney disease (CKD). While the exact prevalence and prognosis of resistant hypertension in CKD patients remain unknown, resistant hypertension likely contributes significantly to increased cardiovascular risk and progression of kidney disease in this population. We review the identification and evaluation of patients with resistant hypertension, including the importance of 24-h ambulatory blood pressure monitoring in the identification of 'white-coat', 'masked' and 'non-dipper' hypertension, the latter of which has particular clinical and therapeutic importance in patients with resistant hypertension and CKD. We then discuss treatment strategies for resistant hypertension that target the pathophysiologic mechanisms underlying resistance to treatment, including persistent volume excess, incomplete renin-angiotensin-aldosterone system blockade and inadequate nocturnal blood pressure control. Finally, we propose a treatment algorithm for evaluation and treatment of resistant hypertension in patients with CKD.