Kidney Disease: The Difference Between Polycystic Kidney Disease 1 (PKD1) And Polycystic Kidney Disease 2 (PKD2)

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PKD1 Compared With PKD2 Genotype and Cardiac Hospitalizations in the Halt Progression of Polycystic Kidney Disease Studies

Cortney Steele, Zhiying Youl, Berenice Y.Gitomerl, Godela M.Brosnahan, & et al.

INTRODUCTION

autosomal dominant polycystic disease (ADPKD) is a genetic disorder characterized by progressive development and enlargement of kidney cysts that ultimately lead to loss of kidney function in most individuals. ADPKD (autosomal dominant polycystic disease) is primarily caused by mutations in the PKDI and PKD2 (polycystic kidney disease 2) genes. Although the hallmark of ADPKD (autosomal dominant polycystic disease) is an increase in total kidney volume with progressive loss of kidney function owing to the accumulation of kidney cysts, cardiovascular complications are a leading cause of death. Notably, poly-cystic l and 2 are expressed in vascular endothelial and vascular smooth muscle cells. Primary cilia defects that characterize ADPKD (autosomal dominant polycystic disease) are associated with dysfunction in endothelial cilia, affecting calcium and nitric oxide signaling that can consequentially lead to vascular disorders, such as hypertension.'

Hypertension occurs in >60% of individuals with ADPKD (autosomal dominant polycystic disease) before the loss of kidney function, resulting in a much earlier diagnosis of hypertension than the general population and is closely associated with total kidney volume. Although hypertension occurs earlier and more frequently in patients with PKD1 (polycystic kidney disease 1) versus those with PKD2 (polycystic kidney disease 2), both genotypes seem to confer an equal risk of developing intracranial aneurysms.ADPKD (autosomal dominant polycystic disease) has also been associated with cardiomyopathies. Nevertheless, it is currently unknown whether mutations in PKD1 (polycystic kidney disease 1) or PKD2 (polycystic kidney disease 2) confer different risks of cardiovascular events. Given the known difference in the prevalence of hypertension, we hypothesized that patients with PKD1 (polycystic kidney disease 1) would have a higher risk of cardiovascular hospitalizations than those with PKD2 who participated in the Halt Progression of Polycystic Kidney Disease (HALT-PKD)study A (NCT00283686) and B(NCTO1885559."

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RESULTS

The baseline characteristics of the research subjects with ADPKD (autosomal dominant polycystic disease) (n = 864) in the HALT-PKD (polycystic kidney disease) study A (NCT00283686) or B (NCTO1885559)with PKD1 (polycystic kidney disease 1) or PKD2 (polycystic kidney disease 2) mutations are found in Table 1. In addition, a subset of individuals (n = 449 from study A)who underwent cardiac magnetic resonance imaging was included in a secondary analysis (Table 1).

Table 1. Baseline characteristics of participants and cardiac hospitalizations

Among the 864 included participants, individuals with the PKD1 (polycystic kidney disease 1) genotype (84%)were slightly younger than those with the PKD2 (polycystic kidney disease 2) genotype. In addition, left ventricular mass (LVM) was significantly greater in those with PKD1 (polycystic kidney disease 1) in comparison to those with PKD2 (polycystic kidney disease 2)in the subset of individuals who underwent cardiac magnetic resonance imaging, with a similar trend for LVM index (LVMI).

First cardiac hospitalization (N = 43)during trial participation was more common in individuals with a PKD2 (polycystic kidney disease 2) genotype (n = 13, 9.2%)compared with those with a PKD1 (polycystic kidney disease 1) genotype(n = 30, 4.1%; P = 0.01)(Supplementary Figure S1). Individuals with PKD2 (polycystic kidney disease 2) mutations were more likely to have cardiac hospitalization over time(Supplementary Figure S2). After adjustment for age, sex, race, and study randomization, PKD2 (polycystic kidney disease 2) was associated with an increased hazard of cardiac hospitalization (hazard ratio = 46.43,95% CI:9.97-216.34 vs.PKD1) (polycystic kidney disease 1) (Table 2). This association remained after further adjustment for cardiac history, baseline systolic blood pressure, body mass index, smoking history, and baseline estimated glomerular filtration rate. In the study, A subgroup, the PKD2 (polycystic kidney disease 2) genotype was associated with lower LVM at baseline as compared with PKD1 (polycystic kidney disease 1) (unadjusted: β-estimate =-8.91, 95%CI:-16.93 to -0.90). Nevertheless, in the adjusted models, there was no longer an association between genotype and baseline LVM (Table 2). There was also no association between genotype and LVMI at baseline.

Table 2. Associations between genotype and first cardiac hospitalization, baseline LVM, and baseline LVMI

DISCUSSlON

In early and late-stage participants in the HALT-PKD studies, mutations in PKD2 (polycystic kidney disease 2) were independently associated with an increased hazard of cardiac hospitalization.' The association remained even after adjustment for demographics, study randomization, and cardiovascular risk factors. After adjustment, there was no association between genotype and LVM or LVMI at baseline.

Cardiac disease has been identified as a major cause of death in those with ADPKD (autosomal dominant polycystic disease) associated with cardiac hypertrophy and coronary artery disease. Hypertension in the ADPKD (autosomal dominant polycystic disease) population is associated with progression to end-stage renal disease and increased cardiovascular complications. Left ventricular hypertrophy, a risk factor for cardiovascular disease, is more prevalent in patients with ADPKD (autosomal dominant polycystic disease) than in the general population."Nevertheless, the prevalence of left ventricular hypertrophy in HALT-PKD was reported to be 3.9%, determined by cardiac magnetic resonance imaging using nonindexed LVM, and 0.93%using LVMI, which is a much lower proportion than reported previously in patients with ADPKD (autosomal dominant polycystic disease) using echocardiography. Notably, hypertension and LVMI are significantly correlated in adults with ADPKD (autosomal dominant polycystic disease).2s6 Furthermore, normotensive patients with ADPKD (autosomal dominant polycystic disease) have increased LVM when compared with healthy matched controls.'We did not observe differences in LVMI between genotypes; however, the low prevalence of left ventricular hypertrophy in this sample may have limited the ability to detect differences between genotypes.

Genetic mutations in PKD1 (polycystic kidney disease 1)(~80% of cases) are more prevalent when compared with mutations in PKD2 (polycystic kidney disease 2)(~～15% of cases). Similarly, our sample consisted of 8%of PKD1 (polycystic kidney disease 1)(chromosome 16pl3.3) cases and 16%of PKD2 (polycystic kidney disease 2) (mutation chromosome 4q22.1)cases. PKD1 (polycystic kidney disease 1) cases are linked to an increased risk of progressive renal failure and more severe symptoms when compared with PKD2 (polycystic kidney disease 2). Reduced kidney function is associated with a higher cardiac event risk; however, we unexpectedly found that patients with PKD2 (polycystic kidney disease 2) had an increased risk of cardiac hospitalization. Of note, HALT inclusion criteria required preexisting hypertension, therefore likely selecting more severely affected patients within the PKD2 (polycystic kidney disease 2) spectrum. Notably, idiopathic dilated cardiomyopathy has been described to associate more strongly with PKD2 (polycystic kidney disease 2) versus PKD1 (polycystic kidney disease 1) mutations in humans, and polycystin-2 modulates intracellular calcium cycling contributing to the development of heart failure in PKD2 (polycystic kidney disease 2)-mutant fish Chebib et al.5 observed that both PKD1 (polycystic kidney disease 1) and PKD2 (polycystic kidney disease 2) mutations may be predisposing factors for the development of cardiomyopathy. Also of note, the PKD2 (polycystic kidney disease 2) locus(4q21) is relatively close to genetic loci (4q25)that has been associated with an increased risk of atrial fibrillation. These factors could all influence cardiac hospitalization risk; however, there is not yet a molecular basis for the clinical observation of this study. If our findings are confirmed in other populations with ADPKD (autosomal dominant polycystic disease), further mechanistic studies need to be conducted to explain differences between genotypes and find therapeutic targets.

Strengths of this analysis include the use of a sizable multicenter trial with a well-characterized cohort. Our assessment is also novel as the association between PKD (polycystic kidney disease) genotype and cardiac hospitalization to our knowledge has not been evaluated previously. Hospitalizations were adjudicated by an independent committee. Furthermore, as PKD2 (polycystic kidney disease 2) is known to confer an overall milder phenotype than PKD1 (polycystic kidney disease 1), this information may be of clinical significance to this population.

Our study was limited to HALT-PKD (polycystic kidney disease) participants who may not be reflective of the general ADPKD (autosomal dominant polycystic disease) population. In addition, the CIs in some analyses were quite wide, and the small number of cardiac hospitalizations and limited power may have led to a chance finding. Another limitation was the high proportion of events identified as non-myocardial infarction unspecified chest pain adjudicated as cardiovascular. We also recognize that it would have been preferable to define cardiovascular death or major adverse cardiac events as an endpoint; however, this was not possible owing to the low incidence of these events in the trial. Finally, although significant, these statistical associations do not reveal causality, and residual confounding may exist, including cardiovascular risk factors we are unable to adjust for, such as medication use and lipoproteins.

In conclusion, we have revealed for the first time a possible association of a PKD2 (polycystic kidney disease 2) mutation with an increased hazard of cardiac hospitalization as compared with PKD1 (polycystic kidney disease 1). Nevertheless, owing to the limitations of this analysis, the findings should be interpreted cautiously, and further research is needed to validate and further elucidate this observation.

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DISCLOSURE

ACB is a consultant for Otsuka, Reata, and Sanofi.ASLYis a consultant for Regulus Therapeutics, Calico Life Sciences, and Navitor Pharmaceuticals and has served on an advisory board for Otsuka Pharmaceuticals. All the other authors declared no competing interests.

ACKNOWLEDGMENTS

The HALT studies were supported by the National Institute of Diabetes and Digestive and Kidney grants U01 DK062402,U01 DK062410, U01 CK082230,U01 DK062408, and UO1 DK062401, the National Center for Research Re-sources General Clinical Research Centers (RR000039 to Emory University,RR000585 to the Mayo Clinic,RRO00054 to Tufts Medical Center, RRO00051 to the University of Colorado, RRO23940 to the University of Kansas Medical Center, and RR001032 to Beth Israel Deaconess Medical Center), the National Center for Advancing Translational Sciences Clinical and Translational Science Awards (RR025008 and TR000454 to Emory University,RRO24150 and TRO0135 to the Mayo Clinic, RRO25752 and TR001064 to Tufts University, RR025780 and TRO01082 to the University of Colorado, RR025758 and TR001102 to Beth Israel Deaconess Medical Center, RR033179 and TR000001 to the University of Kansas Medical Center, and RR024989 and TR000439 to Cleveland Clinic), by funding from the Zell Family Foundation (to the University of Colorado),and by a grant from the PKD Foundation. The funding agencies had no direct role in the conduct of the study; the collection, management, analyses, and interpretation of the data; or preparation or approval of the manuscript. Kristen Nowak is supported by K01 DK103678. Cortney Steele is supported by the National Institute of Diabetes and Digestive and Kidney (grant 5T32DK007135-46).