The Natural Course of Total Kidney Volume in Patients with Autosomal Dominant Polycystic Kidney Disease undergoing Hemodialysis

Objectives: The natural course of native kidneys after hemodialysis initiation in patients with autosomal dominant polycystic kidney disease (ADPKD) remains poorly understood.Methods: We measured the total volumes of native kidneys in 12 patients who had at least one enhanced computed tomography (CT) image both before and after initiation of hemodialysis (group 1) and in 18 patients who had no image before dialysis but more than two images after dialysis (group 2). In patients with images, the last image was used for analysis only after dialysis.Results: The mean total kidney volume (TKV) (± SD) before hemodialysis initiation was 3132 ± 1413 mL and the mean TKV of the last image was 3047 ± 1323 mL in group 1. The mean TKV change rate (%) was - 5.2 ± 27.4% (P > 0.05) during follow-up of 3.9 ± 1.9 years in group 1. The mean TKV change rate was 2.8 ± 34.4% (P > 0.05) in group 2. The follow-up period after dialysis initiation ranged from 4.2 ± 4.7 to 8.0 ± 5.2 years.Conclusions: The results suggest that the TKV of native polycystic kidneys decreases substantially after hemodialysis initiation. This reduction occurs mainly during the early post-hemodialysis period and followed by a slow enlargement of TKV.

Curcumin Therapy to Treat Vascular Dysfunction in Children and Young Adults with ADPKD

Background and Objectives: Clinical manifestations of autosomal dominant polycystic kidney disease (ADPKD), including evidence of vascular dysfunction, can begin in childhood. Curcumin is a polyphenol found in turmeric that reduces vascular dysfunction in rodent models and humans without ADPKD. It also slows kidney cystic progression in a murine model of ADPKD. We hypothesized that oral curcumin therapy would reduce vascular endothelial dysfunction and arterial stiffness in children/young adults with ADPKD. Design, Setting, Participants, and Measurements: In a randomized, placebo-controlled, double-blind trial, 68 children/ young adults 6-25 years of age with ADPKD and an estimated glomerular filtration rate >80 mL/min/1.73 m2 were randomized to either curcumin supplementation (25 mg/kg body weight/day) or placebo, administered in powder form for 12 months. The co-primary outcomes were brachial artery flow-mediated dilation [FMDBA] and aortic pulse-wave velocity [aPWV]. We also assessed change in circulating/urine biomarkers of oxidative stress/inflammation and kidney growth (height-adjusted total kidney volume]) by magnetic resonance imaging. In a sub-group of participants ≥18 years, vascular oxidative stress was measured as the change in FMDBA following an acute infusion of ascorbic acid. Results: Enrolled participants were 18±5 [mean±s.d.] years; 54% female; baseline FMDBA was 9.3±4.1 % change, and baseline aPWV was 512±94 cm/sec. Fifty-seven participants completed the trial. Neither co-primary endpoint changed with curcumin (estimated change [95% confidence interval] for FMDBA (% change): curcumin: 1.14 [-0.84, 3.13]; placebo: 0.33 [-1.34, 2.00]; estimated difference for change: 0.81 [-1.21, 2.84], p=0.48; aPWV (cm/sec: curcumin: 0.6 [-25.7, 26.9]; placebo: 6.5 [-20.4, 33.5]; estimated difference for change: -5.9 [-35.8, 24.0], p=0.67) (intent to treat). There was no curcumin-specific reduction in vascular oxidative stress, nor changes in mechanistic biomarkers. Height-adjusted total kidney volume also did not change as compared to placebo. Conclusions: Curcumin supplementation does not improve vascular function or slow kidney growth in children/young adults with ADPKD.

Early childhood height-adjusted total kidney volume as a risk marker of kidney survival in ARPKD

Autosomal recessive polycystic kidney disease (ARPKD) is characterized by bilateral fibrocystic changes resulting in pronounced kidney enlargement. Impairment of kidney function is highly variable and widely available prognostic markers are urgently needed as a base for clinical decision-making and future clinical trials. In this observational study we analyzed the longitudinal development of sonographic kidney measurements in a cohort of 456 ARPKD patients from the international registry study ARegPKD. We furthermore evaluated correlations of sonomorphometric findings and functional kidney disease with the aim to describe the natural disease course and to identify potential prognostic markers. Kidney pole-to-pole (PTP) length and estimated total kidney volume (eTKV) increase with growth throughout childhood and adolescence despite individual variability. Height-adjusted PTP length decreases over time, but such a trend cannot be seen for height-adjusted eTKV (haeTKV) where we even observed a slight mean linear increase of 4.5 ml/m per year during childhood and adolescence for the overall cohort. Patients with two null PKHD1 variants had larger first documented haeTKV values than children with missense variants (median (IQR) haeTKV 793 (450–1098) ml/m in Null/null, 403 (260–538) ml/m in Null/mis, 230 (169–357) ml/m in Mis/mis). In the overall cohort, estimated glomerular filtration rate decreases with increasing haeTKV (median (IQR) haeTKV 210 (150–267) ml/m in CKD stage 1, 472 (266–880) ml/m in stage 5 without kidney replacement therapy). Strikingly, there is a clear correlation between haeTKV in the first eighteen months of life and kidney survival in childhood and adolescence with ten-year kidney survival rates ranging from 20% in patients of the highest to 94% in the lowest quartile. Early childhood haeTKV may become an easily obtainable prognostic marker of kidney disease in ARPKD, e.g. for the identification of patients for clinical studies.

Synergistic effects of sinapic acid and ellagic acid ameliorate streptozotocin-induced diabetic nephropathy by inhibiting apoptosis, DNA damage, and structural deterioration in rats

Introduction Diabetic nephropathy (DN), a global problem that threatens human health, is an important reason for chronic kidney disease and kidney failure. In our study, it was aimed to investigate the individual and combined effects of SA and EA in streptozotocin (STZ)-induced rats. Methods The groups are as follows: Control, untreated diabetic, diabetic treated with Sinapic acid (SA), diabetic treated with Ellagic acid (EA), diabetic treated with SA and EA, treated with SA, treated with EA, and treated with SA and EA. Total kidney volume, total glomerulus volume, total filtration space volume, caspase-3, and 8-OHdG immunoreactivity, Malondialdehyde (MDA), Glutathione (GSH), Catalase (CAT), serum urea, and creatinine levels were evaluated by stereological, immunohistochemical, and biochemical methods. Results The findings of the study showed that total kidney volume, total glomerulus volume, total filtration gap volume, caspase-3, and 8-OHdG immunoreactivity, MDA, serum urea, and creatinine levels significantly increased in the untreated diabetic group compared to the control group. Also, severe mesangial and glomerular enlargement, extracellular matrix accumulation, and glomerular and tubular basal membrane thickness were observed in the tubulointerstitial and glomerular of the diabetic rats. However, individual and combined treatments of SA and EA ameliorated these histological changes. Additionally, decreased GSH and CAT in the untreated diabetic group increased by SA and EA treatment. Conclusions The findings suggest that treatment of SA and EA prevent apoptosis and DNA damage and structural changes in STZ-induced DN. However, the combined treatment of SA and EA were more effective than their individual treatments in all parameters except serum urea and creatinine.

Semi-Automated 3D Volumetric Renal Measurements in Polycystic Kidney Disease Using b0-Images—A Feasibility Study

Autosomal dominant polycystic kidney disease (ADPKD) eventually leads to end stage renal disease (ESRD) with an increase in size and number of cysts over time. Progression to ESRD has previously been shown to correlate with total kidney volume (TKV). An accurate and relatively simple method to perform measurement of TKV has been difficult to develop. We propose a semi-automated approach of calculating TKV inclusive of all cysts in ADPKD patients based on b0 images relatively quickly without requiring any calculations or additional MRI time. Our purpose is to evaluate the reliability and reproducibility of our method by raters of various training levels within the environment of an advanced 3D viewer. Thirty patients were retrospectively identified who had DWI performed as part of 1.5T MRI renal examination. Right and left TKVs were calculated by five radiologists of various training levels. Interrater reliability (IRR) was estimated by computing the intraclass correlation (ICC) for all raters. ICC values calculated for TKV measurements between the five raters were 0.989 (95% CI = (0.981, 0.994), p < 0.01) for the right and 0.961 (95% CI = (0.936, 0.979), p < 0.01) for the left. Our method shows excellent intraclass correlation between raters, allowing for excellent interrater reliability.

Effect of tolvaptan in Japanese patients with autosomal dominant polycystic kidney disease: a post hoc analysis of TEMPO 3:4 and TEMPO Extension Japan

Background Autosomal dominant polycystic kidney disease (ADPKD) is a progressive condition that eventually leads to end-stage renal disease. A phase 3 trial of tolvaptan (TEMPO 3:4; NCT00428948) and its open-label extension (TEMPO Extension Japan: TEMPO-EXTJ; NCT01280721) were conducted in patients with ADPKD. In this post hoc analysis, effects on renal function and the safety profile of tolvaptan were assessed over a long-term period that included the 3-year TEMPO 3:4 and the approximately 3-year TEMPO-EXTJ trials. Methods Patients from Japanese trial sites who completed TEMPO 3:4 were offered participation in TEMPO-EXTJ. Patients whose efficacy parameters were measured at year 2 in TEMPO-EXTJ for efficacy evaluation were included. The annual slope of the estimated glomerular filtration rate (eGFR) and growth in total kidney volume (TKV) were analyzed. Results In patients who received tolvaptan in TEMPO 3:4 and TEMPO-EXTJ, the annual slope of eGFR (mL/min/1.73 m2) was − 3.480 in TEMPO 3:4 and − 3.417 in TEMPO-EXTJ, with no apparent effect of an approximately 3.6-month off-treatment interval between the two trials. In patients who received a placebo in TEMPO 3:4 before initiating tolvaptan in TEMPO-EXTJ, the slope of eGFR was significantly less steep from TEMPO 3:4 (− 4.287) to TEMPO-EXTJ (− 3.364), a difference of 0.923 (P = 0.0441). Conclusion The TEMPO-EXTJ trial supports a sustained beneficial effect of tolvaptan on eGFR. In patients who received a placebo in TEMPO 3:4, initiation of tolvaptan in TEMPO-EXTJ was associated with a significant slowing of eGFR decline.

Cinacalcet may suppress kidney enlargement in hemodialysis patients with autosomal dominant polycystic kidney disease

A massively enlarged kidney can impact quality of life of autosomal dominant polycystic kidney disease (ADPKD) patients. A recent in vitro study demonstrated that an allosteric modulator of the calcium sensing receptor decreases adenosine-3′,5′-cyclic monophosphate, an important factor for kidney enlargement in ADPKD. Therefore, the present study was performed to determine whether cinacalcet, a calcium sensing receptor agonist, suppresses kidney enlargement in hemodialysis patients with ADPKD. Alteration of total kidney volume together with clinical parameters was retrospectively examined in 12 hemodialysis patients with ADPKD treated at a single institution in Japan. In the non-cinacalcet group with longer hemodialysis duration (n = 5), total kidney volume had an annual increase of 4.19 ± 1.71% during an overall period of 877 ± 494 days. In contrast, the annual rate of increase in total kidney volume in the cinacalcet group (n = 7) was significantly suppressed after cinacalcet treatment, from 3.26 ± 2.87% during a period of 734 ± 352 days before the start of cinacalcet to − 4.71 ± 6.42% during 918 ± 524 days after initiation of treatment (p = 0.047). The present findings showed that cinacalcet could be a novel therapeutic tool for suppression of kidney enlargement in hemodialysis patients with ADPKD.

MO051EFFECT OF TOLVAPTAN ON THE SUPPRESSION OF TOTAL KIDNEY VOLUME INCREASE IN PATIENTS WITH MODERATE-TO-SEVERE RENAL DYSFUNCTION IN AUTOSOMAL DOMINANT POLYCYSTIC KIDNEY DISEASE

Background and Aims Tolvaptan (TV) slows down the increase in total kidney volume (TKV) in patients with autosomal dominant polycystic kidney disease (ADPKD). The efficacy of TV in patients with moderate-to-severe renal dysfunction (RD) in ADPKD remains unknown. Method This was a single-centre retrospective study involving 27 patients with ADPKD who took TV and visited our hospital in the past six years. The participants were divided into two groups: the normal-to-mild RD (estimated glomerular filtration rate (eGFR) ≥ 45mL/min/1.73m2) group and the moderate-to-severe RD (eGFR &lt; 45mL/min/1.73m2) group. Treatment effects were evaluated using ΔTKV, which was calculated as post-/pre-treatment annual TKV change. Continuous variables are presented using the median [interquartile range]. Results The moderate-to-severe RD group comprised 11 patients. Baseline characteristics of the normal-to-mild vs. moderate-to-severe RD group were as follows: eGFR, 56 [50–69] vs. 29 [24–38] mL/min/1.73m2; age, 48 [39–55] vs. 49 [43–58] years; male gender, 57% vs. 36%; body mass index (BMI) , 26 [23–28] vs. 24 [22–27] kg/m2; TKV 1700 [1084–2574] vs. 1827 [1331–2424] mL; family history of ADPKD, 100% vs. 82%; history of cerebral aneurysm, 19% vs. 36%; hypertension, 81% vs. 82%; hyperuricemia, 13% vs. 27%; dyslipidaemia, 19% vs. 18%; diabetes, 6.1% vs. 9.1% and systolic blood pressure (sBP) on admission 138 [129–144] vs. 131 [128-137] mmHg. No significant differences were noted in all these parameters, except for renal function. The starting dose of TV was 60 mg/day in all cases (0.9 [0.7–1.0] vs. 0.9 [0.8–1.1] mg/kg; P = 0.35). Urine volume (7.5 [5.7–9.6] vs. 4.0 [3.3–4.7] L/day; P = 0.006) and urinary sodium excretion (163 [126–226] vs. 89 [81–120] mEq/day; P = 0.003) were higher in the normal-to-mild RD group. Between the groups, there were no differences in urine protein (0.12 [0.0–0.3] vs. 0.16 [0.08–0.29] g/day; P = 0.31) and ΔeGFR (98% [88–123] vs. 106% [102–112]; P = 0.45), which was calculated as post-/pre-treatment annual eGFR change. Although both groups experienced the therapeutic effects of TV, the efficacy was poorer in the moderate-to-severe RD group (ΔTKV, 82% [76–85] vs. 96% [86–97]; P = 0.001). Conclusion The efficacy of TV patients with moderate-to-severe RD in ADPKD might be modest.