Increase In Total Kidney Volume Research Articles

Calculation of Kidney Volumes with Magnetic Resonance in Patients with Autosomal Dominant Polycystic Kidney Disease: Comparison between Methods

Autosomal dominant polycystic renal disease (ADPKD) is the most frequent kidney inheritable disease, characterized by the presence of numerous bilateral renal cysts, causing a progressive increase in total kidney volume (TKV) and a progressive loss of renal function. Several methods can be used to measure TKV by using MRI, and they differ in complexity, accuracy and time consumption. This study was performed to assess the performance of the ellipsoid method and the semi-automatic segmentation method, both for TKV and SKV (single kidney volume) computation. In total, 40 patients were enrolled, and 78 polycystic kidneys analyzed. Two independent operators with different levels of experience evaluated renal volumetry using both methods. Mean error for ellipsoid method for SKV computation was −2.74 ± 11.79% and 3.25 ± 10.02% for the expert and the beginner operator, respectively (p = 0.0008). A Wilcoxon test showed a statistically significant difference between the two operators for both methods (SKV p = 0.0371 and 0.0034; TKV p = 0.0416 and 0.0171 for the expert and the beginner operator, respectively). No inter-operator significant difference was found for the semi-automatic method, in contrast to the ellipsoid method. Both with a Wilcoxon test and Bland–Altman plot, statistically significant differences were found when comparing SKV and TKV measurements obtained with the two methods for both operators, even if the differences are stronger for the beginner operator than for the expert one. The semi-automatic segmentation method showed more inter-observer reproducibility. The ellipsoid method, in contrast, appears to be affected by greater inter-observer variability, especially when performed by operators with limited experience.

11-OR: Fetal Renal Hypoxia Response to Maternal Overnutrition

Currently, 50% of women of reproductive age are obese, and one in seven live births is affected by hyperglycemia in mothers with gestational diabetes. To examine the impact of intrauterine overnutrition on the kidneys of the offspring, we generated a novel mouse model by feeding female C57BL6J mice with either control diet (CD) or high-fat diet (HFD, 60% Lipid) during gestation and feeding the male offspring with CD after weaning, allocated to two groups of male offspring, CD and HFD. CD and HFD had similar body weights, blood pressure and urinary albumin levels, but lower serum creatinine levels in HFD (CD; n=17, HFD; n=11, p<0.001), which might be due to renal hyperfiltration. Histologically, HFD presented renal tubular vacuolation at 4 weeks of age and glomerulosclerosis and intrarenal arteriosclerotic lesions at 15 weeks of age. Moreover, perirenal beige fat phenotype was lost in HFD at 4 week of age, presenting white adipose cells unlike the small adipose cells in CD, suggesting that maternal overnutrition induced systemic metabolic abnormality in offspring. Synchrotron phase-contrast micro-CT showed that HFD at 14.5 dpc showed asignificant increase in total kidney volume (CD; n=4, HFD; n=6, p<0.001). On the contrary, no significant difference in renal artery diameter was observed (p=0.52). Blood flow is determined by the supplying vascular diameter due to Murrays’ minimum energy hypothesis. Therefore, we studied the ratio of blood flow as the 3rd power of the diameter of fetal renal artery per renal volume, indicating no significant difference between CD and HFD (p=0.42). Despite of preserved blood supply, the protein expression of HIF-1α, the key hypoxic transcription factor, was higher in HFD than that in CD, suggesting increased oxygen demand due to maternal overnutrition-induced renal metabolism. Maternal overnutrition induces supply-demand mismatch leading to renal hypoxia in the fetus, which persists into adulthood in the offspring, which might promote susceptibility to diabetic nephropathy. Disclosure T.Takiyama: None. Y.Takiyama: None. R.Bessho: None. H.Kitsunai: None. Y.Takiyama: Research Support; Boehringer Ingelheim Japan, Inc., Taisho Pharmaceutical Holdings Co., Ltd., Ono Pharmaceutical Co., Ltd., Abbott Japan Co., Ltd., Roche Diabetes Care, MSD Life Science Foundation, Japan Society for the Promotion of Science, Teijin Pharma Limited, Kyowa Kirin Co., Ltd., Sumitomo Dainippon Pharma Co., Ltd., Eli Lilly Japan K.K.

Parasympathetic activity and total fibrotic kidney in autosomal-dominant polycystic kidney disease patients: a pilot study

PurposeRenin–angiotensin system hyperactivation in autosomal-dominant polycystic kidney disease (ADPKD) patients leads to early hypertension. Cystic enlargement probably causes parenchymal hypoxia, renin secretion, and endothelial dysfunction. Sympathetic and parasympathetic balance is altered in this condition, especially during the night, also affecting blood pressure circadian rhythm. Aim of this study was to evaluate sympathetic/parasympathetic balance using heart rate variability (HRV) parameters and find a correlation between HRV and renal damage progression, as total kidney volume enlargement, in ADPKD patients.MethodsSixteen adult ADPKD patients were enrolled in the study. Eleven patients (68.8%) were male, and the median age was 42 years (IQR 36–47.5). HRV parameters were calculated using 24 h-ECG Holter. A kidney magnetic resonance imaging (MRI) scan 3 Tesla was performed to evaluate total kidney volume (TKV) and total fibrotic volume (TFV).ResultsA statistically significant positive linear correlation was observed between length of kidneys and frequency domain parameters as low frequency (LF) (r = 0.595, p < 0.05) and LFday (r = 0.587, p < 0.05). Moreover, a statistically significant positive linear correlation exists between high frequency (HF) and TFV (r = 0.804, p < 0.01) or height-adjusted (ha) TFV (r = 0.801, p < 0.01). Finally, we found a statistically significant positive linear correlation between HFnight and TKV (r = 0.608, p < 0.05), ha-TKV (r = 0.685, p < 0.01), TFV (r = 0.594, p < 0.05), and ha-TFV (r = 0.615, p < 0.05).ConclusionWe suppose that the increase in TKV and TFV could lead to a parasympathetic tone hyperactivation, probably in response to hypoxic stress and vasoconstriction due to cystic enlargement.

Imaging features of immune checkpoint inhibitor-related nephritis with clinical correlation: a retrospective series of biopsy-proven cases.

Imaging appearances of immune checkpoint inhibitor-related nephritis have not yet been described. The primary objective of this study is to describe the appearances of immunotherapy-related nephritis on computerized tomography (CT) and positron emission tomography (PET). The secondary objectives are to investigate the association of radiologic features with clinical outcomes. CT and PET-CT scans before the initiation of immunotherapy (baseline), at nephritis, and after resolution of pathology-proven nephritis cases were reviewed. Total kidney volume, renal parenchymal SUVmax, renal pelvis SUVmax, and blood pool SUVmean were obtained. Thirty-four patients were included. The total kidney volume was significantly higher at nephritis compared to baseline (464.7 ± 96.8 mL vs. 371.7 ± 187.7 mL; p < 0.001). Fifteen patients (44.1%) had > 30% increase in total kidney volume, which was associated with significantly higher renal toxicity grade (p = 0.007), higher peak creatinine level (p = 0.004), and more aggressive medical treatment (p = 0.011). New/increasing perinephric fat stranding was noted in 10 patients (29.4%) at nephritis. Among 8 patients with contrast-enhanced CT at nephritis, one (12.5%) developed bilateral wedge-shaped hypoenhancing cortical. On PET-CT, the renal parenchymal SUVmax-to-blood pool ratio was significantly higher at nephritis compared to baseline (2.13 vs. 1.68; p = 0.035). The renal pelvis SUVmax-to-blood pool SUVmean ratio was significantly lower at nephritis compared to baseline (3.47 vs. 8.22; p = 0.011). Bilateral increase in kidney size, new/increasing perinephric stranding, and bilateral wedge-shaped hypoenhancing cortical foci can occur in immunotherapy-related nephritis. On PET-CT, a diffuse increase in radiotracer uptake throughout the renal cortex and a decrease in radiotracer activity in the renal pelvis can be seen. • CT features of immune checkpoint inhibitor-related nephritis include an increase in kidney volume, new/increasing perinephric stranding, and bilateral ill-defined wedge-shaped hypoenhancing cortical foci. • FDG-PET features of immune checkpoint inhibitor-related nephritis include an increase in FDG uptake throughout the renal cortex and a decrease in FDG activity/excretion in the collecting system. • > 30% increase in total kidney volume is associated with worse toxicity grade and more aggressive medical management.

Radiologic features of immune checkpoint inhibitor-related nephritis with clinical correlation in biopsy-proven cases.

e14585 Background: Radiologic findings associated with biopsy proven immune checkpoint inhibitor (ICI) related nephritis have not been described. The objective of this study is to describe the radiologic features of immunotherapy related nephritis on computerized tomography (CT) and positron emission tomography (PET). A secondary objective is to investigate the association of these radiologic features with renal outcomes. Methods: A retrospective review of all biopsy proven ICI-related nephritis between February 2017 and April 2021 was performed and 34 patients were identified. CT and PET-CT scans before the initiation of immune checkpoint inhibitors (baseline), at nephritis and after resolution of nephritis were reviewed. Total kidney volume, renal parenchymal SUVmax, renal pelvis SUVmax and blood pool SUVmean were obtained. Results: The total kidney volume was significantly higher at nephritis compared to baseline (464.7±96.8 mL vs. 371.7±187.7 mL; p &lt; 0.001). Fifteen patients (44.1%) had &gt; 30% increase in total kidney volume at nephritis. A &gt; 30% increase in total kidney volume was associated with significantly higher renal toxicity grade (p = 0.007), higher peak creatinine level (p = 0.004) and more aggressive medical treatment (p = 0.011). New/increasing perinephric fat stranding was noted in 10 patients (29.4%) at nephritis. Among 8 patients with contrast-enhanced CT at nephritis, 1 patient (12.5%) developed bilateral wedge-shaped hypoenhancing cortical lesions that healed with focal scarring on subsequent scans. On PET-CT, the renal parenchymal SUVmax-to-blood pool SUVmean ratio was significantly higher at nephritis compared to baseline (2.13 vs. 1.68; p = 0.035). The renal pelvis SUVmax-to-blood pool SUVmean ratio was significantly lower at nephritis compered to baseline (3.47 vs. 8.22; p = 0.011). Conclusions: Bilateral increase in kidney size, new/increasing perinephric stranding and bilateral wedge-shaped hypoenhancing cortical lesions can occur in immunotherapy-related nephritis. On PET-CT, diffuse bilateral increase in radiotracer uptake throughout the renal cortex and decrease in radiotracer activity in the renal pelvis can be seen. A &gt; 30% increase in total kidney volume was associated with significantly higher renal toxicity grade and more aggressive medical treatment in a subset of patients. Acknowledgment: National Institute of Health K01 Award (N.A.: K01AI163412).

PKD1 Compared With PKD2 Genotype and Cardiac Hospitalizations in the Halt Progression of Polycystic Kidney Disease Studies

Autosomal dominant polycystic disease (ADPKD) is a genetic disorder characterized by progressive development and enlargement of kidney cysts that ultimately lead to loss of kidney function in most individuals.1 ADPKD is primarily caused by mutations in the PKD1 and PKD2 genes.1 Although the hallmark of ADPKD is an increase in total kidney volume with progressive loss of kidney function owing to the accumulation of kidney cysts, cardiovascular complications are a leading cause of death.2 Notably, polycystin 1 and 2 are expressed in vascular endothelial and vascular smooth muscle cells.

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

Abstract 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 &amp;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.

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.

POS-494 An Open label randomized controlled study to evaluate the role of Metformin to retard the progression of ADPKD

Autosomal dominant polycystic kidney disease (ADPKD) is the most common of the inherited renal cystic diseases, contributes to 7- 10% of ESRD patients requiring dialysis. Currently the treatment for ADPKD lacks an effective therapy to retard the progression of the disease. AMPK (AMP activated protein kinase) activation may decrease cell proliferation in cyst wall and fluid secretion in cyst; thereby retarding kidney growth and disease progression. Metformin , a common oral hypoglycemic agent, activates AMPK. Though animal studies show promising result, human studies are few. Current study was planned with hypothesis that patients receiving metformin may have less increase in total kidney volume (TKV) at the end of 1 year follow up than the patients receiving placebo. 70 ADPKD patients, with eGFR > 45ml/min were randomly assigned to either metformin or placebo arm in 1: 1 block. Diabetics, pregnant, breastfeeding females, patients suffering from liver disease were excluded. BP target was fixed at 130/80 and ACEI/ARB were used as 1st line antihypertensive. Primary outcome was percent change in TKV as measured by MRI with planimetry method. Secondary outcomes were percentage change in eGFR and proteinuria from baseline. difference in flank pain episodes requiring analgesic intake, numbers of minor and major adverse events. All the patients were subjected to a detailed clinical and laboratory evaluation at baseline, along with TKV estimation by MRI . In the metformin group patients were given Tab. Metformin 1000 mg/day in two divided doses to start with and increased to 1 gram twice daily. Patients in the placebo arm were given placebo tablets in BD dose. Patients were followed up at 3 monthly intervals. Physical examination and biochemical evaluation (serum creatinine, eGFR by MDRD formula, and 24 hour urine protein test) were performed at each visit. Repeat MRI were obtained at the end of 12 months. Any adverse effects reported during the study period were noted. Results: Total 60 patients (30 patients in each group) was available for final analysis demographic and biochemical parameters like serum creatinine, eGFR and proteinuria were not different among the two groups at baseline with similar BP control in both arms. Mean TKV, as measured by MRI, at baseline, was 588.33 cc vs 563.71 cc in metformin vs control arm. At MO12 increase of TKV by 0.11% (intervention arm) and 1.01%(control arm) were observed , p value (0.001).When analysed among two age groups (< 45 and >45 years) percent change of TKV in metformin arm becomes even more significantly better (p value 0.00026) in the younger age group. Intervention arm shows better proteinuria control ( M0,169.10 and M12: 141.10mg/day, 15.79% decrease and placebo arm M0:186.62 and M12 182.05 mg/day, 2.89% decrease, p value 0.00004), less eGFR decline though not significant. Pain episodes in metformin vs control arm were 72 vs 63, dyspepsia being the commonest side effect in metformin arm. Conclusion: Treatment with metformin significantly slows the rate of growth of kidney

Genetics May Predict Effectiveness of Tolvaptan in Autosomal Dominant Polycystic Kidney Disease

Background: Tolvaptan is the only therapeutic drug for autosomal dominant polycystic kidney disease (ADPKD). The influence of mutations in polycystic kidney disease 1 and 2 genes (PKD1 and PKD2) on the treatment effects of tolvaptan is not well documented in the literature. Methods: We retrospectively evaluated the relationship between genotype and the efficacy of tolvaptan in 18 patients with ADPKD who had been treated at Toranomon Hospital and undergone genetic testing between April 2016 and February 2020. Results: The annual change in estimated glomerular filtration rate (ΔeGFR/y) from before to after tolvaptan was from a median of −5.5 to −2.5 mL/min/1.73 m² in the PKD1 truncating group, −3.3 to −2.4 mL/min/1.73 m² in the PKD1 non-truncating group, −3.1 to −1.6 mL/min/1.73 m² in the PKD2 group, and −1.9 to −2.6 mL/min/1.73 m² in the group with no PKD1/2 mutation. The median degrees of improvement of ΔeGFR/y were 2.5 (45%), 0.4 (10%), 0.6 (28%), and −0.7 (−37%) mL/min/1.73 m², respectively. Compared with the group of patients with any PKD1/2 mutation, the group with no PKD1/2 mutation showed significantly less improvement in ΔeGFR/y with tolvaptan (0.6 vs. −0.7 mL/min/1.73 m², respectively; p = 0.01) and significantly less improvement in the annual rate of increase in total kidney volume (TKV) with tolvaptan (−6.7 vs. −1.1%, respectively; p = 0.02). Conclusion: Patients with ADPKD and no PKD1/2 mutation showed less improvement in ΔeGFR/y and the annual rate of increase in TKV with tolvaptan. Detecting PKD1/2 mutations may be useful for predicting the effectiveness of tolvaptan.

Autosomal-dominant polycystic kidney disease: tolvaptan use in adolescents and young adults with rapid progression.

The phase 3 Tolvaptan Efficacy and Safety in Management of Autosomal Dominant Polycystic Kidney Disease and Its Outcomes (TEMPO 3:4) clinical trial demonstrated the beneficial effect of tolvaptan on kidney growth and function in subjects aged 18-50 years over a 3-year period. However, it did not specifically assess the use of tolvaptan in adolescents and young adults (AYAs) with ADPKD. A post hoc analysis of the TEMPO 3:4 trials was performed for patients aged 18-24 years. The primary outcome was the annual rate of change in total kidney volume (TKV). The secondary outcome was to evaluate long-term safety of tolvaptan using Hy's law of hepatotoxicity. A total of 51 patients in the 18-24 age group were analyzed (tolvaptan: 29, placebo: 22). The tolvaptan group had a lower mean percentage of TKV growth per year compared to the placebo group (3.9% vs. 6.5%, P = 0.0491). For secondary outcomes, 63 patients in the AYA subgroup were evaluated. In both the AYA and adult groups, none of the patients met the criteria for Hy's law of hepatotoxicity. This post hoc analysis suggests that tolvaptan, with appropriate patient selection and management, can provide effective and acceptably safe treatment in AYAs with ADPKD. Tolvaptan slows the increase in total kidney volume in patients aged 18-24 years with ADPKD. Tolvaptan posed no risk of potential liver injury measured via Hy's law of hepatotoxicity in the AYA stratum. This study suggests that tolvaptan has beneficial outcomes in AYAs. This post hoc analysis suggests the need for additional studies with a larger pediatric patient population. The impact is significant as tolvaptan had not been specifically examined in the AYA patient population previously.

Multiparametric MRI assessment of renal structure and function in acute kidney injury and renal recovery.

BackgroundAcute kidney injury (AKI) is associated with a marked increase in mortality as well as subsequent chronic kidney disease (CKD) and end-stage kidney disease. We performed multiparametric magnetic resonance imaging (MRI) with the aim of identifying potential non-invasive MRI markers of renal pathophysiology in AKI and during recovery. MethodsNine participants underwent inpatient MRI scans at time of AKI; seven had follow-up scans at 3 months and 1 year following AKI. Multiparametric renal MRI assessed total kidney volume (TKV), renal perfusion using arterial spin labelling, T1 mapping and blood oxygen level-dependent (BOLD) R2* mapping.ResultsSerum creatinine concentration had recovered to baseline levels at 1-year post-AKI in all participants. At the time of AKI, participants had increased TKV, increased cortex/medulla T1 and reduced cortical perfusion compared with the expected ranges in healthy volunteers and people with CKD. TKV and T1 values decreased over time after AKI and returned to expected values in most but not all patients by 1 year. Cortical perfusion improved to a lesser extent and remained below the expected range in the majority of patients by 1-year post-AKI. BOLD R2* data showed a non-significant trend to increase over time post-AKI.ConclusionsWe observed a substantial increase in TKV and T1 during AKI and a marked decrease in cortical perfusion. Despite biochemical recovery at 1-year post-AKI, MRI measures indicated persisting abnormalities in some patients. We propose that such patients may be more likely to have further AKI episodes or progress to CKD and further longitudinal studies are required to investigate this.

Autosomal dominant polycystic kidney disease: updated perspectives.

Autosomal dominant polycystic kidney disease (ADPKD) is an inherited multisystem disorder, characterized by renal and extra-renal fluid-filled cyst formation and increased kidney volume that eventually leads to end-stage renal disease. ADPKD is considered the fourth leading cause of end-stage renal disease in the United States and globally. Care of patients with ADPKD was, for a long time, limited to supportive lifestyle measures, due to the lack of therapeutic strategies targeting the main pathways involved in the pathophysiology of ADPKD. As the first FDA approved treatment of ADPKD, Vasopressin (V2) receptor blocking agent, tolvaptan, is an urgently awaited advance for ADPKD patients. In our review, we also shed some lights on what is beyond Tolvaptan as there are other medications in the pipeline and many medications have been or are currently being studied in clinical trials such as Tesevatinib, Metformin and Pravastatin, with the goal of slowing the rate of progression of ADPKD by reducing the increase in total kidney volume or maintaining eGFR. Here, we review updates in the perspectives and management of ADPKD.

Plasma copeptin levels predict disease progression and tolvaptan efficacy in autosomal dominant polycystic kidney disease

In the TEMPO 3:4 Trial, treatment with tolvaptan, a vasopressin V2 receptor antagonist, slowed the increase in total kidney volume and decline in estimated glomerular filtration rate (eGFR) in autosomal dominant polycystic kidney disease (ADPKD). We investigated whether plasma copeptin levels, a marker of plasma vasopressin, are associated with disease progression, and whether pre-treatment copeptin and treatment-induced change in copeptin are associated with tolvaptan treatment efficacy. This post hoc analysis included 1,280 TEMPO 3:4 participants (aged 18-50 years, estimated creatinine clearance≥60 ml/min and total kidney volume≥750 mL) who had plasma samples available at baseline for measurement of copeptin using an automated immunofluorescence assay. In placebo-treated subjects, baseline copeptin predicted kidney growth and eGFR decline over 3 years. These associations were independent of sex, age, and baseline eGFR, but were no longer statistically significant after additional adjustment for baseline total kidney volume. In tolvaptan-treated subjects, copeptin increased from baseline to week 3 (6.3 pmol/L versus 21.9 pmol/L, respectively). In tolvaptan-treated subjects with higher baseline copeptin levels, a larger treatment effect was noted with respect to kidney growth rate and eGFR decline. Tolvaptan-treated subjects with a larger percentage increase in copeptin from baseline to week 3 had a better disease outcome, with less kidney growth and eGFR decline after three years. Copeptin holds promise as a biomarker to predict outcome and tolvaptan treatment efficacy in ADPKD.

Genotype-Clinical Correlations in Polycystic Kidney Disease with No Apparent Family History

Background: Genetic characteristics of polycystic kidney disease (PKD) patients without apparent family history were reported to be different from those with a positive family history. However, the clinical course of PKD patients with no apparent family history is not well documented in the literature. Methods: We evaluated the relationship between genotype and the clinical course of 62 PKD patients with no apparent family history. Results: The annual decline of renal function was faster in the patients with PKD1/PKD2 mutation (PKD1 truncating [–3.08; 95% CI –5.30 to –0.87, p = 0.007], PKD1 nontruncating [–2.10; –3.82 to –0.38, p = 0.02], and PKD2 [–2.31; –4.40 to –0.23, p = 0.03]) than in the other patients without PKD1/PKD2 mutation. Similar results were obtained after adjustment for gender, age, estimated glomerular filtration rate (eGFR), height-adjusted total kidney volume (TKV), and mean arterial pressure (MAP). There was no significant difference in the annual decline of renal function among the different PKD1/PKD2 groups, but Kaplan-Meier analysis showed that progression to eGFR < 15 mL/min/1.73 m² was significantly faster in PKD1 truncating group (p = 0.05). The annual rate of TKV increase was larger in the patients with PKD1/PKD2 mutation (PKD1 truncating [4.63; 95% CI 0.62–8.64, p = 0.03], PKD1 nontruncating [3.79; 0.55–7.03, p = 0.02], and PKD2 [2.11; –1.90 to 6.12, p = 0.29]) than in the other patients without PKD1/PKD2 mutation. Similar results were obtained after adjustment for gender, age, eGFR, and MAP. Conclusion: Detection of PKD1/PKD2 mutation, especially PKD1 truncating, is useful for predicting the renal outcome and rate of TKV increase in PKD patients with no apparent family history.

Tolvaptan: A Review in Autosomal Dominant Polycystic Kidney Disease.

Tolvaptan [Jynarque® (USA); Jinarc® (EU, Canada); Samsca® (Japan)] is a highly selective vasopressin V2 receptor antagonist approved for the treatment of autosomal dominant polycystic kidney disease (ADPKD). In the phaseIII TEMPO3:4 trial, 3years' treatment with tolvaptan slowed the increase in total kidney volume (TKV) and the decline in renal function relative to placebo. The composite secondary endpoint of time to investigator-assessed clinical progression also favoured tolvaptan over placebo. Although tolvaptan did not demonstrate a sustained disease-modifying effect on TKV over the longer term in the TEMPO4:4 extension trial, the effect of tolvaptan in slowing renal function decline was maintained for a further 2years. The phaseIII REPRISE trial confirmed the efficacy of tolvaptan in patients with later-stage ADPKD. Most of the adverse events commonly observed with tolvaptan (e.g. polyuria, nocturia, polydipsia, thirst) are consistent with its pharmacological activity. In the TEMPO trials, tolvaptan was also associated with idiosyncratic hepatotoxicity which was reversible on discontinuation of the drug. Although the use of tolvaptan requires careful consideration and balancing of benefits and risks, it provides a valuable treatment option to slow the progression of ADPKD in patients at risk of or with evidence of rapidly progressing disease.

Determinants of Progression in Early Autosomal Dominant Polycystic Kidney Disease: Is it Blood Pressure or Renin-Angiotensin-Aldosterone-System Blockade?

BackgroundThe HALT PKD trial in early autosomal dominant polycystic kidney disease (ADPKD) showed that intensive control of systolic blood pressure to 95-110 mmHg was associated with a 14% slower rate of kidney volume growth compared to standard control. It is unclear whether this result was due to greater blockade of the renin-angiotensin-aldosterone system (RAAS) by allowing the use of higher drug doses in the low blood pressure arm, or due to the lower blood pressure per se.MethodsIn this secondary analysis of HALT PKD Study A, we categorized participants into high and low dose groups based on the median daily equivalent dose of RAAS blocking drugs used after the initial dose titration period. Using linear mixed models, we compared the percent change in total kidney volume and the slope of estimated glomerular filtration rate (eGFR) between the 2 groups. We also assessed the effects of time-varying dose and time-varying blood pressure parameters on these outcomes.ResultsSubjects in the high dose group (n=252) did not experience a slower increase in total kidney volume than those in the low-dose (n=225) group, after adjustment for age, sex, genotype, and BP arm. The chronic slope of eGFR decline was similar in the 2 groups. Higher time-varying systolic blood pressure was associated with a steeper decline in eGFR.ConclusionADPKD progression (as detected by eGFR decline and TKV increase) was ameliorated by intense blood pressure control as opposed to pharmacologic intensity of RAAS blockade.

Is serum copeptin a modifiable biomarker in autosomal dominant polycystic kidney disease?

The availability of disease-modifying drugs for the management of autosomal dominant polycystic kidney disease (ADPKD) has accelerated the need to accurately predict renal prognosis and/or treatment response in this condition. Arginine vasopressin (AVP) is a critical determinant of postnatal kidney cyst growth in ADPKD. Copeptin (the C-terminal glycoprotein of the precursor AVP peptide) is an accurate surrogate marker of AVP release that is stable and easily measured by immunoassay. Cohort studies show that serum copeptin is correlated with disease severity in ADPKD, and predicts future renal events [decline in renal function and increase in total kidney volume (TKV)]. However, serum copeptin is strongly correlated with creatinine, and its additional value as a prognostic biomarker over estimated glomerular filtration rate and TKV is not certain. It has also been suggested that copeptin could be a predictive biomarker to select ADPKD patients who are most likely to benefit from AVP-modifying therapies, but prospective data to validate this assumption are required. In this regard, long-term randomised clinical trials evaluating the effect of prescribed water intake on renal cyst growth may contribute to addressing this hypothesis. In conclusion, although serum copeptin is aligned with the basic pathogenesis of ADPKD, further rigorous studies are needed to define if it will contribute to enabling the delivery of personalised care in ADPKD.

New treatment paradigms for ADPKD: moving towards precision medicine

The natural history of autosomal dominant polycystic kidney disease (ADPKD) is characterized by a variable rate of cyst development and increase in total kidney volume (TKV), variable kidney function decline and age of onset of end-stage renal disease (ESRD), and variable presentation of renal and extrarenal manifestations. Precision medicine is proposed to improve patient outcomes by tailoring therapy to the specific genetic background, pathophysiology, disease burden, prognosis and status of each individual. This approach to the management of patients with ADPKD is nearing clinical implementation owing to advances in genetics, imaging, biomarker development and therapeutics. In this Review, we discuss pharmacological and non-pharmacological interventions for the treatment of hypertension and proteinuria, and for slowing the rate of cyst growth in patients with ADPKD before the development of ESRD. We provide recommendations for the management of renal complications, including cyst infection, nephrolithiasis, haematuria and chronic pain. The early treatment of patients with ADPKD who are largely asymptomatic is associated with a therapeutic burden but slows cyst growth and delays subsequent loss of kidney function, which ultimately delays the need for renal replacement therapy and has a positive effect on the quality of life of patients.

Effects of TORC1 Inhibition during the Early and Established Phases of Polycystic Kidney Disease

The disease-modifying effects of target of rapamycin complex 1 (TORC1) inhibitors during different stages of polycystic kidney disease (PKD) are not well defined. In this study, male Lewis Polycystic Kidney Disease (LPK) rats (a genetic ortholog of human NPHP9, phenotypically characterised by diffuse distal nephron cystic growth) and Lewis controls received either vehicle (V) or sirolimus (S, 0.2 mg/kg by intraperitoneal injection 5 days per week) during the early (postnatal weeks 3 to 10) or late stages of disease (weeks 10 to 20). In early-stage disease, sirolimus reduced kidney enlargement (by 63%), slowed the rate of increase in total kidney volume (TKV) in serial MRI by 78.2% (LPK+V: 132.3±59.7 vs. LPK+S: 28.8±12.0% per week) but only partly reduced the percentage renal cyst area (by 19%) and did not affect the decline in endogenous creatinine clearance (CrCl) in LPK rats. In late-stage disease, sirolimus reduced kidney enlargement (by 22%) and the rate of increase in TKV by 71.8% (LPK+V: 13.1±6.6 vs. LPK+S: 3.7±3.7% per week) but the percentage renal cyst area was unaltered, and the CrCl only marginally better. Sirolimus reduced renal TORC1 activation but not TORC2, NF-κB DNA binding activity, CCL2 or TNFα expression, and abnormalities in cilia ultrastructure, hypertension and cardiac disease were also not improved. Thus, the relative treatment efficacy of TORC1 inhibition on kidney enlargement was consistent at all disease stages, but the absolute effect was determined by the timing of drug initiation. Furthermore, cystic microarchitecture, renal function and cardiac disease remain abnormal with TORC1 inhibition, indicating that additional approaches to normalise cellular dedifferentiation, inflammation and hypertension are required to completely arrest the progression of PKDs.