Advances in autosomal dominant polycystic kidney disease: improving patient care to slow disease progression – Organised by SANOFI GENZYME

Symposium Summary

Written by Jasna Trbojevic-Stankovic
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Welcome

Thomas Benzing, Germany

Autosomal dominant polycystic kidney disease (ADPKD) is the most common hereditary kidney disease (~1/1000 births), and accounts for 5-10% of cases of end-stage kidney disease (ESKD). There is an urgent need to identify patients at high risk of rapid progression to ESKD, as they may be suitable for disease-modifying therapy. At a virtual satellite symposium held during the 2021 ERA-EDTA fully virtual congress, Professor York Pei and Professor Thomas Weimbs discussed recent research in genetics, kidney imaging, and dietary modifications, and provided insight into how these advances can be implemented to improve care for patients with ADPKD.

Clinical practice update and case presentations in ADPKD

York Pei, Canada

Diagnosis of ADPKD is typically through kidney imaging in the presence of a positive family history. Ultrasound is the most widely used technique using criteria derived from specific age ranges and the number of cysts detected. Magnetic resonance imaging (MRI) may be more appropriate for younger patients (age 16-40) and when more diagnostic certainty is needed—for example, when assessing family members as living kidney donors.

ADPKD is caused by mutations in the PKD1 (70-85% of cases) and in the PKD2 genes (15-35% cases). Professor Pei explained that mutations of the genes affect the protein structure in two ways. There may be a truncated protein product, which includes premature stop codon mutations and frameshift splice site mutations and can be considered as inactivating mutations. The second class of mutation are “non-truncating” with regard to the protein product and include single amino acid changes resulting in a nonsynonymous change of a highly conserved amino acid, as well as inframe insertion or deletions (“indels”). The resulting product may be dysfunctional rather than non-functional.

In the Toronto Genetic Epidemiology Study, about 40% of cases were due to protein-truncating PKD1 mutations, which were the most severe with about half of patients requiring renal replacement therapy by age 50. Of remaining mutations, 31% were PKD2 (the least severe prognosis), and 27% non-protein-truncating PKD1 mutations. PKD1 inframe indels accounted for 4%. However, the accuracy of mutation class-based prognosis is limited when applied to individuals, because extreme kidney disease discordance can occur even in affected relative pairs harboring the same ADPKD mutation. In one study, for example, extreme discordance was found in at least 12% of 307 ADKPD families regardless of the underlying mutated gene or mutation class.

Current clinical indications for genetic testing are lack of apparent family history, equivocal diagnostic imaging, syndromic forms of PKD, disease exclusion in young at-risk subjects (<25 years), living-related donor exclusion, application for life insurance, and prenatal/preimplantation diagnosis. According to Professor Pei, evolving indications may include early onset of severe disease, atypical imaging patterns suggestive of somatic mosaicism, marked within-family variability of disease severity suggesting a possible genetic modifier effect, and disease discordance between imaging and GFR. In the future, by using next generation sequencing (NGS) technology, with a gene panel containing both PKD1 and PKD2, as well as rare cystic disease genes and potential modifiers, it should be possible to advance our understanding of the clinical variability for ADPKD. Turning to kidney imaging-based prognostication, Professor Pei noted that in most patients with ADKPD, eGFR remains stable and within the normal range for three to four decades, yet total kidney volume (TKV) increases on average at 5% a year in adults. After eight years, TKV explained about 42% of the variance in eGFR decline. TKV appears to capture and serve as the best currently available prognosticator of eventual eGFR decline.

The Mayo Clinic Imaging Classification uses age and height-adjusted TKV to classify patients with ADPKD into five at-risk groups based on predicted TKV growth and kidney function decline. Individuals in Classes 1A and 1B have slower kdiney function decline, while Classes 1C, 1D and 1E are associated with more rapid decline in eGFR. When using this classification, it is important to exclude the atypical Class 2 imaging patterns that are present in about 9% of patients. In Class 2, Group A, one or more parts of the kidney are completely spared of the cystic process and the cyst-affected area is unilateral, asymmetric, segmental, or lobsided. In Class 2, Group B, while cysts may be present, decline in eGFR is predominantly caused by loss of kidney mass due to atrophy. It also important to bear in mind that it is possible for patients with ADPKD to have another, superimposed kidney disease (e.g. diabetic nephropathy).

When treating ADPKD, general recommendations are increased water and lower sodium intake, good blood pressure control, and dialysis and kidney transplantation after progression to kidney failure. Patients with rapidly progressive ADPKD may be considered for entry into a clinical trial or for disease-modifying therapy.

Dietary interventions in autosomal-dominant polycystic kidney disease

Thomas Weimbs, United States of America

ADPKD kidneys are exposed to the threat of microcrystals that can precipitate during the concentration of the primary urinary filtrate. In humans, the most significant are calcium oxalate, calcium phosphate, and uric acid crystals. These crystals can damage the epithelium, occlude urine flow, and eventually lead to microscopic kidney stone formation.

Professor Weimbs reported that in rat models when microcrystals lodge in kidney tubules, they activate signalling pathways such as mTOR. This leads to tubule dilation to facilitate the excretion of the crystals into the urine. In healthy rodent models, signalling switches off when crystals are eliminated and normal tubule diameter and flow are re-established. However, when PKD rats are challenged with either hydroxyproline or glyoxylate (both metabolic precursors of oxalate) in the drinking water, or with a high phosphate diet, the results are calcium oxalate and calcium phosphate precipitation, respectively, in the urine and more rapid cyst growth secondary to persistent mTOR activation.

These data suggest that it might be possible to ameliorate PKD disease progression by suppressing crystal formation in the kidneys. Citrate is a natural antagonist of calcium crystal precipitation, and can chelate and prevent calcium oxalate and calcium phosphate precipitation. In pre-clinical studies, when PKD rats are treated with increasing amounts of citrate in the drinking water, there is a dose-dependent and very significant improvement in cyst size and density.

Patients with ADPKD frequently have hypocitraturia and low urine pH. Kidney stones are also common, and their presence increases the rate of disease progression. Hyperuricemia and gout are also common, and are correlated with faster ADPKD progression. Preventive approaches might include control of dietary intake of oxalate, phosphate and uric acid (from purines). Other possibilities are administration of calcium/magnesium with food to reduce absorption of oxalate and phosphate, and supplementation with alkaline citrate to raise urine pH and urine citrate level.

Ketosis may be another promising dietary approach. In a PKD rat model, time-restricted feeding (an eight-hour feeding window) without calorie reduction has been shown to be highly effective in inhibiting mTOR signalling, proliferation, and fibrosis, with reductions in kidney-body weight ratio and cystic area. Similarly, compared with a normal diet, a five-week ad libitum ketogenic diet (high fat, normal protein, and very low carbohydrate) had a dramatic effect in regressing the renal cyst burden. During ketosis, the body changes metabolism from glucose consumption to using fat reserves, in particular fatty acids and the ketones produced by the liver. Supplementation of PKD rats’ drinking water with the ketone beta-hydroxybutyrate (BHB) strongly inhibits disease progression even when the rats are allowed their usual high carbohydrate ad libitum diet.

These animal models suggest that ketosis, achieved by a time-restricted diet, intermittent fasting, or a ketogenic diet, or supplementation with BHB, might offer adjunctive  approaches in patients with ADPKD. In responses to a questionnaire of patients with ADPKD, most of the 131 respondents not only reported significant improvements in body weight, but also in PKD-related health issues, such as blood pressure.

Professor Weimbs commented that these results are surprising when considered in the context of a relentlessly progressive disease. He added that, while this self-selected group reported few or no problems in adherence to the dietary pattern, this is unlikely to apply to less motivated patients. KETO-ADKPD (NCT04680780) is a prospective study that will randomize participants to either control (no diet), a classical ketogenic diet, or intermittent fasting. The study is designed to investigate the feasibility, safety and efficacy of dietary interventions on ADPKD, and to determine which of the two diets is the optimal approach.

A second clinical trial is investigating Ren.Nu, Keto-Adaptive Nutrition for Polycystic Kidney Disease (https://ren-nu.org). This dietary program has been devised specially for PKD patients by Professor Weimbs’ group in collaboration with registered dietitians, and is a 12-week remote training program involving a plant-dominant ketogenic diet, and dietary supplementation with a medical food combining BHB and citrate. The clinical trial is a prospective, 52-week, longitudinal controlled study, and its results will contribute to the growing body of evidence for dietary interventions in ADKPKD.

Further readings

Clinical practice update in ADPKD

Pei Y & Watnick T. Diagnosis and screening of autosomal dominant polycystic kidney disease. Adv Chronic Kidney Dis 2010;17(2):140-52

Pei Y, et al. Imaging-based diagnosis of autosomal dominant polycystic kidney disease. J Am Soc Nephrol 2015;26(3):746-53.

Gansevoort RT, et al. Recommendations for the use of tolvaptan in autosomal dominant polycystic kidney disease: a position statement on behalf of the ERA-EDTA Working Groups on Inherited Kidney Disorders and European Renal Best Practice. Nephrol Dial Transplant 2016;31(3):337-48.

Lanktree MB, et al. Evolving role of genetic testing for the clinical management of autosomal dominant polycystic kidney disease. Nephrol Dial Transplant 2019;34(9):1453-1460.

Irazabal MV, 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):160-72

Dietary interventions in ADPKD

Torres JA, et al. Crystal deposition triggers tubule dilation that accelerates cystogenesis in polycystic kidney disease. J Clin Invest 2019;129(10):4506-4522

Torres JA, et al. Ketosis Ameliorates Renal Cyst Growth in Polycystic Kidney Disease. Cell Metab 2019;30(6):1007-1023.e5

Kipp KR, et al. A mild reduction in food intake slows disease progression in an orthologous mouse model of polycystic kidney disease. Am J Physiol Renal Physiol

2016;310(8):F726-F731

Warner G. Food Restriction Ameliorates the Development of Polycystic Kidney Disease. J Am Soc Nephrol 2016;27(5):1437-47