Predictors of Autosomal Dominant Polycystic Kidney Disease Progression

Abstract

Autosomal dominant polycystic kidney disease is a genetic disorder associated with substantial variability in its natural course within and between affected families. Understanding predictors for rapid progression of this disease has become increasingly important with the emergence of potential new treatments. This systematic review of the literature since 1988 evaluates factors that may predict and/or effect autosomal dominant polycystic kidney disease progression. Predicting factors associated with early adverse structural and/or functional outcomes are considered. These factors include PKD1 mutation (particularly truncating mutation), men, early onset of hypertension, early and frequent gross hematuria, and among women, three or more pregnancies. Increases in total kidney volume and decreases in GFR and renal blood flow greater than expected for a given age also signify rapid disease progression. Concerning laboratory markers include overt proteinuria, macroalbuminuria, and perhaps, elevated serum copeptin levels in affected adults. These factors and others may help to identify patients with autosomal dominant polycystic kidney disease who are most likely to benefit from early intervention with novel treatments.

Autosomal dominant polycystic kidney disease (ADPKD) is a genetic disorder caused by mutations in the PKD1 gene located on chromosome 16p13.3 or the PKD2 gene located on chromosome 4q21.¹ PKD1 and PKD2 encode the proteins polycystin-1 and -2, respectively; mutations disrupt the function of these proteins on the primary cilium, forming fluid-filled cysts that progressively increase in size, leading to gross enlargement of the kidneys and distortion of the renal architecture.² Glomerular hyperfiltration compensates for the progressive loss of healthy glomeruli, and therefore, by the time GFR decline becomes detectable, as much as one half of the original functional glomeruli are irreversibly lost.^3,4 The majority of patients with ADPKD ultimately progress to ESRD.³

The natural course of ADPKD varies significantly, with onset of ESRD reported from childhood to age >80 years, and a median age of 58 years was reported recently for PKD1, which is much more common than PKD2.⁵ Rapid ADPKD progression may be defined as onset of ESRD at age <55 years, development of stage 3 CKD at <40 years old, onset of hypertension at <18 years old, presence of total kidney volume (TKV) greater than that expected for a given age, or presence of multiple complications. Identification of patients at high risk for rapid progression has become increasingly important given the emergence of potential new treatments. These treatments are most likely to be beneficial when started early in the disease course. This systematic review evaluates markers of and factors contributing to ADPKD progression.

Methods

A comprehensive systematic review of the literature was undertaken using several structured steps (Table 1). All authors participated in each step of the review process and ranking of final articles for inclusion.

Table 1.

Summary of systematic review process

Step	Procedure	Result
1	Systematic literature review through Medline, EMBASE, and Biosis for articles published from January of 1988 to May of 2013a	2056 citations
2	Review abstracts; omit articles not dealing with factors affecting ADPKD severity or progression, reviews, case reports, editorials, commentaries, and letters	1078 citations
3	Omit non-English language articles and articles with focus on transplantation, dialysis, or diabetes, with ESRD used as a cutoff for inclusion	863 citations
4	Omit duplicate references; results separated into four categories: randomized clinical trials; other clinical trials; observational, retrospective, or epidemiologic studies; and preclinical studies	666 articles ranked for inclusionb

^aThe searches comprised “ADPKD or autosomal dominant polycystic kidney disease” combined with the following terms: angiogenic growth factor; anxiety, depression, or quality of life; child or pediatric; cyst (number or area) or liver fibrosis index; cyst segmentation; depression and dialysis; diabetes mellitus; epidemiology, hospitalization, or cost; ESRD or renal disease; family history, genetic or allelic heterogeneity, genotype–phenotype correlation, mutation type or position, polycystin, vasopressin, or cAMP; glomerular hyperfiltration; HALT PKD; hematuria; hypertension; intracellular calcium, cell proliferation, or fluid secretion; kidney, liver, or renal disease progression; left ventricular mass hypertrophy; molecular diagnostics; proteinuria or microalbuminuria; psychonephrology; renal blood flow, urine osmolality, biomarker, proteome, copeptin, exosome, or serum uric acid; renal or kidney ultrasonography, computed tomography, or MRI; TKV or height-adjusted TKV; total liver volume; UTI; and vitamin D.

^bAdditional references were identified by the authors on the basis of their personal knowledge of the literature that reported specific information important to ADPKD progression.

Renal Disease Progression in ADPKD

Genetic Factors

A summary of the main studies examining genetic predictors of rapid renal disease progression is provided in Table 2.

Table 2.

Genetic predictors of rapid ADPKD progression: phenotypic differences between PKD1 and PKD2 mutations

Ref./Findings	PKD1	PKD2	P Value
5
Patients, n	392	95
Mean age at hypertension diagnosis, yr	39	49	<0.001
Median age at ESRD onset, yr	58	79	<0.001
6
Patients, n	146	20
Mean age at diagnosis of ADPKD, yr	27	41	<0.001
Mean age at diagnosis of hypertension, yr	35	50	0.001
Mean age at onset of ESRD, yr	54	73	<0.001
7
Patients, n	287	34
Median age at onset of ESRD, yr	53	68	<0.001
8
Patients, n	333	291
Median age at diagnosis of ADPKD caused by symptoms, yr	42	56	NA
Median age at death/ESRD, yr	53	69	<0.001
Median age at ESRD, yr	54	74
9
Patients, n	136	60
Median age at hypertension treatment, yr	46	51	NA
Median age at stage 3 CKD onset, yr	50	66	NA
Median age at ESRD onset, yr	53	Only 21% had ESRD by age 70 yr	NA
Median age at death, yr	67	71	NA
10
Patients, n	185	34
Findings	Patients with PKD1 had significantly larger kidneys and more cysts versus patients with PKD2 mutations; they also had significantly higher frequency of hypertension/higher urinary albumin excretion
11
Patients, n	50	10
Findings	Children with PKD1 had significantly larger kidneys with more and larger cysts than children with PKD2 (mean age of 8.6 versus 8.9 yr); they also had significantly higher daytime/nighttime systolic BP by ambulatory monitoring over 24 h

NA, not available.

Locus Heterogeneity

Several large studies have shown that patients with mutations in PKD1 generally have a more severe form of ADPKD than patients with PKD2 mutations, with a younger age at diagnosis, a higher number of cysts, earlier onset of hypertension, and faster progression to ESRD.^5–11 In the European PKD1-PKD2 study cohort of 624 patients, median ages at death or ESRD onset in patients with PKD1 and PKD2 were 53 and 69 years, respectively (P<0.001).⁸ Similarly, in the recent large Genkys study of 741 patients with ADPKD from northwestern France, median ages at onset of ESRD in PKD1 and PKD2 carriers were 58 and 79 years, respectively.⁵ Some PKD1 families, however, have mild disease that is indistinguishable from PKD2 families, whereas other PKD1 families have a particularly severe course.^3,5 In contrast to different gene loci, this observation may be caused by allelic heterogeneity within the PKD1 locus.

Allele Heterogeneity: Mutation Type and Location

Results from the Genkys study showed that truncating PKD1 mutations (frameshift, nonsense, splice mutations, and large rearrangements), affecting approximately two thirds of PKD1 families, were associated with a significantly younger median age of ESRD onset than nontruncating mutations (in-frame and missense mutations; 55.6 versus 67.9 years [P<0.001]).⁵ In another study, mutations toward the 5′ end of PKD1 were associated with a vascular phenotype and ruptured intracranial aneurysms.¹²

Mutation location within the PKD2 gene has also been suggested to influence outcome in a study of 22 PKD2 families¹³; however, this result was not confirmed in a larger study of 461 subjects from 71 PKD2 families.¹⁴ In the latter study, after adjustment for sex, patients with splice mutations tended to have better renal survival than patients with other types of mutations.

Hypomorphic Alleles

Several families have been described with a mild or atypical disease presentation, in which ADPKD is not explained by the dominant inheritance of a single PKD1 or PKD2 mutation.^15–18 In these families, sequence variants function as hypomorphic alleles, because they do not result in the full phenotype when occurring as the only abnormality in heterozygous subjects, but they do result in severe disease in homozygous (for this variant) individuals or when occurring together with a truncating mutation on the second allele.^16–18 For example, a unique ADPKD family has been described in which 30 affected individuals had mild disease but only 14 individuals carried a PKD2 mutation, whereas the other 16 individuals did not have this mutation but rather a sequence (Y528C missense) variant in PKD1.¹⁵ Expression of this variant in cultured cells confirmed its pathogenicity. Two family members carried both the PKD2 mutation and PKD1 variant, resulting in more severe disease than observed in carriers of the PKD2 mutation alone. Mosaicism for a PKD mutation may also account for an atypical mild phenotype.¹⁹

Modifier Genes

Highly variable disease severity occurs even within families, which cannot be explained by locus or allelic heterogeneity.^3,14,20 Intrafamilial variability may be caused by other genes that modify disease severity.²⁰ Several gene polymorphisms (e.g., in the angiotensin-converting enzyme, endothelial nitric oxide synthase, and α8 integrin genes) have been associated with age at ESRD onset, although usually in men and not women.^21–24 Many of these reports were, however, based on small study populations with lack of correction for population stratification. Additional insight regarding the identity of genes that modify the severity of ADPKD will be provided by the outcome of ongoing large genome-wide association studies. It is also significant that PKD1 mutations may modify the disease course in PKD2 carriers with resultant earlier onset of ESRD, which was described in a case report of a de novo PKD1 splice mutation on the background of a homozygous PKD2 variant.²⁵

Demographic and Familial Factors

A summary of the main studies examining demographic and familial predictors of rapid renal disease progression is provided in Table 3.

Table 3.

Demographic, familial, clinical, and imaging predictors of rapid renal disease progression in ADPKD

Predictor/Cohort Size (No. of Patients)	Type of Observational Study	Major Supporting Refs.
Sex
1215	Retrospective	7
580	Retrospective	26
100	Prospective	40
Race
72	Retrospective	28
Hyperfiltration in childhood
180	Retrospective	32
Gross hematuria
1215	Retrospective	7
580	Retrospective	26
191	Retrospective	35
180	Retrospective	36
100	Prospective	40
Pregnancy
235	Retrospective	37
Multiple UTIs
256	Retrospective	39
180	Retrospective	36
94	Retrospective	38
Cyst rupture
100	Prospective	40
Hypertension
2085	Retrospective	70
1215	Retrospective	7
580	Retrospective	26
543	Retrospective	73
323	Prospective	48
235	Retrospective	37
TKV
312	Prospective	54
241	Prospective	4
229	Prospective	55
RBF
241	Prospective	58
		59

P values for all studies were <0.01.

Sex

Several studies reported more severe disease in men than women, with earlier onset of hypertension, more severe hypertension, and earlier onset of ESRD.^{5–7,14,26,27} In one large retrospective cohort study of 580 patients with ADPKD who were followed for 25 years, men had worse renal function at a given age.²⁶ In a second retrospective study of 1215 patients with ADPKD, median age at onset of ESRD was 4 years younger in men versus women (52 versus 56 years).⁷ Because none of these studies were population-based, the true sex effect remains unknown.

Race

ADPKD occurs in all races, but differences in severity between races have not been well studied. In one small study, African Americans with ADPKD had significantly earlier onset of ESRD than whites (age 43.2 versus 55.4 years), and African Americans with both ADPKD and sickle cell trait reached ESRD even earlier than African Americans with ADPKD alone (38 versus 48 years).²⁸ More studies are needed to define the effect of race and ethnicity on ADPKD progression.

Parental History of Hypertension

Two studies have evaluated the effects of parental hypertension on ADPKD severity in offspring. In a European study of 162 subjects, hypertension in the non-ADPKD parent (versus normotension) was associated with ESRD at a significantly younger age in both male and female offspring (49 versus 54 years).²⁹ Another study from the University of Colorado reported that hypertension in the parent with ADPKD was associated with a higher frequency of hypertension in affected children as well as younger age at diagnosis of hypertension, independent of kidney volume and renal function.³⁰ Effects on ESRD onset in offspring were not examined.

Family History of Early ESRD

One study has explored whether family history of ESRD predicts the mutated gene and hence, the risk of disease progression. Barua et al.³¹ used a large population of 484 patients with ADPKD with known genotype and renal function data (including eGFR and age at ESRD) from 90 ADPKD pedigrees. The investigators found that the presence of one or more affected family members who developed ESRD at age ≤55 years was highly predictive of the PKD1 genotype (positive predictive value=100%; sensitivity=72%). In contrast, the presence of one or more affected family member who had adequate kidney function or developed ESRD at age ≥70 years was highly predictive of the PKD2 genotype (positive predictive value=100%; sensitivity=74%). The study provided a simple but effective prognostic tool by investigating carefully the history of renal function in the pedigree under analysis. Limitations of the study included the small population (only 90 pedigrees); the need to have a detailed family history, which limited the use of the approach for small pedigrees or de novo cases; and the impossibility of predicting age at ESRD in other family members given the overall high intrafamilial variability observed in ADPKD pedigrees.

Clinical Factors

The major studies reporting clinical and imaging characteristics predictive of rapid renal disease progression are summarized in Table 4.

Table 4.

Summary of the most relevant prospective and cross-sectional/retrospective studies where predictors and outcomes of rapid ADPKD progression were analyzed and validated

Patients, N	Baseline or Major Patient Characteristics	Follow-Up Duration, Other Study Features, or Study Type/Summary	Predictors and Outcome (OM)	Refs.
Prospective observational studies
241	Age 15–45 yr; CrCl>70 ml/min; other conditions affecting renal function (e.g., diabetes) excluded	Mean follow-up: 3,4,57 7.9,55 8.5,79 and 6 yr82	TKV, RBF, serum copeptin, total cyst volume, genotype, percent cystic volume; OM: decline in eGFR (P<0.001)	4,10,56–59,83,86 (CRISP)
196	Mean (SD) age (PKD1 and PKD2): 27±14 and 40±14 yr	Follow-up: 22 yr	PKD1 and PKD2; OM: age at onset of stage 3 CKD	9
100	Mean (SD) age 31.2±6.4 yr; mean (SD) estimated CrCl (Cockcroft–Gault): 109.8±25.5 ml/min	Follow-up: 6 mo	TKV and TCV change detectable at 6 mo	40
140	Children, mean age 11 yr (range=5 mo to 18 yr)	Follow-up: 2–5 yr	Increased cysts and KV; OM: disease severity measured by flank, back, or abdominal pain, HTN, inguinal hernia, palpitation, frequency, maximum urine osmolality, GFR (P<0.05)	43
323	Mean (SD) age 53±15 yr	Mean (SD) follow-up 100±38 mo (n=198)	Age, HTN, urinary stones, proteinuria, smoking; OM: disease progression, eGFR decline (P<0.05)	48
312	Children (<18 yr)	Mean follow-up 5.7 yr (range=3–15) for 115 of 185 affected children	Baseline and follow-up KV (mean of two kidneys), cysts; OM: disease severity (P<0.01)	54
229	Mean (SD) age 37±11 yr; mean (SD) eGFR=71±22 ml/min per 1.73 m2 (range=20–152)	Mean follow-up 7.8 yr (range=2.6–15.1)	Increased TKV; OM: eGFR decline (P<0.001)	55
154	Children; mean (SEM) age 9.6±0.5 yr (range=8 mo to 17 yr)	Mean 11 BP measurements, routine echocardiography	HTN; OM: LVMI (P<0.001)	69
200 (ADPKD subset of MDRD)	Measured GFR=13–55 ml/min per 1.73 m2	Secondary subgroup analysis of randomized controlled trial; mean follow-up 2.2 yr	Greater sCr, proteinuria, HTN, young age, low protein diet; OM: renal function decline	78
209 (CRISP)	Mean age 32.1 yr; mean eGFR=89.9 ml/min per 1.73 m2	Baseline and follow-up measurement at 1, 2, and 3 yr	NGAL, IL-8; OM: eGFR and TKV	93
19	Postmenopausal women; Cr<2.5 mg/dl; lack of other serious medical conditions	Postmenopausal estrogen use (n=11) versus no use (n=8); follow-up 1 yr (observational)	Postmenopausal estrogen use; OM: liver volume by CT scan (P<0.03)	109
Randomized interventional studies
72	HTN and LVH; age 20–60 yr; CrCl>30 ml/min per 1.73 m2	Prospective; strict versus standard BP control; follow-up 7 yr	HTN control; OM: LVM (P<0.01)	49
24	Mean age: 41 (amlodipine) to 43 yr (enalapril); CrCl>50 ml/min per 1.73 m2	Follow-up 5 yr	HTN control; OM: decreased urinary albumin excretion (P<0.05)	50
46	ADPKD with HTN; age range=18–65 yr; sCr≤4 mg/dl	Double-blind 3-yr trial comparing ramipril with metoprolol	BP control; OM: renal function, LVM	51
8	Mean (SD) age 38±10 yr; mean (SD) sCr=0.7±0.1 mg/dl; mean (SD) eGFR=113±31 ml/min per 1.73 m2	Conducted over a 2-wk interval	Water intake; OM: urine osmolality<285 mOsm/kg	107
Cross-sectional/retrospective studies
741	Mean (SD) age 53.4±14.8 yr; stages 1–4 CKD; patients with no molecular data excluded	Genotype–phenotype correlation	PKD1 disease, PKD1 truncating mutation; OM: kidney function (P<0.001)	5
336 (267 at risk)	Mean age: 35.4 (PKD1) and 44.5 yr (PKD2); 42 patients had CrCl<70 ml/min or ESRD	Genotype–phenotype correlation	PKD1; OM: kidney function (P<0.001)	6
1215	622 alive without ESRD; 205 died before ESRD; patients with no specific event or younger than cutoff age excluded from analysis for specific predictor	Retrospective	Sex, PKD1, young age at diagnosis, HTN, gross hematuria; OM: renal survival (P<0.001)	7
624	44% of PKD1 and 29% of PKD2 had reached ESRD	Genotype–phenotype correlation	PKD1; OM: kidney function (P<0.001)	8
60	Children with PKD1 (n=50) or PKD2 (n=10); patients without molecular data excluded	Genotype–phenotype correlation	PKD1; OM: bilateral renal cysts (P<0.001)	11
51 PKD1 families	Families with evidence of vascular phenotype in unaffected relatives excluded	Genotype–phenotype correlation	PKD1 mutation position 5′ to 3′; OM: vascular phenotype (P<0.001)	12
234	PKD2 only	Genotype–phenotype correlation	PKD2 mutation location; OM: phenotypic score variability (P=0.002)	13
461	PKD2 only	Genotype–phenotype correlation	Sex, PKD2 mutation other than splice mutations; OM: renal function (P<0.001)	14
Cross-sectional/retrospective studies
704	PKD1 only; 46% had ESRD	Genotype–phenotype correlation	PKD1, modifier genes; OM: phenotype heritability (P<0.05)	20
155	PKD1 only; mean (SD) age 37.4±17.29 yr; ESRD: 31.1%; patients with no molecular data excluded	Genotype–phenotype correlation	ACE DD polymorphism; OM: ESRD<50 yr (P=0.02)	21
173	PKD1 only; patients with linkage to PKD2 or no molecular data excluded	Genotype–phenotype correlation	ENOS Glu298Asp polymorphism in men; OM: age at ESRD (P=0.02)	23
294	PKD1 and PKD2; 41% reached ESRD	Genotype–phenotype correlation	ITGA8 polymorphism; OM: age at ESRD (P=0.03)	24
580	71% alive without ESRD at age 50 yr, 53% at 58 yr, 22% at 70 yr	Retrospective	PKD1, younger age at diagnosis, men, HTN, increased LVM, hepatic cysts in women, three or more pregnancies, gross hematuria, UTIs in men, KV; OM: renal function (P<0.05)	26
157	Study A: from CrCl=30–50 ml/min per 1.73 m2 to ESRD; study B: CrCl=50–60 ml/min per 1.73 m2, followed for 4 yr	Retrospective	Sex, MAP, age; OM: renal function, age at ESRD (P<0.001)	27
58	ESRD	Retrospective	Race; OM: ESRD (P<0.001)	28
162	ESRD (dialysis or renal transplant)	Retrospective	HTN in nonaffected parent; OM: age at renal death (P<0.03)	29
475	Patients’ mean (SD) age 40±11 yr	Retrospective	HTN in affected parent; OM: HTN in offspring (P<0.05)	30
484	Mean age (PKD1 and PKD2): 41 yr (range=2–67) and 56 yr (range=17–88); ESRD: PKD1, n=140 (mean age 48.9 yr) and PKD2, n=24 (mean age 70.2 yr)	Retrospective	Family history of ADPKD-related ESRD; OM: mutated gene	31
180	Children; age 4–18 yr with normal renal function	Retrospective	Glomerular hyperfiltration; OM: total renal volume, renal function (P<0.001)	32
191	Mean (SEM) age 41±1 yr (range=17–81)	Retrospective	Gross hematuria; OM: total renal volume, renal function (P<0.03)	35
108	Patients with history of two or more UTIs	Retrospective	Efficacy of antibiotic prophylaxis in reducing UTIs and gross hematuria and delaying disease progression, gross hematuria at age <30 yr; OM: renal function (P<0.001)	36
235	Mean (SEM) age 42±1 yr; 91 women excluded because of pregnancy at study visit, Cr excretion variability, different laboratory source for Cr data, or missing data	Retrospective	Preexisting HTN; OM: maternal complications in pregnancy (P<0.001)	37
Cross-sectional/retrospective studies
94	Patients who doubled sCr in <36 mo (rapid progressors) or >36 mo (slow progressors)	Retrospective	HTN, UTI, hematuria, overt proteinuria; OM: renal function (P=0.01)	38
256	Stages 1–4 CKD; patients with <6 mo follow-up excluded	Retrospective	Recurrent, persistent pyuria; OM: renal function (P=0.01)	39
32	Children; mean (SD) age 12.3±4.7 yr	Cross-sectional	HTN onset in early-stage ADPKD; OM: renal volume, length (P<0.05)	41
62	Children; mean (SD) age 12.3±4.3 yr	Cross-sectional	HTN; OM: renal volume (P<0.01)	42
199	Children with ADPKD	Retrospective	Very early onset of ADPKD, ADPKD signs, symptoms; OM: KV, HTN, ESRD (P<0.005)	44
147	Age 16–45 yr; CrCl=75–150 ml/min per 1.73 m2	Retrospective	HTN; OM: renal volume (P<0.005)	45
134	Mean (SD) age 42.3±13.1 yr	Retrospective	HTN; OM: clinical severity index (P<0.001)	46
30	Mean age 32 yr (range=19–45); CrCl>80 ml/min per 1.73 m2; patients with less than six sCr measurements or less than three sCr measurements in 1 yr excluded	Retrospective	HTN; OM: renal function (P<0.001)	47
1044	Studies A and B: age 15–49 and 18–64 yr; eGFR≥60 and 25–59 ml/min per 1.73 m2	Cross-sectional	Albuminuria, TKV, RBF; OM: renal function (P<0.001)	52 (HALT PKD baseline data)
103	Mean (SD) age 40±11 yr; mean (SD) GFR 92±36 ml/min	Cross-sectional comparison with 103 age- and sex-matched healthy controls (live kidney donors)	ADPKD status, age quartile; OM: MAP, total renal volume, measured GFR, effective renal plasma flow, renal vascular resistance, filtration fraction (P<0.001)	60
116	Adults; mean (SEM) age 40.7±1.1 yr	Cross-sectional	HTN; OM: LVH frequency (P<0.05)	62
26	Mean (SD) age 26.5±7.4 yr; normotensive by clinic BP; normal renal function	Cross-sectional	24-h systolic BP by ambulatory monitoring; OM: LVMI (P=0.01)	63
46	Mean (SD) age 25.9±8.1 yr; normotensive by clinic BP; normal renal function	Cross-sectional comparison with 35 age- and sex-matched healthy controls	ADPKD; OM: LVMI, diastolic function (P<0.001)	64
18	Mean (SD) age 24.1±6 yr; mean (SD) sCr=74.1±10.6 µM/L	Cross-sectional	Exercise systolic and diastolic BP; OM: LVMI (P=0.001)	65
Cross-sectional/retrospective studies
20	Mean (SD) age 46.7±13.3 yr; mean (SD) sCr=112±33 µM/L; patients with sCR>177 µM/L, cardiovascular complications, diabetes, pulmonary or liver disease, or pregnancy excluded	Cross-sectional	24-h systolic and diastolic BP; OM: LVMI (P<0.001)	66
24	Age range 5.7–24.9 yr; normal renal function	Cross-sectional	HTN; OM: LVMI (P<0.002)	67
85	Children; mean (SEM) age 12±1 yr; normal renal function	Cross-sectional	HTN; OM: LVMI (P<0.001)	68
2085	Mean age 50 yr	Retrospective	HTN; OM: mortality (P<0.001)	70
513	Mean ages for women/men: 37/38 yr (1985–1992) and 39/36 yr (1992–2001)	Retrospective	HTN control; OM: time to ESRD, ADPKD man±HTN (P=0.02), ADPKD woman±HTN (P=0.02–0.03)	71
693	Mean age 55.9 yr (1990–1995) and 60.6 yr (2000–2007)	Retrospective	HTN control; OM: patient survival, age at ESRD (P<0.001)	72
543	Age 15–49 yr; GFR≥60 ml/min per 1.73 m2	Cross-sectional	Systolic BP measured at office, sex; OM: LVMI (P<0.001)	73 (HALT study A baseline data)
31	Mean age 35.8 yr (normotensive)–CrCl 39.6 yr (hypertensive), mean CrCl=91–106 ml/min per 1.73 m2; patients with diabetes, cardiovascular disease, and other conditions affecting endothelial function excluded	Cross-sectional	HTN; OM: endothelial-dependent dilation (P<0.05)	75
15	Mean (SD) age 40.1±10.3 yr; mean (SD) CrCl=87.8±13.7 ml/min per 1.73 m2; patients with diabetes, cardiovascular disease, hypercholesterolemia, or smokers excluded	Cross-sectional	HTN; OM: endothelial dysfunction (P<0.005)	76
144	n=52: HTN and eGFR<60 ml/min per 1.73 m2; n=50: HTN and eGFR≥60 ml/min per 1.73 m2; n=42: normotensive and eGFR≥60 ml/min per 1.73 m2; 51 healthy controls	Cross-sectional	ADPKD versus control; HTN, renal function; OM: peripheral augmentation index, circulating inflammation biomarkers (P<0.05)	77
97	Proteinuria<300 and >300 mg/d: mean age 39 and 48 yr, mean CrCl=82 and 37 ml/min per 1.73 m2	Retrospective	Overt proteinuria (>300 mg/d), microalbuminuria; OM: renal function (P<0.001)	79
Cross-sectional/retrospective studies
102	Mean (SD) age 40±11 yr; mean (SD) measured GFR=77±31 ml/min per 1.73 m2	Cross-sectional	Plasma copeptin; OM: disease severity by measured GFR, effective RBF, total renal volume, albuminuria (P<0.001)	82
102	Mean (SD) age 40±11 yr; mean (SD) measured GFR=77±31 ml/min per 1.73 m2	Cross-sectional	Urinary biomarkers; OM: disease severity by measured GFR, effective RBF, total renal volume (P<0.05)	84
71	Mean (SD) age 16±4 yr (range=8–26); mean (SD) CrCl=130.2±29.4 ml/min per 1.73 m2	Cross-sectional	Serum angiogenic growth factors (particularly Ang-1); OM: renal function (P=0.01)	85
680	Consecutive adult ADPKD patients not in ESRD	Retrospective	Serum uric acid; OM: ESRD hazard ratio (P<0.001)	87
91	Adult normotensive ADPKD patients; normal renal function; no other chronic conditions	Retrospective	Uric acid, serum ADMA, eGFR; OM: endothelial dysfunction (P<0.001)	88
55	Age 22–79 yr; sCr=0.5–11.9 mg/dl (median=1.2); patients with clinical renal infections, on dialysis, or with transplant excluded	Retrospective	Urine excretion of MCP-1; OM: sCr	89
144	n=50: HTN and eGFR>60 ml/min per 1.73 m2; n=52: HTN and eGFR=25–60 ml/min per 1.73 m2; n=42: normotensive and eGFR>60 ml/min per 1.73 m2; patients with vascular disease, diabetes, and severe heart failure excluded	Cross-sectional	Disease severity defined by presence or absence of HTN and renal function (normal versus decreased); OM: levels of serum inflammatory and oxidative stress markers (P<0.001)	90
100	Mean (SD) age 31±6 yr; mean (SD) eGFR=94±18 ml/min per 1.73 m2; CKD stages 1/2	Cross-sectional	FGF23; OM: increased renal phosphate excretion (P=0.07)	91
Test/validation sets: 134/158	Test/validation sets: mean (SD) age 31.4±6.3/32.4±8.7 yr, mean (SD) eGFR=86.4±15.5/88.1±27.8	Retrospective	Proteomic severity score made of 142 peptides; OM: hTKV (P<0.001)	92
284	Mean (SD) age at ESRD 54.1±9.9 yr	Retrospective	Low birth weight; OM: age at ESRD (P=0.01)	95
102	Mean (SD) age 39±12 yr	Cross-sectional	Coffee consumption; OM: caffeine in ADPKD patients versus controls (P<0.001)	97
Cross-sectional/retrospective studies
582	ESRD; patients with systemic disease involving kidney, immunosuppressive therapy, and age at renal death <21 yr excluded	Retrospective	Tobacco consumption; OM: ESRD risk (P=0.002)	98
239	Mean (SEM) age 38.6±0.9 yr (range=2–80); patients with primary PLD diagnosis excluded	Retrospective	Sex; OM: massive hepatic cystic disease (P<0.04)	108

OM, outcome; TCV, total cyst volume; KV, kidney volume; HTN, hypertension; sCr, serum creatinine; Cr, creatinine; CT, computed tomography; LVM, left ventricular mass; ACE DD, angiotensin converting enzyme DD genotype; ENOS, endothelial nitric oxide synthase; ITGA8, integrin α-8 gene; MAP, mean arterial pressure; Ang-1, angiotensin-1; ADMA, asymmetric dimethylarginine; MCP-1, monocyte chemoattractant protein-1; FGF23, fibroblast growth factor-23; hTKV, height-adjusted TKV; PLD, polycystic liver disease.

Hyperfiltration in Childhood

The effect of glomerular hyperfiltration (creatinine clearance [CrCl]≥140 ml/min per 1.73 m²) was evaluated in a cohort of 140 children with ADPKD followed longitudinally for a median of 5.8 years.³² The subset of 32 children with glomerular hyperfiltration showed a higher rate of growth in TKV (corrected for body surface area) over 5 years and a faster decline in renal function than children without glomerular hyperfiltration. Because the final CrCl measures were similar in the two groups of children, it is unclear whether hyperfiltration translates into an earlier onset of ESRD.

Gross Hematuria

Early or frequent episodes of gross hematuria may be signs of more severe disease and contributors to renal function deterioration, perhaps by causing AKI and/or chronic iron toxicity. Cyst ruptures with gross hematuria may lead to the release and deposition of free iron and heme, promoting generation of reactive oxygen species and proinflammatory cytokines.^33,34 An observational study of 191 patients with ADPKD found that patients who had one or more episode of gross hematuria had significantly larger kidneys and were more often hypertensive than patients without an episode.³⁵ Patients who reported more episodes of gross hematuria had worse renal function than patients who had only one episode. Renal survival was significantly worse in 128 patients with ADPKD who had gross hematuria at age <30 years than in 448 patients without gross hematuria or whose first episode occurred at age >30 years (ESRD at 49 versus 59 years).⁷ Similar findings were reported in other studies.³⁶ Although these observations are derived from retrospective studies, they indicate that gross hematuria is associated with more severe disease.

Pregnancy

No prospective study examining the effects of pregnancy on ADPKD renal outcome has been reported. An analysis of historical data from 235 women (605 pregnancies), however, showed that pregnancy did not seem to affect renal function in normotensive women, but hypertensive women with more than three pregnancies had significantly worse renal function than age-adjusted women with fewer pregnancies.³⁷ Survival analysis of 236 women with ADPKD showed significantly shorter renal survival among women with three or more pregnancies.⁷ Because the latter analysis relied on historical data, it is unclear whether the shorter renal survival was because of complications of pregnancy, such as development or exacerbation of hypertension and preeclampsia, or other factors.

Multiple Urinary Tract Infections

Several small retrospective ADPKD studies have suggested that multiple urinary tract infections (UTIs) are associated with a more rapid decline in renal function. An uncontrolled study in 108 patients with a history of two or more UTIs reported that antibiotic prophylaxis significantly reduced the incidence of infection and limited the loss of renal function compared with no prophylaxis.³⁶ In another study, patients classified as fast progressors (defined by doubling of serum creatinine in ≤36 months) had a higher incidence of single and recurrent UTIs than slow progressors.³⁸ A third retrospective, single-center study suggested that asymptomatic pyuria and particularly, overt UTI were associated with faster decline in renal function, but it is unclear whether this result was independent of other factors, such as baseline GFR and TKV.³⁹ In addition, overt UTI was uncommon in that study, occurring in only 33 of 256 patients during a mean observation period of 81 months. It remains, therefore, uncertain whether UTIs play a significant role in the loss of renal function in ADPKD.

Cyst Rupture

One study assessed changes in renal volume over a 6-month period by magnetic resonance imaging (MRI) in a cohort of 100 young patients with ADPKD and found direct evidence for cyst rupture, resulting in a decrease in renal volume in 6 patients.⁴⁰ Compared with the rest of the study population, these six patients had higher baseline TKV and reported more symptoms (flank pain, macrohematuria, infection, and hypertension), suggesting that cyst rupture is a marker of more severe disease.

Hypertension and Kidney Function

Hypertension occurs in up to 80% of patients with ADPKD before significant loss of renal function and seems to be both a marker of more severe disease and a contributor to renal function loss.³ Hypertension is already present in a significant subset of children with ADPKD, and several cross-sectional studies have shown that the prevalence of hypertension in children correlates with kidney size and number of cysts.^41–43 Another observational study of children with ADPKD found that those who were diagnosed by ultrasound at age <18 months had larger kidneys, more cysts, and more frequent hypertension on follow-up than children diagnosed at age >18 months, confirming the relationship between renal structural severity and prevalence of hypertension, even in children with ADPKD.⁴⁴

Similarly, cross-sectional analysis of 147 adults with ADPKD revealed that renal volume was significantly greater in patients with hypertension versus normotension among both men and women, whereas serum creatinine and CrCl did not differ.⁴⁵ Furthermore, TKV assessed by MRI was significantly higher in young (mean age of 31 years) ADPKD patients with hypertension (n=67) versus normotension (n=33).⁴⁰ Another cross-sectional study of 134 patients found a strong and graded association between presence and severity of hypertension and decreased eGFR.⁴⁶

Early onset of hypertension may lead to earlier onset of ESRD. A survival analysis using data from 506 adults with ADPKD revealed that patients with a diagnosis of hypertension at age <35 years developed ESRD 14 years earlier (at 51 versus 65 years old) than patients who were normotensive until >35 years old.⁷ Another small (n=30) retrospective study found that the decline in mean standardized CrCl slope over time was significantly greater in hypertensive versus normotensive patients.⁴⁷ Similarly, in an earlier retrospective study of 157 patients with decreased renal function, patients with higher mean arterial pressure had a faster CrCl decline than patients with lower BP.²⁷ In a prospective observational study of 198 patients with ADPKD followed for a mean of 100 months, hypertension was an independent risk factor of CKD progression.⁴⁸ These data show that early-onset hypertension and severity of hypertension are associated with larger kidneys and progression to ESRD, and thus, they are markers of more severe disease. To date, no randomized clinical trial has been able to show an effect of BP control on progression to ESRD, but these trials were all limited by their small size and short duration.^49–51 The effect of BP control on renal structural and functional disease progression is currently being examined in a large multicenter prospective trial (HALT PKD) involving 1044 patients over 5–8 years; results are expected by the end of 2014.⁵²

Episodes of AKI

Although there is strong evidence in animal models that AKI accelerates the progression of PKD, it has not been studied in humans. Only one case-control study reported that patients with ADPKD hospitalized for pneumonia were significantly more likely to develop AKI (serum creatinine elevation≥0.3 mg/dl) than matched patients without ADPKD with similar severity of pneumonia.⁵³

Renal Volume above Age-Corrected Mean

Two longitudinal observational studies in adults and one study in children showed that greater renal volume is predictive of more rapid ADPKD progression.^4,54–56 In the children’s study (n=108), those patients with early renal enlargement had a significantly faster rate of renal growth (assessed over a mean follow-up of 5.7 years) than other children with ADPKD (26 versus 11 ml/kidney per year adjusted for age).⁵⁴ In a study of 229 adults with ADPKD, sequential ultrasound examinations performed over a mean interval of 7.8 years showed that initial renal volume as well as renal volume growth rate were correlated with the rate of eGFR decline over time.⁵⁵ The Consortium for Radiologic Imaging Studies in Polycystic Kidney Disease (CRISP) enrolled patients with ADPKD with CrCl>70 ml/min and used MRI to determine TKV.^4,56 Age-adjusted renal volume was inversely related to GFR and albuminuria at baseline.⁵⁶ During repeated assessments over 8 years, the strength of the correlation between increase in TKV and decrease in measured (iothalamate clearance) GFR increased.⁵⁷ Receiver-operator characteristic curve analysis indicated that a baseline height-adjusted TKV≥600 cm³/m predicted progression to stage 3 CKD within 8 years with 74% sensitivity and 75% specificity.

Decreased Renal Blood Flow

In CRISP, mean renal blood flow (RBF) measured by MRI decreased progressively over a 3-year period and preceded the decline in GFR.^58,59 Lower baseline RBF was associated with a larger increase in TKV and total cyst volume over 3 years and a decline in measured GFR. On multivariate analysis, RBF was an independent predictor of renal structural and functional disease progression.⁵⁹ A different group of investigators using iothalamate and hippuran clearances in a cross-sectional analysis of 103 subjects also reported a marked decrease in effective renal plasma flow, whereas GFR was preserved in young adult patients with ADPKD compared with matched healthy control subjects.⁶⁰ Although RBF measurements are currently not available for routine clinical practice, they may be useful as outcome parameters for future interventional studies. The early decrease in RBF is also important for elucidating the pathogenesis of renal function loss in ADPKD. It remains to be determined whether it is mainly because of mechanical compression of blood vessels by the cysts, intrinsic vascular abnormalities caused by PKD mutations, or a secondary effect of oxidative stress and inflammation causing vascular dysfunction.

In summary, the best evidence from carefully designed prospective studies and multiple cross-sectional and retrospective studies identifies PKD1 mutations (particularly if truncating), early onset of hypertension, early and multiple episodes of gross hematuria, large kidney volumes, and decrease in RBF or GFR at a young age as the most reliable predictors of rapid renal disease progression (Figure 1).

Figure 1.

Diagram depicting the spectrum of predictors for rapid renal disease progression in ADPKD. Shaded ovals represent the most established predictors.

Cardiovascular Disease Progression in ADPKD

Hypertension and Left Ventricular Hypertrophy

Hypertension is the most commonly reported initial sign of ADPKD and a well recognized risk factor for left ventricular hypertrophy (LVH).⁶¹ In an earlier study, LVH was common in adults with ADPKD, which was shown in an echocardiographic study of 116 consecutive patients, where 41% had LVH at a mean age of only 44 years.⁶² Patients with ADPKD with versus without LVH had a significantly higher prevalence (83% versus 61%) and duration (7.5 versus 3.9 years) of hypertension and worse renal function (serum creatinine of 2.0 versus 1.4 mg/dl). Another study reported higher left ventricular mass index (LVMI) in young normotensive patients with ADPKD than healthy control subjects and found a correlation between 24-hour systolic BP on ambulatory monitoring and LVMI.⁶³ These young patients also had signs of diastolic dysfunction by echocardiogram and higher BP during exercise stress testing than healthy control subjects.^64,65 Levels of neurohormones were not correlated with LVMI, but 24-hour systolic and diastolic BPs were correlated.⁶⁶ These observations highlight the importance of 24-hour BP load on the development of LVH in ADPKD.

Early Increase in LVMI

Even in children and young adults (ages<25 years) with ADPKD, a significantly higher LVMI than in healthy control subjects has been reported, although most LVMI values were in the normal range.⁶⁷ These young adults had higher BP by ambulatory monitoring than control subjects but not children with ADPKD. In another study, children with ADPKD and hypertension or borderline hypertension had significantly higher LVMI than children with ADPKD and normotension.⁶⁸ Similarly, children with ADPKD, but not their unaffected siblings, showed a significant correlation between systolic BP and LVMI; children with hypertension had significantly higher LVMI than children with normotension.⁶⁹ Children with ADPKD also had a significantly higher incidence of mitral valve prolapse than their unaffected siblings.

BP Control

There is indirect evidence from three recent epidemiologic studies that BP control improves cardiovascular and renal outcomes. First, a population-based study using the United Kingdom General Practice Research Database (n=2085) found that antihypertensive drug use increased in frequency in patients with ADPKD over the period from 1991 to 2008, particularly for agents blocking the renin-angiotensin system (RAS).⁷⁰ After adjusting for potential confounders, mortality decreased over the same time period. Second, a study that compared two ADPKD cohorts (n=513) over the 1985–1992 versus 1992–2001 periods found that patients in the later cohort had lower mean arterial pressure and increased use of angiotensin-converting enzyme inhibitors.⁷¹ Cardiovascular outcomes were not determined, but patients in the later cohort had longer renal and overall survival. Third, a study of patients with ADPKD in Denmark (n=693) found improved survival and an increase in age (by 4.7 years) at onset of ESRD between 1990 and 2007, coinciding with increased use of RAS-blocking drugs.⁷²

Small randomized trials of hypertension control showed benefits of strict BP control for LVMI and LVH but not renal function.^49,51

In contrast to earlier results,⁶² the prevalence of LVH was assessed by cardiac MRI in 543 hypertensive patients with ADPKD (mean age of 36 years) with normal renal function who were participating in the HALT PKD trial.⁷³ Baseline data revealed that the prevalence of LVH was only 3.9% by nonindexed left ventricular mass and 0.9% by LVMI, despite a mean duration of diagnosed hypertension of 5.8 years. This low prevalence of LVH may be attributed to the fact that BP was well controlled (mean of approximately 124/82 mmHg at baseline) and that 61% of patients were using RAS blockers. There is, therefore, strong epidemiologic evidence that strict BP control using RAS-blocking drugs ameliorates cardiovascular disease progression in ADPKD.

Aneurysm Rupture

Intracranial aneurysm (ICA) rupture is one of the most dramatic cardiovascular disease manifestations of ADPKD. The only predictor that has been consistently identified is family history of ICA rupture, which was shown in a retrospective study of 608 adults from 199 ADPKD families.⁷⁴ The frequency of ruptured ICAs was significantly higher in patients with ADPKD than unaffected family members, but ruptured ICAs were not randomly distributed; rather, clustering was evident within certain ADPKD families. As mentioned previously, mutations toward the 5′ end of PKD1 may be more likely to cause ICA and other vascular complications.¹²

Endothelial Dysfunction

Endothelial dysfunction is an early and common finding in patients with ADPKD. In one study, patients with ADPKD with and without hypertension exhibited greater endothelial dysfunction (measured by endothelium-dependent dilation of the brachial artery after transient ischemia) than healthy subjects with and without hypertension, respectively.⁷⁵ Carotid intima media thickness was increased in patients with ADPKD and normotension compared with healthy subjects and further increased in patients with ADPKD and hypertension. Other studies have also shown evidence of endothelial dysfunction in early ADPKD before the onset of hypertension and renal dysfunction when measured in the cutaneous microcirculation by laser Doppler examination or peripheral artery tone recordings using finger plethysmography.^76,77 Presence of endothelial dysfunction in early ADPKD likely confers increased atherosclerosis risk, consistent with the observed increase in carotid intima media thickness, and it may contribute to the early decline in RBF described previously. Endothelial dysfunction and carotid intima media thickness are not routinely assessed in clinical practice, but they can serve as markers or treatment targets in research settings.

Association of Laboratory Factors with Renal and Cardiovascular Disease Progression

A summary of the main studies examining laboratory predictors of rapid renal and cardiovascular disease progression is provided in Table 5.

Table 5.

Laboratory predictors associated with renal and cardiovascular disease progression in ADPKD

Predictor	Association/Change	Refs.
Urine predictors
Urine-concentrating capacity	Reduced in children with >10 versus ≤10 cysts	43
MCP-1	Increased in ADPKD; associated with TKV; predictor of stage 3 CKD	57,89
	Increased in ADPKD; associated with TKV	82
NGAL and IL-8	NGAL increased in ADPKD; associated with GFR, TKV, effective RBF	82
	Both increased in ADPKD	93
Kidney injury molecule-1	Increased in ADPKD; associated with GFR, TKV	82
Heart-type-fatty-acid binding protein	Increased in ADPKD; associated with GFR, RBF	82
Collagen-derived peptides and other biomarkers	Increased in ADPKD	92
Serum or other laboratory predictors
HDL cholesterol	Decreased HDL levels associated with GFR decline	78,86
	Low levels associated with TKV increase	86
Vascular endothelial growth factor	In children, correlated with TKV and LVMI; negatively correlated with CrCl	85
Angiopoietin 1	In children, correlated with TKV and LVMI; negatively correlated with urinary protein excretion	85
Serum uric acid	Higher level associated with earlier hypertension onset, larger TKV, ESRD risk	87
	Higher level associated with endothelial dysfunction	88
FGF23	Increased in ADPKD patients versus controls; associated with increased renal phosphate excretion	91
Inflammation-associated biomarkers (MCP-1 and TNF-α)	Overexpression of inflammation factors drives interstitial inflammation and fibrosis	94

MCP-1, monocyte chemoattractant protein-1; FGF23, fibroblast growth factor-23.

Proteinuria and Microalbuminuria

The amount of proteinuria correlates with the risk for progression in many renal diseases, including ADPKD. Among 200 patients with ADPKD participating in the Modification of Diet in Renal Disease (MDRD) Study, higher levels of proteinuria were associated with a steeper decline in GFR.⁷⁸ Another study of 270 consecutive adults with ADPKD identified overt proteinuria (>300 mg/d) in 48 patients (18%), which was associated with worse renal function, higher BP, and larger renal volume.⁷⁹ Patients with versus without overt proteinuria reached a serum creatinine concentration of 1.5 mg/dl at a significantly younger age (44 versus 58 years old). The same study found microalbuminuria in 20 of 49 patients with hypertension and LVH but not overt proteinuria. BP, renal volume, and filtration fraction were significantly higher in patients with microalbuminuria. Similarly, in a study of 100 young patients (mean age of 31 years) with ADPKD and preserved renal function, the degree of albuminuria was correlated with TKV and kidney volume growth rate.⁴⁰ Among 1044 adult participants in the HALT PKD trials at baseline, urine albumin excretion was positively correlated with TKV and negatively correlated with eGFR.⁵² Because TKV is usually not available in clinical practice, increased levels of urinary albumin excretion in adults may be a valuable marker of ADPKD severity before a decline in eGFR is evident. In children, microalbuminuria is not consistently correlated with disease severity.^44,54,68

Serum Copeptin Levels

Copeptin is the carboxy-terminal portion of the precursor for arginine vasopressin and serves as a reliable and stable surrogate of circulating arginine vasopressin levels.^80,81 Because vasopressin induces the production of cAMP, which is a potent stimulator of cyst formation and growth, elevated levels of copeptin may be a marker and/or contributor to rapid ADPKD progression. In a cross-sectional study of 102 patients with ADPKD, plasma copeptin concentrations were correlated with TKV, 24-hour urine albumin excretion, GFR, and effective RBF independent of age, sex, and diuretic use.⁸² More importantly, in the CRISP cohort of 241 patients with preserved renal function at baseline, higher baseline copeptin levels (after adjusting for age and sex) were associated with larger increases in TKV and decreases in GFR during a median follow-up of 8.5 years.⁸³ Copeptin level was associated with plasma osmolality in the former study but not CRISP. More research studies to confirm the potential predictive value of serum copeptin level are necessary before it can be adopted for clinical use.

Additional Investigational Urinary and Serum Biomarkers

Levels of several urinary markers and other laboratory parameters are abnormal in ADPKD (Table 5). Many of these markers have been associated with renal structural and functional disease severity, and some have been associated with cardiac structure.^43,84–88 In a cross-sectional analysis of 102 patients with ADPKD, neutrophil gelatinase-associated lipocalin (NGAL; a marker of proximal tubule damage), kidney injury molecule-1 (a marker of proximal tubule damage), heart-type-fatty-acid binding protein (a marker of distal tubule damage), and monocyte chemoattractant protein-1 (a marker of inflammation) were all significantly increased compared with healthy subjects.⁸⁴ Monocyte chemoattractant protein-1 has been extensively investigated in other studies as well, suggesting that it may become an important predictive marker when further validated by larger population studies.^57,89 Moreover, each of these markers was associated with renal structural or functional parameters. Among these markers, NGAL may be of most value for determining ADPKD severity, because it was associated with both renal structural and functional parameters. Validation of these markers in larger prospective cohorts is still required before their use can be recommended for clinical practice.

Patients with ADPKD, hypertension, and renal dysfunction have significantly higher levels of systemic markers of inflammation than patients with normal renal function (hypertensive or normotensive) or healthy subjects.⁹⁰ In comparison, oxidative stress was apparent even in patients with ADPKD with normotension versus healthy subjects and likely precedes the appearance of hypertension, which may account for the increased levels of angiogenic growth factors described in young patients with ADPKD. Several other serum and laboratory factors have been associated with various aspects of ADPKD severity, including serum uric acid, HDL, fibroblast growth factor-23, collagen-derived peptides, NGAL, IL-8, and TNF-α.^{78,86–88,91–94} Although some of these factors may contribute to ADPKD progression, confirmation in additional studies is required as well as biomarker validation.

Association of Environmental Factors with Renal Disease Progression

A summary of the main studies examining environmental factors of rapid renal disease progression is provided in Table 6.

Table 6.

Environmental predictors of renal disease progression in ADPKD

Environmental Predictor	No. of Patients/ Experimental Platform	Patient Characteristics/Experimental Platform	Study Features	Highest P Value	Major Refs.	Additional Supporting Refs.
High water intake	8	ADPKD patients; normal renal function; patients eating typical diets	Phase 1: baseline measurements; phase 2: water administration to reduce urine osmolality<285 mosM/kg	0.02	106,107	99–105
Caffeine	Cysts epithelial cells	Mural epithelial cell from human ADPKD cysts	cAMP levels determined after caffeine or receptor-mediated agonist stimulation	<0.001	96	97
Low protein intake	200	ADPKD patients from MDRD; reduced renal function	2.2 yr follow-up	0.06	78	NA
Smoking	323	Consecutive ADPKD patients at Istanbul University	Prospective observational (n=198); mean (SD) follow-up=100±38 mo	0.01	48	NA
	582	Patients diagnosed with IgA nephropathy or ADPKD	Retrospective	0.002	98	NA
Low birth weight	284	Retrospective cohort of ADPKD patients with ESRD from Denmark	Retrospective	0.01	95	NA

NA, not applicable.

Birth Weight

In a retrospective analysis of 284 patients with ADPKD, ESRD, and available birth weight, age at ESRD onset increased by 1.7 years for every 1-kg increase in birth weight after adjustment for BP, sex, birth decade, and type of antihypertensive treatment.⁹⁵ This observation needs to be confirmed in other larger ADPKD cohorts, but it is consistent with the notion that people born with low birth weight have a reduced number of nephrons and therefore, are more likely to develop ESRD.

Caffeine

By inhibiting phosphodiesterase, caffeine increased cAMP levels in a concentration-dependent manner in cyst epithelial cell culture, resulting in activation of the extracellular signal-regulated kinase pathway and leading to increased cellular proliferation and transepithelial fluid secretion.⁹⁶ High caffeine intake may, therefore, be a risk factor for cyst enlargement and ADPKD progression, although a small clinical study has suggested no correlation between mild caffeine intake and TKV by ultrasound.⁹⁷ Nevertheless, it is recommended to counsel patients with ADPKD to limit their caffeine intake.

Smoking

In the prospective observational study by Ozkok et al.,⁴⁸ 93 patients with ADPKD were found to be fast progressors (defined as decline in eGFR>1 ml/min per year) and 78 patients were slow progressors (decline<1 ml/min per year) over a mean (SD) follow-up of 100±38 months. Fast progressors were significantly more likely to have a history of smoking than slow progressors, and the number of pack-years smoked was also significantly higher, adding to the increasing evidence that smoking adversely affects CKD progression. In support of this observation, smoking has been found to increase the risk of ESRD in men with inflammatory and noninflammatory renal diseases in a dose-dependent fashion.⁹⁸

High Water Intake

The vasopressin pathway is upregulated in ADPKD because of an early loss of urine concentration capability.^99,100 High water intake as well as vasopressin gene inactivation have been shown to effectively reduce cystogenesis in the polycystic kidney rat.^101,102 On the basis of this rationale, it has been envisioned that high water intake may be effective in delaying disease progression in human ADPKD as well.^103–106 In a small pilot study, Wang et al.¹⁰⁷ showed the feasibility of safely achieving a target urine osmolality≤285 mOsm/kg in eight patients with ADPKD eating normal diets. Larger long-term studies are needed to assess the effect of such fluid intake on renal disease progression in ADPKD.

Low Protein Intake

In the subset of 200 patients with ADPKD in the MDRD study (mean follow-up of 2.2 years), patients in study B (GFR=13–24 ml/min per 1.73 m²) were on a low or very low protein diet.⁷⁸ After controlling for actual protein intake, a trend was observed to a beneficial effect with the very low protein intake group. In study A (GFR=25–55 ml/min per 1.73 m²), however, this effect was not confirmed, questioning the use of a low protein diet in patients with ADPKD with moderately impaired renal function.

Liver Disease Progression in ADPKD

The factors associated with severity of hepatic cysts were evaluated in 239 patients with ADPKD (age range=2–80 years).¹⁰⁸ The incidence and number of hepatic cysts increased with age. Although sex was not associated with hepatic cyst incidence, women were significantly more likely to have >15 hepatic cysts. Liver cyst size was larger in women, and number of cysts was correlated with number of pregnancies, suggesting that estrogens influence the severity of liver cystic disease. Patients with hepatic cysts also had larger TKV and lower CrCl. On logistic regression, increased age, higher renal structural severity index, and decreased CrCl were predictive of the presence of liver cysts, whereas increased age, higher renal severity index, women, and pregnancy were correlated with the number and size of hepatic cysts. Another study compared changes in liver cyst volume between women with ADPKD who took postmenopausal estrogen and women who did not (similar age and number of pregnancies), and it found that 1-year estrogen treatment was associated with a significant increase in total liver and liver cyst volume.¹⁰⁹ At present, no guidelines related to use of hormone-based contraceptives or hormone replacement therapy and risk for liver cyst complications exist for women with ADPKD. Additional studies are needed to better assess this risk.

Conclusions

This systematic review discusses several factors associated with rapid ADPKD progression (Figure 1). PKD1 mutations confer greater risk of rapid progression than PKD2 mutations, with truncating PKD1 mutations having greater significance than nontruncating mutations. Other predictors include men, early onset of hypertension, early onset or repeated episodes of gross hematuria, and in women with hypertension, three or more pregnancies. Greater TKV and early decreases in GFR and RBF predict rapid disease progression. Similarly, the presence of overt proteinuria, microalbuminuria, and elevated serum copeptin levels has been associated with more rapid progression. Hypertension seems to be the main risk factor for early cardiovascular disease; small treatment trials have shown the benefit of strict BP control for prevention or regression of LVH, whereas large epidemiologic studies have indicated a mortality benefit. Increased age and hormonal environment are the major predictors for liver cyst progression. Interestingly, most data used to validate the predictors described in this review derive from retrospective or cross-sectional studies, suggesting that additional long-term prospective studies are needed to better understand the natural history of ADPKD at the population level. A better understanding of the risk predictors involved in rapid renal disease progression may be useful in selecting patients for treatment with new agents directed against mechanisms inherent to disease pathogenesis.

Disclosures

R.W.S. is a consultant with Ikaria, Janssen, Novartis, and Otsuka America Pharmaceutical, Inc. K.F. and S.R. are employees of Otsuka America Pharmaceutical, Inc. The other authors have nothing to disclose.