Autosomal dominant polycystic kidney disease (ADPKD) is the most common genetic cause of end-stage kidney disease. There are two known disease causing genes, PKD1 and PKD2, which encode proteins localized to the primary cilium of the kidney tubular epithelial cells. Mutations in these proteins lead to disrupted intracellular calcium signalling, cell proliferation and the development of fluid-filled renal cysts, distortion of the normal kidney parenchyma, and eventually loss of kidney function. The median age for kidney failure is after the sixth decade of life for those with PKD1 mutations and a decade later for those with mutations in PKD2.
Owing to the delay between disease onset and the eventual renal outcome, the study of renal progression raises unique challenges in this population. Although kidney failure does occur in many who are affected, using the outcome of dialysis or death becomes impractical, as trials targeted to treating early disease would need to be conducted over many decades. The most commonly used measure in the study of kidney disease is creatinine-based glomerular filtration rate (GFR). Again, ADPKD poses a particular challenge as kidney function in those with ADPKD remains markedly preserved early in the disease as a result of glomerular hyperfiltration despite the ongoing structural changes of cyst enlargement . Even patient-reported symptoms of pain, which is prevalent in those with preserved GFR, may not be prominent until the GFR is reduced (<60 ml/min/1.73 m2) or the kidneys are markedly enlarged [3▪]. The standard outcome for many ADPKD clinical trials has become total kidney volume (TKV), usually measured by MRI techniques. Although the use of TKV is grounded in robust observational studies, implementing TKV measures outside a clinical trial remains cumbersome, and without universal accessibility or standardization.
The emergence of potential therapies has triggered a need to identify those most at risk of reaching end-stage renal disease (ESRD), while sparing those unlikely to benefit from any adverse effects and costs. Ideally one would want to focus on factors that associate with a higher risk for disease progression, which are present early in the course of the disease, are easily measurable, and are modifiable with effective therapy.
RISK FACTOR FOR DISEASE PROGRESSION IN AUTOSOMAL DOMINANT POLYCYSTIC KIDNEY DISEASE – MOLECULAR DIAGNOSTICS
There is a significant interfamilial and intrafamilial variability in ADPKD. A major explanation for this variability is locus heterogeneity, with PKD1 mutations being associated with an earlier onset of ESRD than those with PKD2 mutations . Some of the residual variability in disease severity and outcome are explained by the specific type of mutation. The French Genkyst cohort, for example, confirmed that a truncating PKD1 mutation was associated with an age of ESRD onset of 55 years, 67 years for those with a non-PKD1 truncating mutation, and 79 years for those with a mutation in the PKD2 gene [4▪▪].
Hypomorphic alleles have also been described in individuals and families that demonstrate atypical or mild disease presentations. These gene sequence variations often lead to milder disease as they do not completely abrogate polycystin activity, but if they are coupled with another mutation they may result in a more severe phenotype .
TOTAL KIDNEY VOLUME
An important study that contributes to our understanding of the natural history of ADPKD and its genetic determinants is the Consortium for Radiologic Imaging Studies of Polycystic Kidney Disease (CRISP) study. The study followed 241 patients age 15–45 years old with ADPKD and preserved kidney function (creatinine clearance >70 ml/min). The study demonstrated that MRI-based measurement of total cyst volume and TKV could be a reliable and accurate marker of structural and functional changes in ADPKD over a relatively short follow-up period (3 years) . Notwithstanding the significant variability of TKV growth between individual patients, there was a strong inverse association between baseline TKV and the slope of GFR . The study also demonstrated that baseline height-adjusted TKV correlates somewhat with baseline measured GFR (r = 0.22), but its relationship with GFR at year 3 (0.44) and year 8 (0.65) is better . This may reflect the hyperfiltration that exists which dissociates GFR from the structural increase in kidney size early in the disease.
The CRISP study determined TKV by stereology, but this is a time-consuming and resource-intensive exercise that requires special software and trained operators. To overcome this barrier, the CRISP investigators have developed a semiautomated method for segmenting and counting individual cysts from a mid-slice magnetic resonance (MR) image . They compared the manual counting of cysts with this semiautomated approach in a cohort of 241 ADPKD cases . The number of cysts counted by each method correlated well (interclass coefficient of 0.96), but in a minority of cases (six of 241) the disagreement was substantial (>15 cysts). This approach may greatly aid in the characterization and tracking of cyst growth in those followed with MRI. Another alternative is the use of an ellipsoid equation applied to images obtained by MRI or computed interventional (CT) scan. The ellipsoid-based TKV correlated remarkably well with standard TKV when applied to those with ‘typical’ ADPKD, that is excluding those with unilateral, asymmetric, segmental, or lop-sided disease, or those with significant atrophy of one or both kidneys. In a study of 590 patients drawn from the Mayo Clinic Translational PKD Center and validated in 173 CRISP study participants, the use of this ellipsoid-based TKV allowed for the development of height-adjusted TKV ranges for age. The equation derived predicted estimated GFR (eGFR), and allows for a practical classification of ADPKD based on height-adjusted TKV and age. The utility of this tool would be to identify those at highest risk for progression, either as potential candidates for enrolment in clinical trials or those most likely to benefit from early treatment [11▪▪].
URINE OSMOLALITY AND COPEPTIN
An extended study of the original CRISP cohort highlighted additional parameters that identified modifiable factors associated with disease progression. The baseline 24-h urine osmolality, as a surrogate for vasopressin activity, was associated with GFR decline between years 1 and 6 . Studies attempting to use water therapy to inhibit vasopressin have not been conclusive. In a small study of 13 patients with ADPKD, water loading led to an increase in urine volume and a reduction in urine osmolality, but urinary cyclic adenosine monophosphate (cAMP) was not significantly reduced .
The pathophysiologic role of arginine vasopressin has been well established in stimulating cAMP, leading to increased cell proliferation and thus cyst and kidney growth. It is also recognized that patients with ADPKD have impaired concentrating capacity, even when water deprived, suggesting increased vasopressin concentrations . Copeptin, the glycosylated C-terminal portion of the arginine vasopressin precursor peptide, is more stable and more reliably measured than vasopressin itself . In ADPKD, copeptin levels are elevated, and may serve as a surrogate biomarker for disease pathogenesis, correlating negatively with GFR and renal blood flow [16–18]. Data from the CRISP study showed that baseline copeptin levels were associated with morning urine osmolarity, higher blood pressure, increased TKV, and lower GFR . Those with higher baseline copeptin concentration also exhibited higher TKV and more kidney volume growth over the median 8 year observation period . Other studies have showed similar results.
A nonrandomized study in Japanese patients with ADPKD assigned patients to high water intake (n = 10) or ‘standard’ intake (n = 6). This study showed that although increased water intake resulted in lower plasma copeptin levels, there appeared to be a decline in eGFR and increase in TKV with high fluid intake . There are important limitations to this study, namely that it is small and nonrandomized and that there is likely confounding by indication, as the high fluid cohort started off with higher fluid intake, which could simply reflect increased dietary sodium intake or a similar confounder. The question of prescribing increased water intake in ADPKD still deserves a conclusive answer.
Similar to other populations with CKD, hyperuricemia has also been implicated in the development and progression of CKD. In a retrospective analysis of a prospective cohort study involving 680 patients with ADPKD, after adjusting for age, sex, and level of kidney function, there was a 5.8% increase in TKV and 4.1% increase in TKV for every 1 mg/dl increase in uric acid (P = 0.007) . A single center, retrospective study of 365 ADPKD patients in Korea examined the relationship between hyperuricemia with renal progression measured by annualized eGFR decline. Again elevated serum uric acid levels were associated with eGFR decline and TKV at baseline, but this relationship was not independent of age, sex, blood pressure, and initial eGFR level. Of 53 patients treated with uric acid lowering therapy, the annual eGFR decline seemed to be slowed after the treatment was given (−5.3 versus 0.2 ml/min/1.73 m2 per year, P = 0.001) . The correction of hyperuricemia may be an additional clinical target in the management of patients with ADPKD, however, this requires validation in a proper clinical trial.
Other urine biomarkers have also been explored in a subgroup of 107 patients from the CRISP study. Urinary neutrophil gelatinase-associated lipocalin (NGAL) and interleukin-18 were both elevated in those with ADPKD, however, they did not track with changes in TKV or kidney function. Whether alternate urine biomarkers may provide more prognostic information, or whether the lack of communication between expanding cysts and the urinary collecting system prevents the monitoring of disease activity by the urine, remains to be established .
Proteomic studies may also be promising in risk stratification. A study examining the urine proteome identified 657 peptides with altered excretion, of which some reflected markers of acute kidney injury [24▪]. This proteomic data were added to a disease severity score and was validated in predicting height-adjusted TKV. Another study examined microRNA (miRNA), which are small regulatory noncoding RNAs, in urine and patient-derived primary cell cultures from ADPKD patients [25▪]. When compared with those with other causes of CKD, ADPKD patients showed dysregulated miRNA that was associated with kidney tumor suppressors [mir-1(4) and mir-133b(2)] and inflammatory and fibroblast origins. This technique, if validated in prospective studies, may offer yet another biomarker that may help with the monitoring of disease progression or response to treatment. It also remains to be seen how urinary biomarkers will add to other risk measures, such as genetics or TKV assessment.
DETERMINING THE RISK OF PROGRESSION
A composite risk measure including several of the measures discussed in this article will likely yield a more accurate description of a patient's true risk. As an example, a study of 1215 patients found that a diagnosis of ADPKD before the age of 30, gross hematuria before the age of 30, onset of hypertension before age 35, and male sex were all associated with worse renal survival .
The Genkyst registry proposed a risk score for helping identify high-risk patients for clinical trials of targeted therapies. Their PRO-PKD score assigned 1 point each for early onset hypertension and first urologic complication (before age 35), and either 1 point for a PKD1 nontruncating mutation or 2 points for a PKD1 truncating mutation. This score was associated with renal survival, with a score of 1 having a nonsignificant HR of 1.6 and a score of 4 points having a HR of 15.7 (P < 0.001) . For a PRO-PKD score of 0–4 points, the median ages at ESRD were 77.8, 72.4, 57.7, 53.9, and 47.2 years, and the relatives HR for ESRD were 1 = 1.7, 2 = 4.9, 3 = 9.3, and 4 = 22.5, respectively. Other cohorts, such as the European EuroCYST initiative, are being assembled to further the understanding of the natural history and complications associated with the disease [28,29].
INTERVENTIONS TO DELAY RENAL PROGRESSION IN AUTOSOMAL DOMINANT POLYCYSTIC KIDNEY DISEASE – BLOOD PRESSURE MANAGEMENT
Hypertension is highly prevalent in those with ADPKD, and often predates any decline in GFR . Recent trial data have provided valuable input on how the management of those with ADPKD may differ from the conventional CKD patient. The Halt Progression of Polycystic Kidney Disease (HALT-PKD) study was a double-blind, placebo-controlled, and randomized clinical trial that examined both standard (120/70–130/80 mmHg) or low blood pressure (95/60–110/75 mmHg) targets in those with a GFR greater than 60 ml/min [31▪▪]. The study also studied the benefit of an angiotensin-converting-enzyme inhibitor with or without an angiotensin-receptor-blocker to achieve the desired blood pressure in both those with a GFR above 60 ml/min/1.73 m2 and those between 25 and 60 ml/min/1.73 m2[32▪▪]. The study concluded that there was no additional benefit to dual angiotensin blockade in either GFR group, but those treated to the more rigorous blood pressure target experienced a slower increase in TKV, a greater decline in left ventricular mass index, and reduced urinary albumin excretion. There was also no change in GFR in the ‘early’ disease population. It should be noted that increased left ventricular mass index at baseline was low (4%) in this study population, likely accounted for by earlier detection and treatment of hypertension, more rigorous blood pressure control, and an increased use of renin–angiotensin–aldosterone system antagonists before study entry .
Somatostatin receptors also exist in the kidney and may play an inhibitory role on cell proliferation and chloride secretion in ADPKD. The Effect of Longacting Somatostatin Analogue on Kidney and Cyst Growth in Autosomal Dominant Polycystic Kidney Disease (ALADIN) trial randomized ADPKD patients with a GFR greater than 40 ml/min/1.73 m2 to receive either octreotide-long acting release (LAR) (n = 38) or placebo (n = 37) [34▪]. The study involved patients with a baseline TKV of 1527 ml in the octreotide-LAR group and 2161 ml in the placebo group. The mean TKV increased less significantly in the octreotide-LAR group at 1 year, but this difference was not significant at the end of the 3 years. A larger randomized clinical trial to examine the renoprotective effect of somatostatin anologues in ADPKD is warranted.
The rationale to block the cAMP pathway using a selective vasopressin-2 receptor antagonist, tolvaptan, was tested in the Tolvaptan Efficacy and Safety in Management of Autosomal Dominant Polycystic Kidney Disease and its Outcomes (TEMPO) 3:4 trial . The study showed that in a population with enlarged TKV but preserved kidney function, the rate of TKV growth could be slowed (2.8% per year increase compared with 5.5%), and the rate of kidney function decline was slowed. There was also a higher discontinuation rate with the study drug because of the aquaretic effect and important hepatic enzyme elevations. The benefit of tolvaptan for ADPKD will depend on the balance of the expected benefit with the risk of possible adverse events.
Currently, there are no treatments that have been proven to postpone the onset of ESRD or improve mortality in patients with ADPKD. Much of our knowledge about the progression of ADPKD is based on retrospective and cross-sectional studies, but established ADPKD cohorts and registries continue to yield valuable data.
Even in the presence of effective therapy to slow disease progression, the data to show a long-term benefit in hard outcomes, such as ESRD or death, will not likely be available for decades. Instead we must rely on alternate measures of risk assessment. These may include such things as molecular genetics, clinical data such as blood pressure and family history of ESRD  kidney volume measures, novel biomarkers in the urine or blood, or likely some combination of the above. As new therapies move from clinical trials to enter the realm of clinical care, understanding those at risk of progression of ADPKD will help identify the patients that may benefit from treatment and at the right time.
Financial support and sponsorship
Conflicts of interest
A.A. has been involved as a consultant to Otsuka Canada, and has participated in the Otsuka-sponsored TEMPO 3:4 trial and other clinical trials involving patients with ADPKD.
REFERENCES AND RECOMMENDED READING
Papers of particular interest, published within the annual period of review, have been highlighted as:
- ▪ of special interest
- ▪▪ of outstanding interest
1. Hateboer N, v Dijk MA, Bogdanova N, et al. Comparison of phenotypes of polycystic kidney disease types 1 and 2. European PKD1-PKD2 Study Group. Lancet 1999; 353:103–107.
2. Grantham JJ, Chapman AB, Torres VE. Volume progression in autosomal dominant polycystic kidney disease
: the major factor determining clinical outcomes. Clin J Am Soc Nephrol 2006; 1:148–157.
3▪. Miskulin DC, Abebe KZ, Chapman AB, et al. Health-related quality of life in patients with autosomal dominant polycystic kidney disease
and CKD stages 1–4: a cross-sectional study. Am J Kidney Dis 2014; 63:214–226.
A study examining health-related quality of life using SF-36 and Wisconsin Brief Pain Survey with eGFR and height-adjusted TKV in 1046 patients from the HALT-PKD study cohort.
4▪▪. Cornec-Le Gall E, Audrezet MP, Chen JM, et al. Type of PKD1 mutation influences renal outcome in ADPKD. J Am Soc Nephrol 2013; 24:1006–1013.
This study from the Genkyst cohort validates that PKD mutation type is a predictor of age of ESRD onset, with a PKD1 truncating mutation resulting in a more severe phenotype than a PKD1 nontruncating mutation.
5. Rossetti S, Kubly VJ, Consugar MB, et al. Incompletely penetrant PKD1 alleles suggest a role for gene dosage in cyst initiation in polycystic kidney disease. Kidney Int 2009; 75:848–855.
6. Chapman A, Guay-Woodford L, Grantham J, et al. Renal structure in early autosomal-dominant polycystic kidney disease (ADPKD): The Consortium for Radiologic Imaging Studies of Polycystic Kidney Disease (CRISP) cohort. Kidney Int 2003; 64:1035–1045.
7. Grantham J, Torres V, Chapman A, et al. Volume progression in polycystic kidney disease. N Engl J Med 2006; 354:2122–2130.
8. Chapman AB, Bost JE, Torres VE, et al. Kidney volume and functional outcomes in autosomal dominant polycystic kidney disease
. Clin J Am Soc Nephrol 2012; 7:479–486.
9. Bae KT, Tao C, Wang J, et al. Novel approach to estimate kidney and cyst volumes using mid-slice magnetic resonance images in polycystic kidney disease. Am J Nephrol 2013; 38:333–341.
10. Bae KT, Sun H, Lee JG, et al. Novel methodology to evaluate renal cysts in polycystic kidney disease. Am J Nephrol 2014; 39:210–217.
11▪▪. Irazabal MV, Rangel LJ, Bergstralh EJ, et al. Imaging classification of autosomal dominant polycystic kidney disease
: a simple model for selecting patients for clinical trials. J Am Soc Nephrol 2015; 26:160–172.
This study developed a prediction tool using height-adjusted TKV and patient age to predict eGFR decline. The equation was validated in the CRISP study cohort and may be helpful in risk stratifying patients for enrolment into clinical trials.
12. Torres VE, Grantham JJ, Chapman AB, et al. Potentially modifiable factors affecting the progression of autosomal dominant polycystic kidney disease
. Clin J Am Soc Nephrol 2011; 6:640–647.
13. Barash I, Ponda MP, Goldfarb DS, Skolnik EY. A pilot clinical study to evaluate changes in urine osmolality and urine cAMP in response to acute and chronic water loading in autosomal dominant polycystic kidney disease
. Clin J Am Soc Nephrol 2010; 5:693–697.
14. Zittema D, Boertien WE, van Beek AP, et al. Vasopressin
, copeptin, and renal concentrating capacity in patients with autosomal dominant polycystic kidney disease
without renal impairment. Clin J Am Soc Nephrol 2012; 7:906–913.
15. Fenske W, Wanner C. Copeptin: a marker for ADPKD progression? Nephrol Dial Transplant 2012; 27:3985–3987.
16. Boertien WE, Meijer E, Zittema D, et al. Copeptin, a surrogate marker for vasopressin
, is associated with kidney function decline in subjects with autosomal dominant polycystic kidney disease
. Nephrol Dial Transplant 2012; 27:4131–4137.
17. Zittema D, van den Berg E, Meijer E, et al. Kidney function and plasma copeptin levels in healthy kidney donors and autosomal dominant polycystic kidney disease
patients. Clin J Am Soc Nephrol 2014; 9:1553–1562.
18. Meijer E, Bakker SJ, van der Jagt EJ, et al. Copeptin, a surrogate marker of vasopressin
, is associated with disease severity in autosomal dominant polycystic kidney disease
. Clin J Am Soc Nephrol 2011; 6:361–368.
19. Boertien WE, Meijer E, Li J, et al. Relationship of copeptin, a surrogate marker for arginine vasopressin
, with change in total kidney volume
and GFR decline in autosomal dominant polycystic kidney disease
: results from the CRISP cohort. Am J Kidney Dis 2013; 61:420–429.
20. Higashihara E, Nutahara K, Tanbo M, et al. Does increased water intake prevent disease progression in autosomal dominant polycystic kidney disease
? Nephrol Dial Transplant 2014; 29:1710–1719.
21. Helal I, McFann K, Reed B, et al. Serum uric acid, kidney volume and progression in autosomal-dominant polycystic kidney disease. Nephrol Dial Transplant 2013; 28:380–385.
22. Han M, Park HC, Kim H, et al. Hyperuricemia and deterioration of renal function in autosomal dominant polycystic kidney disease
. BMC Nephrol 2014; 15:63.
23. Parikh CR, Dahl NK, Chapman AB, et al. Evaluation of urine biomarkers of kidney injury in polycystic kidney disease. Kidney Int 2012; 81:784–790.
24▪. Kistler AD, Serra AL, Siwy J, et al. Urinary proteomic biomarkers for diagnosis and risk stratification of autosomal dominant polycystic kidney disease
: a multicentric study. PloS One 2013; 8:e53016.
This study described and validated a novel proteomic severity score that could predict height-adjusted TKV.
25▪. Ben-Dov IZ, Tan YC, Morozov P, et al. Urine microRNA as potential biomarkers of autosomal dominant polycystic kidney disease
progression: description of miRNA profiles at baseline. PloS One 2014; 9:e86856.
miRNA-related to kidney tumor suppressors, as well as putative inflammatory and fibrogenic pathways, were shown to be dysregulated in urine specimens in patients with ADPKD.
26. Johnson A, Gabow P. Identification of patients with ADPKD at highest risk for ESRD. J Am Soc Nephrol 1997; 8:1560–1567.
27. Cornec-Le Gall E, Hourmant M, Morin MP, et al. The PRO-PKD score, a new algorithm to predict renal outcome in autosomal dominant polycystic kidney disease
(ADPKD). In: Abstracts of the 51st ERA-EDTA Congress; 31 May–3 June, 2014; Amsterdam, The Netherlands. Nephrol Dial Transplant 2014; 29:iii5–iii6.
28. Petzold K, Gansevoort RT, Ong AC, et al. Building a network of ADPKD reference centres across Europe: the EuroCYST initiative. Nephrol Dial Transplant 2014; 29 (Suppl 4):iv26–iv32.
29. Oh KH, Park SK, Park HC, et al. KNOW-CKD (KoreaN cohort study for Outcome in patients With Chronic Kidney Disease): design and methods. BMC Nephrol 2014; 15:80.
30. Cadnapaphornchai MA, McFann K, Strain JD, et al. Increased left ventricular mass in children with autosomal dominant polycystic kidney disease
and borderline hypertension. Kidney Int 2008; 74:1192–1196.
31▪▪. Schrier RW, Abebe KZ, Perrone RD, et al. Blood pressure in early autosomal dominant polycystic kidney disease
. N Engl J Med 2014; 371:2255–2266.
This double-blind, placebo-controlled randomized controlled trial (RCT) of 558 hypertensive ADPKD patients with a GFR greater than 60 ml/min/1.73 m2 showed that combination angiotensin blockade with lisinopril and telmisartan did not alter the rate of TKV increase as compared with lisinopril alone. However, a low blood pressure target (95/60 to 110/75) was associated with a slower increase in TKV, a greater decline in left ventricular mass index and urinary albumin excretion as compared with standard blood pressure control.
32▪▪. Torres VE, Abebe KZ, Chapman AB, et al. Angiotensin blockade in late autosomal dominant polycystic kidney disease
. N Engl J Med 2014; 371:2267–2276.
This double-blind, placebo-controlled RCT of 486 patients with ADPKD with a GFR 25–60 ml/min/1.73 m2 found no benefit to the addition of an angiotensin II-receptor blocker (telmistartan) to an angiotensin-converting-enzyme inhibitor (lisinopril) in reducing eGFR decline.
33. Alam A, Perrone RD. Left ventricular hypertrophy in ADPKD: changing demographics. Curr Hypertens Rev 2013; 9:27–31.
34▪. Caroli A, Perico N, Perna A, et al. Effect of longacting somatostatin analogue on kidney and cyst growth in autosomal dominant polycystic kidney disease
(ALADIN): a randomised, placebo-controlled, multicentre trial. Lancet 2013; 382:1485–1495.
Although small, this single-blind, placebo-controlled RCT suggests a renoprotective benefit of somatostatin anologues in slowing the increase of TKV in patients with ADPKD.
35. Torres VE, Chapman AB, Devuyst O, et al. Tolvaptan in patients with autosomal dominant polycystic kidney disease
. N Engl J Med 2012; 367:2407–2418.
36. Barua M, Cil O, Paterson AD, et al. Family history of renal disease severity predicts the mutated gene in ADPKD. J Am Soc Nephrol 2009; 20:1833–1838.