Κυριακή 13 Μαΐου 2012

Empiric Use of Potassium Citrate Reduces Kidney-Stone Incidence With the Ketogenic Diet



For nearly a century, the ketogenic diet (KD) has been recognized as an effective nonpharmacologic treatment for epilepsy. Despite positive effects on seizure frequency, repeated studies have shown that the KD is associated with an increased prevalence of kidney stones, ranging from 3% to 6% during a typical 2-year diet duration. Hypercalciuria, urine acidification, and hypocitraturia, all known risk factors for kidney stones, often occur in patients who on the KD.3
In 2000, a study from our group identified that children who had hypercalciuria (urine calcium-to-creatinine ratio typically >0.2) and were on the KD were at highest risk for kidney stones. Past studies have shown that oral potassium citrate (Polycitra K, Cypress Pharmaceuticals, Madison, MS) effectively increases urinary pH, increases urinary citrate, and decreases incidence of kidney stones. From 2000 to 2005, our approach was to treat children on the KD at the time of laboratory-identified hypercalciuria with Polycitra K. In this group, hypercalciuria occurred in 101 (52%) of 195 patients, usually after 3 to 6 months.7 Unfortunately, the incidence of kidney stones did not decrease with this strategy, with 13 (6.7%) developing stones during this period; however, in 10 of these children, hypercalciuria was not noticed, was treated, or the child refused treatment with Polycitra K.
In light of the results from this study, we began empirically giving all children, regardless of hypercalciuria, Polycitra K at KD initiation. We believed that the benefits outweighed any risks and that universal use would avoid confusion and improve compliance. In this cohort study, we examined whether empiric Polycitra K administration could reduce the 6.7% incidence of kidney stones in children who are started on the KD.7

METHODS

Medical charts of all children who were started on the KD at Johns Hopkins Hospital from January 1, 2000, to December 31, 2008, and had at least 1 month of follow-up were analyzed retrospectively. After an initial 24- to 48-hour fast, patients' caloric intake was gradually increased at either a 3:1 or 4:1 (fat to protein or fat to carbohydrates, respectively) ketogenic ratio during a 3-day period.1 Children were provided a fluid allotment of ∼80% to 90% of their recommended daily requirements but often increased to 100%.1 Most children were rarely drinking their fluid requirements even before starting the KD, and the fluid allotment is often an increase over their baseline. Children were typically seen in the clinic every 3 to 4 months for the first year and every 6 months thereafter, at which time all medications, including Polycitra K, were confirmed with parents. The presence of a kidney stone was defined as (1) stones or stone fragments found to have been passed in urine or noted in the diaper, (2) gross or microscopic hematuria concurrent with lower flank pain, or (3) evidence on ultrasound or computed tomography scan of a stone or nephrolithiasis.
From January 2000 to December 2005, 195 children were administered the KD and treated with Polycitra K as described previously, treating only for identified hypercalciuria.7 This group is referred to as the reactive group. From January 2006 to December 2008, all children who started on the KD at our institution were started empirically on Polycitra K at hospital discharge and are further described as the empiric group.
Polycitra K is available in a powdered packet of 30 mEq that can be dissolved in fluid or sprinkled onto ketogenic foods such as heavy whipping cream or eggs, with a taste similar to lemons. The prescribed dosage of Polycitra K, 2 mEq/kg per d divided twice daily, remained consistent in both groups. In general, most young children (<20 kg) received half a packet twice daily for ease of administration, and older patients (>20 kg) received ∼1 packet twice daily. When a child refused, we recommended sodium citrate tablets (Bicitra, Ortho-McNeil-Janssen Pharmaceuticals, Titusville, NJ) instead.
Charts and electronic records were reviewed for patient age, gender, immobility (defined as spending the majority of their time in a wheelchair or stroller past 2 years of age), carbonic anhydrase inhibitor (topiramate or zonisamide) use, kidney-stone occurrence, and Polycitra K use for both groups. Urine pH and serum CO2 were analyzed after 3 months on the KD when available. Urine calcium and creatinine were obtained in the reactive group approximately every 3 to 6 months but no longer monitored regularly in the empiric group because it did not affect management or added cost, and our previous study showed no change in hypercalciuria with oral citrates.7Baseline urine pH was examined for the 50 most recent patients.
This study was approved by the Johns Hopkins institutional review board, and all families consented for their information to be included in a centralized database. Categorical data were analyzed using χ2 test with Yates correction. Means were compared using a paired 2-sample t test. Multiple regression analysis was used to adjust for carbonic anhydrate use and diet duration (in 12-month intervals) when examining for kidney-stone occurrence. The significance level for all tests was P = .05.

RESULTS

Overall Effects of Receiving Polycitra K

Between January 2000 and December 2008, 313 children with intractable epilepsy were started on the KD. Seven children discontinued the KD before 1 month, and 3 children were lost to follow-up; these cases were not included in the analysis. Polycitra K was administered preventively (either because of presence of hypercalciuria in the reactive group (n = 92) or at KD onset in the empiric group (n = 106) to 198 children at some point during their KD care, 4 (2.0%) of whom developed kidney stones. For children who did not receive Polycitra K, 11 (10.5%) of 105 developed kidney stones. Between the 2 groups, preventive use of Polycitra K decreased the incidence of kidney stones as compared with the group that did not receive Polycitra K (P = .003).
Overall, the median time to kidney-stone presentation was 6 months (range: 1–28 months). Only 3 stones were retrieved and analyzed; they were calcium oxalate, calcium carbonate, and uric acid in composition. Although there were sporadic reports about poor taste of the oral citrate powder, there were no adverse effects noted with its use.

Comparison of Reactive to Empiric Polycitra K Approach

From 2000 to 2005, 195 children were treated with the KD and are referred to as the reactive group. Of this group, 161 (83%) were appropriately treated only when hypercalciuria occurred as planned. For children who were not started on Polycitra K, hypercalciuria was never present, laboratory results were not available at clinic visits, or hypercalciuria was not treated because of neurologist or parent decision. In total, 92 (47%) children received Polycitra K in the reactive group, 10 directly as a result of a symptomatic kidney stone.
From 2006 to 2008, 108 children were started on the KD and are referred to as the empiric group. Of this group, 106 (98%) reported compliance with the recommended universal Polycitra K use (P < .001). Two children in the empiric group did not receive Polycitra K. One of these children, a 9-month-old boy, was not given Polycitra K because of parental confusion with provided prescriptions and developed hematuria and a kidney stone after 3 months. Symptoms resolved with extra fluids and Polycitra K, and he remained on the KD for a total of 17 months. A second child, a 4-year-old girl, has repeatedly refused Polycitra K because of taste according to her parents. She has not developed a stone or hypercalciuria to date and has remained on the KD for the past 18 months.
Table 1 summarizes the comparison between the reactive'(n = 195) and empiric (n = 106) approaches, excluding the 2 children in the empiric group who were not given Polycitra K. Empiric administration of Polycitra K at KD onset resulted in a kidney-stone prevalence of 0.9% compared with preventive administration (6.7%; P = .02). Only 1 child in the empiric group who was receiving Polycitra K developed a kidney stone. This 2-year-old girl developed a stone and hematuria after 5 months on the KD. She was not receiving any carbonic anhydrase inhibitor, and her parents reported daily use of Polycitra K as prescribed. Urine pH was 6.0 and serum CO2 was 13 mg/dL at the time of the stone. Lithotripsy was performed, and she has remained on the KD (and Polycitra K) 21 months to date without any additional stones.
Both diet duration and use of carbonic anhydrase inhibitor showed slight differences between the empiric and reactive groups. Mean diet duration in the empiric group was 13.3 months compared with a mean diet duration of 15.6 months in the reactive group (P = .11). Use of carbonic anhydrase inhibitor was 53 (50%) of 106 in the empiric group and 82 (42%) of 195 in the reactive group (P = .19). In a multivariate logistic regression that adjusted for both diet duration and carbonic anhydrase inhibitor use, the an odds ratio was 6.32 (95% confidence interval: 0.79–50.67; P = .08). The mean urine pH in the empiric group was higher (6.8 vs 6.2; P = .002), although there was not a similar increase in serum CO2. As a comparison, the baseline urine pH before starting the KD was 6.8 (SD: 0.9).

DISCUSSION

Overall, these results confirm previous evidence that Polycitra K administration is effective for kidney-stone prevention in children who receive the KD.7 The results are perhaps more convincing now than in our previous study, with a fivefold overall decrease in kidney-stone incidence with its use overall, compared with a threefold reduction previously.7 Polycitra K was well tolerated as a supplement, and no clear adverse effects were reported.
Comparing the 2 approaches of Polycitra K administration at our center, there was a sevenfold drop in the incidence of kidney stones with an empiric, universal treatment approach since 2006 (0.9% vs 6.7%). This approach is easier to follow because there is no longer any need for regular monitoring of the urine calcium-to-creatinine ratio. In addition, the ketogenic diet team can simply confirm with parents that oral citrates are being administered, similarly to multivitamins and calcium. Using Polycitra K from the start of the KD may also theoretically prevent stones from beginning to form, because no urine calcium-to-creatinine values were obtained until the 3-month clinic visit in the reactive approach. We are now recommending Polycitra K for all children who are in the reactive cohort (started on the KD before 2006) and still remain on the KD to date.
Relative costs need to be considered for any treatment, and the average cost for Polycitra K for the median 14 months in this study is approximately $630 (www.drugstore.com). Using cost analysis to adjust for the overall fivefold decrease in incidence with use, the number of children needed to treat to prevent 1 kidney stone is 11.7, hence $7371 worth of Polycitra K. The cost for treatment of an individual child with a kidney stone, including pediatric urology clinic visits, renal/bladder ultrasounds, urinalysis, and analgesic medications is approximately $2100. If necessary, the costs of admission for intravenous fluids, pain management, and time off work and school would then approach the combined cost of preventive oral potassium citrates. Although not always required, lithotripsy would cost an additional $7950 at our institution.
As would be predicted theoretically, urine pH within the empiric group was significantly higher than in the reactive group and identical to baseline values before the KD. This was even higher than the median urine pH of 6.0 reported before 2000, before oral citrates were first prescribed. Alternatively, serum CO2 was not different between the groups, suggesting that Polycitra K may not affect serum acidosis and its therapeutic effects may be primarily attributable to urine alkalosis. A future potential method to monitor compliance with Polycitra K might be to review urine pH data at KD clinic visits. In addition, possibly increasing the dosage if the urine pH is low (eg, <6.5) may be valuable in further avoiding kidney stones, as evident in the single child since 2006 with a stone despite Polycitra K and a urine pH of 6.0.

CONCLUSIONS

We strongly believe that universal use of Polycitra K is warranted for all children who start the KD, with clear benefits outweighing risks. We advise initial education about the importance of regular Polycitra K use at the time of KD onset and subsequent reinforcement at each follow-up clinic. Additional studies may help to determine whether higher dosages of Polycitra K would be completely preventive or could perhaps be combined with other supplements such as multivitamins to aid compliance.

ACKNOWLEDGMENTS

This study was supported in part at Johns Hopkins by the Pediatric Clinical Research Unit, National Institutes of Health/National Center for Research Resources grant M01-RR00052, and the Carson Harris Foundation.
We acknowledge the support of Dr Lori Jordan with the relative cost analysis.


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