Sirolimus therapy to halt the progression of ADPKD

Abstract

Activation of mammalian target of rapamycin (mTOR) pathways may contribute to uncontrolled cell proliferation and secondary cyst growth in patients with autosomal dominant polycystic kidney disease (ADPKD). To assess the effects of mTOR inhibition on disease progression, we performed a randomized, crossover study (The SIRENA Study) comparing a 6-month treatment with sirolimus or conventional therapy alone on the growth of kidney volume and its compartments in 21 patients with ADPKD and GFR>or=40 ml/min per 1.73 m2. In 10 of the 15 patients who completed the study, aphthous stomatitis complicated sirolimus treatment but was effectively controlled by topical therapy. Compared with pretreatment, posttreatment mean total kidney volume increased less on sirolimus (46+/-81 ml; P=0.047) than on conventional therapy (70+/-72 ml; P=0.002), but we did not detect a difference between the two treatments (P=0.45). Cyst volume was stable on sirolimus and increased by 55+/-75 ml (P=0.013) on conventional therapy, whereas parenchymal volume increased by 26+/-30 ml (P=0.005) on sirolimus and was stable on conventional therapy. Percentage changes in cyst and parenchyma volumes were significantly different between the two treatment periods. Sirolimus had no appreciable effects on intermediate volume and GFR. Albuminuria and proteinuria marginally but significantly increased during sirolimus treatment. In summary, sirolimus halted cyst growth and increased parenchymal volume in patients with ADPKD. Whether these effects translate into improved long-term outcomes requires further investigation.

Figure 1.

Renal volume changes during sirolimus and conventional treatment. (A) Absolute changes in TKV, TCV, and parenchymal and intermediate volumes during the two treatment periods in 15 patients with ADPKD. Kidney volumes are computed using a specifically designed volumetric quantification method based on Otsu's thresholding classification method. ○, Individual values; heavy lines, average values; thin lines, SEM. (B) Relative changes in TKV, TCV, and parenchymal and intermediate volumes during the two treatment periods in 15 patients with ADPKD. Relative changes are computed with respect to absolute volumes at the start of each treatment period. ○, Individual values; heavy lines, average values; thin lines, SEM.

Figure 2.

Trend to increase the blood trough level of sirolimus despite mean dosage drug reduction during the 180 days of follow-up. (A and B) Daily sirolimus doses (A) and blood sirolimus trough levels (B) averaged over 30-day time intervals during the sirolimus treatment period in 15 patients with ADPKD. Data are means ± SE.

Figure 3.

ROC curve identifies the cutoff threshold of sirolimus dosage normalized to patient body weight that predicts treatment effect in reducing or reversing cyst volume growth. The vertical axis, sensitivity, represents the percentage probability that the reduction or reversal in cyst volume growth is detected by sirolimus dosage ratio higher than a given value. The horizontal axis, specificity, represents the percentage probability that sirolimus dosage ratio lower than a given value does not result in reduction or limitation in cyst volume growth. According to the ROC curve analysis, the highest accuracy in predicting treatment effect is at a threshold of 0.049 mg/kg sirolimus dosage to body weight ratio (sensitivity 75%, specificity 86%). The 45° dotted line indicates failure to identify a sirolimus dosage ratio that discriminates between effect and no effect of treatment. AUC, area under the curve for ROC.

Figure 4.

Contrast-enhanced CT volumetric quantification technique and visualization of TCV changes. (A and B) CT image of a representative patient (A) and result of image analysis for the same slice (B), showing voxels classified as cysts (dark gray), parenchyma (white), and intermediate volume (light gray). Upper left corner insets show the regions enclosed by white boxes at high magnification. (C and D) Three-dimensional representation of the image data for the same patient (C) and the resulting volumetric quantification (D), showing the spatial distribution of renal cysts (translucent), intermediate volume (orange), and parenchyma (red). (E and F) Local changes in cyst volume occurring during sirolimus (E) and conventional treatment (F) for a representative patient, color-coded over the outer surface of the identified cyst volume (red for expansion, blue for shrinkage). Local changes are computed as the distance between the cyst volume surfaces at the start and end of the two treatment periods. TCV changes for the patient are −40.27 ml during sirolimus and 121.7 ml during conventional treatment.