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Keywords:

  • Ketogenic diet;
  • Topiramate;
  • Zonisamide;
  • Carbonic anhydrase;
  • Renal stones

Abstract

  1. Top of page
  2. Abstract
  3. METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

Summary:  Purpose: Because carbonic anhydrase inhibitors and the ketogenic diet are each known risk factors for kidney stones, simultaneous use of these therapies has been discouraged. The objective of this study was to establish the prevalence of nephrolithiasis in children in this combination-therapy population.

Methods: Since 1996, 301 children have been started on the ketogenic diet at our institution. A retrospective cohort study of renal calculi in ketogenic diet patients was performed to evaluate the increased risk with combined use of a carbonic anhydrase inhibitor.

Results: In 15 (6.7%) of 221 children on the ketogenic diet without the use of carbonic anhydrase inhibitors, stones developed. In five (6.3%) of the 80 children on the diet in combination with topiramate or zonisamide, stones developed. There was no difference between these two groups (p = 0.82). No child was treated with either acetazolamide or more than one carbonic anhydrase inhibitor simultaneously. Prior ketogenic diet duration was shorter (10.4 vs. 22.4 months; p = 0.03), and more children had either a family history of renal stones or significant urologic abnormalities (80 vs. 27%; p = 0.04) in the combination-therapy group.

Conclusions: The combined use of carbonic anhydrase inhibitors and the ketogenic diet does not increase the risk of kidney stones. We recommend that all patients treated with combination therapy should be treated with increased hydration. Urine alkalinization should be considered for children with previous renal abnormalities, family histories of kidney stones, hematuria, or elevated urine calcium-to-creatinine ratios. If renal stones are found, we advocate discontinuation of the carbonic anhydrase inhibitor.

The use of carbonic anhydrase inhibitors in the treatment of epilepsy has been well established, originally with the use of acetazolamide (AZM), and recently with topiramate (TPM) and zonisamide (ZNS). Carbonic anhydrase inhibitors are known to be a risk factor for calcium phosphate renal calculi through both increased calcium excretion and decreased citrate in the urine (1,2).

TPM is a sulfamate-substituted monosaccharide created from d-fructose. Its multiple mechanisms of action include weak carbonic anhydrase inhibition (2,3). Based on a study of 1,183 adults, the incidence of nephrolithiasis with TPM is ∼1.5%(4). Five of seven stones in this study were calcium phosphate in composition (4). This incidence is similar to that of AZM (2).

ZNS is a sulfonamide agent structurally similar to serotonin and acts by blockade of T-type calcium channels and γ-aminobutyric acid (GABA) potentiation (5). ZNS also has weak carbonic anhydrase activity, although much less than AZM (6). Initial trials revealed that kidney stones developed in 40 (4.0%) of 991 patients (7). The incidence of proven renal stones in adults taking ZNS was found to be 3.5 and 4.4% in two separate studies by Leppik (8,9). In a recent review of seven U.S. clinical trials, 2.8% had kidney stones (10). Stones have been predominantly calcium phosphate or oxalate and secondarily uric acid (7,9,11). A preliminary report of ZNS and TPM used in combination in 40 adults and children found no cases of renal calculi (12). Another found a single patient in 35 (6). Carbonic anhydrase inhibitors alkalinize the urine weakly (4).

The ketogenic diet is a high-fat, adequate-protein, low-carbohydrate diet used for the past 80 years in the treatment of difficult-to-control epilepsy (13). The ketogenic diet can cause hypercalciuria, urine acidification, and hypocitraturia; increasing the risk of uric acid and less frequently calcium phosphate and oxalate stones (14). These factors are similar to carbonic anhydrase inhibition, with the major exception of urine acidification (4). The reported incidence of kidney stones in children on the ketogenic diet, 5.4%, is higher than that with carbonic anhydrase inhibitors alone (14). These children with renal calculi can be effectively treated with urine alkalinization and hydration while remaining on the ketogenic diet (14). Without specific data, the literature warns against the concurrent use of both carbonic anhydrase inhibitors and the ketogenic diet (15,16).

METHODS

  1. Top of page
  2. Abstract
  3. METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

A retrospective cohort study reviewed the medical records of all patients enrolled on the ketogenic diet over a 6-year period from January 1996 until December 2001. All cases with renal stones were reviewed for simultaneous therapy with ZNS, AZM, or TPM for ≥1-month duration. No child had previously diagnosed renal stones before starting the ketogenic diet. The Johns Hopkins Committee on Clinical Investigation approved the protocol, and informed consent was obtained.

The diet had been initiated in the standard Hopkins protocol (13). Older children were generally on a 4:1 diet, with younger patients receiving 3:1. Calories were calculated based on basal metabolic needs plus activity. Fluids were targeted at 80% of estimated daily allowance. All children taking a carbonic anhydrase inhibitor at the time of the ketogenic diet received 100% of the estimated required fluid intake as of July 1998. Children were followed up by phone contact and seen in clinic every 3–4 months after discharge to monitor seizure control, weight, health, and ketosis. Patient and family histories, medications, laboratory values, and symptoms were recorded after clinic visits in a database. All children that were treated with the ketogenic diet at our institution received epilepsy management from our center throughout their therapy. Kidney stones were diagnosed by pain, hematuria, or stone fragments in the urine. Urine calcium-to-creatinine ratios were assessed on random urine evaluations and included in the data if done within 1 month of stone diagnosis.

TPM began being used in our patients in 1996, and ZNS, in 2000. Since 1996, 301 patients have been started on the ketogenic diet, with 75 patients since 2000. No child has ever been on a combination of more than one of the two agents and the diet. No child was treated with AZM. Seventy-four patients were either given TPM or continued prior treatment in combination with the ketogenic diet to manage the epilepsy. Six children have been treated with ZNS at the same time as the diet.

Means were tested by using a two-tailed t test with unequal variances. Categorical data were analyzed by using Pearson's χ2 for independence of rows and columns. The significance level for all tests was p = 0.05.

RESULTS

  1. Top of page
  2. Abstract
  3. METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

Incidence of stones with the ketogenic diet alone

Stones developed in 15 (6.8%) of 221 children on the ketogenic diet without the simultaneous use of carbonic anhydrase inhibitors. This group is summarized along with the cases of combination therapy stones in Table 1. Of those that were recovered and analyzed, six were uric acid, and five were calcium oxalate/phosphate. All children with documented stones were managed first medically with increased fluids and urine alkalinization by using oral potassium citrate to a urine pH of 6.5. Five children required lithotripsy for renal stones, with prompt resolution. All but one child remained on the ketogenic diet.

Table 1.  Comparison of kidney stone cases on the ketogenic diet with and without carbonic anhydrase inhibition
 Combination therapy (80)Ketogenic diet alone (221)p value
Incidence5 (6.3%)15 (6.8%)0.82
Age (yr) (mean)4.8 (SD, 2.4; range, 6.5)5.1 (SD, 4.5; range, 16.5)0.86
Positive family or personal history of renal abnormalities80%27%0.04
Diet duration (mo)10.4 (SD, 6.7; range, 17)22.4 (SD, 15.0; range, 42)0.03
Urine Ca/Cr ratio (mean)0.97 (SD, 0.64; range, 1.45)0.37 (SD, 0.11; range, 1.28)0.11
Elevated urine Ca/Cr ratios100%75%0.22
Urine pH6.1 (SD, 0.82; range, 2)5.7 (SD, 0.66; range, 2)0.36
Lithotripsy required050.18

Incidence of stones with carbonic anhydrase coadministration

Five (6.3%) of 80 children receiving combination carbonic anhydrase inhibitors and the ketogenic diet had documented renal stones and are described in Table 2. All five cases had been treated with TPM; none of the six children taking ZNS with the diet had renal calculi. There was no difference in incidence between those on the ketogenic diet with and without carbonic anhydrase inhibitors (p = 0.82). The average dose of TPM in patients with kidney stones, 8.4 mg/kg/day, was not different from that of patients without stones, 7.3 mg/kg/day. One child had a calcium carbonate stone; the other cases had no stone recovered for analysis. All children remained on the ketogenic diet with full recoveries after increased fluids and urine alkalinization. No child required lithotripsy.

Table 2.  Patients with coadministration renal stones
Case no.Age (yr)GenderDuration of combination before stone (mo)Dose of topiramate (mg/kg/day)Ketogenic diet ratioHematuriaFamily history of renal abnormalitiesPredisposing risk factorsUrine calcium/ creatinine ratioStopped topiramate
11.5F893:1NoYesRight ureteropelvic  junction obstruction1.5Yes
24.0M634:1NoNoNone1.0Yes
35.0M10104:1YesYesNone1.7No
45.5F7143.5:1YesNoNeurogenic bladder,  prior pyelonephritis0.4Yes
58.0F564:1YesYesNone0.25No

Risk factor analysis

Aspects of the children in whom renal calculi developed are summarized in Table 1 according to whether they were treated with the ketogenic diet alone or with carbonic anhydrase inhibitors. Four (80%) of five patients with combination therapy and renal calculi had either a family history of urologic abnormalities or had their own previous abnormalities, compared with four (27%) of 15 on ketogenic diet monotherapy (p = 0.04). There was no difference in age between the two groups (mean, 4.8 years for combination-therapy stones vs. 5.1 years; p = 0.86). Diet ratio was similar between the two groups and those without stones. Ketogenic diet duration at the time of renal stones was a mean of 10.4 months in the combination-therapy cases compared with 22.4 months in the ketogenic diet–alone group (p = 0.03). Urine calcium-to-creatinine ratios were available in all five combination-therapy stone patients and in 12 of 15 patients on the ketogenic diet alone. All of the combination-therapy patients had elevated urine calcium-to-creatinine ratios at the time of stone diagnosis, compared with nine (75%) of the 12 cases on the diet alone (p = 0.22). The elevation also was higher in the combination-therapy population, although it did not reach significance (0.97 vs. 0.37; p = 0.11). There was no difference between the urine pH of those patients with combination-therapy stones and that of those on the ketogenic diet alone (6.1 vs. 5.7; p = 0.36). Although there was a difference in the number of cases requiring lithotripsy between the combination-therapy patients (none of five) and the ketogenic diet–alone population (five of 15), this also was not statistically significant, likely because of small sample size (p = 0.18).

DISCUSSION

  1. Top of page
  2. Abstract
  3. METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

Our experience indicates that the combined use of carbonic anhydrase inhibitors and the ketogenic diet does not increase the risk of kidney stones. The 6.3% incidence is higher than that reported for TPM (1.5%) and ZNS alone (3–4%). However, we saw no evidence of increased risk with the use of these agents above that of the ketogenic diet alone.

It is unclear from our limited study whether the ketogenic diet or carbonic anhydrase inhibition is the predominant risk factor. However, certain factors indicate that the ketogenic diet may be responsible. For one, the incidence was essentially identical to that with the ketogenic diet alone rather than carbonic anhydrase inhibition alone. In addition, many of our children were previously symptom free with TPM for months before the diet was initiated. Analysis of the stone composition in this study was not revealing, and the universally seen hypercalciuria can be identified in both situations.

In this small sample, the patients in whom stones developed with combination therapy were more likely to have a family or previous history of renal abnormalities. In reports of ZNS- and TPM-associated cases, family histories of renal calculi also were important risk factors (3,8). Additionally, the mean urine calcium-to-creatinine ratio was more abnormal in the combination stone population, although both groups had significant elevations overall. Last, stones developed in combination-therapy patients sooner after initiating the ketogenic diet than in patients on the ketogenic diet alone. We speculate that although there was no increased incidence with combination therapy, stones may form more quickly.

We currently attempt to prevent renal calculi in combination therapy by first increasing fluid intake from 80 to 100%. Fluid liberalization does not seem to affect the efficacy of the ketogenic diet and may prevent stone formation because of increased urine flow. Second, we would suggest urine alkalinization in combination-therapy patients with family histories or prior renal abnormalities. Urine alkalinization will help dissolve uric acid stones and decrease future formation of calcium stones. Third, we currently screen all patients on the ketogenic diet for hematuria with urine testing strips weekly and calcium-to-creatinine ratios every 3 months. If microscopic hematuria and hypercalciuria is identified, we add oral polycitrate (14). Any evidence of hematuria, dysuria, or crystalluria should be evaluated by both a renal ultrasound and nephrology referral. Last, although there is no evidence that outcomes improve with carbonic anhydrase inhibitor elimination, we do recommend its discontinuation in the case of a renal stone. We do not advocate routine discontinuation of the ketogenic diet if it has been effective and otherwise well tolerated.

In summary, we believe that the combined use of carbonic anhydrase inhibitors and the ketogenic diet does not increase the risk of kidney stones above that of the ketogenic diet alone. We recommend that all patients treated with combination therapy should be treated with increased hydration and monitoring for hematuria and hypercalciuria. Urine alkalinization should be considered for children with previous renal abnormalities, family histories, hematuria, or elevated urine calcium-to-creatinine ratios. If renal stones are found, we advocate discontinuation of the carbonic anhydrase inhibitor.

REFERENCES

  1. Top of page
  2. Abstract
  3. METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES
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