Night-time use of thiazide diuretics for improved reduction in stone risk

in stone formers with elevated urine calcium

Hasan Fattah

8/6/2013

• The regulation of calcium reabsorption in the kidney is crucial for the maintenance of Ca2+ balance

• Hoenderop et al. Identified the transient receptor protein-vanilloid TRPV5 as the responsible protein in this process.

Eur J Physiol (2009)

Clinical relevance

• CKD associates with Ca2+ homeostasis abnormality, Moreover, CKD patients also have greatly reduced renal klotho levels. Together with the fact that klotho can regulate the activity of TRPV5 and NCX1 via Na+/K+-ATPase.

• Hypercalciuria and nephrolithias, often treated with thiazide diuretics.

• Thiazide is a well known diuretic frequently used to treat arterial hypertension.

• The development of hypocalciuria, as one of its side-effects, is used to its advantage in the treatment of idiopathic hypercalciuria

data demonstrated Thiazide-induced hypocalciuria due to increased passive Ca2R reabsorption

• Nijenhuis et al. showed that a chronic treatment of rats with a high dose of hydrochlorothiazide results in decreased mRNA levels of genes encoding for TRPV5, calbindin-D28k, and NCX1.

• chronic treatment of rats with HCTZ induced ECV contraction and reduced urinary Ca2 excretion. Na repletion abolished ECV contraction and prevented the hypocalciuria

• chronic treatment with a relatively low dose of hydrochlorothiazide results in a strong reduction of urinary Ca2 excretion in both wild-type and TRPV5-/-.

• micropuncture data showed that Na, fluid, and Ca2 reabsorption in PTs is increased after HCTZ treatment, while fractional Ca2 delivery in DCTs was reduced

• protein levels of the proximal tubular Na+/H+ exchanger NHE3 were significantly increased.

• The lifetime incidence of kidney stones is approximately 13 % for men and 7 % for women

• The incidence of nephrolithiasis in the populations of industrialized countries is 0.5% to 1% annually.

• For those individuals with a stone, the likelihood of a recurrence is as high as 50% in 5 years.

• Even those with an asymptomatic stone have an approximately 50% chance of becoming symptomatic from their stone within a 5-year period

• Following an initial stone event, the 5-year recurrence rate in the absence of specific treatment is 35 to 50 percent

History • In 1937 and 1938, research on the mechanism of acidemia

produced by sulfonamides demonstrated that they also had a diuretic effect

• Until 1957, the only effective available diuretics were IV or IM mercurial agents, which were difficult to use; their use was restricted mostly to patients with heart failure.

• The modern era of diuretic therapy began in 1957 when Novello and Sprague synthesized the thiazide diuretic chlorothiazide, which later distinguished itself from a carbonic anhydrase inhibitor by causing an increase in chloride rather than bicarbonate excretion.

• In 1958 Beyer reported that the drug had natriuretic properties

• In 1959 Lamberg and Kuhlback found that chlorothiazide (1 gm BID) and hydrochlorothiazide (100 mg BID) reduced urinary calcium excretion.

• in 1970 Yendt in uncontrolled studies reported reduced stone recurrence rates using hydrochlorothiazide in doses from 100 mg daily to 100 mg BID

• This was subsequently followed by at least 10 (RCT) using a variety of thiazide diuretics.

Looking at data

• RCT , “stone clinic effect”, and regression to the mean.

• 10 trials examined the effects of several different thiazide diuretics on preventing calcium-containing kidney stone recurrence, 7 of which showed reduced recurrence rates of calcium-containing kidney stones.

• when HCTZ used, The lowest dose employed was 50 mg daily.

Author, Year Treatment Selection/% Hypercalciuria Follow-Up (years) n Treated/n Placebo RR

Brocks, 1981 (17) Bendroflumethiazide 2.5 mg TID None 1.6 33/29 NS

Scholz, 1982 (18) HCTZ 25 mg BID None 1 25/26 NS

Laerum, 1984 (12) HCTZ 25 mg BID None/20% 3 25/25 0.39

Wilson, 1984 (16) HCTZ 100 mg daily None 2.8 23/21 0.48

Robertson, 1985 (15) Bendroflumethazide 2.5 mg TID None 3 to 5 13/9 0.38

Mortensen, 1986 (13)

Bendroflumethazide 2.5 mg + KCl None 2 12/10 NS

Ettinger, 1988 (10) Chlorthalidone 25/50 mg

None/13% to 15.8% 3 19/23/31 25 mg/50

mg/placebo 0.23

Ohkawa, 1992 (14) Trichlormethiazide 4 mg Hypercalciuria 2.1 to 2.2 82/93 0.42

Borghi, 1993 (9) Indapamide 2.5 mg daily Hypercalciuria 3 43/14 0.21

Fernandez-Rodriguez, 2006 (11) HCTZ 50 mg daily None/52% 3 50/50 0.56

Conclusions from RCTs • A consistent finding in these trials is that stone-

formation rate between treated and control groups did not begin to diverge until after at least 1 year of therapy

• No RCT has used low-dose HCTZ (12.5 to 25 mg daily) to examine reduction in calcium-containing kidney stone recurrence. Whether this dose would be effective is unknown

• In the treatment of nephrolithiasis, it has been shown that thiazide and thiazide-like diuretics, especially HCTZ, are commonly not used in an evidence-based fashion

Conclusions from RCTs

• 35% of HCTZ treated patients received >50 mg/d in one report

• Interestingly, in only 2 of 10 RCTs was hypercalciuria an inclusion criterion, and despite this fact, 7 of 8 trials of adequate duration showed a reduction of kidney stone-formation rate with thiazide diuretics.

Hypercalciuria definition?

• Although the current traditional definitions of abnormal 24-hour urine values are widely accepted, it is unclear how these cutpoints were selected.

• There was substantial variability in the selection of study subjects, and the cutpoints for the definition of abnormal were not selected in a consistent manner

• even as urinary calcium excretion increases within the “normal” range, the risk of stone formation increases, as shown by Curhan et al. in an analysis of the Nurses Health Studies (NHS) I and II and the Health Professions Follow-Up Study (HPFS).

• An increase in relative risk for kidney stone formation was seen with urinary calcium excretion 100 mg/d in NHS I, 150 mg/d in NHS II, and 125 mg/d in HPFS

Considerations: • It is crucial to recognize that the urinary factors are

continuous variables, and their effects on stone formation are also likely to be continuous, although not necessarily linear. Accordingly, specific cutpoints for "abnormal" are not appropriate but rather should serve only as approximate guides.

• For example, the risk of stone formation began to increase even within the "normal" ranges of calcium excretion and urine calcium concentration

• much larger relative risks for calcium concentration than for absolute amounts of calcium adjusted for total volume were found.

Multivariate relative risks for kidney stones according to categories of 24-hour urinary excretion within Nurses' Health Study I, Nurses' Health Study II and the

Health Professionals Follow-up Study

NHS I

NHS II HPFS

Ca mg/ day Cases Control RR 95% CI

Cases Control RR 95% CI Cases Control RR 95%

CI

<150 83 41 1.00 — 39 13 1.00 —

68 36 1.00 —

150–199 53 19 1.45 0.73–2.89

36 8 2.05 0.67–6.25 58 23 1.23 0.63–

2.37 200–249 62 12 3.06 1.38–6.79

30 4 4.68 1.19–18.41 65 26 1.31 0.67–

2.56 250–299 34 12 1.47 0.63–3.45

28 2 12.66 1.76–91.24 50 9 2.56 1.09–

6.02 300–349 29 7 2.21 0.81–6.05 36 3 14.62 2.66–80.26

35 5 3.77 1.26–11.26

350+ 36 8 2.58 0.93–7.20

48 11 2.44 0.96–6.18

Kidney International (2001)

Multivariate relative risks for kidney stones according to categories of 24-hour urinary concentration within Nurses' Health Study I, Nurses' Health Study II and the

Health Professionals Follow-up Study

NHS I NHS II

HPFS

Ca mg/L

Cases Control RR 95% CI Cases Control RR 95% CI Cases Control RR 95% CI

<75 59 44 1.00 — 25 9 1.00 — 49 34 1.00 —

75–99 44 16 1.91 0.93–3.94 15 7 0.96 0.26–

3.49 36 14 2.20 0.98–4.93

100–124 44 13 2.24 1.03–4.88 14 5 1.34 0.33–

5.54 41 18 1.55 0.72–3.33

125–149 31 9 2.10 0.83–5.30 23 4 4.11 0.89–

18.94 41 9 3.33 1.30–8.50

150–199 50 7 4.18 1.56–

11.22 33 1 32.34 2.71–385.5 82 25 2.18 1.02–

4.67

200+ 69 10 4.34 1.59–11.88 59 4 51.09 4.27–

611.1 92 12 4.30 1.71–10.84

P, trend <0.001 <0.001 0.005

Conclusion from trial:

• The traditional definitions of normal 24-hour urine values need to be reassessed, as a substantial proportion of controls would be defined as abnormal, and the association with risk of stone formation may be continuous rather than dichotomous.

• given that men and women have similar 24-hour urine volumes and that the concentration is the critical determinant of the likelihood of crystal formation in the urine, there appears to be no known physiological basis for separate definitions of abnormal for men and women.

Other potential mechanisms

• Thazides have favorable effects on other urinary constituents (magnesium and oxalate) that may reduce stone risk.

• They increase magnesium excretion, which may reduce stone formation, In addition, prolonged thiazide use (1 year) may reduce urinary oxalate excretion.

• The authors of these studies speculated that with long-term thiazide administration intestinal calcium absorption declines. The resultant increase in intestinal luminal calcium would then bind oxalate and reduce its absorption

Thiazides trials conclusion:

• Given the fact that most patients enrolled in RCTs were not hypercalciuric, that thiazide diuretics may have effects on other urinary risk factors that play a role in stone recurrence, the most prudent approach would be to use those drugs that were shown to be beneficial in RCTs in adequate doses. This would require the use of indapamide at 2.5 mg/d, chlorthalidone at 25 to 50 mg/d, or HCTZ at 25 mg twice daily or 50 mg/daily.

comparative effectiveness review

AHRQ Publication No. 12-EHC049-EF July 2012

what is the effectiveness and comparative effectiveness of different pharmacological therapies on final health outcomes

and intermediate stone outcomes?

• In patients with multiple past calcium stones, we found moderate strength of evidence that treatment reduces risk of composite recurrent stones versus control for thiazide diuretics (RR, 0.53 [CI, 0.41 to 0.68], citrate (RR, 0.26 [CI, 0.14 to 0.48]), and allopurinol (RR, 0.59 [CI, 0.42 to 0.84]).

• We found low strength of evidence that neither the addition of citrate (RR, 0.94 [CI, 0.52 to 1.68]) nor allopurinol (RR, 0.79 [CI, 0.18 to 3.49]) to thiazide reduces risk of recurrent stones compared with thiazide treatment alone.

What Is the Evidence That Stone Characteristics and Baseline Biochemistry Results Predict Effectiveness of Treatment To

Reduce Risk of Recurrent Stones?

• No RCTs reported and prospectively compared subsequent stone recurrence outcomes between treatments stratified by followup biochemistry levels or by changes in these measures from pretreatment baseline.

• no elegible RCT data available regarding whether changes in urine supersaturation measures predict reduced risk of recurrent stones with drug treatment.

Side effects:

• There is a lack of data on the metabolic effects of thiazides used to prevent recurrent calcium nephrolithiasis.

• It remains unclear if metabolic effects occur and increase the risk of cardiovascular disease in otherwise healthy patients with recurrent nephrolithiasis on thiazide prophylaxis.

• Further research is needed to elucidate other alternatives for the treatment of recurrent nephrolithiasis.

THE JOURNAL OF UROLOGY 2007

Bergsland et al Am J Physiol Renal Physiol 2009.

Protocol headline:

• hypothesis: thiazide-type diuretics will be more effective in

lowering urine calcium excretion, calcium oxalate supersaturation (CaOx SS), and calcium phosphate supersaturation (CaP SS) if taken at night as compared to the daytime. They will therefore be more effective in reducing kidney stone recurrence in nephrolithiasis patients with elevated urine calcium.

• Inclusion Criteria Patients with a higher urine calcium excretion (urine

Ca >200 mg/d or > 4 mg/kg body weight) and recurrent calcium kidney stones (at least 2 episodes) that are currently being treated with thiazide-type diuretics.

• Exclusion Criteria Patients with primary hyperparathyroidism, renal

tubular acidosis, chronic kidney disease (serum creatinine > 1.5 mg/dl), inflammatory bowel disease, patients taking thiazides with a history of hypertension.

• Study Design • 15-20 stone formers from the Metabolic Stone Clinic who have

previously documented elevated urine calcium excretion and are currently on a thiazide diuretic.

• measure urine chemistries off of their respective thiazide after a 7-day washout period. Pt will be asked to collect urine samples in two 12-hour intervals: the 1st sample starts after awakening to before supper; 2nd sample begins after that and extends overnight with fasting after dinner (except for water). These measurements will be used as controls.

• Then patients will be started back on diuretics (either 25mg of chlorthalidone for the primary study or 25mg of hydrochlorothiazide for a second substudy) which they will take in the daytime; after a 6-day acclimation period, two 12-hour urine samples will be collected as in the washout period.

• For the third study period, the patients will then begin taking the thiazide after dinner. After a 6-day acclimation period, the third set of urine collections will be done.