co m m e nt a r y
cases for disease development22, 23 and has also recently been described in NPHP. 24 The increasing number of JSRD genes, the variable phenotype only partly associated with genic and allelic effects, plus cases with missing mutations, indicate that this step toward complex inheritance is also a possibility in JSRD. The overlapping phenotypes of JSRD, MKS, NPHP, and SLS, plus the overlapping group of genes involved in causing these diseases, highlight deficiencies in the existing forms of disease classification. Although the phenotypic description of a family is clearly what initially determines the disease classification and focuses the search for the molecular cause, it is limited as a final disease classifier. Increasingly, it will be important to base the disease classification on the gene that is mutated. Although this is complicated by allelic effects, genetic background, and possible other complex inheritance, it is the most logical basis for classifying genetic diseases and an essential starting point for comprehensive genotype–phenotype studies. REFERENCES 1.
Ferland RJ, Eyaid W, Collura RV et al. Abnormal cerebellar development and axonal decussation due to mutations in AHI1 in Joubert syndrome. Nat Genet 2004; 36: 1008–1013. 2. Parisi MA, Bennett CL, Eckert ML et al. The NPHP1 gene deletion associated with juvenile nephronophthisis is present in a subset of individuals with Joubert syndrome. Am J Hum Genet 2004; 75: 82–91. 3. Sayer JA, Otto EA, O’Toole JF et al. The centrosomal protein nephrocystin-6 is mutated in Joubert syndrome and activates transcription factor ATF4. Nat Genet 2006; 38: 674–681. 4. Baala L, Romano S, Khaddour R et al. The MeckelGruber syndrome gene, MKS3, is mutated in Joubert syndrome. Am J Hum Genet 2007; 80: 186–194. 5. Delous M, Baala L, Salomon R et al. The ciliary gene RPGRIP1L is mutated in cerebello-oculo-renal syndrome (Joubert syndrome type B) and Meckel syndrome. Nat Genet 2007; 39: 875–881. 6. Arts HH, Doherty D, van Beersum SE et al. Mutations in the gene encoding the basal body protein RPGRIP1L, a nephrocystin-4 interactor, cause Joubert syndrome. Nat Genet 2007; 39: 882–888. 7. Grotewold L, Ruther U. The Fused toes (Ft) mouse mutation causes anteroposterior and dorsoventral polydactyly. Dev Biol 2002; 251: 129–141. 8. Anselme I, Laclef C, Lanaud M et al. Defects in brain patterning and head morphogenesis in the mouse mutant Fused toes. Dev Biol 2007; 304: 208–220. 9. Wolf MTF, Saunier S, O’Toole JF et al. Mutational analysis of RPGRIP1L gene in patients with Joubert syndrome and nephronophthisis. Kidney Int 2007; 72: 1520–1526. 10. Dryja TP, Adams SM, Grimsby JL et al. Null RPGRIP1 alleles in patients with Leber congenital amaurosis. Am J Hum Genet 2001; 68: 1295–1298. Kidney International (2007) 72
11. Roepman R, Letteboer SJ, Arts HH et al. Interaction of nephrocystin-4 and RPGRIP1 is disrupted by nephronophthisis or Leber congenital amaurosis-associated mutations. Proc Natl Acad Sci USA 2005; 102: 18520–18525. 12. Hildebrandt F, Zhou W. Nephronophthisisassociated ciliopathies. J Am Soc Nephrol 2007; 18: 1855–1871. 13. Parisi MA, Doherty D, Chance PF, Glass IA. Joubert syndrome (and related disorders) (OMIM 213300). Eur J Hum Genet 2007; 15: 511–521. 14. Badano JL, Mitsuma N, Beales PL, Katsanis N. The ciliopathies: an emerging class of human genetic disorders. Annu Rev Genomics Hum Genet 2006; 7: 125–148. 15. Singla V, Reiter JF. The primary cilium as the cell’s antenna: signaling at a sensory organelle. Science 2006; 313: 629–633. 16. Attanasio M, Uhlenhaut NH, Sousa VH et al. Loss of GLIS2 causes nephronophthisis in humans and mice by increased apoptosis and fibrosis. Nat Genet 2007; 39: 1018–1024. 17. Smith UM, Consugar M, Tee LJ et al. The transmembrane protein meckelin (MKS3) is mutated in Meckel-Gruber syndrome and the wpk rat. Nat Genet 2006; 38: 191–196. 18. Baala L, Audollent S, Martinovic J et al. Pleiotropic effects of CEP290 (NPHP6) mutations extend to
19.
20.
21.
22.
23.
24.
Meckel syndrome. Am J Hum Genet 2007; 81: 170–179. Frank V, den Hollander AI, Bruchle NO et al. Mutations of the CEP290 gene encoding a centrosomal protein cause Meckel-Gruber sydrome. Hum Mutat 2007, Epub 17 August 2007. doi:10.1002/humu.20614. Helou J, Otto EA, Attanasio M et al. Mutation analysis of NPHP6/CEP290 in patients with Joubert syndrome and Senior–Løken syndrome. J Med Genet 2007; 44: 657–663. Hildebrandt F, Otto E, Rensing C et al. A novel gene encoding an SH3 domain protein is mutated in nephronophthisis type 1. Nat Genet 1997; 17: 149–153. Beales PL, Badano JL, Ross AJ et al. Genetic interaction of BBS1 mutations with alleles at other BBS loci can result in non-Mendelian Bardet-Biedl syndrome. Am J Hum Genet 2003; 72: 1187–1199. Badano JL, Kim JC, Hoskins BE et al. Heterozygous mutations in BBS1, BBS2 and BBS6 have a potential epistatic effect on Bardet-Biedl patients with two mutations at a second BBS locus. Hum Mol Genet 2003; 12: 1651–1659. Hoefele J, Wolf MT, O’Toole J F. et al. Evidence of oligogenic inheritance in nephronophthisis. J Am Soc Nephrol 2007; 18: 2789–2795.
see original article on page 1483
Thiazide diuretic monotherapy for hypertension: Diuretic’s dark side just got darker BH Rovin1 and LA Hebert1 Diuretic monotherapy is the current recommendation of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure for initial antihypertensive therapy. There is mounting concern, however, that the benefits of diuretic’s superior blood pressure control may be offset by its multiple metabolic disturbances that increase cardiovascular risk. Reungjui et al. document a new concern, nephrotoxicity by thiazide monotherapy. This and other recently published evidence of diuretic’s ‘dark side’ is discussed. Kidney International (2007) 72, 1423–1426. doi:10.1038/sj.ki.5002656
In this issue of Kidney International, Reungjui and colleagues1 convincingly show that chronic hydrochlorothiazide 1Department of Internal Medicine, Ohio State
University Medical Center, Columbus, Ohio, USA Correspondence: LA Hebert, Ohio State University Medical Center, 1654 Upham Drive, Columbus, Ohio 43210, USA. E-mail:
[email protected]
administration causes focal glomerular and tubular interstitial injury in rats independent of diuretic-induced hypokalemia, hyperglycemia, hyperuricemia, and blood pressure (BP) changes. This work adds significantly to the list of ‘metabolic dysfunctions’ of thiazide diuretic2 that could negate the cardiovascular and renal benefits expected 1423
co mmentar y
of thiazide diuretic therapy because of its ability to control both hypertension and volume status. The potential for chronic thiazide monotherapy to negate its cardiovascular benefits can be viewed as diuretic’s ‘dark side.’3 Because thiazide diuretic therapy has the potential to be both good and bad, it has been suggested by many (reviewed by Hebert et al.3 and Campese4) that diuretic should not be the initial choice for hypertension management, if only monotherapy is required. Instead, hypertension monotherapy should involve a drug without an obvious dark side, such as an angiotensin-converting enzyme inhibitor (ACEI).3–5 Nonetheless, largely on the basis of the outcome of the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT), the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure has endorsed thiazide (hydrochlorothiazide or equivalent thiazide) as first-line therapy for most hypertensives.6 Although the ALLHAT investigators have acknowledged diuretic’s metabolic perturbations, they discount them as clinically significant because they did not seem to cause harm in ALLHAT.7 Others, however, have expressed concern because the diuretic cohort did not do as well as might be expected considering the diuretic cohort’s monopoly on BP and volume control.3,4 Furthermore, new light has recently been shed on diuretic’s dark side by the Trialists’ Collaboration metaanalysis of over 100,000 patients followed in randomized trials of ACEI therapy.8 These issues are discussed next. Evidence for thiazide diuretic’s dark side as revealed in ALLHAT and in the Trialists’ Collaboration report
ALLHAT compared thiazide (chlorthalidone), ACEI (lisinopril), α1-blocker (doxazosin), and calcium channel blocker (CCB; amlodipine), each as monotherapy in hypertensives with cardiovascular disease or its risk factors. Entirely on the basis of subset analyses, ALLHAT declared diuretic the winner. This has evoked numerous critical commentaries (reviewed by Hebert et al.,3 Campese,4 Messerli and Kuteyeva,9 and Grimm10). 1424
We suggest that ALLHAT’s favorable impression of thiazide diuretic probably is due to a study design that biased the outcome in favor of the diuretic cohort.3 Specifically, ALLHAT is the only major hypertension trial that deliberately recruited hypertensives with cardiovascular disease, and then made diuretic one of the randomized therapies. This is a design flaw because patients with cardiovascular disease are especially vulnerable to fluid overload, which can (even when incipient) worsen hypertension, pulmonary congestion, and myocardial ischemia. Neither ACEI nor CCB as monotherapy is recommended for volume control. Thus, ALLHAT’s design advantaged the diuretic cohort, especially at the expense of the ACEI cohort. Note that the studies that demonstrated ACEI’s cardiovascular protection added diuretic to ACEI therapy, if needed.8 We refer to this practice as ‘optimal ACEI therapy.’ Another ALLHAT design flaw is that ALLHAT required titration of the blinded monotherapy to achieve the BP goal. To see how this is a design flaw, consider the following. The managing physician observes worsening hypertension. Incipient fluid overload is suspected. Nevertheless, the physician follows study protocol and increases the dose of the assigned monotherapy, hoping it is a diuretic. Unfortunately, it is ACEI or CCB. Over the ensuing weeks, fluid retention and hypertension worsen. The patient returns now with an ALLHAT end point (myocardial infarction, congestive heart failure, or stroke), which is counted against the ACEI or CCB cohort. If standard of care had been followed (timely use of diuretic), such end points might have been avoided.3 The ALLHAT design flaws gave the diuretic cohort a monopoly on BP and volume control. In so doing, they hid diuretic’s dark side. This is revealed by an examination of ALLHAT’s primary outcome measure, combined non-fatal myocardial infarction and fatal coronary heart disease (CHD). This showed the diuretic and ACEI cohorts in a statistical tie (mean CHD risk reduction 0.99, 95% confidence interval 0.91–1.08, favoring
ACEI). The statistical tie is paradoxical considering the diuretic cohort’s significantly better BP control (systolic BP 2.5 mm Hg lower overall, 3 mm Hg lower in patients >65 years old, and 4 mm Hg lower in black patients 8 ). These large BP differences should have translated into lower CHD risk.8 Also, among the randomized monotherapies, only diuretic controlled volume status. This can influence CHD risk independently of BP. For example, increased volume status can worsen myocardial ischemia by increasing cardiac output, or by increasing left ventricular end diastolic pressure—thereby decreasing subendocardial blood flow. In this light, it is remarkable that diuretic could not lower CHD risk better than ACEI. This is clear evidence of diuretic’s dark side. The strongest evidence of diuretic’s dark side is provided by the recent Trialists’ Collaboration report. 8 This is an advance over the previous relevant metaanalyses because an additional 48,745 patients were available for study, and more sophisticated statistical techniques were used.8 The Trialists’ key finding is that, in comparison to the comparator therapies (diuretic, βblocker, or CCB), ACEI is associated with a 9% reduction in major CHD events (95% confidence interval 3%– 14%, P = 0.004), which is independent of BP control. Further detail is provided in Figure 1. ALLHAT did not describe a BP-independent benefit of ACEI (Figure 1, Box 1), probably because, of the randomized ACEI trials, only ALLHAT did not use ACEI optimally (with diuretic if needed). The Trialists’ report also reveals diuretic’s dark side as follows. If, at a given level of BP reduction, diuretic was just as effective in lowering CHD risk as optimal ACEI therapy—the lower line in Figure 1—then the 2.5-mm Hg-lower BP in the ALLHAT diuretic cohort versus its comparator (non-optimal ACEI therapy) should have reduced CHD risk by nearly 20% (Figure 1, Box 3). In fact, in ALLHAT the mean CHD risk reduction comparing the diuretic cohort to the ACEI cohort was a non-significant 1%, and it favored the ACEI cohort (Figure 1, Box 2). Furthermore, the Kidney International (2007) 72
co m m e nt a r y
1 Evidence for BP-independent effects of ACEI in coronary heart disease. ACEI is associated with a 9% coronary heart disease (CHD) risk reduction (95% confidence interval 3%–14%, P = 0.004). ALLHAT did not find this, probably because in ALLHAT ACEIs were not used optimally (with diuretic, if needed).
JMIC-B
ALLHAT diur
Log odds ratio (risk reduction)
3 Theoretical CHD risk reduction by diuretic in ALLHAT if diuretic was as protective against CHD as ACEI used optimally. In ALLHAT, systolic BP was 2.5 mm Hg lower in the diuretic than in the ACEI cohort. Thus, if reduction of BP by diuretic was just as effective as that by optimal ACEI therapy in reducing CHD risk, the 2.5-mm Hg-greater BP reduction by diuretic than by its comparator (non-optimal ACEI) should have reduced CHD risk by nearly 20% (arrow). This did not occur (see Box 2). This is evidence of diuretic’s dark side relative to optimal ACEI therapy.
Value
CAMELOT CA STOP-2 CA RENAAL DIAB-HYCAR
CHARM add CHARM pre SCAT
EUROPA
ACEI trials
CAMELOT pla
PART2
0.50
STOP-2d/b-b ALLHAT CA ANBP-2
IDNT pla
UKPDS-HDS
IDNT CA CAPPP
LIFE
Val-HEFT
1.0
PROGRESS
2.0
ABCD nor HOPE CHARM alt PEACE SCOPE
ARB trials
2 Diuretic versus ACEI in ALLHAT. BP was higher in the ACEI cohort than in the diuretic cohort, but the CHD outcomes for the cohorts were the same. This is evidence of diuretic’s dark side in relationship to ACEI.
ABCD hyp
0.25 –8
–6
–4
–2
0
2
4
Figure 1 | Association of BP reduction with risk reduction for fatal and non-fatal myocardial infarction in randomized trials of angiotensinconverting enzyme inhibitor (ACEI) or angiotensin receptor blocker (ARB) against a comparator therapy (diuretic, β-blocker, or calcium channel blocker). The fitted lines represent the summary meta-regressions for the outcomes of the ACEI trials (lower line) and the ARB trials (upper line). See Boxes 1, 2, and 3 for further analysis. The ACEI trials' meta-regression line can be regarded as the 'optimal ACEI therapy' line, because all trials, except ALLHAT, used ACEI optimally (with diuretic, if needed). (Adapted from ref. 8.)
lower confidence interval for CHD risk reduction for diuretic versus ACEI was 7%, far less than the nearly 20% CHD risk reduction expected based on diuretic’s 2.5-mm Hg-better BP control. This analysis does not even take into account diuretic’s monopoly on volume control. Clearly diuretic has a dark side relative to ACEI that can negate diuretic’s cardiovascular benefits achieved by BP and volume control. Mechanisms of diuretic’s dark side
Thiazide diuretics induce hypokalemia, hyperlipidemia, hyperuricemia, and stimulation of the renin–angiotensin system, all of which probably increase cardiovascular risk (reviewed by Hebert et al.3). An appealing hypothesis is that the diuretic-induced increased aldosterone levels may be vasculotoxic through genomic and non-genomic mechanisms. 11 This could mediate, in part, diuretic’s renal dark side elucidated by Reungjui et al., 1 and diuretic’s Kidney International (2007) 72
cardiovascular dark side elucidated by the Trialists’ Collaboration.8 Hemodynamic effects could also be involved in thiazide’s dark side. ACEI and diuretic comparably reduce brachial artery pressure; however, diuretic maintains a higher central aortic pressure,12 which can increase cardiovascular risks. Clinical implications of diuretic’s dark side
In routine hypertension management, thiazide monotherapy is worrisome in young hypertensives, who might be exposed to diuretic for decades,4 and in obese hypertensives, whose metabolic syndrome can be exacerbated by diuretic.13 Thus, a strong case can be made for initial therapy with ACEI, followed by diuretic if needed.3,4 When ACEI and diuretic therapy are combined, diuretic’s dark-side mechanisms probably are mitigated.3 In chronic kidney disease (CKD) management, diuretic therapy is often needed to control volume status and BP. Nevertheless, in both the Modification of
Diet in Renal Disease (MDRD) trial and the African American Study of Kidney Disease and Hypertension (AASK), about half of CKD patients did not receive diuretics, yet generally they achieved their BP goals.14 Perhaps overzealous use of diuretics in CKD management accounts for the reported association of greater diuretic use with faster decline in glomerular filtration rate.15 Thus, the ideal may be to reduce salt intake rather than to ‘push’ diuretics.14 If diuretic is needed, chlorthalidone (half-life about 50 hours) can be recommended, because it is about twice as potent at lowering BP as hydrochlorothiazide (half-life about 6 hours).4 Loop diuretics are more effective in CKD than thiazide diuretics.14 Whether loop diuretics carry less risk than thiazide diuretics is not clear. However, loop diuretics share at least some of thiazide’s metabolic dysfunctions.1 Those who favor diuretics as primary hypertension management point 1425
co mmentar y
out diuretic’s lower cost as compared with ACEI, and that many of diuretic’s metabolic dysfunctions are treatable.10 However, treating diuretic’s metabolic dysfunctions also incurs cost. An even greater cost is incurred if diuretic’s metabolic dysfunctions go untreated because they are unrecognized or because the patient cannot afford the treatment. In this context, ACEI is a bargain, particularly generic ACEI.3 ACKNOWLEDGMENTS This work was supported in part by National Institutes of Health grants PO1 DK55546, UO1 DK48621, and MO1 RR00034.
3.
4.
5. 6.
7.
REFERENCES 1.
2.
Reungjui S, Hu H, Mu W et al. Thiazide-induced subtle renal injury not observed in states of equivalent hypokalemia. Kidney Int 2007; 72: 1483–1492. Houston MC. ALLHAT debate: diuretics are
1426
8.
9.
not preferred, first-line initial therapy for hypertension. Arch Intern Med 2004; 164: 570– 571; author reply 571–572. Hebert LA, Rovin BH, Hebert CJ. The design of ALLHAT may have biased the study’s outcome in favor of the diuretic cohort. Nat Clin Pract Nephrol 2007; 3: 60–61. Campese VM. Diuretics are preferred over angiotensin II-converting enzyme inhibitors for initial therapy of uncomplicated hypertension. Am J Kidney Dis 2007; 50: 197–202. Messerli FH, Grossman E, Leonetti G. Antihypertensive therapy and new onset diabetes. J Hypertens 2004; 22: 1845–1847. Chobanian AV, Bakris GL, Black HR et al. The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: the JNC 7 report. JAMA 2003; 289: 2560–2572. Davis BR, Furberg CD, Wright JT Jr. et al. ALLHAT: setting the record straight. Ann Intern Med 2004; 141: 39–46. Turnbull F, Neal B, Pfeffer M et al. Blood pressuredependent and independent effects of agents that inhibit the renin-angiotensin system. J Hypertens 2007; 25: 951–958. Messerli FH, Kuteyeva O. Bashing diuretics or
10.
11.
12.
13.
14. 15.
failure of surrogate endpoint? J Hypertens 2007; 25: 949–950. Grimm R. Diuretics are preferred over angiotensin II-converting enzyme inhibitors for initial therapy of uncomplicated hypertension. Am J Kidney Dis 2007; 50: 188–196. Haddad N, Rajan J, Nagaraja HN et al. Usual ACE inhibitor therapy in CKD patients is associated with lower plasma aldosterone levels than usual angiotensin receptor blocker therapy. Kidney Blood Press Res 2007; 30: 299–305. Jiang XJ, O’Rourke MF, Zhang YQ et al. Superior effect of an angiotensin-converting enzyme inhibitor over a diuretic for reducing aortic systolic pressure. J Hypertens 2007; 25: 1095–1099. Scholze J, Grimm E, Herrmann D et al. Optimal treatment of obesity-related hypertension: the Hypertension-Obesity-Sibutramine (HOS) study. Circulation 2007; 115: 1991–1998. Wilmer WA, Rovin BH, Hebert CJ et al. Management of glomerular proteinuria: a commentary. J Am Soc Nephrol 2003; 14: 3217–3232. Hawkins RG, Houston MC. Is population-wide diuretic use directly associated with the incidence of end-stage renal disease in the United States? A hypothesis. Am J Hypertens 2005; 18: 744–749.
Kidney International (2007) 72