Urinary supersaturation in a Randomized trial among Individuals with Nephrolithiasis comparing Empiric versus selective therapy (URINE): design and rationale of a clinical trial
Clinical guidelines disagree on whether the identification of abnormal urine chemistries should occur before starting diet and medication interventions to prevent the recurrence of kidney stone events. We describe the rationale and design of the Urinary supersaturation in a Randomized trial among Individuals with Nephrolithiasis comparing Empiric versus selective therapy (URINE) study, a randomized trial comparing two multi-component interventions to improve urinary supersaturation. Participants are randomized (1:1 ratio) to the empiric or selective arm. The target sample size is 56 participants. Adults ≥ 18 years of age with idiopathic calcium stone disease and two symptomatic stone events within the previous 5 years. Exclusion criteria include systemic conditions predisposing to kidney stones and pharmacologic treatment for stone prevention at baseline. Participants in the empiric arm receive standard diet therapy recommendations, thiazide, and potassium citrate. Participants in the selective arm receive tailored diet and nutrient recommendations and medications based on baseline and 1-month follow-up of 24-h urine testing results. The primary endpoints are urinary supersaturations of calcium oxalate and calcium phosphate at 2 months of follow-up. Secondary endpoints include side effects, diet and medication adherence, and changes in 24-h urine volume, calcium, oxalate, citrate, and pH. Short-term changes in urinary supersaturation may not reflect changes in future risk of stone events. The URINE study will provide foundational data to compare the effectiveness of two prevention strategies for kidney stone disease.
Redlining has led to increasing rates of nephrolithiasis in minoritized populations: a hypothesis
PURPOSE OF REVIEW/OBJECTIVE:The persistent rise in kidney stone prevalence in recent decades has prompted much speculation as to the causes. There has been some discussion about the effect of heat on nephrolithiasis. Here, we review recent data and postulate that heat may play a role in stone formation on a large scale and among African-Americans in particular. RECENT FINDINGS/RESULTS:African-Americans are the race/ancestry group with faster rates of increasing incidence and prevalence of kidney stones. We make the observation that urban heat islands in the United States have resulted in part from the effects of redlining, a practice of systematic segregation and racism in housing that led to the development of neighborhoods with substantial disparities in environmental conditions. SUMMARY/CONCLUSIONS:In this thought experiment, we propose that the disproportionate rise in the prevalence of nephrolithiasis in minoritized populations correlates with increased temperatures specifically in neighborhoods adversely affected by the practice of redlining. We discuss phenomena in support of this hypothesis and ongoing work to test this theory.
An Evaluation of Alternative Technology-Supported Counseling Approaches to Promote Multiple Lifestyle Behavior Changes in Patients With Type 2 Diabetes and Chronic Kidney Disease
OBJECTIVES/OBJECTIVE:Although technology-supported interventions are effective for reducing chronic disease risk, little is known about the relative and combined efficacy of mobile health strategies aimed at multiple lifestyle factors. The purpose of this clinical trial is to evaluate the efficacy of technology-supported behavioral intervention strategies for managing multiple lifestyle-related health outcomes in overweight adults with type 2 diabetes (T2D) and chronic kidney disease (CKD). DESIGN AND METHODS/METHODS:, age â‰¥40Â years), T2D, and CKD stages 2-4 were randomized to an advice control group, or remotely delivered programs consisting of synchronous group-based education (all groups), plus (1) Social Cognitive Theory-based behavioral counseling and/or (2) mobile self-monitoring of diet and physical activity. All programs targeted weight loss, greater physical activity, and lower intakes of sodium and phosphorus-containing food additives. RESULTS:Of 256 randomized participants, 186 (73%) completed 6-month assessments. Compared to the ADVICE group, mHealth interventions did not result in significant changes in weight loss, or urinary sodium and phosphorus excretion. In aggregate analyses, groups receiving mobile self-monitoring had greater weight loss at 3Â months (PÂ =Â .02), but between 3 and 6Â months, weight losses plateaued, and by 6Â months, the differences were no longer statistically significant. CONCLUSIONS:When engaging patients with T2D and CKD in multiple behavior changes, self-monitoring diet and physical activity demonstrated significantly larger short-term weight losses. Theory-based behavioral counseling alone was no better than baseline advice and demonstrated no interaction effect with self-monitoring.
Beyond the Urine Anion Gap: In Support of the Direct Measurement of Urinary Ammonium
Ammonium is a major urinary buffer that is necessary for the normal excretion of the daily acid load. Its urinary rate of excretion (UNH4) may be increased several fold in the presence of extrarenal metabolic acidosis. Therefore, measurement of UNH4 can provide important clues about causes of metabolic acidosis. Because UNH4 is not commonly measured in clinical laboratories, the urinary anion gap (UAG) was proposed as its surrogate about four decades ago and it is still frequently used for that purpose. Several published studies strongly suggest that UAG is not a good index of UNH4 and support the concept that direct measurement of UNH4 is an important parameter to define in clinical nephrology. Low UNH4 levels have recently been found to be associated with a higher risk of metabolic acidosis, loss of kidney function, and death in persons with chronic kidney disease, while surrogates like the UAG do not recapitulate this risk. In order to advance the field it is necessary for the medical community to become more familiar with UNH4 levels in a variety of clinical settings. Herein, we have reviewed the literature, searching for available data on UNH4 under normal and various pathological conditions, in an attempt to establish reference values to interpret UNH4 results if and when UNH4 measurements become available as a routine clinical test. In addition, we present original data in two large populations which provide further evidence that the UAG is not a good predictor of UNH4. Measurement of urine NH4 holds promise to aid clinicians in the care of patients and we encourage further research to determine its best diagnostic usage.
Preemptive Removal of Small, Asymptomatic Kidney Stones [Editorial]
Cystinuria: an update on pathophysiology, genetics, and clinical management
Cystinuria is the most common genetic cause of nephrolithiasis in children. It is considered a heritable aminoaciduria as the genetic defect affects the reabsorption of cystine and three other amino acids (ornithine, lysine, and arginine) in the renal proximal tubule. Patients affected by this condition have elevated excretion of cystine in the urine, and because of this amino acid's low solubility at normal urine pH, patients tend to form cystine calculi. To date, two genes have been identified as disease-causative: SLC3A1 and SLC7A9, encoding for the two subunits of the heterodimeric transporter. The clinical features of this condition are solely related to nephrolithiasis. The diagnosis is usually made during infancy or adolescence, but cases of late diagnosis are common. The goal of therapy is to reduce excretion and increase the solubility of cystine, through both modifications of dietary habits and pharmacological treatment. However, therapeutic interventions are not always sufficient, and patients often have to undergo several surgical procedures during their lives to treat recurrent nephrolithiasis. The goal of this literature review is to synthesize the available evidence on diagnosis and management of patients affected by cystinuria in order to provide physicians with a practical tool that can be used in daily clinical practice. This review also aims to shed some light on new therapy directions with the aim of ameliorating kidney outcomes while improving adherence to treatment and quality of life of cystinuric patients.
Comparison of empiric preventative pharmacologic therapies on stone recurrence among patients with kidney stone disease
OBJECTIVE:To compare the frequency of stone-related events among patients receiving thiazides, alkali citrate, and allopurinol without prior 24-hour urine testing. Â It is unknown whether one preventative pharmacological therapy (PPT) medicationÂ class is more beneficial for reducing kidney stone recurrence when prescribed empirically. MATERIALS AND METHODS/METHODS:Using medical claims data from working-age adults with kidney stone disease diagnoses (2008-2018), we identified those prescribed thiazides, alkali citrate, or allopurinol. We excluded those who received 24-hour urine testing prior to initiating PPT and those with less than three years of follow-up. We fit multivariable regression models to estimate the association between the occurrence of a stone-related event (emergency department visit, hospitalization, or surgery for stones) and PPT medication class. RESULTS:Our cohort consisted of 1,834 (60%), 654 (21%), and 558 (18%) patients empirically prescribed thiazides, alkali citrate, or allopurinol, respectively. After controlling for patient factors including medication adherence and concomitant conditions that increase recurrence risk, the adjusted rate of any stone event was lowestÂ for the thiazide group (14.8%) compared toÂ alkali citrateÂ (20.4%) orÂ allopurinol (20.4%)Â (each p<0.001).Â Thiazides, compared to allopurinol, were associated with 32% lower odds of a subsequent stone event by three years (OR 0.68, 95% CI 0.53-0.88). No such association was observed when comparing alkali citrate to allopurinol (OR 1.00, 95% CI 0.75-1.34). CONCLUSIONS:Empiric PPT with thiazides is associated with significantly lower odds of subsequent stone-related events. When 24-hour urine testing is unavailable, thiazides may be preferred over alkali citrate or allopurinol for empiric PPT.
Comparison of Selective Versus Empiric Pharmacologic Preventive Therapy of Kidney Stone Recurrence with High-Risk Features
OBJECTIVE:To compare the frequency of stone-related events among subgroups of high-risk patients with and without 24-hour urine testing before PPT prescription.Â While recent studies show, on average, no benefit to a selective approach to preventive pharmacological therapy (PPT) for urinary stone disease (USD), there could be heterogeneity in treatment effect across patient subgroups. MATERIALS AND METHODS/METHODS:Using medical claims data from working-age adults and their dependents with USD (2008-2019), we identified those with a prescription fill for a PPT agent (thiazide diuretic, alkali therapy, or allopurinol). We then stratified patients into subgroups based on the presence of a concomitant condition or other factors that raised their stone recurrence risk. Finally, we fit multivariable regression models to measure the association between stone-related events (emergency department visit, hospitalization, and surgery) and 24-hour urine testing before PPT prescription by high-risk subgroup. RESULTS:Overall, 8,369 adults with USD had a concomitant condition that raised their recurrence risk. Thirty-three percent (n=2,722) of these patients were prescribed PPT after 24-hour urine testing (median follow-up, 590 days), and 67% (n=5,647) received PPT empirically (median follow-up, 533 days). Compared to patients treated empirically, those with a history of recurrent USD had a significantly lower hazard of a subsequent stone-related event if they received selective PPT (hazard ratio, 0.83; 95% CI, 0.71-0.96). No significant associations were noted for selective PPT in the other high-risk subgroups. CONCLUSIONS:Patients with a history of recurrent USD benefit from PPT when guided by findings from 24-hour urine testing.
Plant-Based Milk Alternatives and Risk Factors for Kidney Stones and Chronic Kidney Disease
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.
Update on Uric Acid and the Kidney
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.