Kidney Energetics and Cyst Burden in Autosomal Dominant Polycystic Kidney Disease: A Pilot Study

Abstract

Rationale & objective: In this pilot study, we hypothesized that autosomal dominant polycystic kidney disease (ADPKD) is characterized by impaired kidney oxidative metabolism that associates with kidney size and cyst burden.

Study design: Cross-sectional study.

Setting & participants: Twenty adults with ADPKD (age, 31±6 years; 65% women; body mass index [BMI], 26.8 [22.7-30.4] kg/m²; estimated glomerular filtration rate [eGFR, 2021 CKD-EPI creatinine], 103±18mL/min/1.73m²; height-adjusted total kidney volume [HTKV], 731±370mL/m; Mayo classifications 1B [5%], 1C [42%], 1D [21%], and 1E [32%]) and 11 controls in normal weight category (NWC) (age, 25±3 years; 45% women; BMI, 22.5 [21.7-24.2] kg/m2; eGFR, 113±15mL/min/1.73m²; HTKV, 159±31mL/m) at the University of Colorado Anschutz Medical Campus.

Predictors: ADPKD status (yes/no) and severity (Mayo classifications).

Outcome: HTKV and cyst burden by magnetic resonance imaging, kidney oxidative metabolism, and perfusion by ¹¹C-acetate positron emission tomography/computed tomography, insulin sensitivity by hyperinsulinemic-euglycemic clamps (presented as ratio of M-value of steady state insulin concentration [M/I]).

Analytical approach: For categorical variables, χ²/Fisher's exact tests, and for continuous variables t tests/Mann-Whitney U tests. Pearson correlation was used to estimate the relationships between variables.

Results: Compared with NWC individuals, the participants with ADPKD exhibited lower mean±SD M/I ratio (0.586±0.205 vs 0.424±0.171 [mg/kg lean/min]/(μIU/mL), P=0.04), lower median cortical perfusion (1.93 [IQR, 1.80-2.09] vs 0.68 [IQR, 0.47-1.04] mL/min/g, P<0.001) and lower median total kidney oxidative metabolism (0.17 [IQR, 0.16-0.19] vs. 0.14 [IQR, 0.12-0.15] min^-1, P=0.001) in voxel-wise models excluding cysts. HTKV correlated inversely with cortical perfusion (r: -0.83, P < 0.001), total kidney oxidative metabolism (r: -0.61, P<0.001) and M/I (r: -0.41, P = 0.03).

Limitations: Small sample size and cross-sectional design.

Conclusions: Adults with ADPKD and preserved kidney function exhibited impaired renal perfusion and kidney oxidative metabolism across a wide range of cysts and kidney enlargements.

Funding: Grants from government (National Institutes of Health, Centers for Disease Control and Prevention) and not-for-profit (JDRF) entities.

Trial registration: Registered at ClinicalTrials.gov with study numbers NCT04407481 and NCT04074668.

Plain-language summary: In our study, we explored how a common genetic kidney condition, autosomal dominant polycystic kidney disease (ADPKD), relates to kidney metabolism. ADPKD leads to the growth of numerous cysts in the kidneys, which can impact their ability to work properly. We wanted to understand the kidneys' ability to process oxygen and blood flow in ADPKD. Our approach involved using advanced imaging techniques to observe kidney metabolism and blood flow in people with ADPKD compared with healthy individuals. We discovered that those with ADPKD had significant changes in kidney oxygen metabolism even when their kidney function was still normal. These findings are crucial as they provide deeper insights into ADPKD, potentially guiding future treatments to target these changes.

Keywords: Hyperinsulinemic-euglycemic clamps; kidney MRI; kidney PET; polycystic kidney disease.

Figure 1.

Boxplots of ¹¹C-acetate tracer parameters by group Abbreviations: NWC, controls in normal weight category; ADPKD, autosomal dominant polycystic kidney disease; BMI: body mass index; F, cortex perfusion; K1, ¹¹C tracer uptake rate; k2, total oxidative metabolism. *p<0.05, **p<0.01, ***p<0.001 from Mann-Whitney U tests between NWC and overall ADPKD comparison. BMI and ¹¹C-acetate tracer parameters shown by group. BMI is overall slightly lower and less varied in NWC compared to the ADPKD group (p=0.01). Average perfusion, ¹¹C tracer uptake rate, and total oxidative metabolism were significantly lower in participants with ADPKD relative to NWC (p<0.001 for all parameters).

Figure 2.

Volumes of metabolically active kidney tissue The bar graphs display the proportions of K₁ and k₂ voxels with activity levels in the kidneys based on voxel values falling below or above 2 standard deviations of the mean of the NWC. Each bar represents each participant’s activity levels. PET data was available for 20 ADPKD participants (1 missing left kidney) and 11 NWC. One ADPKD participant had insufficient data for classification of the disease. Participants with ADPKD demonstrated lower active levels of kidney tissues relative to NWC. Abbreviations: NWC, controls in normal weight category; ADPKD, autosomal dominant polycystic kidney disease; K1, ¹¹C tracer uptake rate; k2, total oxidative metabolism.

Figure 3.

Heatmap of correlations among clamp, DXA and PET parameters Significant unadjusted correlation coefficients are shown (p<0.05). Blank tiles without a correlation coefficient indicate non-significant unadjusted correlation. Correlation direction shown in color gradient ranging from negative (red) to positive (blue). Significance stars are associated with multivariable linear regression output. Abbreviations: DXA, dual-energy X-ray absorptiometry; PET, position emission tomography; M/I, insulin sensitivity index (M-value/mean insulin concentration); VAT, visceral adipose tissue; TKV, total kidney volume; F, cortex perfusion; K1, ¹¹C tracer uptake rate; k2, total oxidative metabolism. *p<0.05, **p<0.01, ***p<0.001 in multivariable linear regression adjusting for age and sex. ^†Multivariable linear regression between height adjusted TKV and PET driven parameters were adjusted for age, sex, and BMI.