Review

Authors: David S Goldfarb

Careful phenotyping of patients to classify those with kidney stones has a long and important history in revealing the chemical basis for stone formation. Advances in our genetic understanding of kidney stones will lead to incredible insights regarding the pathophysiology of this common disorder. At this time, both evaluation of urine chemistry and genotyping of patients are extremely useful in the setting of a university and research-based kidney stone clinic. For much of the world, in a more clinically focused setting, these techniques are neither available nor absolutely necessary. Careful implementation of an empiric prescription based on stone composition would have an important effect to reduce stone recurrence in the world's many stone formers. Increased fluid intake, generic dietary manipulations, and prescription of potassium citrate and thiazides are all appropriate empiric therapies for people with calcium and uric acid kidney stones.

Topics: Calcium; Diet, Sodium-Restricted; Dietary Approaches To Stop Hypertension; Fluid Therapy; Genetic Testing; Humans; Kidney Calculi; Potassium Citrate; Recurrence; Thiazides; Treatment Outcome; Uric Acid

PubMed: 30478476
DOI: 10.1007/s00240-018-1090-6

Review

Authors: Carsten A Wagner, Nilufar Mohebbi

The formation of various types of kidney stones is strongly influenced by urinary pH. An alkaline pH favors the crystallization of calcium- and phosphate-containing stones, whereas and acidic urine pH promotes uric acid or cystine stones. The activity of many transport processes involved in calcium, citrate and phosphate handling are sensitive to changes in systemic or local pH as shown for several phosphate transporters, the citrate transporter NaDC1 and the TRPV5 calcium channel. Defects in urinary acidification (excretion of inappropriately alkaline or acidic urines, respectively) contribute to kidney stone disease. The low excretion of ammonium in patients with metabolic syndrome has been linked to more acidic urine and a higher incidence of uric acid stones. In this state, insulin resistance may reduce ammonium excretion by the proximal tubule. On the other hand, defensive mechanisms may protect from kidney stone formation in conditions such as hypercalciuria where high luminal calcium concentrations stimulate urinary acidification and reduce urinary concentration via a calcium-sensing receptor, resulting in the excretion of acidic and diluted urine. This review will discuss a few aspects that relate to the capacity of the kidney to regulate pH and its impact on the excretion of solutes that participate in the formation or prevention of stones.

Topics: Acidosis; Animals; Calcium; Humans; Hydrogen-Ion Concentration; Kidney; Kidney Calculi; Metabolic Syndrome; Quaternary Ammonium Compounds; Uric Acid

PubMed: 21170875
DOI: No ID Found

Review

Authors: Fredric L Coe, Elaine M Worcester, Andrew P Evan...

The most common presentation of nephrolithiasis is idiopathic calcium stones in patients without systemic disease. Most stones are primarily composed of calcium oxalate and form on a base of interstitial apatite deposits, known as Randall's plaque. By contrast some stones are composed largely of calcium phosphate, as either hydroxyapatite or brushite (calcium monohydrogen phosphate), and are usually accompanied by deposits of calcium phosphate in the Bellini ducts. These deposits result in local tissue damage and might serve as a site of mineral overgrowth. Stone formation is driven by supersaturation of urine with calcium oxalate and brushite. The level of supersaturation is related to fluid intake as well as to the levels of urinary citrate and calcium. Risk of stone formation is increased when urine citrate excretion is <400 mg per day, and treatment with potassium citrate has been used to prevent stones. Urine calcium levels >200 mg per day also increase stone risk and often result in negative calcium balance. Reduced renal calcium reabsorption has a role in idiopathic hypercalciuria. Low sodium diets and thiazide-type diuretics lower urine calcium levels and potentially reduce the risk of stone recurrence and bone disease.

Topics: Apatites; Calcium; Humans; Hypercalciuria; Kidney Calculi

PubMed: 27452364
DOI: 10.1038/nrneph.2016.101

Authors: Pietro Manuel Ferraro, Eric N Taylor, Gary C Curhan...

RATIONALE & OBJECTIVE

Most previous studies of the relationship between urinary factors and kidney stone risk have either assumed a linear effect of urinary parameters on kidney stone risk or implemented arbitrary thresholds suggesting biologically implausible "all-or-nothing" effects. In addition, little is known about the hierarchy of effects of urinary factors on kidney stone risk. This study evaluated the independent associations between urine chemistries and kidney stone formation and examined their magnitude and shape.

STUDY DESIGN

Prospective cohort study.

SETTING & PARTICIPANTS

We analyzed 9,045 24-hour urine collections from 6,217 participants of the Health Professionals Follow-Up Study and Nurses' Health Studies I and II.

EXPOSURE

Urine volume and pH, and concentrations of calcium, citrate, oxalate, potassium, magnesium, uric acid, phosphorus, and sodium.

OUTCOME

Incident symptomatic kidney stones.

ANALYTICAL APPROACH

Multivariable logistic regression analysis incorporating restricted cubic splines to explore potentially nonlinear relationships between urinary factors and the risk of forming a kidney stone. Optimal inflection point analysis was implemented for each factor, and dominance analysis was performed to establish the relative importance of each urinary factor.

RESULTS

Each urinary factor was significantly associated with stone formation except for urine pH. Higher urinary levels of calcium, oxalate, phosphorus, and sodium were associated with a higher risk of stone formation whereas higher urine volume, uric acid, citrate, potassium, and magnesium were associated with a lower risk. The relationships were substantially linear for urine calcium, uric acid, and sodium. By contrast, the magnitudes of the relationships were modestly attenuated at levels above the inflection points for urine oxalate, citrate, volume, phosphorus, potassium, and magnesium. Dominance analysis identified 3 categories of factors' relative importance: higher (calcium, volume, and citrate), intermediate (oxalate, potassium, and magnesium), and lower (uric acid, phosphorus, and sodium).

LIMITATIONS

Predominantly White participants, lack of information on stone composition.

CONCLUSIONS

Urine chemistries have complex relationships and differential relative associations with the risk of kidney stone formation.

PLAIN-LANGUAGE SUMMARY

Kidney stones are common and likely to recur. Certain urinary factors play a role in the development of stones, but their independent roles, relative importance, and shapes of association with stone formation are not well-characterized. We analyzed 24-hour urine collections from individuals with and without kidney stones. Stones were less likely in those with higher urine volume, citrate, potassium, magnesium, and uric acid and were more likely in those with higher calcium, oxalate, phosphorus, and sodium. The acidity of the urine was not related to stones. The urinary parameters showed different degrees of relative importance, with calcium, volume, and citrate being greatest. All parameters exhibited a linear or close-to-linear shape of association with stone formation.

Topics: Humans; Kidney Calculi; Female; Male; Prospective Studies; Middle Aged; Uric Acid; Adult; Risk Factors; Magnesium; Potassium; Calcium; Cohort Studies; Aged; Citric Acid; Sodium; Hydrogen-Ion Concentration; Risk Assessment; Oxalates; Urinalysis; Phosphorus

PubMed: 38583757
DOI: 10.1053/j.ajkd.2024.02.010

Meta-Analysis

Authors: Wei Zhang, Ming Bai, Yan Yu...

BACKGROUND

Regional citrate anticoagulation (RCA) is a widely used strategy for continuous renal replacement therapy (CRRT). Most of the current guidelines recommend liver failure as one of the contraindications for citrate anticoagulation. However, some studies suggested that the use of citrate for CRRT in liver failure patients did not increase the risk of citrate-related complications. The purpose of this systematic review is to summarize the current evidences on the safety and efficacy of RCA for CRRT in liver failure patients.

METHODS

We performed a comprehensive search on PubMed, Embase, and the Cochrane Library databases from the inception to March 1, 2018. Studies enrolled adult (age > 18 years) patients with various levels of liver dysfunction underwent RCA-CRRT were included in this systematic review.

RESULTS

After the study screening, 10 observational studies with 1241 liver dysfunction patients were included in this systematic review. The pooled rate of citrate accumulation and bleeding was 12% [3%, 22%] and 5% [2%, 8%], respectively. Compared with the baseline data, the serum pH, bicarbonate, and base excess (BE), the rate of metabolic alkalosis, the serum ionized calcium (ionCa) and total calcium (totCa) level, and the ratio of total calcium/ionized calcium (totCa/ionCa) significantly increased at the end of observation. However, no significant increase was observed in serum citrate (MD - 65.82 [- 194.19, 62.55]), lactate (MD 0.49 [- 0.27, 1.26]) and total bilirubin concentration (MD 0.79 [- 0.70, 2.29]) at the end of CRRT. Compared with non-liver failure patients, the live failure patients showed no significant difference in the pH (MD - 0.04 [- 0.13, 0.05]), serum lactate level (MD 0.69 [- 0.26, 1.64]), and totCa/ionCa ratio (MD 0.03 [- 0.12, 0.18]) during CRRT. The median of mean filter lifespan was 55.9 h, with a range from 22.7 to 72 h.

CONCLUSIONS

Regional citrate anticoagulation seems to be a safe anticoagulation method in liver failure patients underwent CRRT and could yield a favorable filter lifespan. Closely monitoring the acid base status and electrolyte balance may be more necessary during RCA-CRRT in patients with liver failure.

Topics: Acid-Base Equilibrium; Adult; Anticoagulants; Citric Acid; Hemorrhage; Humans; Liver Failure; Renal Replacement Therapy

PubMed: 30678706
DOI: 10.1186/s13054-019-2317-9

Review

Authors: Luisella Cianferotti, Giuseppe Bifolco, Carla Caffarelli...

Hip fractures are a major health issue considerably impacting patients' quality of life and well-being. This is particularly evident in elderly subjects, in which the decline in bone and muscle mass coexists and predisposes individuals to fall and fracture. Among interventions to be implemented in hip fractured patients, the assessment and management of nutritional status is pivotal, particularly in subjects older than 65. Nutrition plays a central role in both primary and secondary preventions of fracture. An adequate protein intake improves muscle mass and strength and the intestinal absorption of calcium. Other nutrients with recognized beneficial effects on bone health are calcium, vitamins D, K, and C, potassium, magnesium, folate, and carotenoids. With reference to calcium, results from longitudinal studies showed that the consumption of dairy foods has a protective role against fractures. Moreover, the most recent systematic reviews and meta-analyses and one umbrella review demonstrated that the combination of calcium and vitamin D supplementation significantly reduces hip fracture risk, with presumed higher efficacy in older and institutionalized subjects. Owing to these reasons, the adequate intake of calcium, vitamin D, protein, and other macro and micronutrients has been successfully implemented in the Fracture Liaison Services (FLSs) that represent the most reliable model of management for hip fracture patients. In this narrative review, papers (randomized controlled trials, prospective and intervention studies, and systematic reviews) retrieved by records from three different databases (PubMed, Embase, and Medline) have been analyzed, and the available information on the screening, assessment, and management of nutritional and vitamin D status and calcium intake in patients with hip fractures is presented along with specific prevention and treatment measures.

Topics: Humans; Hip Fractures; Vitamin D; Nutritional Status; Aged; Dietary Supplements; Calcium, Dietary; Female; Aged, 80 and over; Male; Musculoskeletal System; Calcium

PubMed: 38892706
DOI: 10.3390/nu16111773

Authors: Emmanuel A Adomako, Xilong Li, Khashayar Sakhaee...

KEY POINTS

The occurrence of calcium phosphate stones has increased over the past five decades, and this is most notable in female stone formers. High urine pH and hypocitraturia are the most discriminatory urine parameters between calcium phosphate and calcium oxalate stone formers. High urine pH in calcium phosphate stone formers is independent of the effect of dietary alkali and acid.

BACKGROUND

Urinary parameters, including urine pH and citrate, are recognized as critical in the pathophysiology of calcium-based stones. The factors contributing to variation in these parameters between calcium oxalate (CaOx) and calcium phosphate (CaP) stone formers (SFs) are, however, not well-understood. In this study, using readily available laboratory data, we explore these differences to delineate the odds of forming CaP versus CaOx stones.

METHODS

In this single-center retrospective study, we compared serum and urinary parameters between adult CaP SFs, CaOx SFs, and non–stone formers.

RESULTS

Urine pH was higher and urine citrate lower in CaP SFs compared with same-sex CaOx SFs and non–stone formers. In CaP SFs, higher urine pH and lower citrate were independent of markers of dietary acid intake and gastrointestinal alkali absorption, suggesting abnormal renal citrate handling and urinary alkali excretion. In a multivariable model, urine pH and urine citrate were most discriminatory between CaP SFs and CaOx SFs (receiver-operating characteristic area under the curve of 0.73 and 0.65, respectively). An increase in urine pH by 0.35, a decrease in urine citrate by 220 mg/d, a doubling of urine calcium, and female sex all independently doubled the risk of CaP stone formation compared with CaOx stones.

CONCLUSIONS

High urine pH and hypocitraturia are two clinical parameters that distinguish the urine phenotype of CaP SFs from CaOx SFs. Alkalinuria is due to intrinsic differences in the kidney independent of intestinal alkali absorption and is accentuated in the female sex.

Topics: Citric Acid; Phosphates; Citrates; Calcium Phosphates; Hydrogen-Ion Concentration

PubMed: 37307531
DOI: 10.34067/KID.0000000000000184

Authors: Ryan W Walker, Shijia Zhang, Joycelynn A Coleman-Barnett...

The calcium sensing receptor (CaSR) in the distal nephron decreases the propensity for calcium stones. Here we investigate if the apical CaSR in the proximal tubule also prevents stone formation acting via regulation of apical dicarboxylate and citrate transport. Urinary citrate, partially reabsorbed as a dicarboxylate in the proximal tubule lumen, inhibits stone formation by complexing calcium. We previously demonstrated a novel apical calcium-sensitive dicarboxylate transport system in OK proximal tubule cells. This calcium-sensitive process has the potential to modulate the amount of citrate available to complex increased urinary calcium. Using isotope labeled succinate uptake in OK cells along with various pharmacologic tools we examined whether the CaSR alters apical dicarboxylate transport and through which signal transduction pathways this occurs. Our results indicate that in the proximal tubule CaSR adjusts apical dicarboxylate transport, and does so via a CaSR → G → PKC signaling pathway. Thus, the CaSR may decrease the propensity for stone formation via actions in both proximal and distal nephron segments.

Topics: Animals; Biological Transport; Calcium; Cells, Cultured; Citric Acid; Dicarboxylic Acids; Kidney Tubules, Distal; Kidney Tubules, Proximal; Opossums; Receptors, Calcium-Sensing; Renal Elimination

PubMed: 29383416
DOI: 10.1007/s00240-018-1035-0

Meta-Analysis Review

Authors: Rebecca Phillips, Vishwanath S Hanchanale, Andy Myatt...

BACKGROUND

Kidney stones affect people worldwide and have a high rate of recurrence even with treatment. Recurrences are particularly prevalent in people with low urinary citrate levels. These people have a higher incidence of calcium phosphate and calcium oxalate stones. Oral citrate therapy increases the urinary citrate levels, which in turn binds with calcium and inhibits the crystallisation thus reduces stone formation. Despite the widespread use of oral citrate therapy for prevention and treatment of calcium oxalate stones, the evidence to support its clinical efficacy remains uncertain.

OBJECTIVES

The objective of this review was to determine the efficacy and adverse events associated with citrate salts for the treatment and prevention of calcium containing kidney stones.

SEARCH METHODS

We searched the Cochrane Kidney and Transplant Specialised Register to 29 July 2015 through contact with the Trials' Search Co-ordinator using search terms relevant to this review.

SELECTION CRITERIA

We included randomised controlled trials (RCTs) that assessed the efficacy and adverse events associated with citrate salts for the treatment and prevention of calcium containing kidney stones in adults treated for a minimum of six months.

DATA COLLECTION AND ANALYSIS

Two authors assessed studies for inclusion in this review. Data were extracted according to predetermined criteria. Summary estimates of effect were obtained using a random-effects model, and results were expressed as risk ratios (RR) and their 95% confidence intervals (CI) for dichotomous outcomes, and mean difference (MD) and 95% CI for continuous outcomes.

MAIN RESULTS

We included seven studies that included a total of 477 participants, most of whom had oxalate stones. Of these, three studies (247 participants) compared potassium citrate with placebo or no intervention; three (166 participants) compared potassium-sodium citrate with no intervention; and one (64 participants) compared potassium-magnesium citrate with placebo. Overall, quality of the reporting of the included studies was considered moderate to poor, and there was a high risk of attrition bias in two studies.Compared with placebo or no intervention, citrate therapy significantly reduced the stone size (4 studies, 160 participants: RR 2.35, 95% CI 1.36 to 4.05). New stone formation was significantly lower with citrate therapy compared to control (7 studies, 324 participants: RR 0.26, 95% CI 0.10 to 0.68). The beneficial effect on stone size stability was also evident (4 studies, 160 participants: RR 1.97, 95% CI 1.19 to 3.26). Adverse events were reported in four studies, with the main side effects being upper gastrointestinal disturbance and one patient reported a rash. There were more gastrointestinal adverse events in the citrate group; however this was not significant (4 studies, 271 participants: RR 2.55, 95% CI 0.71 to 9.16). There were significantly more dropouts due to adverse events with citrate therapy compared to control (4 studies, 271 participants: RR 4.45, 95% CI 1.28 to 15.50). The need for retreatment was significantly less with citrate therapy compared to control (2 studies, 157 participants: RR 0.22, 95% CI 0.06 to 0.89).

AUTHORS' CONCLUSIONS

Citrate salts prevent new stone formation and reduce further stone growth in patients with residual stones that predominantly contain oxalate. The quality of reported literature remains moderate to poor; hence a well-designed statistically powered multi-centre RCT is needed in order to answer relevant questions concerning the efficacy of citrate salts.

Topics: Adult; Calcium Oxalate; Calcium Phosphates; Citrates; Drug Combinations; Humans; Kidney Calculi; Magnesium Compounds; Potassium Compounds; Randomized Controlled Trials as Topic; Recurrence; Secondary Prevention

PubMed: 26439475
DOI: 10.1002/14651858.CD010057.pub2

Authors: Chloé Medrano, Olivier Cointault, Laurence Lavayssiere...

BACKGROUND

There is an unmet need to develop safe and successful heparin-free regional anticoagulation modalities in haemodialysed patients at risk of bleeding. Whether the addition of citrate as a prefilter injection or in the dialysate itself is required to reach anticoagulation objectives when calcium-free dialysate is used as regional anticoagulation remains unclear.

METHODS

In this monocentric retrospective study, we report our experience of 908 dialysis sessions performed with a calcium-free citrate-containing dialysate and calcium reinjection according to the ionic dialysance, without additional heparin.

RESULTS

Premature termination for filter clotting occurred in 20 sessions (2.2%) and duration of session was >4.5 h in 135 (15%; maximum duration 6 h). In addition, we could investigate the citrate, calcium and acid-basis status during haemodialysis sessions performed with (citrate group,  = 20 sessions) or without (citrate-free group,  = 19 sessions) citrate in the dialysate. In 20 sessions performed in patients with underlying liver disorders and using calcium-free citrate-containing dialysate, patients' ionized calcium (iCa) and serum citrate levels were stable and remained within the normal range, respectively. Post-filter iCa was below 0.4 mmol/L in 19/20 sessions and citrate was 0.304 mmol/L (range: 0.011; 0.548). In 19 sessions that used calcium and citrate-free dialysate, post-filter iCa was 0.41 mmol/L (0.34; 0.5) and all sessions extended to 4 h or beyond.

CONCLUSIONS

Regional anticoagulation of haemodialysis with a calcium-free dialysate and calcium reinjection according to the ionic dialysance is safe. Adding citrate to the dialysate is not mandatory to prevent dialysis circuit clotting in most patients.

PubMed: 34950464
DOI: 10.1093/ckj/sfab087