23NaMRI Assessed Cyst Sodium Concentration in Polycystic Kidney Disease to Identify Cyst Metabolic Activity: A Proof of Concept Study

Autosomal dominant polycystic kidney disease (ADPKD) is the most common form of inherited kidney cystic disease and appears as a heterogeneous disease with different progression rates even within the same family. The assessment of ADPKD progression is critical to allow early initiation of kidney protective measures and specific treatment. Therefore, surrogate prognostic biomarkers are required. Currently kidney cystic phenotype evaluation is restricted to assessment of total kidney volume (TKV) and growth, age-adjusted glomerular filtration rate (GFR), GFR decline, genetic testing and family history1Chebib F.T. Torres V.E. Assessing Risk of Rapid Progression in Autosomal Dominant Polycystic Kidney Disease and Special Considerations for Disease-Modifying Therapy.Am J Kidney Dis. 2021; 78: 282-292https://doi.org/10.1053/j.ajkd.2020.12.020Abstract Full Text Full Text PDF PubMed Scopus (38) Google Scholar. Using proton-based magnetic resonance imaging (MRI) is of considerable value in terms of prognosis; and provides information relating to morphological characteristics but it is restricted to structural data alone2Kline T.L. Korfiatis P. Edwards M.E. et al.Automatic total kidney volume measurement on follow-up magnetic resonance images to facilitate monitoring of autosomal dominant polycystic kidney disease progression.Nephrol Dial Transplant. 2016; 31: 241-248https://doi.org/10.1093/ndt/gfv314Crossref PubMed Scopus (47) Google Scholar. Image texture analysis, diffusion tensor imaging, T2 mapping, and magnetization transfer ratio are promising new techniques to detect early structural change in cystic kidneys 3Kline T.L. Korfiatis P. Edwards M.E. et al.Image texture features predict renal function decline in patients with autosomal dominant polycystic kidney disease.Kidney Int. 2017; 92: 1206-1216https://doi.org/10.1016/j.kint.2017.03.026Abstract Full Text Full Text PDF PubMed Scopus (51) Google Scholar. There are also emerging urinary and serologic biomarkers which may be potentially be used to assess inflammation, proliferation, tubular injury, and metabolic processes4Lanktree M.B. Chapman A.B. New treatment paradigms for ADPKD: moving towards precision medicine.Nat Rev Nephrol. 2017; 13: 750-768https://doi.org/10.1038/nrneph.2017.127Crossref PubMed Scopus (54) Google Scholar. In a previous study we demonstrated the ability to discriminate the corticomedullary gradient within the kidney in healthy individuals and in patients with CKD. In our exploratory analysis of the corticomedullary gradient, we were able to measure the sodium concentration in the patients' cysts. In this present study, we aimed to report the technical feasibility of measuring sodium content of cysts in ADPKD patients. We studied 4 ADPKD patients recruited from the London Regional Renal Program (Ontario, Canada) with wide ranges of kidney function who fasted for eight hours prior to the study visit. Urine samples were collected to measure fasting urinary osmolarity, before the MRI scan. This was an entirely exploratory study and thus there was no estimate of an appropriate sample size. MRI was carried out on a GE MR750 3T (GE Healthcare) instrument. Proton anatomical images were acquired using the MRI built-in body coil. A custom-built two loop (18cm in diameter) butterfly radiofrequency surface coil tuned for sodium frequency (33.786 MHz) was used to acquire kidney sodium images as reported previously (8). We report data from four ADPKD patients, median (min-max) age was 58 (37-74) years old, BMI 28.2 (21.2 – 29.6) kg/m2, Na 143 (139-145) mmol/L, urea 10 (2.6-28.1 mmol/L), eGFR (CKDEPI) 31 (8-101) mL/min/1.73m2, urine osmolarity 399 (239-441) mosm/L, sodium excretion fraction 1.28 (0.53 – 4.1)%. The characteristics of each patient are described in Table 1. Within a representative 23NaMRI image, a previously unappreciated but characteristically wide range of kidney cystic sodium content is evident, indicative of both tubular origin and metabolic activity. Figure 1 shows proton anatomic sodium MRI scans sodium picture and merge of both proton and sodium for the 4 ADPKD patients.Table 1Patient 1Patient 2Patient 3Patient 4Age (yo)in his 60sin his 30sin his 50sin his 50sGender (M/F)MMMFWeight (kg)917581.684.5Height (cm)183173166170BMI (kg/m2)27.125.129.629.2Sodium (mmol/L)139140143145Urea (mmol/L)28.110.12.65.3Creatinine (μmol/L)64425878107eGFR (mL/min/1.73m2)82710154CRP (mg/dL)4.13.84.60.8Urines osmolarity (mosm/L)332239408431EFNa (%)1.81.70.50.6Tolvaptan(Y/N)NYYNDiuretics(Y/N)YNNYMAYO clinic status1A1AKidney volume (mL/m)7731200Abbreviations: eGFR= estimated glomerular filtration rate, EFNa= excretion fraction of sodium Open table in a new tab Abbreviations: eGFR= estimated glomerular filtration rate, EFNa= excretion fraction of sodium ADPKD is characterized by extremely active cysts, often exchanging their entire fluid contents multiple times in a single day5Gardner K.D. Composition of fluid in twelve cysts of a polycystic kidney.N Engl J Med. 1969; 281: 985-988https://doi.org/10.1056/NEJM196910302811804Crossref Scopus (64) Google Scholar. In preclinical models, renal cyst sodium content is influenced by the cyst’s location within the kidney and its daily fluid activity. Sodium content is heterogenous between cysts and would require multiple aspiration to acquire these data in humans- impossible to achieve. Functional imaging relating to the sodium content would potentially provide clinicians and researchers the ability to probe metabolic activity of the cystic disease, both at rest and potentially when actively challenged with therapeutic agents. There are no clinical data about sodium content in cyst in the intact human currently available. To our knowledge, this is the first report which demonstrates the ability to acquire sodium images of ADPKD kidneys. This will allow both improved prognostic prediction, and potentially also the ability to assess suitability and/or response to disease modifying therapeutic approaches early in the treatment course. A dedicated clinical trial exploring modification of salt content after tolvaptan in ADPKD will be of great interest. Although we showed the feasibility of scanning sodium content in the ADPKD kidney, 23NaMRI remains limited by image resolution and signal-to-noise ratio (SNR) due to sodium’s low gyromagnetic ratio and its low biological concentration. Higher resolution and SNR would require longer imaging time that may not be practical in a clinical setting. Low image resolution could lead to gross partial volume (PV) effects. The acquisition parameters for this study were selected to achieve an acceptable resolution and SNR within 31 minutes of scan time. It would have been interesting to have genetic and kidney volume. Unfortunately we were unable to provide all kidney volume measurements or genetic testing results for these patients. In conclusion, after establishing the feasibility of 23NaMRI to measure sodium cyst content, it seems suitable to use 23NaMRI to probe the biological differences in cyst populations and potentially to refine diagnosis, prognosis and selection of patients for established and emerging ADPKD therapies. Item S1: Detailed Methods Conceptualization, formal analysis, validation (SL); formal analysis, methodology, software (AA); conceptualization, funding and resource acquisition, supervision, validation (CM). Each author contributed important intellectual content during manuscript drafting or revision and accepts accountability for the overall work by ensuring that questions pertaining to the accuracy or integrity of any portion of the work are appropriately investigated and resolved. This project was funded by the Can-SOLVE CKD Network and the Canadian Institutes of Health Research Strategy for Patient-Oriented Research. The authors declare that they have no relevant financial interests. Received June 12, 2023. Evaluated by 2 external peer reviewers, with direct editorial input from an Associate Editor and the Editor-in-Chief. Accepted in revised form January 11, 2024. 6Akbari A. Lemoine S. Salerno F. et al.Functional Sodium MRI Helps to Measure Corticomedullary Sodium Content in Normal and Diseased Human Kidneys.Radiology. 2022; 303: 384-389https://doi.org/10.1148/radiol.211238Crossref Google Scholar, 6.. The following is/are the supplementary data to this article: Download .pdf (.63 MB) Help with pdf files

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