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Year : 2019  |  Volume : 5  |  Issue : 3  |  Page : 69-72

Advances in polycystic kidney disease and its nutritional management

Department of Nephrology, Dr. Ram Manohar Lohia Institute of Medical Sciences, Lucknow, Uttar Pradesh, India

Date of Submission26-Dec-2019
Date of Acceptance10-Jan-2020
Date of Web Publication17-Feb-2020

Correspondence Address:
Dr. Namrata Rao
Department of Nephrology, Dr. Ram Manohar Lohia Institute of Medical Sciences, Lucknow, Uttar Pradesh
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/jrnm.jrnm_60_19

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Autosomal dominant polycystic kidney disease (ADPKD) is the most common inherited disorder causing chronic kidney disease (CKD) and end-stage renal disease (ESRD). Disease-modifying agents are being developed at a fast pace; however, approved management strategies still need to be improved. including water intake. Low sodium, low protein, and phosphorus diet, remains the cornerstone of the dietary management of these patients.

Keywords: Hypertension, nutritional management, polycystic kidney disease, sodium, total kidney volume

How to cite this article:
Rao N. Advances in polycystic kidney disease and its nutritional management. J Renal Nutr Metab 2019;5:69-72

How to cite this URL:
Rao N. Advances in polycystic kidney disease and its nutritional management. J Renal Nutr Metab [serial online] 2019 [cited 2022 Aug 20];5:69-72. Available from: http://www.jrnm.in/text.asp?2019/5/3/69/278613

  Introduction Top

Autosomal dominant polycystic kidney disease (ADPKD) is the most common inherited disorder causing chronic kidney disease (CKD) and end-stage renal disease (ESRD).[1] The relentless cyst formation in the kidneys leads to compression and loss of normal kidney parenchyma, thereby resulting ultimately in the loss of glomerular filtration rate (GFR). In the past few years, pathogenetic mechanisms of cystogenesis and disease progression have been elucidated in greater detail. Similarly, novel diagnostic techniques and classification schema have been introduced that can greatly facilitate prognostication and risk prediction. Furthermore, therapies targeting the various upregulated intracellular pathways are rapidly making the transition from bench to the bedside. Nutritional management in CKD has a proven role in retarding progression and ameliorating metabolic side-effects of the disease. Apart from sodium, protein and phosphorus restriction as in garden-variety CKD, specific nutritional aspects in ADPKD management deserve to be mentioned, such as caloric and caffeine restriction and excessive water intake. Certain nutraceuticals have been found to have a role in retarding cystogenesis and can be tried as adjunctive therapies in future.

  Advances in Pathogenesis of Autosomal Dominant Polycystic Kidney Disease Top

ADPKD is an autosomal dominant disorder, meaning that an individual has a 50% chance of inheriting the disease from a parent. Two causative genes, PKD-1 (encoding polycystin-1 localized to primary cilia and tight junctions) and PKD-2 (encoding polycystin-2, which is a cation channel in primary cilia and endoplasmic reticulum) have been identified. The disease is genetically heterogeneous and has high phenotypic variability. For example, PKD-2 mutations (up to 15% of cases) and nontruncating PKD-1 mutations can present with milder/late-onset disease. While the disease is dominant in inheritance, at the cellular level, a somatic second-hit mutation has been suggested to cause functional loss of the unaffected allele, which when it reaches 100%, is thought to result in cystogenesis.[2]

The reduction of polycystins below a threshold level leads to reduction in intracellular calcium, resulting in increased cyclic adenosine monophosphate (cAMP levels), activation of protein kinase A and increased arginine vasopressin (AVP) sensitivity of collecting duct cells. This results in impaired tubulogenesis and cellular proliferation. Excessive epithelial chloride secretion occurring as a result of upregulated cAMP-activated transporter (encoded by CFTR), helps generate and maintain fluid in the cysts. Other activated pathways in the pathogenesis of ADPKD include the mammalian target of rapamycin (mTOR), Wingless/Integrated (Wnt) and the hedgehog signaling pathways. Furthermore, recent metabolomic studies have identified cyst epithelial cells to have enhanced aerobic glycolysis in comparison to normal epithelial cells.[3]

  Advances in the Diagnosis and Prognostication of Autosomal Dominant Polycystic Kidney Disease Top

Ultrasound (US) examination is the most common modality used for presymptomatic diagnosis of individuals with family history of ADPKD and unified diagnostic criteria which take age and number of cysts into account, have a high negative predictive value when used in individuals over the age of 40. In younger individuals, magnetic resonance imaging (MRI) is superior to US.[4] Genetic testing is not routinely ordered, except when being evaluated as potential kidney donors or for reproductive counseling. Currently, the molecular diagnosis of ADPKD is being performed by DNA sequencing technology. At this time, presymptomatic screening of children is not recommended.

Total kidney volume (TKV) is the most well-studied biomarker of disease progression and GFR decline in ADPKD.[1] While evaluating volumes by MRI, planimetry is the gold standard measurement technique, but stereology is faster and well validated in detecting small changes in kidney volume while on treatment. Advanced MR techniques are being investigated for evaluation of early stages of the disease, such as blood oxygen level-dependent MRI, and MR elastography. The mayo clinic imaging classification developed by Irazabal et al. can predict an estimated GFR (eGFR) decline based on age and height-adjusted TKV in typical cases of ADPKD (Class 1A to 1E).[5] Another tool for prognostication is the PRO-PKD score, which utilizes clinical (sex [male-1 point] and age at onset of hypertension and urologic complications [2 points each, for onset before 35 years]) and genetic (truncating PKD1 [4 points], nontruncating PKD1 [2 points] and PKD2 mutations [0 points]). A score of >6 predicts rapid GFR decline, with ESRD before 60 years of age with a 90% positive predictive value.[6] Following the FDA approval of tolvaptan for use in ADPKD and its inclusion in the position statement by the European Renal Association-EDTA working group as well, these prognostication schemas have attained renewed importance.

  Advances in Pharmacologic Management of Autosomal Dominant Polycystic Kidney Disease Top

Hypertension management

With the evidence from HALT-PKD Study A trial (which enrolled 15–49-year-old patients with an eGFR >60 ml/min/1.73 m2), intensive BP control (using lisinopril and telmisartan to a target of < 120/70 mmHg) was associated with a slower TKV increase, lower left ventricular mass index and initially, high GFR decline (likely hemodynamic) which was followed by marginally slower decline after 4 months.[7] From a post hoc analysis, it appears that intensive BP control is the most beneficial in the Mayo Classes 1D and 1E, both in terms of slower TKV increase and lower GFR decline.[8]

  Disease-Modifying Therapies Top


Tolvaptan antagonizes vasopressin-mediated cAMP increase in cyst epithelial cells, thereby slowing cyst formation as well as cyst growth. The approval of V2 receptor antagonist tolvaptan in ADPKD followed the pivotal TEMPO 3:4 and REPRISE trials.[9],[10] The TEMPO 3:4 trial enrolled 18–50-year-old patients, with estimated creatinine clearance >60 ml/min/1.73 m2, and TKV >750 ml, randomized to tolvaptan or placebo. Tolvaptan showed a slower TKV increase and slower GFR decline at the end of 3 years. The REPRISE trial enrolled patients with lower eGFR (up to 25 ml/min/1.73 m2) and higher age (up to 65 years) and showed slower eGFR decline in the tolvaptan group at the end of 1 year. While being approved for all patients with eGFR >45 ml/min/1.73 m2, it is recommended to start therapy with tolvaptan in patients who are deemed to be rapid progressors – classes 1C-E of the Mayo classification, those with documented eGFR decline of >2.5 ml/min/1.73 m2/year, those with documented TKV increase of >5%/year, those <45 years of age having an US kidney length >16.5 cm, and those with a PRO-PKD score >6. At the start of tolvaptan therapy, acute drop of eGFR occurs similar to the use of renin-angiotensin system inhibitors and the typical starting dose is 45 mg in the morning and 15 mg in the afternoon (as in the TEMPO 3:4 trial) uptitrated up to 90 mg and 30 mg as tolerated. It is also recommended to continue treatment beyond 3 years as the effects of tolvaptan on TKV increase are sustained. However, once the patient reaches ESRD, tolvaptan should be stopped to allow for any GFR rise which might postpone renal replacement therapies. The notable adverse effects of tolvaptan are hepatotoxicity, dehydration, precipitation of acute urinary retention, hypernatremia, hyperglycemia, and hyperuricemia precipitating acute gouty arthritis.

Octreotide and lanreotide

Somatostatin decreases cAMP production in cyst epithelial cells. Octreotide showed beneficial effects on hepatic and kidney cyst expansion in mouse models, following which clinical studies have also been performed, some of which have been completed and show beneficial effects on TKV increase and GFR decline.[11] However, somatostatin analogs can cause dysglycemia and gallstone disease in the long term.

  Other Potential Therapies in Ongoing Clinical Trials Top

Drugs, which are “repurposed:” statins have been shown to prevent cyst growth in mouse models, and one intervention trial is currently recruiting patients with early ADPKD. Similarly, mTOR inhibitors showed a promising role in inhibiting cystogenesis in mouse models; however, the same could not be translated to clinical trials, as the drugs at higher doses have significant adverse effects limiting their utility.[1] Metformin, an oral antidiabetic agent activates AMP kinase which downregulates mTOR and CFTR (both of which have major roles in cyst growth) is currently being evaluated in two phase 2 trials.[12] 2-deoxyglucose is a glycolysis inhibitor that has shown cyst inhibitory effects, as cyst epithelial cells are primarily dependent on aerobic glycolysis for ATP generation. PPAR agonists (fenofibrate, a PPAR-α agonist and rosiglitazone and pioglitazone, PPAR-γ agonists) also cause AMP kinase activation mediated cyst inhibition as well as decreased fibrogenesis, and are being evaluated in an ongoing trial.[13] Niacinamide, a form of Vitamin B3, inhibits sirtuin 1 which may have a role in cyst growth. Two ongoing trials are evaluating niacinamide in ADPKD patients with preserved GFR. Tesevatinib, a tyrosine kinase inhibitor, is being evaluated in a placebo-controlled randomized trial in patients with preserved GFR and TKV >900 ml. Etanercept, a TNF-α inhibitor and resveratrol, mTOR and nuclear factor kappa B inhibitor have also shown promise in mouse models.

Drugs, which are “targeted:” Antisense oligonucleotides (ASO) are short nucleotide sequences that reduce expression of targetted mRNAs, thereby reducing protein production. ASOs have been developed against mTOR, angiotensinogen, and STAT3, which are being tried in preclinical studies. miRNAs are noncoding RNAs which modulate expression of mRNAs, and are being evaluated in mouse models. Many other growth factors and cytokines have been implicated in the pathogenesis of ADPKD; however, many monoclonal antibodies against these receptors have failed to show promising results.

  Nutritional Management in Autosomal Dominant Polycystic Kidney Disease Top

Water intake

Fluid prescription is still controversial. Overhydration is a common strategy prescribed to ADPKD patients with an advantage of preventing renal calculi and no serious adverse effects. Water intake inhibits AVP, secondarily suppressing cAMP activity and cyst growth. Mouse models support this notion, and small human studies also demonstrated reduced GFR decline and kidney volume increase.[14] Up to 3.5–5 L/day of fluid intake is commonly recommended and safely tolerated. One way to monitor the adequacy of overhydration is to check urine osmolality and plasma copeptin levels (copeptin is cosecreted with AVP) for suppression with regard to baseline levels.

Caloric intake

Mouse models have shown substantial inhibition of cysts with food restriction, predominantly by inhibition of mTOR and its downstream pathways. A clinical trial with 40 participants is underway, testing caloric restriction and intermittent fasting primarily evaluating feasibility and weight loss, and secondarily at TKV changes.[15] Furthermore, as the overweight and obese participants in the HALT-PKD study showed faster GFR declines as well as TKV increase, maintaining a body mass index <25 kg/m2 should be recommended.[7] Two dietary regimens have some supporting evidence in ADPKD – the Dietary Approaches to Stop Hypertension diet (high in fruits and vegetables, low in fat diet) and PREDIMED diet (high in vegetables, fish and white meat, low in red meat, aerated drinks, and commercial bakery).

Sodium intake

It is advisable to reduce sodium intake to <2.3 g/day, as suggested by the majority of guidelines, in the light of findings from the HALT-PKD studies.[7] Dietary sodium was significantly associated with TKV increase, eGFR decline, and the development of ESRD in these studies.

Protein intake

The MDRD and CRISP studies demonstrated slower GFR declines with lower protein intakes; though, the prescription of very low protein diets would require stronger evidence.[16],[17] Till then, a daily protein intake of 0.8 g/kg/day can be prescribed.

Phosphorus intake

ADPKD patients have been found to have high FGF23 levels compared to other etiologies for CKD; therefore, phosphorus restriction to <800 mg/day may be recommended.[18] This would mean careful avoidance of red meats, processed foods, and aerated drinks.

Caffeine restriction

Caffeine inhibits phosphodiesterases which can increase cAMP levels in the distal tubules. However, caffeine is a weak phosphodiesterase inhibitor and unlikely to cause clinically significant effects. Even in the absence of specific evidence, ADPKD patients can be advised to consume <3 cups of coffee a day.

  Use of Nutraceuticals in Autosomal Dominant Polycystic Kidney Disease Top

Nutraceuticals are herb and plant-derived compounds with pharmacologic activity. While studies in mouse models have demonstrated the efficacy of some of these agents, human studies are lacking at this time. Some examples include triptolide (derived from Tripterygium wilfordii, a Chinese herb), curcumin (from turmeric plant, Curcuma longa), ginkgolide B (from Gingko biloba), stevioside and steviol (sweeteners derived from Stevia rebudiana), which have cyst-inhibitory and anti-inflammatory effects.[19],[20]

  Conclusion Top

It is now possible to diagnose, classify, and assess patients with ADPKD for progression, with far greater accuracy than before. Disease-modifying agents are being developed at a fast pace; however, approved management strategies still need to be improved. Higher water intake, along with low sodium, low protein, and phosphorus diet, remains the cornerstone of the dietary management of these patients. Pending strong evidence, caloric restriction cannot be prescribed to patients; however, they can be encouraged to maintain physical activity and attempt weight reduction to achieve a healthy body mass index.

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.

  References Top

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Chebib FT, Torres VE. Autosomal dominant polycystic kidney disease: Core curriculum 2016. Am J Kidney Dis 2016;67:792-810.  Back to cited text no. 2
Riwanto M, Kapoor S, Rodriguez D, Edenhofer I, Segerer S, Wüthrich RP. Inhibition of aerobic glycolysis attenuates disease progression in polycystic kidney disease. PLoS One 2016;11:e0146654.  Back to cited text no. 3
Magistroni R, Corsi C, Martí T, Torra R. A review of the imaging techniques for measuring kidney and cyst volume in establishing autosomal dominant polycystic kidney disease progression. Am J Nephrol 2018;48:67-78.  Back to cited text no. 4
Irazabal MV, Rangel LJ, Bergstralh EJ, Osborn SL, Harmon AJ, Sundsbak JL, et al. Imaging classification of autosomal dominant polycystic kidney disease: A simple model for selecting patients for clinical trials. J Am Soc Nephrol 2015;26:160-72.  Back to cited text no. 5
Cornec-Le Gall E, Audrézet MP, Rousseau A, Hourmant M, Renaudineau E, Charasse C, et al. The PROPKD Score: A new algorithm to predict renal survival in autosomal dominant polycystic kidney disease. J Am Soc Nephrol 2016;27:942-51.  Back to cited text no. 6
Schrier RW, Abebe KZ, Perrone RD, Torres VE, Braun WE, Steinman TI, et al. Blood pressure in early autosomal dominant polycystic kidney disease. N Engl J Med 2014;371:2255-66.  Back to cited text no. 7
Irazabal MV, Abebe KZ, Bae KT, Perrone RD, Chapman AB, Schrier RW, et al. Prognostic enrichment design in clinical trials for autosomal dominant polycystic kidney disease: The HALT-PKD clinical trial. Nephrol Dial Transplant 2017;32:1857-65.  Back to cited text no. 8
Torres VE, Chapman AB, Devuyst O, Gansevoort RT, Grantham JJ, Higashihara E, et al. Tolvaptan in patients with autosomal dominant polycystic kidney disease. N Engl J Med 2012;367:2407-18.  Back to cited text no. 9
Torres VE, Chapman AB, Devuyst O, Gansevoort RT, Perrone RD, Koch G, et al. Tolvaptan in later-stage autosomal dominant polycystic kidney disease. N Engl J Med 2017;377:1930-42.  Back to cited text no. 10
Caroli A, Perico N, Perna A, Antiga L, Brambilla P, Pisani 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;382:1485-95.  Back to cited text no. 11
Seliger SL, Abebe KZ, Hallows KR, Miskulin DC, Perrone RD, Watnick T, et al. A Randomized clinical trial of metformin to treat autosomal dominant polycystic kidney disease. Am J Nephrol 2018;47:352-60.  Back to cited text no. 12
Yoshihara D, Kurahashi H, Morita M, Kugita M, Hiki Y, Aukema HM, et al. PPAR-gamma agonist ameliorates kidney and liver disease in an orthologous rat model of human autosomal recessive polycystic kidney disease. Am J Physiol Renal Physiol 2011;300:F465-74.  Back to cited text no. 13
Higashihara E, Nutahara K, Tanbo M, Hara H, Miyazaki I, Kobayashi K, et al. Does increased water intake prevent disease progression in autosomal dominant polycystic kidney disease? Nephrol Dial Transplant 2014;29:1710-9.  Back to cited text no. 14
Warner G, Hein KZ, Nin V, Edwards M, Chini CC, Hopp K, et al. Food restriction ameliorates the development of polycystic kidney disease. J Am Soc Nephrol 2016;27:1437-47.  Back to cited text no. 15
Klahr S, Breyer JA, Beck GJ, Dennis VW, Hartman JA, Roth D, et al. Dietary protein restriction, blood pressure control, and the progression of polycystic kidney disease. Modification of diet in renal disease study group. J Am Soc Nephrol 1995;5:2037-47.  Back to cited text no. 16
Tprres VE, Grantham JJ, Chapman AB, Mrug M, Bae KT, King BF Jr., et al. Consortium for Renal Imaging Studies of Polycystic Kidney Disease (CRISP): Potentially modifiable factors affecting the progression of autosomal dominant polycystic kidney disease. Clin J Am Soc Nephrol 2011;6:640-7.  Back to cited text no. 17
Pavik I, Jaeger P, Kistler AD, Poster D, Krauer F, Cavelti-Weder C, et al. Patients with autosomal dominant polycystic kidney disease have elevated fibroblast growth factor 23 levels and a renal leak of phosphate. Kidney Int 2011;79:234-40.  Back to cited text no. 18
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