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Autosomal dominant polycystic kidney disease (ADPKD) is characterised by the formation and growth of multiple cysts within the kidney that distort and destroy the kidney structure and function. Hypertension occurs ubiquitously as the disease progresses, and macroscopic haematuria, flank pain, rupture of cysts, cyst infection and kidney stones are all common. Some, but not all, patients will progress to end stage kidney disease (ESKD). Extra-renal disease can also occur with cysts in other organs, cerebral aneurysms, aortic root dilatation and cardiac valvular abnormalities.

The most common cause of inherited kidney disease

ADPKD is the fifth most common cause of ESKD (Figure 1) and accounts for 7.3% of patients on renal replacement therapy (dialysis and transplant) in Aotearoa New Zealand.[[1]] This figure is consistent with reports from overseas where ADPKD accounts for 5–10% of patient with ESKD.[[6]] The number of patients with polycystic kidney disease (PCKD) who do not start renal replacement therapy is uncertain. ADPKD affects all races; however, ethnic differences in incidence and outcome in Aotearoa New Zealand are uncertain. The prevalence is generally reported as 1:400–1:1000 from early landmark studies from Denmark[[7]] and the USA.[[8]]

Figure 1: Primary renal disease of patients starting dialysis in Aotearoa New Zealand.

(Adapted from ANZDATA).[[1]]

PCKD1 and PCKD2 encode the integral membrane protein polycystin-1 and polycystin-2 respectively, which interact via signalling pathways in primary cilia, and account for the majority of cases.[[9]] Ten to fifteen percent of patients will have no mutation in these genes due to mutations in additional rare cystic disease genes or somatic mosaicism, the presence of two genetically distinct cell populations within one individual resulting from a somatic mutation during embryogenesis. Genetic testing is available in New Zealand and is usually ordered after discussion with the Genetics Health Service NZ.

Standard therapy of ADPKD

No direct randomised controlled trials have been undertaken in this area; however, general lifestyle interventions are recommended targeted at maintaining a healthy weight, avoiding dehydration, not smoking, and limiting dietary sodium to 100mmol/day and protein intake to 0.75–1gm/kg/day.[[10,11]]

Early detection and aggressive treatment of hypertension is vital. Use of agents to block the renin angiotensin system are safe and effective; however, individualised therapy based on co-morbidities and stage of chronic kidney disease is appropriate.[[10]]

Research in the last decade

Individuals with the PCKD1 gene tend to have a more severe phenotype, and make up the majority of ADPKD patients who progress to ESKD in middle age. Nevertheless, disease progression can vary considerably, even within families.[[12]] It is now well established that renal outcome in the individual patient, is a function of current kidney size (height-adjusted total kidney volume), kidney function, and age. The Mayo ADPKD calculator incorporates these parameters to predict renal outcomes over a period of 5–40 years.[[13]] Expensive and potentially hazardous therapies need to be targeted at those who are most likely to benefit from them, and the Mayo calculator is an effective tool for the clinician assessing possible benefit of new therapies in an ADPKD patient.

There has been very active research in pharmacological treatment of ADPKD with therapies including statins,[[14,15]] mTor inhibitors,[[16,17]] and somatostatin analogues.[[18]] Various agents are being trialled including: metformin, pioglitazone, tyrosine kinase inhibitors, oral glucosyl-ceramide synthase inhibitors, and non-peptide vasopressin 2 receptor antagonists.[[19]]

Tolvaptan, a new hope for PCKD

Tolvaptan is a vasopressin 2 receptor antagonist that acts on collecting ducts to ameliorate the effect of cyclic AMP, which would otherwise stimulate the secretion of fluid.[[20]] Clinically, this causes a picture of polyuria due to loss of free water. The TEMPO 3:4 trial showed tolvaptan slowed decline in renal function and reduced kidney growth in patients with well-preserved renal function (estimated glomerular filtration rate (eGFR) >60m/min/1.73m[[2]]).[[21]] The REPRISE trial also demonstrated tolvaptan preserved renal function in patients with more advanced renal impairment (eGFR 25–65ml/min/1.73m[[2]]).[[22]]

However, tolvaptan is not without side-effects and not all patients with ADPKD will progress to ESKD. Key side effects include thirst, polyuria and nocturia, as would be expected with its aquaretic profile. Idiosyncratic hepatic dysfunction also occurs, and liver function must be closely monitored in patients. In addition, the long-term effects of tolvaptan are uncertain, with follow up out to five years suggesting benefit.[[23]] Nevertheless, tolvaptan is the first medication licensed to use as directed therapy for PCKD and is now available in a number of counties (Table 1).

The various current guidelines for tolvaptan use in ADPKD target patients with substantial current kidney enlargement, and (in individuals > 45 years) historical evidence of significant previous kidney function decline over time.[[10,19,26]] The studies have shown useful delay in progression to, but not prevention of eventual ESKD.[[21–24]] It is possible that in the future, new protocols may be devised targeting at an earlier stage in their natural history and achieving the “holy grail”, of long-term normal kidney function.[[27]]

In December 2016, a clinician application for tolvaptan for ADPKD was made to Te Pātaka Whaioranga, The Pharmaceutical Management Agency (PHARMAC), with the Nephrology subcommittee recommending that tolvaptan for patients with be listed on the pharmaceutical schedule with a high priority if a registered product becomes available. Tolvaptan has been Medsafe registered in Aotearoa New Zealand since May 2019, and was recommended for use in selected patients with ADPKD subject to special authority criteria in August 2019 (Figure 2).[[28]]

View Table 1 & Figure 2.

Despite these clinician and committee recommendations, subsidised access to Tolvaptan has not occurred. The Samsca brand can currently be brought in (15mg or 30mg tablets) which cost $2680 per pack of 10—not including GST or mark up. Tolvaptan is typically started at twice daily doses of 45mg and 15mg and increased to a tolerated maximum dose of 90mg and 30mg. Approximately 55–60.6% of patients are usually able to tolerate the maximal dose.[[21,22]] Thus, the minimum cost for a starting dose of tolvapatan is over $35,000 per annum. The alternative is for dialysis (~$70,000 per year) or kidney transplantation (~$100,000 initially and then ~$13,000 per year).The Te Pātaka Whaioranga Nephrology subcommittee noted in their review that the cost of dialysis, which would be postponed rather than not required, would generally be balanced against the cost of treatment with tolvaptan.[[28]] The National Institute for Health and Care Excellence (NICE) and Australian Pharmaceutical Benefits Scheme (PBS ) concluded the cost-effectiveness of tolvaptan in patients with stage 2–3 chronic kidney disease with rapid disease progression based on their cost effectiveness analysis, and this aligns with the proposed special authority guidelines proposed.[[29,30]]

The patient’s voice

As one of five whānau members spanning over four generations in two countries with confirmed ADPKD, the impact and burden of the disease has been and continues to be significant. The disease burden on my whānau has included early death, increased morbidity and whānau suffering.

The disease burden of ADPKD is reflected in the health system through increased hospital admissions, costly dialysis and transplant. The financial impact is considerable.

Funding tolvaptan would greatly diminish the impact and burden of ADPKD on individuals in Aotearoa New Zealand, their whānau and the health system. The hope of not needing dialysis and/or transplant for those individuals who are eligible for this therapy would be life changing.

Conclusion

ADPKD disease is a common cause of kidney failure. Selected therapy is available to slow the progression of this disease. The authors call upon Te Pātaka Whaioranga to urgently complete negotiations to support funding for tolvaptan in selected patients.

Summary

Abstract

Autosomal dominant polycystic kidney disease (ADPKD) is the fifth most common cause of end stage kidney disease (ESKD) in Aotearoa New Zealand.[[1]] Identification of two genes, PCKD1 and PCKD2, which cause the majority of this disease, has played a key role in the development of DNA-sequence molecular diagnostics.[[2,3]] ADPKD is characterised by the formation and growth of multiple cysts within the kidney, with some but not all patients progressing to ESKD. The diagnosis of ADPKD is based on the presence of family history, and radiological imaging although increasingly genetic testing is being used for screening and diagnosis.[[4]]

Once diagnosed, standard management of ADPKD includes laboratory monitoring of chronic kidney disease (CKD) parameters, lowering of blood pressure, and a high fluid intake. Over the last decade much research has been undertaken for targeted therapies for ADPKD; however, despite funding of these medications overseas since May 2015, and applications to Te Pātaka Whaioranga, The Pharmaceutical Management Agency (PHARMAC), these therapies remain unavailable to New Zealanders resulting in an increased burden of disease to individuals and the whānau and financial cost to the health system.[[5]]

Aim

Method

Results

Conclusion

Author Information

Tracy Chan: Renal Fellow, Waitematā District Health Board, Auckland, New Zealand. Walter van der Merwe: Nephrologist and Hypertension Specialist, Level 4, 87-89 Albert Steet, Auckland New Zealand. Janak R de Zoysa: Nephrologist, Waitematā District Health Board, Auckland, New Zealand; Associate Professor of Medicine, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand.

Acknowledgements

The authors would like to thank patient, VW, who wished to remain anonymous, for their comments and contributing a section of this paper: “The patient’s voice”. The authors would also like to thank Dr Janeen Miner, General Practitioner, for her review of this manuscript and helpful comments.

Correspondence

Tracy Chan: Renal Fellow, Waitematā District Health Board, Auckland, New Zealand.

Correspondence Email

tracy.chan@waitematadhb.govt.nz

Competing Interests

Nil.

1. ANZDATA Registry. 44th Report, Chapter 1: Incidence of Renal Replacement Therapy for End Stage Kidney, Australia and New Zealand Dialysis and Transplant Registry, Adelaide, Australia. 2021. Available at: http://www.anzdata.org.au

2. Hughes J, Ward CJ, Peral B, Aspinwall R, Clark K, San Milla´n JL, GambleV, Harris PC. The polycystic kidney disease 1 (PKD1) gene encodes a novel protein with multiple cell recognition domains. Nature Genetics 1995;10:151-160.

3. Mochizuki T, Wu G, Hayashi T, Xenophontos SL, Veldhuisen B, Saris JJ, Reynolds DM, Cai Y, Gabow PA, Pierides A, Kimberling WJ, Breuning MH, Deltas CC, Peters DJ, Somlo S. PKD2, a gene for polycystic kidney disease that encodes an integral membrane protein. Science 1996;272:1339-1342.

4. Cornec-Le Gall E, Alam A, Perrone RD. Autosomal dominant polycystic kidney disease. Lancet 2019;393:919-35.

5. European Medicines Agency. Public Assessment Report Jinarc. http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_Public_assessment_report/human/002788/WC500187923.pdf. Accessed September 2021.

6. Grantham JJ. Autosomal dominant polycystic kidney disease. N Engl J Med 2008;359:1477-85.

7. 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.

8. Iglesias CG et al. Epidemiology of adult polycystic kidney disease, Olmsted County, Minnesota: 1935–1980. Am. J. Kidney Dis. 1983;2:630–639.

9. Nauli SM, Alenghat FJ, Luo Y, Williams E, Vassilev P, Li X, Elia AEH, Lu W, Brown EM, Quinn SJ, Ingber DE, Zhou J. Polycystins 1 and 2 mediate mechanosensation in the primary cilium of kidney cells. Nat Genet 2003;33:129-137.

10. Rangan GK, Alexander SI, Campbell KL, Dexter MA, Lee VW, Lopez-Vargas P, Mai J, Mallett A, Patel C, Patel M, Tchan MC, Tong A, Tunnicliffe DJ, Vladica P, Savige J. KHA-CARI guideline recommendations for the diagnosis and management of autosomal dominant polycystic kidney disease. Nephrology (Carlton) 2016;21(8):705-16.

11. Torres VE, Abebe KZ, Schrier RW, Perrone RD, Chapman AB, Yu AS, Braun WE, Steinman TI, Brosnahan G, Hogan MC, Rahbari FF, Grantham JJ, Bae KT, Moore CG, Flessner MF. Dietary salt restriction is beneficial to the management of autosomal dominant polycystic kidney disease. Kidney Int 2017;91(2):493-500.

12. Lankford MB, Guiard E, Li W et al. Intrafamilial variability of ADPKD. Kidney.Int.Rep 2019;4:995-1003

13. Irazabal MV, Rangel LJ, Bergstralh SL 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(1):160-172.

14. Cadnapaphornchai MA, George DM, McFann K, Wang W, Gitomer B, Strain JD, Schrier RW (2014) Effect of pravastatin on total kidney volume, left ventricular mass index, and microalbuminuria in pediatric autosomal dominant polycystic kidney disease. Clin J Am Soc Nephrol 9:889–896.

15. van Dijk MA, Kamper AM, van Veen S, Souverijn JH, Blauw GJ. Effect of simvastatin on renal function in autosomal dominant polycystic kidney disease. Nephrol Dial Transplant 2001;16:2152-2157.

16. He Q, Lin C, Ji S, Chen J. Efficacy and safety of mTOR inhibitor therapy in patients with early-stage autosomal dominant polycystic kidney disease: a meta-analysis of randomized controlled trials. Am J Med Sci. 2012 Dec;344(6):491-7.

17. Walz G, Budde K, Mannaa M, Nürnberger J, Wanner C, Sommerer C, Kunzendorf U, Banas B, Hörl WH, Obermüller N, Arns W, Pavenstädt H, Gaedeke J, Büchert M, May C, Gschaidmeier H, Kramer S, Eckardt KU. Everolimus in patients with autosomal dominant polycystic kidney disease. N Engl J Med. 2010 Aug 26;363(9):830-40.

18. Griffiths J, Mills MT, Ong AC. Long-acting somatostatin analogue treatments in autosomal dominant polycystic kidney disease and polycystic liver disease: a systematic review and meta-analysis. BMJ Open. 2020 Jan 9;10(1):e032620.

19. Testa F, Magistroni R (2020) ADPKD current management and ongoing trials. J Nephrol 2020;33:223-237, 2020.

20. Reif GA, Yamaguchi T, Nivens E, Fujiki H, Pinto CS, Wallace DP. Tolvaptan inhibits ERK-dependent cell proliferation, Cl− secretion, and in vitro cyst growth of human ADPKD cells stimulated by vasopressin. Am J Physiol Renal Physiol 301:F1005-F1013, 2001.

21. Torres VE, Chapman AB, Devuyst O, Gansevoort RT, Grantham JJ, Higashihara E, Perrone RD, Krasa HB, Ouyang J, Czerwiec FS; TEMPO 3:4 Trial Investigators. Tolvaptan in patients with autosomal dominant polycystic kidney disease. N Engl J Med 2012;367:2407-2418.

22. Torres VE, Chapman AB, Devuyst O, Gansevoort RT, Perrone RD, Koch G, Ouyang J, McQuade RD, Blais JD, Czerwiec FS, Sergeyeva O. Tolvaptan in Later-Stage Autosomal Dominant Polycystic Kidney Disease. N Engl J Med 2017;377:1930-–1942.

23. Torres VE, Chapman AB, Devuyst O, Gansevoort RT, Perrone RD, Dandurand A, Ouyang J, Czerwiec FS, Blais JD, TEMPO 4:4 Trial Investigators. Multicenter, open-label, extension trial to evaluate the long-term efficacy and safety of early versus delayed treatment with tolvaptan in autosomal dominant polycystic kidney disease: the TEMPO4:4 Trial.Nephrol Dial Transplant 2018;33:477-489.

24. Australian Government Therapeutic Goods Administration. Australian Public Assessment Report for Tolvaptan Feburary 2018. Accessed October 2021. https://www.tga.gov.au/sites/default/files/auspar-tolvaptan-180209.pdf

25. Murphy B. EMA recommends treatment for rare kidney condition. The Pharmaceutical Journal, PJ, 21/28 March 2015, Vol 294, No 7854/5;294(7854/5).

26. Chebib FD, Perrone RD, Chapman AB et al. A practical guide to management of rapidly progressive ADPKD with tolvaptan. J.Am.Soc.Nephrol 2018;29(10):2458–2470.

27. Liu F, Feng C, Shen H, Hualdong F, and Mao J. Tolvaptan in pediatric Autosomal Dominant Polycystic Kidney Disease: where to from here? Kidney Dis. 2021:7:343-349.

28. PTAC–minutes-2019-08. https://pharmac.govt.nz/assets/ptac-minutes-2019-08.pdf. Accessed 18th October 2021.

29. NICE Guidance. Tolvaptan for treating autosomal dominant polycystic kidney disease. Technology appraisal guidance [TA358]. Published 28th October 2015

30. Public Summary Document July 2018 Pharmaceutical Benefits Advisory Committee meeting. 7.18 Tolvatan.

For the PDF of this article,
contact nzmj@nzma.org.nz

View Article PDF

Autosomal dominant polycystic kidney disease (ADPKD) is characterised by the formation and growth of multiple cysts within the kidney that distort and destroy the kidney structure and function. Hypertension occurs ubiquitously as the disease progresses, and macroscopic haematuria, flank pain, rupture of cysts, cyst infection and kidney stones are all common. Some, but not all, patients will progress to end stage kidney disease (ESKD). Extra-renal disease can also occur with cysts in other organs, cerebral aneurysms, aortic root dilatation and cardiac valvular abnormalities.

The most common cause of inherited kidney disease

ADPKD is the fifth most common cause of ESKD (Figure 1) and accounts for 7.3% of patients on renal replacement therapy (dialysis and transplant) in Aotearoa New Zealand.[[1]] This figure is consistent with reports from overseas where ADPKD accounts for 5–10% of patient with ESKD.[[6]] The number of patients with polycystic kidney disease (PCKD) who do not start renal replacement therapy is uncertain. ADPKD affects all races; however, ethnic differences in incidence and outcome in Aotearoa New Zealand are uncertain. The prevalence is generally reported as 1:400–1:1000 from early landmark studies from Denmark[[7]] and the USA.[[8]]

Figure 1: Primary renal disease of patients starting dialysis in Aotearoa New Zealand.

(Adapted from ANZDATA).[[1]]

PCKD1 and PCKD2 encode the integral membrane protein polycystin-1 and polycystin-2 respectively, which interact via signalling pathways in primary cilia, and account for the majority of cases.[[9]] Ten to fifteen percent of patients will have no mutation in these genes due to mutations in additional rare cystic disease genes or somatic mosaicism, the presence of two genetically distinct cell populations within one individual resulting from a somatic mutation during embryogenesis. Genetic testing is available in New Zealand and is usually ordered after discussion with the Genetics Health Service NZ.

Standard therapy of ADPKD

No direct randomised controlled trials have been undertaken in this area; however, general lifestyle interventions are recommended targeted at maintaining a healthy weight, avoiding dehydration, not smoking, and limiting dietary sodium to 100mmol/day and protein intake to 0.75–1gm/kg/day.[[10,11]]

Early detection and aggressive treatment of hypertension is vital. Use of agents to block the renin angiotensin system are safe and effective; however, individualised therapy based on co-morbidities and stage of chronic kidney disease is appropriate.[[10]]

Research in the last decade

Individuals with the PCKD1 gene tend to have a more severe phenotype, and make up the majority of ADPKD patients who progress to ESKD in middle age. Nevertheless, disease progression can vary considerably, even within families.[[12]] It is now well established that renal outcome in the individual patient, is a function of current kidney size (height-adjusted total kidney volume), kidney function, and age. The Mayo ADPKD calculator incorporates these parameters to predict renal outcomes over a period of 5–40 years.[[13]] Expensive and potentially hazardous therapies need to be targeted at those who are most likely to benefit from them, and the Mayo calculator is an effective tool for the clinician assessing possible benefit of new therapies in an ADPKD patient.

There has been very active research in pharmacological treatment of ADPKD with therapies including statins,[[14,15]] mTor inhibitors,[[16,17]] and somatostatin analogues.[[18]] Various agents are being trialled including: metformin, pioglitazone, tyrosine kinase inhibitors, oral glucosyl-ceramide synthase inhibitors, and non-peptide vasopressin 2 receptor antagonists.[[19]]

Tolvaptan, a new hope for PCKD

Tolvaptan is a vasopressin 2 receptor antagonist that acts on collecting ducts to ameliorate the effect of cyclic AMP, which would otherwise stimulate the secretion of fluid.[[20]] Clinically, this causes a picture of polyuria due to loss of free water. The TEMPO 3:4 trial showed tolvaptan slowed decline in renal function and reduced kidney growth in patients with well-preserved renal function (estimated glomerular filtration rate (eGFR) >60m/min/1.73m[[2]]).[[21]] The REPRISE trial also demonstrated tolvaptan preserved renal function in patients with more advanced renal impairment (eGFR 25–65ml/min/1.73m[[2]]).[[22]]

However, tolvaptan is not without side-effects and not all patients with ADPKD will progress to ESKD. Key side effects include thirst, polyuria and nocturia, as would be expected with its aquaretic profile. Idiosyncratic hepatic dysfunction also occurs, and liver function must be closely monitored in patients. In addition, the long-term effects of tolvaptan are uncertain, with follow up out to five years suggesting benefit.[[23]] Nevertheless, tolvaptan is the first medication licensed to use as directed therapy for PCKD and is now available in a number of counties (Table 1).

The various current guidelines for tolvaptan use in ADPKD target patients with substantial current kidney enlargement, and (in individuals > 45 years) historical evidence of significant previous kidney function decline over time.[[10,19,26]] The studies have shown useful delay in progression to, but not prevention of eventual ESKD.[[21–24]] It is possible that in the future, new protocols may be devised targeting at an earlier stage in their natural history and achieving the “holy grail”, of long-term normal kidney function.[[27]]

In December 2016, a clinician application for tolvaptan for ADPKD was made to Te Pātaka Whaioranga, The Pharmaceutical Management Agency (PHARMAC), with the Nephrology subcommittee recommending that tolvaptan for patients with be listed on the pharmaceutical schedule with a high priority if a registered product becomes available. Tolvaptan has been Medsafe registered in Aotearoa New Zealand since May 2019, and was recommended for use in selected patients with ADPKD subject to special authority criteria in August 2019 (Figure 2).[[28]]

View Table 1 & Figure 2.

Despite these clinician and committee recommendations, subsidised access to Tolvaptan has not occurred. The Samsca brand can currently be brought in (15mg or 30mg tablets) which cost $2680 per pack of 10—not including GST or mark up. Tolvaptan is typically started at twice daily doses of 45mg and 15mg and increased to a tolerated maximum dose of 90mg and 30mg. Approximately 55–60.6% of patients are usually able to tolerate the maximal dose.[[21,22]] Thus, the minimum cost for a starting dose of tolvapatan is over $35,000 per annum. The alternative is for dialysis (~$70,000 per year) or kidney transplantation (~$100,000 initially and then ~$13,000 per year).The Te Pātaka Whaioranga Nephrology subcommittee noted in their review that the cost of dialysis, which would be postponed rather than not required, would generally be balanced against the cost of treatment with tolvaptan.[[28]] The National Institute for Health and Care Excellence (NICE) and Australian Pharmaceutical Benefits Scheme (PBS ) concluded the cost-effectiveness of tolvaptan in patients with stage 2–3 chronic kidney disease with rapid disease progression based on their cost effectiveness analysis, and this aligns with the proposed special authority guidelines proposed.[[29,30]]

The patient’s voice

As one of five whānau members spanning over four generations in two countries with confirmed ADPKD, the impact and burden of the disease has been and continues to be significant. The disease burden on my whānau has included early death, increased morbidity and whānau suffering.

The disease burden of ADPKD is reflected in the health system through increased hospital admissions, costly dialysis and transplant. The financial impact is considerable.

Funding tolvaptan would greatly diminish the impact and burden of ADPKD on individuals in Aotearoa New Zealand, their whānau and the health system. The hope of not needing dialysis and/or transplant for those individuals who are eligible for this therapy would be life changing.

Conclusion

ADPKD disease is a common cause of kidney failure. Selected therapy is available to slow the progression of this disease. The authors call upon Te Pātaka Whaioranga to urgently complete negotiations to support funding for tolvaptan in selected patients.

Summary

Abstract

Autosomal dominant polycystic kidney disease (ADPKD) is the fifth most common cause of end stage kidney disease (ESKD) in Aotearoa New Zealand.[[1]] Identification of two genes, PCKD1 and PCKD2, which cause the majority of this disease, has played a key role in the development of DNA-sequence molecular diagnostics.[[2,3]] ADPKD is characterised by the formation and growth of multiple cysts within the kidney, with some but not all patients progressing to ESKD. The diagnosis of ADPKD is based on the presence of family history, and radiological imaging although increasingly genetic testing is being used for screening and diagnosis.[[4]]

Once diagnosed, standard management of ADPKD includes laboratory monitoring of chronic kidney disease (CKD) parameters, lowering of blood pressure, and a high fluid intake. Over the last decade much research has been undertaken for targeted therapies for ADPKD; however, despite funding of these medications overseas since May 2015, and applications to Te Pātaka Whaioranga, The Pharmaceutical Management Agency (PHARMAC), these therapies remain unavailable to New Zealanders resulting in an increased burden of disease to individuals and the whānau and financial cost to the health system.[[5]]

Aim

Method

Results

Conclusion

Author Information

Tracy Chan: Renal Fellow, Waitematā District Health Board, Auckland, New Zealand. Walter van der Merwe: Nephrologist and Hypertension Specialist, Level 4, 87-89 Albert Steet, Auckland New Zealand. Janak R de Zoysa: Nephrologist, Waitematā District Health Board, Auckland, New Zealand; Associate Professor of Medicine, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand.

Acknowledgements

The authors would like to thank patient, VW, who wished to remain anonymous, for their comments and contributing a section of this paper: “The patient’s voice”. The authors would also like to thank Dr Janeen Miner, General Practitioner, for her review of this manuscript and helpful comments.

Correspondence

Tracy Chan: Renal Fellow, Waitematā District Health Board, Auckland, New Zealand.

Correspondence Email

tracy.chan@waitematadhb.govt.nz

Competing Interests

Nil.

1. ANZDATA Registry. 44th Report, Chapter 1: Incidence of Renal Replacement Therapy for End Stage Kidney, Australia and New Zealand Dialysis and Transplant Registry, Adelaide, Australia. 2021. Available at: http://www.anzdata.org.au

2. Hughes J, Ward CJ, Peral B, Aspinwall R, Clark K, San Milla´n JL, GambleV, Harris PC. The polycystic kidney disease 1 (PKD1) gene encodes a novel protein with multiple cell recognition domains. Nature Genetics 1995;10:151-160.

3. Mochizuki T, Wu G, Hayashi T, Xenophontos SL, Veldhuisen B, Saris JJ, Reynolds DM, Cai Y, Gabow PA, Pierides A, Kimberling WJ, Breuning MH, Deltas CC, Peters DJ, Somlo S. PKD2, a gene for polycystic kidney disease that encodes an integral membrane protein. Science 1996;272:1339-1342.

4. Cornec-Le Gall E, Alam A, Perrone RD. Autosomal dominant polycystic kidney disease. Lancet 2019;393:919-35.

5. European Medicines Agency. Public Assessment Report Jinarc. http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_Public_assessment_report/human/002788/WC500187923.pdf. Accessed September 2021.

6. Grantham JJ. Autosomal dominant polycystic kidney disease. N Engl J Med 2008;359:1477-85.

7. 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.

8. Iglesias CG et al. Epidemiology of adult polycystic kidney disease, Olmsted County, Minnesota: 1935–1980. Am. J. Kidney Dis. 1983;2:630–639.

9. Nauli SM, Alenghat FJ, Luo Y, Williams E, Vassilev P, Li X, Elia AEH, Lu W, Brown EM, Quinn SJ, Ingber DE, Zhou J. Polycystins 1 and 2 mediate mechanosensation in the primary cilium of kidney cells. Nat Genet 2003;33:129-137.

10. Rangan GK, Alexander SI, Campbell KL, Dexter MA, Lee VW, Lopez-Vargas P, Mai J, Mallett A, Patel C, Patel M, Tchan MC, Tong A, Tunnicliffe DJ, Vladica P, Savige J. KHA-CARI guideline recommendations for the diagnosis and management of autosomal dominant polycystic kidney disease. Nephrology (Carlton) 2016;21(8):705-16.

11. Torres VE, Abebe KZ, Schrier RW, Perrone RD, Chapman AB, Yu AS, Braun WE, Steinman TI, Brosnahan G, Hogan MC, Rahbari FF, Grantham JJ, Bae KT, Moore CG, Flessner MF. Dietary salt restriction is beneficial to the management of autosomal dominant polycystic kidney disease. Kidney Int 2017;91(2):493-500.

12. Lankford MB, Guiard E, Li W et al. Intrafamilial variability of ADPKD. Kidney.Int.Rep 2019;4:995-1003

13. Irazabal MV, Rangel LJ, Bergstralh SL 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(1):160-172.

14. Cadnapaphornchai MA, George DM, McFann K, Wang W, Gitomer B, Strain JD, Schrier RW (2014) Effect of pravastatin on total kidney volume, left ventricular mass index, and microalbuminuria in pediatric autosomal dominant polycystic kidney disease. Clin J Am Soc Nephrol 9:889–896.

15. van Dijk MA, Kamper AM, van Veen S, Souverijn JH, Blauw GJ. Effect of simvastatin on renal function in autosomal dominant polycystic kidney disease. Nephrol Dial Transplant 2001;16:2152-2157.

16. He Q, Lin C, Ji S, Chen J. Efficacy and safety of mTOR inhibitor therapy in patients with early-stage autosomal dominant polycystic kidney disease: a meta-analysis of randomized controlled trials. Am J Med Sci. 2012 Dec;344(6):491-7.

17. Walz G, Budde K, Mannaa M, Nürnberger J, Wanner C, Sommerer C, Kunzendorf U, Banas B, Hörl WH, Obermüller N, Arns W, Pavenstädt H, Gaedeke J, Büchert M, May C, Gschaidmeier H, Kramer S, Eckardt KU. Everolimus in patients with autosomal dominant polycystic kidney disease. N Engl J Med. 2010 Aug 26;363(9):830-40.

18. Griffiths J, Mills MT, Ong AC. Long-acting somatostatin analogue treatments in autosomal dominant polycystic kidney disease and polycystic liver disease: a systematic review and meta-analysis. BMJ Open. 2020 Jan 9;10(1):e032620.

19. Testa F, Magistroni R (2020) ADPKD current management and ongoing trials. J Nephrol 2020;33:223-237, 2020.

20. Reif GA, Yamaguchi T, Nivens E, Fujiki H, Pinto CS, Wallace DP. Tolvaptan inhibits ERK-dependent cell proliferation, Cl− secretion, and in vitro cyst growth of human ADPKD cells stimulated by vasopressin. Am J Physiol Renal Physiol 301:F1005-F1013, 2001.

21. Torres VE, Chapman AB, Devuyst O, Gansevoort RT, Grantham JJ, Higashihara E, Perrone RD, Krasa HB, Ouyang J, Czerwiec FS; TEMPO 3:4 Trial Investigators. Tolvaptan in patients with autosomal dominant polycystic kidney disease. N Engl J Med 2012;367:2407-2418.

22. Torres VE, Chapman AB, Devuyst O, Gansevoort RT, Perrone RD, Koch G, Ouyang J, McQuade RD, Blais JD, Czerwiec FS, Sergeyeva O. Tolvaptan in Later-Stage Autosomal Dominant Polycystic Kidney Disease. N Engl J Med 2017;377:1930-–1942.

23. Torres VE, Chapman AB, Devuyst O, Gansevoort RT, Perrone RD, Dandurand A, Ouyang J, Czerwiec FS, Blais JD, TEMPO 4:4 Trial Investigators. Multicenter, open-label, extension trial to evaluate the long-term efficacy and safety of early versus delayed treatment with tolvaptan in autosomal dominant polycystic kidney disease: the TEMPO4:4 Trial.Nephrol Dial Transplant 2018;33:477-489.

24. Australian Government Therapeutic Goods Administration. Australian Public Assessment Report for Tolvaptan Feburary 2018. Accessed October 2021. https://www.tga.gov.au/sites/default/files/auspar-tolvaptan-180209.pdf

25. Murphy B. EMA recommends treatment for rare kidney condition. The Pharmaceutical Journal, PJ, 21/28 March 2015, Vol 294, No 7854/5;294(7854/5).

26. Chebib FD, Perrone RD, Chapman AB et al. A practical guide to management of rapidly progressive ADPKD with tolvaptan. J.Am.Soc.Nephrol 2018;29(10):2458–2470.

27. Liu F, Feng C, Shen H, Hualdong F, and Mao J. Tolvaptan in pediatric Autosomal Dominant Polycystic Kidney Disease: where to from here? Kidney Dis. 2021:7:343-349.

28. PTAC–minutes-2019-08. https://pharmac.govt.nz/assets/ptac-minutes-2019-08.pdf. Accessed 18th October 2021.

29. NICE Guidance. Tolvaptan for treating autosomal dominant polycystic kidney disease. Technology appraisal guidance [TA358]. Published 28th October 2015

30. Public Summary Document July 2018 Pharmaceutical Benefits Advisory Committee meeting. 7.18 Tolvatan.

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Autosomal dominant polycystic kidney disease (ADPKD) is characterised by the formation and growth of multiple cysts within the kidney that distort and destroy the kidney structure and function. Hypertension occurs ubiquitously as the disease progresses, and macroscopic haematuria, flank pain, rupture of cysts, cyst infection and kidney stones are all common. Some, but not all, patients will progress to end stage kidney disease (ESKD). Extra-renal disease can also occur with cysts in other organs, cerebral aneurysms, aortic root dilatation and cardiac valvular abnormalities.

The most common cause of inherited kidney disease

ADPKD is the fifth most common cause of ESKD (Figure 1) and accounts for 7.3% of patients on renal replacement therapy (dialysis and transplant) in Aotearoa New Zealand.[[1]] This figure is consistent with reports from overseas where ADPKD accounts for 5–10% of patient with ESKD.[[6]] The number of patients with polycystic kidney disease (PCKD) who do not start renal replacement therapy is uncertain. ADPKD affects all races; however, ethnic differences in incidence and outcome in Aotearoa New Zealand are uncertain. The prevalence is generally reported as 1:400–1:1000 from early landmark studies from Denmark[[7]] and the USA.[[8]]

Figure 1: Primary renal disease of patients starting dialysis in Aotearoa New Zealand.

(Adapted from ANZDATA).[[1]]

PCKD1 and PCKD2 encode the integral membrane protein polycystin-1 and polycystin-2 respectively, which interact via signalling pathways in primary cilia, and account for the majority of cases.[[9]] Ten to fifteen percent of patients will have no mutation in these genes due to mutations in additional rare cystic disease genes or somatic mosaicism, the presence of two genetically distinct cell populations within one individual resulting from a somatic mutation during embryogenesis. Genetic testing is available in New Zealand and is usually ordered after discussion with the Genetics Health Service NZ.

Standard therapy of ADPKD

No direct randomised controlled trials have been undertaken in this area; however, general lifestyle interventions are recommended targeted at maintaining a healthy weight, avoiding dehydration, not smoking, and limiting dietary sodium to 100mmol/day and protein intake to 0.75–1gm/kg/day.[[10,11]]

Early detection and aggressive treatment of hypertension is vital. Use of agents to block the renin angiotensin system are safe and effective; however, individualised therapy based on co-morbidities and stage of chronic kidney disease is appropriate.[[10]]

Research in the last decade

Individuals with the PCKD1 gene tend to have a more severe phenotype, and make up the majority of ADPKD patients who progress to ESKD in middle age. Nevertheless, disease progression can vary considerably, even within families.[[12]] It is now well established that renal outcome in the individual patient, is a function of current kidney size (height-adjusted total kidney volume), kidney function, and age. The Mayo ADPKD calculator incorporates these parameters to predict renal outcomes over a period of 5–40 years.[[13]] Expensive and potentially hazardous therapies need to be targeted at those who are most likely to benefit from them, and the Mayo calculator is an effective tool for the clinician assessing possible benefit of new therapies in an ADPKD patient.

There has been very active research in pharmacological treatment of ADPKD with therapies including statins,[[14,15]] mTor inhibitors,[[16,17]] and somatostatin analogues.[[18]] Various agents are being trialled including: metformin, pioglitazone, tyrosine kinase inhibitors, oral glucosyl-ceramide synthase inhibitors, and non-peptide vasopressin 2 receptor antagonists.[[19]]

Tolvaptan, a new hope for PCKD

Tolvaptan is a vasopressin 2 receptor antagonist that acts on collecting ducts to ameliorate the effect of cyclic AMP, which would otherwise stimulate the secretion of fluid.[[20]] Clinically, this causes a picture of polyuria due to loss of free water. The TEMPO 3:4 trial showed tolvaptan slowed decline in renal function and reduced kidney growth in patients with well-preserved renal function (estimated glomerular filtration rate (eGFR) >60m/min/1.73m[[2]]).[[21]] The REPRISE trial also demonstrated tolvaptan preserved renal function in patients with more advanced renal impairment (eGFR 25–65ml/min/1.73m[[2]]).[[22]]

However, tolvaptan is not without side-effects and not all patients with ADPKD will progress to ESKD. Key side effects include thirst, polyuria and nocturia, as would be expected with its aquaretic profile. Idiosyncratic hepatic dysfunction also occurs, and liver function must be closely monitored in patients. In addition, the long-term effects of tolvaptan are uncertain, with follow up out to five years suggesting benefit.[[23]] Nevertheless, tolvaptan is the first medication licensed to use as directed therapy for PCKD and is now available in a number of counties (Table 1).

The various current guidelines for tolvaptan use in ADPKD target patients with substantial current kidney enlargement, and (in individuals > 45 years) historical evidence of significant previous kidney function decline over time.[[10,19,26]] The studies have shown useful delay in progression to, but not prevention of eventual ESKD.[[21–24]] It is possible that in the future, new protocols may be devised targeting at an earlier stage in their natural history and achieving the “holy grail”, of long-term normal kidney function.[[27]]

In December 2016, a clinician application for tolvaptan for ADPKD was made to Te Pātaka Whaioranga, The Pharmaceutical Management Agency (PHARMAC), with the Nephrology subcommittee recommending that tolvaptan for patients with be listed on the pharmaceutical schedule with a high priority if a registered product becomes available. Tolvaptan has been Medsafe registered in Aotearoa New Zealand since May 2019, and was recommended for use in selected patients with ADPKD subject to special authority criteria in August 2019 (Figure 2).[[28]]

View Table 1 & Figure 2.

Despite these clinician and committee recommendations, subsidised access to Tolvaptan has not occurred. The Samsca brand can currently be brought in (15mg or 30mg tablets) which cost $2680 per pack of 10—not including GST or mark up. Tolvaptan is typically started at twice daily doses of 45mg and 15mg and increased to a tolerated maximum dose of 90mg and 30mg. Approximately 55–60.6% of patients are usually able to tolerate the maximal dose.[[21,22]] Thus, the minimum cost for a starting dose of tolvapatan is over $35,000 per annum. The alternative is for dialysis (~$70,000 per year) or kidney transplantation (~$100,000 initially and then ~$13,000 per year).The Te Pātaka Whaioranga Nephrology subcommittee noted in their review that the cost of dialysis, which would be postponed rather than not required, would generally be balanced against the cost of treatment with tolvaptan.[[28]] The National Institute for Health and Care Excellence (NICE) and Australian Pharmaceutical Benefits Scheme (PBS ) concluded the cost-effectiveness of tolvaptan in patients with stage 2–3 chronic kidney disease with rapid disease progression based on their cost effectiveness analysis, and this aligns with the proposed special authority guidelines proposed.[[29,30]]

The patient’s voice

As one of five whānau members spanning over four generations in two countries with confirmed ADPKD, the impact and burden of the disease has been and continues to be significant. The disease burden on my whānau has included early death, increased morbidity and whānau suffering.

The disease burden of ADPKD is reflected in the health system through increased hospital admissions, costly dialysis and transplant. The financial impact is considerable.

Funding tolvaptan would greatly diminish the impact and burden of ADPKD on individuals in Aotearoa New Zealand, their whānau and the health system. The hope of not needing dialysis and/or transplant for those individuals who are eligible for this therapy would be life changing.

Conclusion

ADPKD disease is a common cause of kidney failure. Selected therapy is available to slow the progression of this disease. The authors call upon Te Pātaka Whaioranga to urgently complete negotiations to support funding for tolvaptan in selected patients.

Summary

Abstract

Autosomal dominant polycystic kidney disease (ADPKD) is the fifth most common cause of end stage kidney disease (ESKD) in Aotearoa New Zealand.[[1]] Identification of two genes, PCKD1 and PCKD2, which cause the majority of this disease, has played a key role in the development of DNA-sequence molecular diagnostics.[[2,3]] ADPKD is characterised by the formation and growth of multiple cysts within the kidney, with some but not all patients progressing to ESKD. The diagnosis of ADPKD is based on the presence of family history, and radiological imaging although increasingly genetic testing is being used for screening and diagnosis.[[4]]

Once diagnosed, standard management of ADPKD includes laboratory monitoring of chronic kidney disease (CKD) parameters, lowering of blood pressure, and a high fluid intake. Over the last decade much research has been undertaken for targeted therapies for ADPKD; however, despite funding of these medications overseas since May 2015, and applications to Te Pātaka Whaioranga, The Pharmaceutical Management Agency (PHARMAC), these therapies remain unavailable to New Zealanders resulting in an increased burden of disease to individuals and the whānau and financial cost to the health system.[[5]]

Aim

Method

Results

Conclusion

Author Information

Tracy Chan: Renal Fellow, Waitematā District Health Board, Auckland, New Zealand. Walter van der Merwe: Nephrologist and Hypertension Specialist, Level 4, 87-89 Albert Steet, Auckland New Zealand. Janak R de Zoysa: Nephrologist, Waitematā District Health Board, Auckland, New Zealand; Associate Professor of Medicine, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand.

Acknowledgements

The authors would like to thank patient, VW, who wished to remain anonymous, for their comments and contributing a section of this paper: “The patient’s voice”. The authors would also like to thank Dr Janeen Miner, General Practitioner, for her review of this manuscript and helpful comments.

Correspondence

Tracy Chan: Renal Fellow, Waitematā District Health Board, Auckland, New Zealand.

Correspondence Email

tracy.chan@waitematadhb.govt.nz

Competing Interests

Nil.

1. ANZDATA Registry. 44th Report, Chapter 1: Incidence of Renal Replacement Therapy for End Stage Kidney, Australia and New Zealand Dialysis and Transplant Registry, Adelaide, Australia. 2021. Available at: http://www.anzdata.org.au

2. Hughes J, Ward CJ, Peral B, Aspinwall R, Clark K, San Milla´n JL, GambleV, Harris PC. The polycystic kidney disease 1 (PKD1) gene encodes a novel protein with multiple cell recognition domains. Nature Genetics 1995;10:151-160.

3. Mochizuki T, Wu G, Hayashi T, Xenophontos SL, Veldhuisen B, Saris JJ, Reynolds DM, Cai Y, Gabow PA, Pierides A, Kimberling WJ, Breuning MH, Deltas CC, Peters DJ, Somlo S. PKD2, a gene for polycystic kidney disease that encodes an integral membrane protein. Science 1996;272:1339-1342.

4. Cornec-Le Gall E, Alam A, Perrone RD. Autosomal dominant polycystic kidney disease. Lancet 2019;393:919-35.

5. European Medicines Agency. Public Assessment Report Jinarc. http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_Public_assessment_report/human/002788/WC500187923.pdf. Accessed September 2021.

6. Grantham JJ. Autosomal dominant polycystic kidney disease. N Engl J Med 2008;359:1477-85.

7. 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.

8. Iglesias CG et al. Epidemiology of adult polycystic kidney disease, Olmsted County, Minnesota: 1935–1980. Am. J. Kidney Dis. 1983;2:630–639.

9. Nauli SM, Alenghat FJ, Luo Y, Williams E, Vassilev P, Li X, Elia AEH, Lu W, Brown EM, Quinn SJ, Ingber DE, Zhou J. Polycystins 1 and 2 mediate mechanosensation in the primary cilium of kidney cells. Nat Genet 2003;33:129-137.

10. Rangan GK, Alexander SI, Campbell KL, Dexter MA, Lee VW, Lopez-Vargas P, Mai J, Mallett A, Patel C, Patel M, Tchan MC, Tong A, Tunnicliffe DJ, Vladica P, Savige J. KHA-CARI guideline recommendations for the diagnosis and management of autosomal dominant polycystic kidney disease. Nephrology (Carlton) 2016;21(8):705-16.

11. Torres VE, Abebe KZ, Schrier RW, Perrone RD, Chapman AB, Yu AS, Braun WE, Steinman TI, Brosnahan G, Hogan MC, Rahbari FF, Grantham JJ, Bae KT, Moore CG, Flessner MF. Dietary salt restriction is beneficial to the management of autosomal dominant polycystic kidney disease. Kidney Int 2017;91(2):493-500.

12. Lankford MB, Guiard E, Li W et al. Intrafamilial variability of ADPKD. Kidney.Int.Rep 2019;4:995-1003

13. Irazabal MV, Rangel LJ, Bergstralh SL 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(1):160-172.

14. Cadnapaphornchai MA, George DM, McFann K, Wang W, Gitomer B, Strain JD, Schrier RW (2014) Effect of pravastatin on total kidney volume, left ventricular mass index, and microalbuminuria in pediatric autosomal dominant polycystic kidney disease. Clin J Am Soc Nephrol 9:889–896.

15. van Dijk MA, Kamper AM, van Veen S, Souverijn JH, Blauw GJ. Effect of simvastatin on renal function in autosomal dominant polycystic kidney disease. Nephrol Dial Transplant 2001;16:2152-2157.

16. He Q, Lin C, Ji S, Chen J. Efficacy and safety of mTOR inhibitor therapy in patients with early-stage autosomal dominant polycystic kidney disease: a meta-analysis of randomized controlled trials. Am J Med Sci. 2012 Dec;344(6):491-7.

17. Walz G, Budde K, Mannaa M, Nürnberger J, Wanner C, Sommerer C, Kunzendorf U, Banas B, Hörl WH, Obermüller N, Arns W, Pavenstädt H, Gaedeke J, Büchert M, May C, Gschaidmeier H, Kramer S, Eckardt KU. Everolimus in patients with autosomal dominant polycystic kidney disease. N Engl J Med. 2010 Aug 26;363(9):830-40.

18. Griffiths J, Mills MT, Ong AC. Long-acting somatostatin analogue treatments in autosomal dominant polycystic kidney disease and polycystic liver disease: a systematic review and meta-analysis. BMJ Open. 2020 Jan 9;10(1):e032620.

19. Testa F, Magistroni R (2020) ADPKD current management and ongoing trials. J Nephrol 2020;33:223-237, 2020.

20. Reif GA, Yamaguchi T, Nivens E, Fujiki H, Pinto CS, Wallace DP. Tolvaptan inhibits ERK-dependent cell proliferation, Cl− secretion, and in vitro cyst growth of human ADPKD cells stimulated by vasopressin. Am J Physiol Renal Physiol 301:F1005-F1013, 2001.

21. Torres VE, Chapman AB, Devuyst O, Gansevoort RT, Grantham JJ, Higashihara E, Perrone RD, Krasa HB, Ouyang J, Czerwiec FS; TEMPO 3:4 Trial Investigators. Tolvaptan in patients with autosomal dominant polycystic kidney disease. N Engl J Med 2012;367:2407-2418.

22. Torres VE, Chapman AB, Devuyst O, Gansevoort RT, Perrone RD, Koch G, Ouyang J, McQuade RD, Blais JD, Czerwiec FS, Sergeyeva O. Tolvaptan in Later-Stage Autosomal Dominant Polycystic Kidney Disease. N Engl J Med 2017;377:1930-–1942.

23. Torres VE, Chapman AB, Devuyst O, Gansevoort RT, Perrone RD, Dandurand A, Ouyang J, Czerwiec FS, Blais JD, TEMPO 4:4 Trial Investigators. Multicenter, open-label, extension trial to evaluate the long-term efficacy and safety of early versus delayed treatment with tolvaptan in autosomal dominant polycystic kidney disease: the TEMPO4:4 Trial.Nephrol Dial Transplant 2018;33:477-489.

24. Australian Government Therapeutic Goods Administration. Australian Public Assessment Report for Tolvaptan Feburary 2018. Accessed October 2021. https://www.tga.gov.au/sites/default/files/auspar-tolvaptan-180209.pdf

25. Murphy B. EMA recommends treatment for rare kidney condition. The Pharmaceutical Journal, PJ, 21/28 March 2015, Vol 294, No 7854/5;294(7854/5).

26. Chebib FD, Perrone RD, Chapman AB et al. A practical guide to management of rapidly progressive ADPKD with tolvaptan. J.Am.Soc.Nephrol 2018;29(10):2458–2470.

27. Liu F, Feng C, Shen H, Hualdong F, and Mao J. Tolvaptan in pediatric Autosomal Dominant Polycystic Kidney Disease: where to from here? Kidney Dis. 2021:7:343-349.

28. PTAC–minutes-2019-08. https://pharmac.govt.nz/assets/ptac-minutes-2019-08.pdf. Accessed 18th October 2021.

29. NICE Guidance. Tolvaptan for treating autosomal dominant polycystic kidney disease. Technology appraisal guidance [TA358]. Published 28th October 2015

30. Public Summary Document July 2018 Pharmaceutical Benefits Advisory Committee meeting. 7.18 Tolvatan.

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