Plasma metabolites and physical function in patients undergoing hemodialysis.

Impaired physical function contributes to falls, fractures, and mortality among patients undergoing dialysis. Using a metabolomic approach, we identified metabolite alterations and effect size-based composite scores for constructs of impaired gait speed and grip strength. 108 participants incident to dialysis had targeted plasma metabolomics via liquid chromatography-mass spectrometry and physical function assessed (i.e., 4 m walk, handgrip strength). Physical function measures were categorized as above/ below median, with grip utilizing sex-based medians. To develop composite scores, metabolites were identified via Wilcoxon uncorrected p < 0.05 and effect size > 0.40. Receiver operating characteristic analyses tested whether scores differentiated between above/below function groups. Participants were 54% male, 77% Black and 53 ± 14 y with dialysis vintage of 101 ± 50 days. Median (IQR) grip strength was 35.5 (11.1) kg (males) and 20 (8.4) kg (females); median gait speed was 0.82 (0.34) m/s. Of 246 measured metabolites, composite scores were composed of 22 and 12 metabolites for grip strength and gait speed, respectively. Area under the curve for metabolite composite was 0.88 (gait) and 0.911 (grip). Composite scores of physical function performed better than clinical parameters alone in patients on dialysis. These results provide potential pathways for interventions and needed validation in an independent cohort.

Gut Microbiota and Uremic Retention Solutes in Adults With Moderate CKD: A 6-Day Controlled Feeding Study.

OBJECTIVE: To determine serum and urine concentrations of the uremic retention solutes (URSs), indoxyl sulfate (IS), p-cresol sulfate (PCS), and trimethylamine N-oxide (TMAO), and gut microbiota composition in individuals with moderate chronic kidney disease (CKD) compared with matched adults without CKD in a 6-day controlled feeding study. DESIGN AND METHODS: This study was a secondary analysis in which 8 adults with moderate CKD were matched for age, sex, and race with 8 adults without CKD in a parallel-arm, 6-day controlled feeding study. IS, PCS, and TMAO were quantified using liquid chromatography-mass spectrometry in fecal samples, fasting serum, and fasting spot urine samples collected at the end of the feeding period. RESULTS: Fasting serum URS concentrations were 2.8 to 4.9x higher in CKD compared to controls (all P < .05). No differences were found in the composition of the gut microbiota between patients with and without CKD when analyzing samples for α-diversity, ß-diversity, and only minor abundance differences across taxa were apparent. Estimated glomerular filtration rate (eGFR) was inversely related to each serum URS in the whole cohort (all P < .01). However, within groups the relationships between eGFR and serum URS remained strong for CKD patients for IS and TMAO (both P < .05) but weakened for PCS (P = .10). eGFR was only correlated with urine PCS in the whole cohort (P = .03); within groups, no correlation for eGFR with any urine URS was observed. Only urine TMAO was higher in CKD compared to controls (P < .05). CONCLUSION: Serum URS concentrations are elevated in adults with CKD compared to matched non-CKD adults without differences in gut microbiota composition after consuming the same controlled study diet for 6 days. Future studies are needed to determine if specific dietary components may differentially alter the microbiota and URS.

Using machine learning to detect sarcopenia from electronic health records.

Introduction: Sarcopenia (low muscle mass and strength) causes dysmobility and loss of independence. Sarcopenia is often not directly coded or described in electronic health records (EHR). The objective was to improve sarcopenia detection using structured data from EHR. Methods: Adults undergoing musculoskeletal testing (December 2017-March 2020) were classified as meeting sarcopenia thresholds for 0 (controls), ≥1 (Sarcopenia-1), or ≥2 (Sarcopenia-2) tests. Electronic health record diagnoses, medications, and laboratory testing were extracted from the Indiana Network for Patient Care. Five machine learning models were applied to EHR data for predicting sarcopenia. Results: Of 1304 participants, 1055 were controls, 249 met Sarcopenia-1 and 76 met Sarcopenia-2. Sarcopenic participants were older, with higher fat mass, Charlson Comorbidity Index, and more chronic diseases. All models performed better for Sarcopenia-2 than Sarcopenia-1. The top performing models for Sarcopenia-1 were Logistic Regression [area under the curve (AUC) 71.59 (95% confidence interval [CI], 71.51-71.66)] and Multi-Layer Perceptron [AUC 71.48 (95%CI, 71.00-71.97)]. The top performing models for Sarcopenia-2 were Logistic Regression [AUC 91.44 (95%CI, 91.28-91.60)] and Support Vector Machine [AUC 90.81 (95%CI, 88.41-93.20)]. For the best Logistic Regression Model, important sarcopenia predictors included diabetes mellitus, digestive system complaints, signs and symptoms involving the nervous, musculoskeletal and respiratory systems, metabolic disorders, and kidney or urinary tract disorders. Opioids, corticosteroids, and antihyperlipidemic drugs were also more common among sarcopenic participants. Conclusions: Applying machine learning models, sarcopenia can be predicted from structured data in EHR, which may be developed through future studies to facilitate large-scale early detection and intervention in clinical populations.

Short-term beetroot juice supplementation improves muscle speed and power but does not reduce blood pressure or oxidative stress in 65-79 y old men and women.

We have previously demonstrated that acute ingestion of inorganic nitrate (NO3-)-rich beetroot juice (BRJ), a source of nitric oxide (NO) via the NO3- → nitrite (NO2-) → NO pathway, can improve muscle speed and power in older individuals. It is not known, however, whether this effect is maintained or perhaps even enhanced with repeated ingestion, or if tolerance develops as with organic nitrates, e.g., nitroglycerin. Using a double-blind, placebo-controlled, crossover design, we therefore studied 16 community-dwelling older (age 71 ± 5 y) individuals after both acute and short-term (i.e., daily for 2 wk) BRJ supplementation. Blood samples were drawn and blood pressure was measured periodically during each ∼3 h experiment, with muscle function determined using isokinetic dynamometry. Acute ingestion of BRJ containing 18.2 ± 6.2 mmol of NO3- increased plasma NO3- and NO2- concentrations 23 ± 11 and 2.7 ± 2.1-fold over placebo, respectively. This was accompanied by 5 ± 11% and 7 ± 13% increases in maximal knee extensor speed (Vmax) and power (Pmax), respectively. After daily supplementation for 2 wk, BRJ ingestion elevated NO3- and NO2- levels 24 ± 12 and 3.3 ± 4.0-fold, respectively, whereas Vmax and Pmax were 7 ± 9% and 9 ± 11% higher than baseline. No changes were observed in blood pressure or in plasma markers of oxidative stress with either acute or short-term NO3- supplementation. We conclude that both acute and short-term dietary NO3- supplementation result in similar improvements in muscle function in older individuals. The magnitudes of these improvements are sufficient to offset the decline resulting from a decade or more of aging and are therefore likely to be clinically significant.

The influence of acute dietary nitrate supplementation on skeletal muscle fatigue and recovery in older women.

Older individuals fatigue more rapidly during, and recover more slowly from, dynamic exercise. Women are particularly vulnerable to these deleterious effects of aging, which increases their risk of falling. We have shown that dietary nitrate (NO3 - ), a source of nitric oxide (NO) via the NO3 - → nitrite (NO2 - ) → NO pathway, enhances muscle speed and power in older individuals in the non-fatigued state; however, it is unclear if it reduces fatigability and/or improves recoverability in this population. Using a double-blind, placebo-controlled, crossover design, we studied 18 older (age 70 ± 4 years) women who were administered an acute dose of beetroot juice (BRJ) containing either 15.6 ± 3.6 or <0.05 mmol of NO3 - . Blood samples were drawn throughout each ~3 h visit for plasma NO3 - and NO2 - analysis. Peak torque was measured during, and periodically for 10 min after, 50 maximal knee extensions performed at 3.14 rad/s on an isokinetic dynamometer. Ingestion of NO3 - -containing BRJ increased plasma NO3 - and NO2 - concentrations by 21 ± 8 and 4 ± 4 fold, respectively. However, there were no differences in muscle fatigue or recovery. Dietary NO3 - increases plasma NO3 - and NO2 - concentrations but does not reduce fatigability during or enhance recoverability after high intensity exercise in older women.

The influence of acute dietary nitrate supplementation on skeletal muscle fatigue and recovery in older women.

Older individuals fatigue more rapidly during, and recover more slowly from, dynamic exercise. Women are particularly vulnerable to these deleterious effects of aging, which increases their risk of falling. We have shown that dietary nitrate (NO 3 - ), a source of nitric oxide (NO) via the NO 3 - → nitrite (NO 2 - ) → NO pathway, enhances muscle speed and power in older individuals in the non-fatigued state; however, it is unclear if it reduces fatigability and/or improves recoverability in this population. Using a double-blind, placebo-controlled, crossover design, we studied 18 older (age 70 ± 4 y) women who were administered an acute dose of beetroot juice (BRJ) containing either 15.6±3.6 or <0.05 mmol of NO 3 - . Blood samples were drawn throughout each ∼3 h visit for plasma NO 3 - and NO 2 - analysis. Peak torque was measured during, and periodically for 10 min after, 50 maximal knee extensions performed at 3.14 rad/s on an isokinetic dynamometer. Ingestion of NO 3 - -containing BRJ increased plasma NO 3 - and NO 2 - concentrations by 21±8 and 4±4 fold, respectively. However, there were no differences in muscle fatigue or recovery. Dietary NO 3 - increases plasma NO 3 - and NO 2 - concentrations but does not reduce fatigability during or enhance recoverability after high intensity exercise in older women.

Skeletal Muscle Complications in Chronic Kidney Disease.

PURPOSE OF REVIEW: To provide an overview of the recent literature investigating the pathophysiology of skeletal muscle changes, interventions for skeletal muscle, and effects of exercise in chronic kidney disease (CKD). RECENT FINDINGS: There are multiple CKD-related changes that negatively impact muscle size and function. However, the variability in the assessment of muscle size, in particular, hinders the ability to truly understand the impact it may have in CKD. Exercise interventions to improve muscle size and function demonstrate inconsistent responses that warrant further investigation to optimize exercise prescription. Despite progress in the field, there are many gaps in the knowledge of the pathophysiology of sarcopenia of CKD. Identifying these gaps will help in the design of interventions that can be tested to target muscle loss and its consequences such as impaired mobility, falls, and poor quality of life in patients with CKD.

Incidence and Importance of Calcium Deposition in Kidney Biopsy Specimens.

INTRODUCTION: Calcification on native kidney biopsy specimens is often noted by pathologists, but the consequence is unknown. METHODS: We searched the pathology reports in the Biopsy Biobank Cohort of Indiana for native biopsy specimens with calcification. RESULTS: Of the 4,364 specimens, 416 (9.8%) had calcification. We compared clinical and histopathology findings in those with calcification (n = 429) compared to those without calcification (n = 3,936). Patients with calcification were older, had more comorbidities, lower estimated glomerular filtration rates (eGFR), were more likely to have hyaline arteriosclerosis, interstitial fibrosis/tubular atrophy, and a primary pathologic diagnosis of acute tubular injury or acute tubular necrosis when compared to patients without calcification. Patients with calcium oxalate deposition alone, compared to calcium phosphate or mixed calcifications, had fewer comorbidities but were more likely to have a history of gastric bypass surgery or malabsorption and take vitamin D. In patients with two or more years of follow-up, multivariate analyses showed the presence of calcification (HR 0.59, 0.38-0.92, p = 0.02) and higher eGFR (HR 0.76, 0.73-0.79, p < 0.001), was associated with decreased likelihood of progressing to end-stage renal disease. The presence of calcification was also associated with a reduced slope/decline in eGFR compared to known biopsy and clinical risk factors for decline in kidney function. We hypothesized this was due to more recoverable acute kidney injury (AKI) and found more severe acute kidney injury network stage in patients with kidney calcification but also greater improvement over time. DISCUSSION/CONCLUSION: In summary, we demonstrated that calcification on kidney biopsy specimens was associated with a better prognosis than those without calcification due to the association with recoverable AKI.

The kidney protects against sepsis by producing systemic uromodulin.

Sepsis is a significant cause of mortality in hospitalized patients. Concomitant development of acute kidney injury (AKI) increases sepsis mortality through unclear mechanisms. Although electrolyte disturbances and toxic metabolite buildup during AKI could be important, it is possible that the kidney produces a protective molecule lost during sepsis with AKI. We have previously demonstrated that systemic Tamm-Horsfall protein (THP; uromodulin), a kidney-derived protein with immunomodulatory properties, falls in AKI. Using a mouse sepsis model without severe kidney injury, we showed that the kidney increases circulating THP by enhancing the basolateral release of THP from medullary thick ascending limb cells. In patients with sepsis, changes in circulating THP were positively associated with a critical illness. THP was also found de novo in injured lungs. Genetic ablation of THP in mice led to increased mortality and bacterial burden during sepsis. Consistent with the increased bacterial burden, the presence of THP in vitro and in vivo led macrophages and monocytes to upregulate a transcriptional program promoting cell migration, phagocytosis, and chemotaxis, and treatment of macrophages with purified THP increases phagocytosis. Rescue of septic THP-/- mice with exogenous systemic THP improved survival. Together, these findings suggest that through releasing THP, the kidney modulates the immune response in sepsis by enhancing mononuclear phagocyte function, and systemic THP has therapeutic potential in sepsis.NEW & NOTEWORTHY Specific therapies to improve outcomes in sepsis with kidney injury have been limited by an unclear understanding of how kidney injury increases sepsis mortality. Here, we identified Tamm-Horsfall protein, known to protect in ischemic acute kidney injury, as protective in preclinical sepsis models. Tamm-Horsfall protein also increased in clinical sepsis without severe kidney injury and concentrated in injured organs. Further study could lead to novel sepsis therapeutics.

Vasopressin for Post-kidney Transplant Hypotension.

Introduction: Hypotension after deceased donor kidney transplant (DDKT) is a risk factor for delayed graft function (DGF) and poor graft survival (GS). We hypothesize that vasopressin use in hypotensive DDKT recipients (DDKTRs) to increase blood pressure (BP) reduces DGF rates and is safe without increasing mortality. Methods: Group with vasopressin "study group" (n = 45) was defined as DDKTRs between 2012 and 2017 who required vasopressin for hypotension systolic BP (SBP) <120 mm Hg or diastolic BP (DBP) <60 mm Hg. DDKTRs with no-vasopressin "comparison group" (n = 90) were propensity score-matched DDKTRs between 2012 and 2017 without vasopressin use. Primary outcomes were GS, creatinine and allograft biopsy rate at 1 year, DGF rate, and death during transplant hospitalization. Results: Vasopressin group had lower mean maximum and minimum SBP and DBP in the operating room (OR). Median vasopressin start time post-DDKT was 2 hours (interquartile range [IQR] 1-6), and duration of use was 42 hours (IQR 24-63). DGF, creatinine at 1 year, and allograft biopsy rates were comparable. No deaths occurred during transplant hospitalization. Multivariable analysis did not find an effect of vasopressin use on GS. Conclusion: Treatment of hypotensive DDKTRs with vasopressin is safe and facilitated similar graft function and survival with that of nonhypotensive patients. In the absence of a randomized control trial, our study supports the safety of vasopressin therapy to prevent the adverse effects of hypotension.

Pharmacogenomics of Hypertension in CKD: The CKD-PGX Study.

Background: Patients with CKD often have uncontrolled hypertension despite polypharmacy. Pharmacogenomic drug-gene interactions (DGIs) may affect the metabolism or efficacy of antihypertensive agents. We report changes in hypertension control after providing a panel of 11 pharmacogenomic predictors of antihypertensive response. Methods: A prospective cohort with CKD and hypertension was followed to assess feasibility of pharmacogenomic testing implementation, self-reported provider utilization, and BP control. The analysis population included 382 subjects with hypertension who were genotyped for cross-sectional assessment of DGIs, and 335 subjects followed for 1 year to assess systolic BP (SBP) and diastolic BP (DBP). Results: Most participants (58%) with uncontrolled hypertension had a DGI reducing the efficacy of one or more antihypertensive agents. Subjects with a DGI had 1.85-fold (95% CI, 1.2- to 2.8-fold) higher odds of uncontrolled hypertension, as compared with those without a DGI, adjusted for race, health system (safety-net hospital versus other locations), and advanced CKD (eGFR <30 ml/min). CYP2C9-reduced metabolism genotypes were associated with losartan response and uncontrolled hypertension (odds ratio [OR], 5.2; 95% CI, 1.9 to 14.7). CYP2D6-intermediate or -poor metabolizers had less frequent uncontrolled hypertension compared with normal metabolizers taking metoprolol or carvedilol (OR, 0.55; 95% CI, 0.3 to 0.95). In 335 subjects completing 1-year follow-up, SBP (-4.0 mm Hg; 95% CI, 1.6 to 6.5 mm Hg) and DBP (-3.3 mm Hg; 95% CI, 2.0 to 4.6 mm Hg) were improved. No significant difference in SBP or DBP change were found between individuals with and without a DGI. Conclusions: There is a potential role for the addition of pharmacogenomic testing to optimize antihypertensive regimens in patients with CKD.

Postdialysis serum phosphate equilibrium in hemodialysis patients on a controlled diet and no binders.

BACKGROUND: Studies evaluating the change in serum phosphate post hemodialysis (HD) demonstrate an initial decline during dialysis but a rebound post dialysis. However, previous studies were done on usual diet and phosphate binders, with limited number of blood draws, confounding conclusions. We determined serum phosphate reduction, rebound, and equilibrium over 48 h in HD patients consuming a controlled, low phosphorus diet without binders. METHODS: Serum phosphate (mg/dL) was analyzed before and after a HD treatment and frequently during the ensuing 48 h intradialytic period in the clinical research unit. Thirteen subjects were enrolled and had been off phosphate binders for 10 days and consumed a standardized low phosphate (900 mg/day) diet for 3 weeks prior to the assessments. Linear regression was used to determine relationships between the pre-HD serum phosphate, decline post-HD (post-HD drop); and a 48 h area under curve (AUC) using the trapezoidal method as a measure of overall phosphate levels from the end of dialysis to 48 h post dialysis. Repeated Measures ANOVA with Dunnett's posthoc test was used to determine rebound. RESULTS: Five of 13 subjects returned to >90% of their pre-HD serum phosphate within the first 24 h post-HD, and serum phosphate was 94 ± 0.11% (range 63%-113%) by 48 h after the completion of HD. The 48 h AUC of serum phosphate during the interdialytic period was correlated with both pre dialysis phosphorus (r = 0.85; p = 0.0002) and the pre-post drop in serum phosphate during dialysis (r = 0.69; p = 0.0085). In contrast, the net ultrafiltration was not related to the 48 h AUC of serum phosphorus (r = 0.20; p = 0.51). CONCLUSIONS: In hemodialysis patients on standard low phosphorus diet and no phosphate binders, the interdialytic serum phosphorus level, assessed as AUC, is determined by the pre dialysis phosphorus and net-change in serum phosphorus during the dialysis treatment, but not the ultrafiltration volume [Correction added on 25 January, after first online publication: In the last sentence of the Abstract, the word "potassium" has been replaced with "phosphorus" to improve accuracy.].

A randomized phase 1b cross-over study of the safety of low-dose pioglitazone for treatment of autosomal dominant polycystic kidney disease.

BACKGROUND: Autosomal dominant polycystic kidney disease (ADPKD) is one of the most common monogenetic disorders in humans and is characterized by numerous fluid-filled cysts that grow slowly, resulting in end-stage renal disease in the majority of patients. Preclinical studies have indicated that treatment with low-dose thiazolidinediones, such as pioglitazone, decrease cyst growth in rodent models of PKD. METHODS: This Phase 1b cross-over study compared the safety of treatment with a low dose (15 mg) of the peroxisome proliferator-activated receptor-γ (PPAR-γ) agonist pioglitazone or placebo in PKD patients, with each treatment given for 1 year. The study monitored known side effects of PPAR-γ agonist treatment, including fluid retention and edema. Liver enzymes and risk of hypoglycemia were assessed throughout the study. As a secondary objective, the efficacy of low-dose pioglitazone was followed using a primary assessment of total kidney volume (TKV), blood pressure (BP) and kidney function. RESULTS: Eighteen patients were randomized and 15 completed both arms. Compared with placebo, allocation to pioglitazone resulted in a significant decrease in total body water as assessed by bioimpedance analysis {mean difference 0.16 Ω [95% confidence interval (CI) 0.24-2.96], P = 0.024} and no differences in episodes of heart failure, clinical edema or change in echocardiography. Allocation to pioglitazone led to no difference in the percent change in TKV of -3.5% (95% CI -8.4-1.4, P = 0.14), diastolic BP and microalbumin:creatinine ratio. CONCLUSIONS: In this small pilot trial in people with ADPKD but without diabetes, pioglitazone 15 mg was found to be as safe as placebo. Larger and longer-term randomized trials powered to assess effects on TKV are needed.

Intestinal Phosphorus Absorption in Moderate CKD and Healthy Adults Determined Using a Radioisotopic Tracer.

BACKGROUND: Reducing intestinal phosphorus absorption is a cornerstone in CKD-MBD management. Yet, knowledge gaps include how CKD pathophysiology affects intestinal phosphorus absorption. In vivo rodent studies suggest that intestinal phosphorus absorption remains inappropriately normal in early-moderate CKD, despite declining 1,25-dihydroxyvitamin D (1,25D). We measured intestinal phosphorus absorption in patients with moderate CKD versus healthy adults using a direct radiotracer method. METHODS: Patients with CKD and healthy adults matched for age, sex, and race were enrolled in this 8-day controlled diet study: the first 6 days outpatient and the final 2 days inpatient. Oral and intravenous doses of 33P and serial blood and urine sampling determined intestinal phosphorus absorption during the final 2 days. Secondary outcomes included fasting biochemistries and 24-hour urine phosphorus (uP). RESULTS: In total, n=8 patients with CKD (eGFR=29-55 ml/min per 1.73 m2) and n=8 matched healthy controls completed the study. On a controlled diet, no difference in fractional intestinal phosphorus absorption was detected between patients with CKD and healthy adults (0.69 versus 0.62, respectively; P=0.52), and this was similar for 24-hour uP (884 versus 935 mg/d, respectively; P=0.70). Fractional intestinal phosphorus absorption was not significantly related to 24-hour uP. Patients with CKD had higher serum intact PTH and intact FGF23 and lower 1,25D. The relationship between 1,25D and fractional intestinal phosphorus absorption was not statistically significant. CONCLUSIONS: Intestinal phosphorus absorption with typical dietary intake did not differ in patients with moderate CKD compared with controls, despite lower serum 1,25D levels. In this setting, a relationship between 24-hour uP and fractional or absolute intestinal absorption was not evident. Further investigation is needed to determine what factors influence intestinal phosphorus absorption in CKD and the apparent lack of compensation by the intestine to limit phosphorus absorption in the face of declining kidney function and reduced 1,25D. Whether this is evident across a range of dietary phosphorus intakes, as well as CKD severity, also needs to be determined. CLINICAL TRIAL REGISTRY NAME AND REGISTRATION NUMBER: Phosphorus Absorption in Healthy Adults and in Patients with Moderate Chronic Kidney Disease, NCT03108222.

Skeletal muscle metabolic responses to physical activity are muscle type specific in a rat model of chronic kidney disease.

Chronic kidney disease (CKD) leads to musculoskeletal impairments that are impacted by muscle metabolism. We tested the hypothesis that 10-weeks of voluntary wheel running can improve skeletal muscle mitochondria activity and function in a rat model of CKD. Groups included (n = 12-14/group): (1) normal littermates (NL); (2) CKD, and; (3) CKD-10 weeks of voluntary wheel running (CKD-W). At 35-weeks old the following assays were performed in the soleus and extensor digitorum longus (EDL): targeted metabolomics, mitochondrial respiration, and protein expression. Amino acid-related compounds were reduced in CKD muscle and not restored by physical activity. Mitochondrial respiration in the CKD soleus was increased compared to NL, but not impacted by physical activity. The EDL respiration was not different between NL and CKD, but increased in CKD-wheel rats compared to CKD and NL groups. Our results demonstrate that the soleus may be more susceptible to CKD-induced changes of mitochondrial complex content and respiration, while in the EDL, these alterations were in response the physiological load induced by mild physical activity. Future studies should focus on therapies to improve mitochondrial function in both types of muscle to determine if such treatments can improve the ability to adapt to physical activity in CKD.

Clinical, histopathologic and molecular features of idiopathic and diabetic nodular mesangial sclerosis in humans.

BACKGROUND: Idiopathic nodular mesangial sclerosis, also called idiopathic nodular glomerulosclerosis (ING), is a rare clinical entity with an unclear pathogenesis. The hallmark of this disease is the presence of nodular mesangial sclerosis on histology without clinical evidence of diabetes mellitus or other predisposing diagnoses. To achieve insights into its pathogenesis, we queried the clinical, histopathologic and transcriptomic features of ING and nodular diabetic nephropathy (DN). METHODS: All renal biopsy reports accessioned at Indiana University Health from 2001 to 2016 were reviewed to identify 48 ING cases. Clinical and histopathologic features were compared between individuals with ING and DN (n = 751). Glomeruli of ING (n = 5), DN (n = 18) and reference (REF) nephrectomy (n = 9) samples were isolated by laser microdissection and RNA was sequenced. Immunohistochemistry of proline-rich 36 (PRR36) protein was performed. RESULTS: ING subjects were frequently hypertensive (95.8%) with a smoking history (66.7%). ING subjects were older, had lower proteinuria and had less hyaline arteriolosclerosis than DN subjects. Butanoate metabolism was an enriched pathway in ING samples compared with either REF or DN samples. The top differentially expressed gene, PRR36, had increased expression in glomeruli 248-fold [false discovery rate (FDR) P = 5.93 × 10-6] compared with the REF and increased 109-fold (FDR P = 1.85 × 10-6) compared with DN samples. Immunohistochemistry revealed a reduced proportion of cells with perinuclear reaction in ING samples as compared to DN. CONCLUSIONS: Despite similar clinical and histopathologic characteristics in ING and DN, the uncovered transcriptomic signature suggests that ING has distinct molecular features from nodular DN. Further study is warranted to understand these relationships.

Klotho: An Emerging Factor With Ergogenic Potential.

Sarcopenia and impaired cardiorespiratory fitness are commonly observed in older individuals and patients with chronic kidney disease (CKD). Declines in skeletal muscle function and aerobic capacity can progress into impaired physical function and inability to perform activities of daily living. Physical function is highly associated with important clinical outcomes such as hospitalization, functional independence, quality of life, and mortality. While lifestyle modifications such as exercise and dietary interventions have been shown to prevent and reverse declines in physical function, the utility of these treatment strategies is limited by poor widespread adoption and adherence due to a wide variety of both perceived and actual barriers to exercise. Therefore, identifying novel treatment targets to manage physical function decline is critically important. Klotho, a remarkable protein with powerful anti-aging properties has recently been investigated for its role in musculoskeletal health and physical function. Klotho is involved in several key processes that regulate skeletal muscle function, such as muscle regeneration, mitochondrial biogenesis, endothelial function, oxidative stress, and inflammation. This is particularly important for older adults and patients with CKD, which are known states of Klotho deficiency. Emerging data support the existence of Klotho-related benefits to exercise and for potential Klotho-based therapeutic interventions for the treatment of sarcopenia and its progression to physical disability. However, significant gaps in our understanding of Klotho must first be overcome before we can consider its potential ergogenic benefits. These advances will be critical to establish the optimal approach to future Klotho-based interventional trials and to determine if Klotho can regulate physical dysfunction.

Plant-Based Diets, the Gut Microbiota, and Trimethylamine N-Oxide Production in Chronic Kidney Disease: Therapeutic Potential and Methodological Considerations.

High circulating trimethylamine-N-oxide (TMAO) is associated with an increased risk of cardiovascular disease and mortality in people with chronic kidney disease (CKD). In individuals with CKD, reduced kidney function leads to decreased excretion of TMAO, which results in accumulation in the circulation. Higher circulating TMAO has been linked to higher intake of animal-based foods in omnivorous diets. Thus, plant-based diets have been suggested as an intervention to slow the progression of CKD and reduce cardiovascular risk, perhaps explained in part by reduced TMAO production. This article reviews the current evidence on plant-based diets as a dietary intervention to decrease gut-derived TMAO production in patients with CKD, while highlighting methodological issues that present challenges to advancing research and subsequent translation of this approach. Overall, we find that plant-based diets are promising for reducing gut-derived TMAO production in patients with CKD but that further interventional studies are warranted.

Dose-Response Effect of Dietary Nitrate on Muscle Contractility and Blood Pressure in Older Subjects: A Pilot Study.

We have recently demonstrated that dietary nitrate, a source of nitric oxide (NO) via the nitrate → nitrite → NO enterosalivary pathway, can improve muscle contractility in healthy older men and women. Nitrate ingestion has also been shown to reduce blood pressure in some, but not all, studies of older individuals. However, the optimal dose for eliciting these beneficial effects is unknown. A pilot randomized, double-blind, placebo-controlled crossover study was therefore performed to determine the effects of ingesting 3.3 mL/kg of concentrated beetroot juice containing 0, 200, or 400 µmol/kg of nitrate in 9 healthy older subjects (mean age 70 ± 1 years). Maximal knee extensor power (Pmax) and speed (Vmax) were measured ~2.5 hours after nitrate ingestion using isokinetic dynamometry. Blood pressure was monitored periodically throughout each study. Pmax (in W/kg) was higher (p < .05) after the lower dose (3.9 ± 0.4) compared to the placebo (3.7 ± 0.4) or higher dose (3.7 ± 0.4). Vmax (in rad/s) also tended to be higher (p = .08) after the lower dose (11.9 ± 0.7) compared to the placebo (10.8 ± 0.8) or higher dose (11.2 ± 0.8). Eight out of 9 subjects achieved a higher Pmax and Vmax after the lower versus the higher dose. These dose-related changes in muscle contractility generally paralleled changes in breath NO levels. No significant changes were found in systolic, diastolic, or mean arterial blood pressure. A lower dose of nitrate increases muscle speed and power in healthy older individuals, but these improvements are lost at a higher dose. Blood pressure, on the other hand, is not reduced even with a higher dose.

Spot Urine Samples to Estimate Na and K Intake in Patients With Chronic Kidney Disease and Healthy Adults: A Secondary Analysis From a Controlled Feeding Study.

OBJECTIVE: The objective of this study was to assess the agreement between estimated 24-hour urinary sodium excretion (e24hUNa) and estimated 24-hour urinary potassium excretion (e24hUK), calculated from a spot urine sample using several available equations and actual sodium and potassium intake from a controlled diet in both healthy participants and those with chronic kidney disease (CKD). DESIGN AND METHODS: This study is a secondary analysis of a controlled feeding study in CKD patients matched to healthy controls. Participants (n = 16) consumed the controlled diet, which provided ∼2400 mg Na/day and ∼3000 mg K/day, for 8 days. On days 7 and 8, participants consumed all meals and collected all urine in an inpatient research setting, and they were discharged on day 9. The day 7 morning spot urine sample was used to calculate e24hUNa and e24hUK, which was compared with known sodium and potassium intake, respectively. RESULTS: Average e24hUNa from the INTERSALT and Tanaka-Na equations were higher than actual sodium intake by 373 mg and 559 mg, respectively, though the differences were not significant. e24hUNa from the Nerbass-SALTED equation in CKD participants was significantly higher than actual sodium intake by ∼2000 mg (P < .001), though e24hUNa from the Nerbass-RRID equation was not different from intake. e24hUK from the Tanaka-K equation was significantly lower than actual potassium intake (P < .001). For both e24hUNa and e24hUK for all participants, agreement with actual intake was poor, and e24hUNa and e24hUK were not correlated with actual sodium or potassium intake, respectively. CONCLUSION: e24hUNa and e24hUK are poor indicators of true sodium and potassium intake, respectively, in both healthy and CKD participants. Findings should be confirmed in larger sample sizes with varying levels of dietary sodium and potassium.