Faculty Bibliography

OBJECTIVE:Patients with kidney stones are counseled to eat a diet low in animal protein, sodium, and oxalate and rich in fruits and vegetables, with a modest amount of calcium, usually from dairy products. Restriction of sodium, potassium, and oxalate may also be recommended in patients with chronic kidney disease. Recently, plant-based diets have gained popularity owing to health, environmental, and animal welfare considerations. Our objective was to compare concentrations of ingredients important for kidney stones and chronic kidney disease in popular brands of milk alternatives. DESIGN AND METHODS/METHODS:Sodium, calcium, and potassium contents were obtained from nutrition labels. The oxalate content was measured by ion chromatography coupled with mass spectrometry. RESULTS:The calcium content is highest in macadamia followed by soy, almond, rice, and dairy milk; it is lowest in cashew, hazelnut, and coconut milk. Almond milk has the highest oxalate concentration, followed by cashew, hazelnut, and soy. Coconut and flax milk have undetectable oxalate levels; coconut milk also has comparatively low sodium, calcium, and potassium, while flax milk has the most sodium. Overall, oat milk has the most similar parameters to dairy milk (moderate calcium, potassium and sodium with low oxalate). Rice, macadamia, and soy milk also have similar parameters to dairy milk. CONCLUSION/CONCLUSIONS:As consumption of plant-based dairy substitutes increases, it is important for healthcare providers and patients with renal conditions to be aware of their nutritional composition. Oat, macadamia, rice, and soy milk compare favorably in terms of kidney stone risk factors with dairy milk, whereas almond and cashew milk have more potential stone risk factors. Coconut milk may be a favorable dairy substitute for patients with chronic kidney disease based on low potassium, sodium, and oxalate. Further study is warranted to determine the effect of plant-based milk alternatives on urine chemistry.

PURPOSE OF REVIEW/OBJECTIVE:In this review, we report on new findings regarding associations of uric acid with kidney health. We discuss kidney stones, effects of uric acid in chronic kidney disease (CKD), and management of gout in CKD. Recent studies on neuroprotective effects of raising uric acid provide interesting data regarding nephrolithiasis. RECENT FINDINGS/RESULTS:Elevated urate levels have been implicated in the progression of chronic kidney disease (CKD), but the results from PERL and CKD-FIX studies did not demonstrate that allopurinol slowed CKD progression. The SURE-PD3 sought to determine if increasing uric acid would slow the progression of Parkinson's disease. Results ultimately did not support this hypothesis, but high urinary uric acid levels caused uric acid stones, not calcium stones. Low urinary pH remains the key to the formation of uric acid stones. Thiazolidinediones improve insulin resistance, which is associated with an increase in urine pH. The most recent research has not supported the hypothesis that lowering serum uric acid levels will slow the progression of CKD or provide neuroprotection in Parkinson's disease. It is still unclear as to why uric acid stone formers have a high net acid excretion. The STOP-GOUT trial demonstrates that there was a lack of significant adverse events with higher urate-lowering dosages of allopurinol and febuxostat, despite patients' kidney function. This may push other studies to administer higher dosages per ACR guidelines. Future studies could then demonstrate decreased progression of CKD.

Methotrexate is used in the treatment of many malignancies, rheumatological diseases, and inflammatory bowel disease. Toxicity from use is associated with severe morbidity and mortality. Rescue treatments include intravenous hydration, folinic acid, and, in some centers, glucarpidase. We conducted systematic reviews of the literature following published EXtracorporeal TReatments In Poisoning (EXTRIP) methods to determine the utility of extracorporeal treatments in the management of methotrexate toxicity. The quality of the evidence and the strength of recommendations (either "strong" or "weak/conditional") were graded according to the GRADE approach. A formal voting process using a modified Delphi method assessed the level of agreement between panelists on the final recommendations. A total of 92 articles met inclusion criteria. Toxicokinetic data were available on 90 patients (89 with impaired kidney function). Methotrexate was considered to be moderately dialyzable by intermittent hemodialysis. Data were available for clinical analysis on 109 patients (high-dose methotrexate [>0.5 g/m²]: 91 patients; low-dose [≤0.5 g/m²]: 18). Overall mortality in these publications was 19.5% and 26.7% in those with high-dose and low-dose methotrexate-related toxicity, respectively. Although one observational study reported lower mortality in patients treated with glucarpidase compared with those treated with hemodialysis, there were important limitations in the study. For patients with severe methotrexate toxicity receiving standard care, the EXTRIP workgroup: (1) suggested against extracorporeal treatments when glucarpidase is not administered; (2) recommended against extracorporeal treatments when glucarpidase is administered; and (3) recommended against extracorporeal treatments instead of administering glucarpidase. The quality of evidence for these recommendations was very low. Rationales for these recommendations included: (1) extracorporeal treatments mainly remove drugs in the intravascular compartment, whereas methotrexate rapidly distributes into cells; (2) extracorporeal treatments remove folinic acid; (3) in rare cases where fast removal of methotrexate is required, glucarpidase will outperform any extracorporeal treatment; and (4) extracorporeal treatments do not appear to reduce the incidence and magnitude of methotrexate toxicity.

PURPOSE OF REVIEW/OBJECTIVE:Hypernatremia is a relatively frequent electrolyte disorder seen in critically ill patients. As many as 27% of patients in intensive care units (ICUs) develop hypernatremia of variable severity during an ICU stay. Debate among specialists often ensues as to whether to correct hypernatremia or not. Some practitioners, particularly intensivists, believe that correction of hypernatremia with fluids may cause expansion of the extracellular fluid volume (ECFV) thereby worsening ventilation and impeding extubation. Other practitioners, including many nephrologists, do not expect correction of hypernatremia to lead to clinically apparent ECFV expansion, and fear other deleterious effects of hypernatremia. In this review we address the controversy regarding appropriate practice. FINDINGS/RESULTS:There are no randomized, clinical trials (RCTs) to guide the administration of electrolyte-free fluid administration in hypernatremic patients. However, there are associations, demonstrated in the literature, suggesting that hypernatremia of any severity will increase the mortality and length of stay in these patients. These associations generally support the practice of correction of hypernatremia. In addition, our knowledge of the distribution of total body water influences us towards correcting hypernatremia as an appropriate therapy. We do not expect that adequate RCTs addressing this question will be performed. SUMMARY/CONCLUSIONS:Allowing persistence of any degree of hypernatremia is associated with increased mortality, length of stay (LOS) and postdischarge mortality. We expect that proper use of electrolyte-free water intake will avoid adverse outcomes.

Introduction/UNASSIGNED:Because of phenotypic overlap between monogenic urinary stone diseases (USD), gene-specific analyses can result in missed diagnoses. We used targeted next generation sequencing (tNGS), including known and candidate monogenic USD genes, to analyze suspected primary hyperoxaluria (PH) or Dent disease (DD) patients genetically unresolved (negative; N) after Sanger analysis of the known genes. Cohorts consisted of 285 PH (PHN) and 59 DD (DDN) families. Methods/UNASSIGNED:Variants were assessed using disease-specific and population databases plus variant assessment tools and categorized using the American College of Medical Genetics (ACMG) guidelines. Prior Sanger analysis identified 47 novel PH or DD gene pathogenic variants. Results/UNASSIGNED:accounted for 1 pedigree each. Of the 48 defined pathogenic variants, 27.1% were truncating and 39.6% were novel. Most patients were diagnosed before 18 years of age (76.1%), and 70.3% of biallelic patients were homozygous, mainly from consanguineous families. Conclusion/UNASSIGNED:Overall, in patients suspected of DD or PH, 23.9% and 7.3% of cases, respectively, were caused by pathogenic variants in other genes. This study shows the value of a tNGS screening approach to increase the diagnosis of monogenic USD, which can optimize therapies and facilitate enrollment in clinical trials.

Cystic fibrosis (CF) may predispose patients to urinary stone disease (USD), but reported prevalence of USD in patients with CF in previous small studies is variable. To date, analysis of risk factors for USD within the CF population has been limited. We studied 29,396 patients in the Cystic Fibrosis Foundation Patient Registry to calculate age and sex-stratified prevalence of USD. For adult patients, we examined age and multivariable-adjusted cross-sectional associations between demographic and clinical factors, CFTR mutation class, and prevalent USD. Prevalence of USD was 0.4% (95% CI 0.3-0.5%) under age 18 years, 3.1% (2.7-3.6%) at 18-24 years, 6.4% (5.8-7.1%) at 25-34 years, 7.5% (6.5-8.5%) at 35-44 years, and 6.7% (5.8-7.8%) at 45 years and older. Prevalence for women was higher than men at younger (< 45 years) but not older ages (P value for interaction < 0.0005). Multivariable odds of prevalent USD were significantly increased for severe CFTR mutations, OR 1.53 (1.14-2.06), diabetes, OR 1.24 (1.03-1.50), hypertension, OR 1.58 (1.29-1.93), and chronic macrolide therapy, OR 1.27 (1.07-1.52). BMI was not associated with USD. USD prevalence in CF is similar to that in the general population. With the exception of BMI, known risk factors for USD in the general population also appear to be important for patients with CF. We identified several novel associations in CF patients, including greater prevalence of USD in individuals with severe CFTR mutations and among young women.

The incidence of kidney stones is increasing in the US population. Oxalate, a major factor for stone formation, is degraded by gut bacteria reducing its intestinal absorption. Intestinal O. formigenes colonization has been associated with a lower risk for recurrent kidney stones in humans. In the current study, we used a clinical trial of the eradication of Helicobacter pylori to assess the effects of an antibiotic course on O. formigenes colonization, urine electrolytes, and the composition of the intestinal microbiome. Of 69 healthy adult subjects recruited, 19 received antibiotics for H. pylori eradication, while 46 were followed as controls. Serial fecal samples were examined for O. formigenes presence and microbiota characteristics. Urine, collected serially fasting and following a standard meal, was tested for oxalate and electrolyte concentrations. O. formigenes prevalence was 50%. Colonization was significantly and persistently suppressed in antibiotic-exposed subjects but remained stable in controls. Urinary pH increased after antibiotics, but urinary oxalate did not differ between the control and treatment groups. In subjects not on antibiotics, the O. formigenes-positive samples had higher alpha-diversity and significantly differed in Beta-diversity from the O. formigenes-negative samples. Specific taxa varied in abundance in relation to urinary oxalate levels. These studies identified significant antibiotic effects on O. formigenes colonization and urinary electrolytes and showed that overall microbiome structure differed in subjects according to O. formigenes presence. Identifying a consortium of bacterial taxa associated with urinary oxalate may provide clues for the primary prevention of kidney stones in healthy adults.

BACKGROUND:Chronic kidney disease (CKD) is often complicated by anaemia, which is associated with disease progression and increased hospital visits, decreased quality of life, and increased mortality. METHODS:A comprehensive literature search of English language peer-reviewed articles in PubMed/MedLine published between 1998 and 2020 related to the treatment of anaemia of CKD was conducted. The United States Renal Database System and Dialysis Outcomes and Practice Patterns Study (DOPPS) data reports, the Centers for Disease Control and Prevention and the US Food and Drug Administration websites, and published congress abstracts in 2020 were surveyed for relevant information. RESULTS:Subgroups of patients with anaemia of CKD present a clinical challenge throughout the disease spectrum, including those with end-stage kidney disease, advanced age or resistance to or ineligibility for current standards of care (ie, oral or intravenous iron supplementation, erythropoietin-stimulating agents and red blood cell transfusions). In addition, those with an increased risk of adverse events because of comorbid conditions, such as cardiovascular diseases or diabetes, comprise special populations of patients with an unmet need for interventions to improve clinical outcomes. These comorbidities must be managed in parallel and may have a synergistic effect on overall disease severity. CONCLUSIONS:Several therapies provide promising opportunities to address gaps with a standard of care, including hypoxia-inducible factor prolyl hydroxylase inhibitors, which stimulate haematopoiesis through promoting modest increases in serum erythropoietin and improved iron homeostasis. The critical issues in the management of anaemia of CKD in these challenging phenotypes and the clinical utility of new therapeutic agents in development for the treatment of anaemia of CKD should be assessed and the information should be made available to healthcare providers.

OBJECTIVE:The objective of the study was to evaluate the feasibility and acceptability of mobile health (mHealth) phosphorus management programs in hemodialysis (HD) patients. METHODS:Patients receiving thrice-weekly HD who had 3-month average serum phosphorus of >5.5 mg/dL were randomized to one of the three self-directed phosphorus management programs delivered using tablet PCs: (1) educational videos and handouts (Education), (2) education intervention plus mobile self-monitoring with email feedback (Monitoring), or (3) education and monitoring interventions plus social cognitive theory-based behavioral videos (Combined). Feasibility and acceptability were assessed based on enrollment and retention and training needs (feasibility) and adherence to self-monitoring and reported satisfaction (acceptability). RESULTS:Of 312 patients, 56 expressed interest, and 40 were enrolled. The majority of participants (80%) completed the 6-month study; none withdrew for intervention-related reasons. The Monitoring and Combined groups received 44 ± 15 minutes of technology training, which was considered adequate by most (75%). Self-monitoring rates were initially high, with 78% and 71% of the participants recording at least one meal and phosphate binder in week 1, respectively, but decreased over time to 15% and 9% in the final week. Most participants reported that self-monitoring helped them stay motivated (64%), track nutrients (80%), and understand how to change diet (76%), and nearly two-thirds of participants (64%) stated that they would like to continue using the tablet PC to manage their health. However, few participants (16%) indicated that self-monitoring was worth the effort. The Monitoring and Combined groups did not differ from the Education group in study outcomes. CONCLUSION/CONCLUSIONS:Although the mHealth programs were generally well received, self-monitoring rates decreased substantially over time and were unaffected by social cognitive theory-based videos. Self-directed mHealth programs may be a useful adjunct to standard care but should be compared to more resource intensive programs (e.g., involving more "live" contact with a dietitian) to determine overall cost-effectiveness and role in HD care.