Abstract

Autosomal dominant polycystic kidney disease (ADPKD) is the most frequent inherited kidney disease. It is characterized by the growth of renal cysts that lead to enlarged kidneys and end-stage renal disease. Polycystic kidney disease 1 (PKD1) and PKD2 have been identified as genes associated with ADPKD and their significance in the molecular pathology of polycystic kidney disease has been investigated. A drug to ameliorate the disease has been approved; therefore, it becomes important to identify patients at high risk of renal disease progression. Genetic tests, image analysis methods, and clinical factors have been established for predicting renal disease progression. This review describes genetic and clinical features and discusses ongoing studies in Korean patients with ADPKD.

Introduction

Autosomal dominant polycystic kidney disease (ADPKD) is the most common progressive disease of the kidney and is characterized by the development of large fluid-filled renal cysts. These cysts compress and destroy the surrounding renal tissue, leading to progressive loss of function by age 5 - 60 years, with approximately 50% of patients progressing to end-stage renal disease (ESKD) by age 70 years. The main feature of ADPKD is renal cysts, but other organs are also involved, manifesting as liver and pancreatic cysts, cerebral aneurysms, heart valve abnormalities, and colonic diverticular. Furthermore, although ADPKD shows a typical family pedigree of autosomal dominant disease, a high degree of phenotypic variability exists even among family members carrying the same mutation. This article will focus on recent advances in the diagnosis and treatment of ADPKD. This paper describes the genetic and clinical characteristics of Korean patients with ADPKD and discusses the ongoing studies in these patients.

Keywords: Autosomal dominant polycystic kidney disease; PKD1; PKD2; Disease progression; Tolvaptan;Cistanche benefits

Click here to buy Cistanche extract

Epidemiology

ADPKD occurs worldwide in all ethnic groups. It is difficult to estimate the exact prevalence of ADPKD because the rate of disease progression varies from patient to patient, as does the severity. Dalgaard estimated the prevalence of ADPKD at birth to be 1 / 400 to 1000. Suwabe et al. reported that from 1980 to 2016, the age- and sex-adjusted annual prevalence of confirmed and suspected ADPKD was 3.06 per 100,000 person-years, and the point prevalence of confirmed or suspected ADPKD in Olmsted County, Minnesota, USA, was 68/100,000 on January 1, 2010. However, in 19 EU countries, the lowest prevalence estimate of ADPKD using renal replacement registry data and published population-based prevalence was 3.29/10,000. in Korea, although there is no national prevalence survey of ADPKD, the disease prevalence is indirectly reflected by the single public health insurance system. According to the data from the Healthcare Grand Data Center, the number of patients with ADPKD in Korea is estimated to be 5,320 in 2019 according to the International Classification of Diseases, 10th Revision (ICD-10) code Q61.2 (polycystic kidney, autosomal dominant).In 2019, the population of Korea is about 51 million, so the prevalence of patients with ADPKD is estimated to be about 1 in 10,000. Kalatharan et al. reported that the sensitivity of the ICD-10 coding algorithm to identify ADPKD was 33.7% and the specificity was 86.2%. This suggests that ICD-10 coding may have overlooked a large number of patients with ADPKD.

Although the prevalence of ADPKD in the general population can only be estimated by indirect methods, more detailed information on the proportion of patients with ADPKD in ESKD can be obtained from several registries.ADPKD accounts for 10% of patients with ESKD. According to the European Renal Association-European Dialysis and Transplantation Association (ERA-EDTA) Renal Replacement Therapy (RRT) Registry, the prevalence of RRT caused by ADPKD was 91.1 / 1 million population and the percentage of ADPKD among prevalent RRT patients was 9.8%. Data from the ESRD Registry Committee of the Korean Society of Nephrology showed that patients with cystic kidney disease accounted for 1.6% in 2018.

Cistanche supplement

Etiology and pathogenesis

Two genetic mutations, polycystic kidney disease 1 (PKD1; chromosome 16p13.3) and PKD2 (chromosome 4q21) account for 85% and 15% of cases, sequentially, respectively. Recently, mutations in two additional genes, GANAB and DNAJB11, have been identified in the mild polycystic kidney disease and variant polycystic liver disease (PLD) families.

PKD1 and PKD2 produce polycystin-1 (PC1) and polycystin-2 (PC2), respectively.PC1 is an integral membrane protein with 11 transmembrane structural domains, a short cytoplasmic tail, and a large extracellular region involved in protein-protein interactions or protein-carbohydrate interactions. the c-terminal tail of PC1 interacts with the corresponding region of PC2 to form a PC1-PC2 complex assembled in a 1:3 ratio. pc2 is a calcium-permeable six-transmembrane protein that regulates intracellular Ca2+ concentration. the PC1-PC2 complex localizes to the axis and base of primary cilia and regulates, in response to mechanical stimulation, the ADPKD is thought to be caused by alterations in cilia function, Wnt signaling, intracellular calcium homeostasis, 3 ' -5 ' -cyclic adenosine monophosphate (cAMP) levels, Ras/ mitogen-activated protein kinase signaling, and the ability to concentrate due to PKD1 or PKD2 mutations. These abnormalities produce dedifferentiation, excessive fluid secretion, and hyperplasia, leading to cyst development.

Clinical presentation and complications

Renal manifestations

The main structural change in ADPKD is that both kidneys are enlarged and filled with cysts. The size of the renal cysts varies from a few millimeters to tens of centimeters, and the size of the kidneys varies from patient to patient. Most patients with ADPKD have hypertension prior to the decline in renal function, and 35% of children and more than 80% of patients with ESKD have hypertension. Renal function decline is the most serious renal complication, with ESKD occurring in approximately 50% of patients at age 70 years. several risk factors for renal function decline have been suggested and will be discussed later. About 60% of patients have back, flank, or abdominal pain associated with cyst enlargement. Complications such as cyst bleeding, cyst infection, or urinary tract stones can cause severe pain. chibi and Torres reported that 20% ~ 35% of patients had urinary tract stones, up to 60% had cyst bleeding/crude hematuria and 30% ~ 50% had urinary tract infections.

Herbal Cistanche

Analysis of initial symptoms and comorbidities in 364 Korean patients in the ADPKD subcohort of the Chronic Kidney Disease patients Outcomes Cohort Study (KN - CKD) showed that 87.6% of patients had hypertension, 23.4% had hyper uric acid blood, 29.1% of patients had urinary stones, and 55.9% of patients had hemorrhagic cysts. However, the prevalence of pain (12.9% of patients), hematuria (4.9% of patients), urinary tract infection (2.2% of patients), and renal cyst infection (4.1% of patients) was low. lee et al. analyzed the clinical characteristics of 166 Korean patients with ADPKD, including 29 patients with ESKD. They reported that 65% of patients had hypertension, 50% had abdominal or tummy pain, 29% had palpable masses, 42% had proteinuria, and 18% had hematuria. 55 patients had CT scans, 29% had cystic bleeding, 27% had urinary stones, 15% had cystic infection, and 14% had pyelonephritis. Hwang et al. reported the clinical characteristics of 34 Korean patients with ADPKD who reached ESKD. Among these patients, 85% had hypertension, 69% had severe hematuria, 16% had urinary stones, and 29% had upper urinary tract infections (Table 1).

Extra-renal manifestation

Hepatic cysts are the most common extra-renal manifestation. It occurs in approximately 80% of patients with ADPKD aged 35 years or older. Severe hepatic cysts are most commonly seen in women and are associated with exogenous estrogen use and multiple pregnancies, but the exact mechanism of hepatic cyst enlargement is not known. However, after 48 years of age, 58% of female patients with severe PLD showed regression in height-regulated total liver volume (htTLV), while male patients showed a sustained increase in htTLV.

The prevalence of intracranial aneurysms (ICAN) is approximately 9% ~ 12%, which is 4 times higher than the general population. The prevalence of ICAN was higher in patients with a positive family history of hemorrhagic stroke or ICAN (21.6%) than in those with a negative family history of hemorrhagic stroke or ICAN (11.0%; relative risk, 1.968).

Other common extrarenal manifestations of ADPKD include cysts in other organs (e.g., pancreas, seminal vesicles, and ovaries), valve disease, arterial aneurysms, and colonic diverticula. the ADPKD subcohort of KD - CKD showed that 77.5% of patients had liver cysts, 12.3% had unruptured ICAN, 1.4% had intracranial hemorrhage, and 1.4% had subarachnoid hemorrhage. lee et al. et al. reported that 58% of 166 patients had liver cysts, 15% had heart valve insufficiency, and 8.4% had a cerebral hemorrhage or infarction. Hwang et al. reported that of 34 patients who reached ESKD, 85% had liver cysts and 16% had a stroke (Table 1). ADPKD can present with a variety of renal and extrarenal manifestations, and the incidence of these manifestations is variable. The clinical presentation of Korean patients with ADPKD does not differ from the pattern previously reported in other countries.

Cistanche tubulosa

REFERENCES

1. Chapman AB, Devuyst O, Eckardt KU, et al. Autosomal-dominant polycystic kidney disease (ADPKD): executive summary from a Kidney Disease: Improving Global Outcomes (KDIGO) Controversies Conference. Kidney Int 2015;88:17-27.

2. Churchill DN, Bear JC, Morgan J, Payne RH, McMana-mon PJ, Gault MH. Prognosis of adult onset polycystic kidney disease re-evaluated. Kidney Int 1984;26:190-193.

3. Chapman AB. Approaches to testing new treatments in autosomal dominant polycystic kidney disease: insights from the CRISP and HALT-PKD studies. Clin J Am Soc Nephrol 2008;3:1197-1204.

4. Gabow PA. Autosomal dominant polycystic kidney disease. N Engl J Med 1993;329:332-342.

5. Dalgaard OZ. Bilateral polycystic disease of the kidneys; a follow-up of two hundred and eighty-four patients and their families. Acta Med Scand Suppl 1957;328:1-255.

6. Suwabe T, Shukoor S, Chamberlain AM, et al. Epidemiology of autosomal dominant polycystic kidney disease in Olmsted county. Clin J Am Soc Nephrol 2020;15:69-79.

7. Willey CJ, Blais JD, Hall AK, Krasa HB, Makin AJ, Czerwiec FS. Prevalence of autosomal dominant polycystic kidney disease in the European Union. Nephrol Dial Transplant 2017;32:1356-1363.

8. Healthcare Bigdata Hub. Frequent disease statistics of outpatients in 2019 [Internet]. Wonju (KR): Health Insurance Review & Assessment Service, 2019 [cited 2021 Jun 17].

9. Kalatharan V, McArthur E, Nash DM, et al. Diagnostic accuracy of administrative codes for autosomal dominant polycystic kidney disease in clinic patients with cystic kidney disease. Clin Kidney J 2020;14:612-616.

10. Spithoven EM, Kramer A, Meijer E, et al. Renal replacement therapy for autosomal dominant polycystic kidney disease (ADPKD) in Europe: prevalence and survival: an analysis of data from the ERA-EDTA Registry. Nephrol Dial Transplant 2014;29 Suppl 4:iv15-25.

11. ESRD Registry Committee. Current renal replacement therapy in Korea: Insan Memorial Dialysis Registry, 2018 [Internet]. Seoul (KR): ESRD Registry Committee, 2019 [cited 2021 Jun 17].

12. Harris PC, Torres VE. Polycystic kidney disease. Annu Rev Med 2009;60:321-337.

13. Porath B, Gainullin VG, Cornec-Le Gall E, et al. Mutations in GANAB, encoding the glucosidase iiα subunit, cause autosomal-dominant polycystic kidney and liver disease. Am J Hum Genet 2016;98:1193-1207.

14. Cornec-Le Gall E, Olson RJ, Besse W, et al. Monoallelic mutations to DNAJB11 cause atypical autosomal-dominant polycystic kidney disease. Am J Hum Genet 2018;102:832-844.

15. Sandford R, Sgotto B, Aparicio S, et al. Comparative analysis of the polycystic kidney disease 1 (PKD1) gene reveals an integral membrane glycoprotein with multiple evolutionary conserved domains. Hum Mol Genet 1997;6:1483- 1489.

16. Hughes J, Ward CJ, Peral B, et al. The polycystic kidney disease 1 (PKD1) gene encodes a novel protein with multiple cell recognition domains. Nat Genet 1995;10:151-160.

17. Su Q, Hu F, Ge X, et al. Structure of the human PKD1- PKD2 complex. Science 2018;361:eaat9819.

18. Yang Y, Ehrlich BE. Structural studies of the C-terminal tail of polycystin-2 (PC2) reveal insights into the mechanisms used for the functional regulation of PC2. J Physiol 2016;594:4141-4149.

19. Torres VE, Harris PC. Mechanisms of disease: autosomal dominant and recessive polycystic kidney diseases. Nat Clin Pract Nephrol 2006;2:40-55.

20. Massella L, Mekahli D, Paripovic D, et al. Prevalence of hypertension in children with early-stage ADPKD. Clin J Am Soc Nephrol 2018;13:874-883.

21. Chebib FT, Torres VE. Autosomal dominant polycystic kidney disease: core curriculum 2016. Am J Kidney Dis 2016;67:792-810.

22. Oh KH, Kang M, Kang E, et al. The KNOW-CKD study: what we have learned about chronic kidney diseases. Kidney Res Clin Pract 2020;39:121-135.

23. Kim H, Koh J, Park SK, et al. Baseline characteristics of the autosomal-dominant polycystic kidney disease sub-cohort of the Korean cohort study for outcomes in patients with chronic kidney disease. Nephrology (Carlton) 2019;24:422-429.

24. Lee KB, Kim H, Lee YR, et al. Clinical progression and complications of autosomal dominant polycystic kidney disease in Korea. Korean J Nephrol 1999;18:707-713.

25. Hwang YH, Ahn C, Hwang DY, et al. Clinical characteristics of end-stage renal disease in Korean autosomal dominant polycystic kidney disease. Korean J Nephrol 2001;20:212-220.

26. Hogan MC, Abebe K, Torres VE, et al. Liver involvement in early autosomal-dominant polycystic kidney disease. Clin Gastroenterol Hepatol 2015;13:155-164.

27. Chebib FT, Jung Y, Heyer CM, et al. Effect of genotype on the severity and volume progression of polycystic liver disease in autosomal dominant polycystic kidney disease. Nephrol Dial Transplant 2016;31:952-960.

28. Shrestha R, McKinley C, Russ P, et al. Postmenopausal estrogen therapy selectively stimulates hepatic enlargement in women with autosomal dominant polycystic kidney disease. Hepatology 1997;26:1282-1286.

29. Irazabal MV, Huston J 3rd, Kubly V, et al. Extended follow-up of unruptured intracranial aneurysms detected by presymptomatic screening in patients with autosomal dominant polycystic kidney disease. Clin J Am Soc Nephrol 2011;6:1274-1285.

30. Xu HW, Yu SQ, Mei CL, Li MH. Screening for intracranial aneurysm in 355 patients with autosomal-dominant polycystic kidney disease. Stroke 2011;42:204-206.