Increased Expression of Orexin-A in Patients Affected by Polycystic Kidney Disease.

Orexin-A is a neuropeptide product of the lateral hypothalamus that acts on two receptors, OX1R and OX2R. The orexinergic system is involved in feeding, sleep, and pressure regulation. Recently, orexin-A levels have been found to be negatively correlated with renal function. Here, we analyzed orexin-A levels as well as the incidence of SNPs in the hypocretin neuropeptide precursor (HCRT) and its receptors, HCRTR1 and HCRTR2, in 64 patients affected by autosomal dominant polycystic kidney disease (ADPKD) bearing truncating mutations in the PKD1 or PKD2 genes. Twenty-four healthy volunteers constituted the control group. Serum orexin-A was assessed by ELISA, while the SNPs were investigated through Sanger sequencing. Correlations with the main clinical features of PKD patients were assessed. PKD patients showed impaired renal function (mean eGFR 67.8 ± 34.53) and a statistically higher systolic blood pressure compared with the control group (p < 0.001). Additionally, orexin-A levels in PKD patients were statistically higher than those in healthy controls (477.07 ± 69.42 pg/mL vs. 321.49 ± 78.01 pg/mL; p < 0.001). Furthermore, orexin-A inversely correlated with blood pressure (p = 0.0085), while a direct correlation with eGFR in PKD patients was found. None of the analyzed SNPs showed any association with orexin-A levels in PKD. In conclusion, our data highlights the emerging role of orexin-A in renal physiology and its potential relevance to PKD. Further research is essential to elucidate the intricate mechanisms underlying orexin-A signaling in renal function and its therapeutic implications for PKD and associated cardiovascular complications.

Coregulation Analysis of Mechanistic Biomarkers in Autosomal Dominant Polycystic Kidney Disease.

Autosomal dominant polycystic kidney disease (ADPKD) is the most common hereditary kidney disorder leading to deterioration of kidney function and end stage kidney disease (ESKD). A number of molecular processes are dysregulated in ADPKD but the exact mechanism of disease progression is not fully understood. We measured protein biomarkers being linked to ADPKD-associated molecular processes via ELISA in urine and serum in a cohort of ADPKD patients as well as age, gender and eGFR matched CKD patients and healthy controls. ANOVA and t-tests were used to determine differences between cohorts. Spearman correlation coefficient analysis was performed to assess coregulation patterns of individual biomarkers and renal function. Urinary epidermal growth factor (EGF) and serum apelin (APLN) levels were significantly downregulated in ADPKD patients. Serum vascular endothelial growth factor alpha (VEGFA) and urinary angiotensinogen (AGT) were significantly upregulated in ADPKD patients as compared with healthy controls. Arginine vasopressin (AVP) was significantly upregulated in ADPKD patients as compared with CKD patients. Serum VEGFA and VIM concentrations were positively correlated and urinary EGF levels were negatively correlated with urinary AGT levels. Urinary EGF and AGT levels were furthermore significantly associated with estimated glomerular filtration rate (eGFR) in ADPKD patients. In summary, altered protein concentrations in body fluids of ADPKD patients were found for the mechanistic markers EGF, APLN, VEGFA, AGT, AVP, and VIM. In particular, the connection between EGF and AGT during progression of ADPKD warrants further investigation.

Tolvaptan in Later-Stage Autosomal Dominant Polycystic Kidney Disease.

BACKGROUND: In a previous trial involving patients with early autosomal dominant polycystic kidney disease (ADPKD; estimated creatinine clearance, ≥60 ml per minute), the vasopressin V2-receptor antagonist tolvaptan slowed the growth in total kidney volume and the decline in the estimated glomerular filtration rate (GFR) but also caused more elevations in aminotransferase and bilirubin levels. The efficacy and safety of tolvaptan in patients with later-stage ADPKD are unknown. METHODS: We conducted a phase 3, randomized withdrawal, multicenter, placebo-controlled, double-blind trial. After an 8-week prerandomization period that included sequential placebo and tolvaptan run-in phases, during which each patient's ability to take tolvaptan without dose-limiting side effects was assessed, 1370 patients with ADPKD who were either 18 to 55 years of age with an estimated GFR of 25 to 65 ml per minute per 1.73 m2 of body-surface area or 56 to 65 years of age with an estimated GFR of 25 to 44 ml per minute per 1.73 m2 were randomly assigned in a 1:1 ratio to receive tolvaptan or placebo for 12 months. The primary end point was the change in the estimated GFR from baseline to follow-up, with adjustment for the exact duration that each patient participated (interpolated to 1 year). Safety assessments were conducted monthly. RESULTS: The change from baseline in the estimated GFR was -2.34 ml per minute per 1.73 m2 (95% confidence interval [CI], -2.81 to -1.87) in the tolvaptan group, as compared with -3.61 ml per minute per 1.73 m2 (95% CI, -4.08 to -3.14) in the placebo group (difference, 1.27 ml per minute per 1.73 m2; 95% CI, 0.86 to 1.68; P<0.001). Elevations in the alanine aminotransferase level (to >3 times the upper limit of the normal range) occurred in 38 of 681 patients (5.6%) in the tolvaptan group and in 8 of 685 (1.2%) in the placebo group. Elevations in the aminotransferase level were reversible after stopping tolvaptan. No elevations in the bilirubin level of more than twice the upper limit of the normal range were detected. CONCLUSIONS: Tolvaptan resulted in a slower decline than placebo in the estimated GFR over a 1-year period in patients with later-stage ADPKD. (Funded by Otsuka Pharmaceuticals and Otsuka Pharmaceutical Development and Commercialization; REPRISE ClinicalTrials.gov number, NCT02160145 .).

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.

Cardiac function assessed by myocardial deformation in adult polycystic kidney disease patients.

BACKGROUND: Patients with autosomal dominant polycystic kidney disease (ADPKD) have an increased risk of cardiovascular morbidity and mortality. Impaired left ventricular (LV) global longitudinal strain (GLS) can be a sign of subclinical cardiac dysfunction even in patients with otherwise preserved ejection fraction (EF). Transmitral early filling velocity to early diastolic strain rate (E/SRe) is a novel measure of LV filling pressure, which is often affected early in cardiac disease. METHODS: A total of 110 ADPKD patients not on dialysis were included in this prospective study. All patients underwent an extensive echocardiographic examination including two-dimensional speckle tracking. GLS and strain rates were measured. The distribution of GLS and E/SRe was determined and patient characteristics were compared by median levels of GLS (- 17.8%) and E/SRe (91.4 cm). Twenty healthy participants were included as control group. RESULTS: There was a significantly worse GLS in the ADPKD patients (mean: - 17.8 ± 2.5%) compared to the healthy controls (mean: - 21.9 ± 1.9%), p < 0.001. The same was true for E/SRe (mean: 10.0 ± 0.3 cm) compared to the control group (mean: 6.5 ± 0.3 cm), p < 0.001. In simple logistic regression, male gender (OR: 4.74 [2.10-10.71], p < 0.001), fasting glucose (odds ratio (OR) 1.05 [1.01-1.10], p = 0.024), htTKV (OR: 1.07 [1.01-1.13], p = 0.013), HDL cholesterol (OR: 0.97 [0.94, 0.996], p = 0.025), triglycerides (OR: 1.01 [1.00-1.02], p = 0.039), hemoglobin (OR: 1.50 [1.11-2.04], p = 0.009), and ß-blocker use (OR: 1.07 [1.01, 1.13], p = 0.013) were all associated with higher GLS. After multivariate logistic regression with backward model selection, only male gender (OR: 5.78 [2.27-14.71], p < 0.001) and ß-blocker use (OR: 14.00 [1.60, 122.51], p = 0.017) remained significant. In simple logistic regression models, BMI (OR: 1.11 [1.02-1.20], p = 0.015), systolic blood pressure (OR: 1.03 [1.00-1.06], p = 0.027) and ß-blocker use (OR: 17.12 [2.15-136.20], p = 0.007) were associated with higher E/SRe - a novel measure of left ventricular filling pressure. After backward elimination, only ß-blocker use (OR: 17.22 [2.16, 137.14], p = 0.007) remained significant. CONCLUSION: Higher GLS and E/SRe are common in ADPKD patients, even in patients with preserved eGFR and normal left ventricular EF. GLS and E/SRe may aid in cardiovascular risk stratification in patients with ADPKD as they represent early markers of cardiac dysfunction.

Plasma metabolites and lipids associate with kidney function and kidney volume in hypertensive ADPKD patients early in the disease course.

BACKGROUND: Autosomal dominant polycystic kidney disease (ADPKD) is the most common hereditary kidney disease and is characterized by gradual cyst growth and expansion, increase in kidney volume with an ultimate decline in kidney function leading to end stage renal disease (ESRD). Given the decades long period of stable kidney function while cyst growth occurs, it is important to identify those patients who will progress to ESRD. Recent data from our and other laboratories have demonstrated that metabolic reprogramming may play a key role in cystic epithelial proliferation resulting in cyst growth in ADPKD. Height corrected total kidney volume (ht-TKV) accurately reflects cyst burden and predicts future loss of kidney function. We hypothesize that specific plasma metabolites will correlate with eGFR and ht-TKV early in ADPKD, both predictors of disease progression, potentially indicative of early physiologic derangements of renal disease severity. METHODS: To investigate the predictive role of plasma metabolites on eGFR and/or ht-TKV, we used a non-targeted GC-TOF/MS-based metabolomics approach on hypertensive ADPKD patients in the early course of their disease. Patient data was obtained from the HALT-A randomized clinical trial at baseline including estimated glomerular filtration rate (eGFR) and measured ht-TKV. To identify individual metabolites whose intensities are significantly correlated with eGFR and ht-TKV, association analyses were performed using linear regression with each metabolite signal level as the primary predictor variable and baseline eGFR and ht-TKV as the continuous outcomes of interest, while adjusting for covariates. Significance was determined by Storey's false discovery rate (FDR) q-values to correct for multiple testing. RESULTS: Twelve metabolites significantly correlated with eGFR and two triglycerides significantly correlated with baseline ht-TKV at FDR q-value < 0.05. Specific significant metabolites, including pseudo-uridine, indole-3-lactate, uric acid, isothreonic acid, and creatinine, have been previously shown to accumulate in plasma and/or urine in both diabetic and cystic renal diseases with advanced renal insufficiency. CONCLUSIONS: This study identifies metabolic derangements in early ADPKD which may be prognostic for ADPKD disease progression. CLINICAL TRIAL: HALT Progression of Polycystic Kidney Disease (HALT PKD) Study A; Clinical www.clinicaltrials.gov identifier: NCT00283686; first posted January 30, 2006, last update posted March 19, 2015.

TRPP2 dysfunction decreases ATP-evoked calcium, induces cell aggregation and stimulates proliferation in T lymphocytes.

BACKGROUND: Autosomal dominant polycystic kidney disease (ADPKD) is mainly characterised by the development and enlargement of renal cysts that lead to end-stage renal disease (ESRD) in adult patients. Other clinical manifestations of this pathology include hypertension, haematuria, abdominal pain, cardiovascular system alterations and intracranial aneurysms. ADPKD is linked to mutations in either PKD1 or PKD2 that codifies polycystin-1 (PC1) and polycystin-2 (PC2 or TRPP2), respectively. PC1 and TRPP2 are membrane proteins that function as receptor-channel elements able to regulate calcium homeostasis. The function of polycystins has been mainly studied in kidney cells; but the role of these proteins in T lymphocytes is not well defined. METHODS: T lymphocytes were produced from ADPKD1 and ADPKD2 patients as well as from non-ADPKD subjects undergoing renal replacement therapy (RRT) and healthy controls. Protein expression and phosphorylation levels were analysed by western blotting, cell proliferation was calculated by direct counting using trypan blue assay and intracellular calcium concentration was measured by Fura-2 method. RESULTS: PKD2 mutations lead to the significant reduction of TRPP2 expression in T lymphocytes derived from ADPKD patients. Furthermore, a smaller TRPP2 truncated protein in T lymphocytes of patients carrying the mutation R872X in PKD2 was also observed, suggesting that TRPP2 mutated proteins may be stably expressed. The silencing or mutation of PKD2 causes a strong reduction of ATP-evoked calcium in Jurkat cells and ADPKD2 T lymphocytes, respectively. Moreover, T lymphocytes derived from both ADPKD1 and ADPKD2 patients show increased cell proliferation, basal chemotaxis and cell aggregation compared with T lymphocytes from non-ADPKD subjects. Similarly to observations made in kidney cells, mutations in PKD1 and PKD2 dysregulate ERK, mTOR, NFkB and MIF pathways in T lymphocytes. CONCLUSIONS: Because the alteration of ERK, mTOR, NFkB and MIF signalling found in T lymphocytes of ADPKD patients may contribute to the development of interstitial inflammation promoting cyst growth and kidney failure (ESRD), the targeting of inflammasome proteins could be an intriguing option to delay the progression of ADPKD.

Different Effects of Iron Indices on Mortality in Patients With Autosomal Dominant Polycystic Kidney Disease After Long-Term Hemodialysis: A Nationwide Population-Based Study.

OBJECTIVE: Iron supplementation and erythropoietin stimulating agents (ESAs) are essential for maintaining hemoglobin levels in hemodialysis patients. However, patients with autosomal-dominant polycystic kidney disease (PKD) have higher endogenous erythropoietin levels, so their recommended iron indices for hemodialysis patients may differ. This study evaluated iron profiles, including ferritin levels and transferrin saturation (TSAT) to identify factors affecting mortality in patients on dialysis, and those associated with mortality in patients with and without PKD. DESIGN: This cohort study from the Taiwan Renal Registry Data System stratified mortality risk by the presence of PKD recorded as the underlying disease. SUBJECTS: We enrolled 1346 hemodialysis patients with PKD and 82,873 hemodialysis patients without PKD. MAIN OUTCOME MEASURE: The primary outcome was 3-year all-cause mortality. Predictors included time-averaged and baseline serum ferritin levels and TSAT. Multivariate Cox regression analysis adjusting for age, comorbidities, and relevant laboratory parameters was used to estimate the all-cause hazard ratios (HRs) for mortality. RESULTS: The mean ages of patients with and without PKD were 56.2±13.2 and 61.7±13.5 years and the median follow-up time was 37 (15-76) months. The adjusted mortality risks for time-averaged ferritin levels >800 ng/mL (HR=1.52; 95% confidence interval: 1.40-1.65) or TSAT levels >50% (HR=1.46; 95% confidence interval: 1.30-1.65) were significantly higher among patients without PKD than those for patients with normal iron indices. However, a U-shaped curve of mortality against ferritin/TSAT levels was not observed in patients with PKD. In the sensitivity test, there was no difference among PKD patients who underwent regular ESA therapy and those who did not. CONCLUSION: Iron indices have different effects on mortality among patients with and without PKD. Iron supplementation, recommended serum ferritin levels, or TSAT should be monitored in hemodialysis patients, especially those without PKD. Clinicians should consider treating anemia in hemodialysis patients individually, especially in PKD.

Levels of Endocan, Angiopoietin-2, and Hypoxia-Inducible Factor-1a in Patients with Autosomal Dominant Polycystic Kidney Disease and Different Levels of Renal Function.

BACKGROUND: Endothelial dysfunction leading to unbalanced vasoconstriction and ischemia of renal parenchyma is increasingly proposed as an alternative pathway of renal damage in autosomal dominant polycystic kidney disease (ADPKD). However, human studies investigating the evolution of such phenomena are limited. This study investigated the levels of emerging biomarkers of endothelial function, angiogenesis and hypoxia, in ADPKD patients with different renal function. METHODS: The study population consisted of three groups: 26 ADPKD patients with impaired renal function (Group A; estimated glomerular filtration rate [eGFR] 45-70 mL/min/1.73 m2), 26 ADPKD patients with preserved renal function (Group B; eGFR >70 mL/min/1.73 m2), and 26 age- and sex-matched controls with no history of renal disease. Circulating levels of endocan (endothelial cell-specific molecule-1) angiopoietin-2, and hypoxia-inducible factor-1a (HIF-1a) were determined by enzyme-linked immunosorbent assay techniques. RESULTS: Patients in Group A had significantly higher levels of endocan (7.17 ± 0.43 ng/mL), angiopoietin-2 (5,595.43 ± 3,390), and HIF-1a (163.68 ± 37.84 pg/mL) compared to patients in Group B (6.86 ± 0.59 ng/mL, p = 0.017, 3,854.41 ± 3,014.30, p = 0.018, 136.84 ± 42.10 pg/mL, p = 0.019 respectively) or controls (4.83 ± 0.69 ng/mL, 1,069 ± 427.88 pg/mL, 70.20 ± 17.49 pg/mL, p < 0.001 for all comparisons). Of note, patients in Group B had also higher levels of all markers compared to controls (p < 0.001) despite having similar renal function. In correlation analyses within ADPKD patients, we noted strong correlations of all studied markers with asymmetric dimethylarginine (ADMA; endocan r = 0.908, p < 0.001, angiopoietin-2 r = 0.983, p < 0.001 and HIF-1a r = 0.998, p < 0.001), and only weak or modest correlations with eGFR. CONCLUSIONS: This study suggests that endothelial dysfunction causing microcirculatory changes, linked to angiogenesis and hypoxia, may come early in the course of ADPKD and could be a key regulator of renal injury progression.

Serum Fas Ligand, Serum Myostatin and Urine TGF-ß1 Are Elevated in Autosomal Dominant Polycystic Kidney Disease Patients with Impaired and Preserved Renal Function.

BACKGROUND/AIMS: The pathophysiology of renal disease progression in autosomal dominant polycystic disease (ADPKD) is largely unknown. Recent evidence suggests microvascular dysfunction leading to renal ischemia, as an additional pathway for renal function decline. This study examined the levels of serum Fas ligand (FasL), serum myostatin and urine transforming growth factor-beta 1 (TGF-ß1) and their association with markers of endothelial dysfunction, in ADPKD patients with preserved or impaired renal function. METHODS: Seventy-eight participants were enrolled in the study, divided in three groups: Group A consisted of 26 ADPKD patients with impaired renal function (eGFR 45-70 ml/min/1.73m2), Group B of 26 ADPKD patients with preserved renal function (eGFR > 70 ml/min/1.73m2), and Group C of 26 age- and sex- matched controls with no history of renal disease. Serum FasL, myostatin and urine levels of TGF-ß1 were measured as biomarkers of vascular dysfunction, apoptosis and fibrosis with ELISA techniques. RESULTS: Group A patients had significantly higher levels of FasL (13.12±1.69 ng/mL), myostatin (4.62±0.59 ng/mL) and urine logTGF-ß1 (3.56±0.49 ng/24h) compared to Group B (9.6±1.28 ng/mL, 3.06±0.35, and 2.09±0.37, respectively, p< 0.001 for all comparisons) or controls (6.59±1.17 ng/mL, 2.18±0.45 ng/ml, and 1.58±0.21, respectively, p< 0.001 for all comparisons). Patients in Group B had also higher levels of all markers compared to controls (p< 0.001), despite having similar renal function. In ADKPD patients negative associations of eGFR with FasL (r=-0.799, p< 0.001), myostatin (r=-0.856, p< 0.001) and TGF-ß1 (r=-0.476, p< 0.001) but positive correlations of these markers with asymmetric dimethylarginine (ADMA) (r=0.825; r=0.749; and r=0.599, respectively p< 0.001) were noted. Multivariate analysis demonstrated that FasL was independently associated with high urine TGF-ß1 (OR 3.774, 95%CI 1.180-12.072, p=0.025). CONCLUSIONS: ADPKD patients with moderately preserved renal function have higher levels of FasL, myostatin and urine TGF-ß1 than controls. These results indicate that an interplay between endothelial dysfunction and renal ischemia with mechanisms linked to apoptosis and fibrosis may be present even in early stages of ADPKD.

The Association of Fibroblast Growth Factor 23 with Arterial Stiffness and Atherosclerosis in Patients with Autosomal Dominant Polycystic Kidney Disease.

BACKGROUND/AIMS: In patients with autosomal dominant polycystic kidney disease (ADPKD), cardiovascular events are the most frequent cause of mortality and morbidity. The aim of our study is to investigate the association between serum fibroblast growth factor-23 (FGF-23) and arterial stiffness (AS) as determined with brachial-ankle pulse wave velocity (baPWV) and atherosclerosis development as determined with carotid artery intima-media thickness (CA- IMT). METHODS: This cross-sectional study was conducted with totally 86 ADPKD patients, 50 (58.1%) female and 36 (41.9%) male, with a mean age of 49.5 ± 13.9 years. Patients were compared with healthy control group with similar distribution of age and gender. AS was assessed with baPWW, and atherosclerosis development was assessed with CA-IMT. CA-IMT > 9 mm was considered as increased atherosclerosis. Serum FGF-23 and soluble klotho (s-KL) levels were measured with enzyme-linked immunosorbent assay. Due to skewed distribution of variables, statistical calculations of FGF-23 and s-KL were performed with log10. RESULTS: According to the CKD stages, 46 (53.5%) patients had stage 1-2, 32 (37.2%) had stage 3-4, and 8 (9.3%) had predialysis stage 5 disease. Mean log10FGF-23 was 2.43 ± 0.41 pg/mL, and mean log10s-KL was 1.28 ± 0.09 ng/mL. Mean baPWV was 7.48 ± 1.68 m/sec, and mean CA-IMT was 0.63 ± 0.14 mm. Among patients at various stages of CKD, systolic blood pressure (SBP) (p = 0.003), diastolic blood pressure (DBP) (p = 0.002), creatinine, 1.25hydroxy(OH)2VitaminD3, log10FGF-23, baPWV, CA-IMT were higher (p < 0.001)andlog10s-KL were lower (p < 0.001) in comparison to healthy individuals. FGF-23 was positively correlated with creatinine, 1.25(OH)2VitD3 (p < 0.001), baPWV (p = 0.002) and CA-IMT (p = 0.005), and negatively correlated with eGFR (p < 0.001). CONCLUSION: In patients with ADPKD, as the disease stage advanced, serum FGF-23 levels increased while s-KL decreased. In ADPKD patients, AS and atherosclerosis development increased as compared to healthy subjects, and as CKD advanced. In ADPKD patients, the effect of serum FGF-23 on the development of AS and atherosclerosis in peripheral vessels is independent of s-KL.

Tolvaptan promotes urinary excretion of sodium and urea: a retrospective cohort study.

BACKGROUND: Tolvaptan (TLV) promotes aquaresis; however, little is known about its effect on solute excretion in chronic kidney disease (CKD). METHODS: We retrospectively studied CKD patients with decompensated heart failure (HF) or those with autosomal dominant polycystic kidney disease (ADPKD) receiving TLV. Patients with an increased urine volume of more than twice of daily variance were defined as "responders" in HF. We compared the ability of the urinary osmolality (U-OSM) change and urinary creatinine concentration ([U-Cr]) change to discriminate "responders". The fractional excretion of sodium (FeNa) and urea nitrogen (FeUN), and blood urea nitrogen (BUN) were monitored. RESULTS: In 30 responders among 53 HF patients, TLV increased FeUN significantly from 36.1 to 44.2% after starting TLV, but not FeNa. Since U-OSM is determined partially by urinary UN concentration, the decrease of [U-Cr] after treatment outperformed the U-OSM decrement to discriminate responders, as shown in receiver operating characteristic curve analysis and significantly higher net reclassification index. In 13 ADPKD patients, TLV increased FeUN (34.8, 47.3%, p = 0.02), and significant decrease of BUN by 2.3 (95% confidence interval 0.4-4.2) mg/dL was observed even 3 months after the intervention. Systolic blood pressure decreased significantly by 14.2 (95% confidence interval 4.0-24.4) mmHg along with the increase in FeNa, leading to reduced dosage of antihypertensives in 6 patients. CONCLUSION: TLV promotes the excretion of sodium and urea. The change in [U-Cr] is useful for early discrimination of responders. Hypotension should be carefully monitored during high-dose TLV therapy.

Clinical experience with white blood cell-PET/CT in autosomal dominant polycystic kidney disease patients with suspected cyst infection: A prospective case series.

AIMS: Cyst infection (CI) is a common problem in patients with autosomal dominant polycystic kidney disease (ADPKD). Localization is of great importance in CI. We describe the clinical experience with [18F] FDG-labelled white-blood cell (WBC) PET/CT in detecting CI in ADPKD. METHODS: Nineteen ADPKD patients (M:F = 7:12) suspected of having CI were enrolled in this prospective study. All underwent WBC-PET/CT and MRI or CT. The degree of their WBC accumulation was evaluated from the maximal standardized uptake value of cystic wall. RESULTS: Cyst infection was diagnosed in 14 cases [definite (n = 6), probable (n = 1), or possible (n = 7); kidney (n = 11), or liver (n = 3)]. There was no difference in fever or laboratory findings (White blood cell count, C-reactive protein, culture results, and eGFR). The blood culture was positive only in a subset of CI patients (n = 4). Cyst fluid culture yielded bacterial growth in 80% of aspirates. WBC-PET/CT detected 64% of CI cases, whereas conventional imaging, 50%. WBC-PET/CT showed false-positive results in two of five cases with no CI. The reasons for false negatives with WBC-PET/CT were poor host immune reaction, low virulence, or prior antibiotic therapy. Haemorrhagic cysts were the most common cause of false positivity in WBC-PET/CT. However, WBC-PET/CT detected CI in three cases, in which the conventional imaging failed to find CI. CONCLUSIONS: Clinical information may play little role in the diagnosis of CI. WBC-PET/CT can be used to detect CI with better sensitivity in ADPKD patients, circumventing the exposure to contrast media.

Carbohydrate antigen 19-9 is significantly elevated in autosomal dominant polycystic kidney disease.

AIM: Liver cysts are the most common extrarenal manifestation in patients with autosomal dominant polycystic kidney disease (ADPKD). Carbohydrate antigen 19-9 (CA19-9) is generally used as a marker for biliopancreatic malignancies, although CA19-9 levels in patients with ADPKD are largely unknown. METHODS: A prospective observational study of 53 ADPKD patients and 83 non-ADPKD control subjects was performed. The serum levels of CA19-9 were studied to evaluate the association with clinical parameters and liver cysts. RESULTS: The serum CA19-9 levels were significantly higher in the ADPKD group than in the control group (32.9 U/mL vs. 9.8 U/mL, respectively, P < 0.001). The serum CA19-9 levels in the ADPKD group were positively correlated with the mean blood pressure (rho = 0.335, P < 0.05), gamma-glutamyl transferase (GTP) levels (rho = 0.541, P < 0.001), the largest cyst size (rho = 0.536, P < 0.001) and the liver cyst volume (rho = 0.682, P < 0.001). Multiple regression analyses showed that the gamma-GTP levels (P < 0.001) and the liver cyst volumes (P < 0.001) were independent predictors for serum CA19-9 levels. CONCLUSIONS: Serum CA19-9 levels are significantly elevated and appear to be dependent on the gamma-GTP levels and the volume of liver cysts in patients with ADPKD. Our findings indicate that the measurement of the baseline CA19-9 level in each patient with ADPKD may be useful for the interpretation of the value and the differential diagnosis of liver diseases, particularly the liver cyst infection.

Do metabolic derangements in end-stage polycystic kidney disease differ versus other primary kidney diseases?

AIM: Autosomal dominant polycystic kidney disease (ADPKD), a systemic disorder caused by mutation in genes encoding polycystins, has been reported to lead to metabolic derangements including new-onset diabetes mellitus after kidney transplantation. We analyzed markers of insulin resistance (IR), inflammation, nutritional status and insulin-like growth factor-1 (IGF-1) in end-stage renal disease (ESRD) patients with ADPKD and ESRD patients with other primary kidney diseases. METHODS: In a post hoc cross-sectional analysis in 254 non-diabetic CKD 5 patients starting on dialysis, glucose metabolism (insulin, IGF-1, homeostasis model assessment of IR, HOMA-IR), inflammation (high sensitivity C-reactive protein, interleukin-6, and tumour necrosis factor), nutritional status, and bone mineral density (BMD), were assessed. Survival was recorded for median time of 28 months (IQR 15-48 months). RESULTS: Neither indices of IR, nor IGF-1, inflammatory status, nutritional status, or BMD were different in patients with ADPKD as compared to other aetiologies of ESRD. Kaplan-Meier curves showed better survival among the ADPKD group versus other aetiologies, even after an exclusion of diabetic patients. CONCLUSIONS: The ESRD phenotype did not differ in ADPKD versus other primary kidney diseases in terms of markers of IR, inflammation, and nutritional status. This argues against the proposition that ADPKD patients are more prone to develop metabolic derangements beyond those generally observed in advanced CKD. However, additional studies are warranted to further elucidate systemic metabolic aspects of ADPKD.

Association of plasma somatostatin with disease severity and progression in patients with autosomal dominant polycystic kidney disease.

BACKGROUND: Somatostatin (SST) inhibits intracellular cyclic adenosine monophosphate (cAMP) production and thus may modify cyst formation in autosomal dominant polycystic kidney disease (ADPKD). We investigated whether endogenous plasma SST concentration is associated with disease severity and progression in patients with ADPKD, and whether plasma SST concentrations change during treatment with a vasopressin V2 receptor antagonist or SST analogue. METHODS: In this observational study, fasting concentrations of SST were measured in 127 ADPKD patients (diagnosed upon the revised Ravine criteria) by ELISA. cAMP was measured in 24 h urine by Radio Immuno Assay. Kidney function was measured (mGFR) as 125I-iothalamate clearance, and total kidney volume was measured by MRI volumetry and adjusted for height (htTKV). Disease progression was expressed as annual change in mGFR and htTKV. Additionally, baseline versus follow-up SST concentrations were compared in ADPKD patients during vasopressin V2 receptor antagonist (tolvaptan) (n = 27) or SST analogue (lanreotide) treatment (n = 25). RESULTS: In 127 ADPKD patients, 41 ± 11 years, 44% female, eGFR 73 ± 32 ml/min/1.73m2, mGFR 75 ± 32 ml/min/1.73m2 and htTKV 826 (521-1297) ml/m, SST concentration was 48.5 (34.3-77.8) pg/ml. At baseline, SST was associated with urinary cAMP, mGFR and htTKV (p = 0.02, p = 0.004 and p = 0.02, respectively), but these associations lost significance after adjustment for age and sex or protein intake (p = 0.09, p = 0.06 and p = 0.15 respectively). Baseline SST was not associated with annual change in mGFR, or htTKV during follow-up (st. ß = - 0.02, p = 0.87 and st. ß = - 0.07, p = 0.54 respectively). During treatment with tolvaptan SST levels remained stable 38.2 (23.8-70.7) pg/mL vs. 39.8 (31.2-58.5) pg/mL, p = 0.85), whereas SST levels decreased significantly during treatment with lanreotide (42.5 (33.2-55.0) pg/ml vs. 29.3 (24.8-37.6), p = 0.008). CONCLUSIONS: Fasting plasma SST concentration is not associated with disease severity or progression in patients with ADPKD. Treatment with lanreotide caused a decrease in SST concentration. These data suggest that plasma SST cannot be used as a biomarker to assess prognosis in ADPKD, but leave the possibility open that change in SST concentration during lanreotide treatment may reflect therapy efficacy.

Elevated factor H-related protein 1 and factor H pathogenic variants decrease complement regulation in IgA nephropathy.

IgA nephropathy (IgAN), a frequent cause of chronic kidney disease worldwide, is characterized by mesangial deposition of galactose-deficient IgA1-containing immune complexes. Complement involvement in IgAN pathogenesis is suggested by the glomerular deposition of complement components and the strong protection from IgAN development conferred by the deletion of the CFHR3 and CFHR1 genes (ΔCFHR3-CFHR1). Here we searched for correlations between clinical progression and levels of factor H (FH) and FH-related protein 1 (FHR-1) using well-characterized patient cohorts consisting of 112 patients with IgAN, 46 with non-complement-related autosomal dominant polycystic kidney disease (ADPKD), and 76 control individuals. Patients with either IgAN or ADPKD presented normal FH but abnormally elevated FHR-1 levels and FHR-1/FH ratios compared to control individuals. Highest FHR-1 levels and FHR-1/FH ratios are found in patients with IgAN with disease progression and in patients with ADPKD who have reached chronic kidney disease, suggesting that renal function impairment elevates the FHR-1/FH ratio, which may increase FHR-1/FH competition for activated C3 fragments. Interestingly, ΔCFHR3-CFHR1 homozygotes are protected from IgAN, but not from ADPKD, and we found five IgAN patients with low FH carrying CFH or CFI pathogenic variants. These data support a decreased FH activity in IgAN due to increased FHR-1/FH competition or pathogenic CFH variants. They also suggest that alternative pathway complement activation in patients with IgAN, initially triggered by galactose-deficient IgA1-containing immune complexes, may exacerbate in a vicious circle as renal function deterioration increase FHR-1 levels. Thus, a role of FHR-1 in IgAN pathogenesis is to compete with complement regulation by FH.

Fibulin Levels in Autosomal Dominant Polycystic Kidney Disease and Its Relationship to Arterial Stiffness.

BACKGROUND: The objective of the present study was to evaluate fibulin 1 levels in different stages of patients with autosomal dominant polycystic kidney disease (ADPKD) and investigate possible connections between fibulin-1 and arterial stiffness. METHODS: For this cross-sectional study, we included 74 patients with ADPKD (mean age, 50.92 ± 15.70 years) and 32 healthy controls (mean age, 49.53 ± 7.32 years). Patients with ADPKD were classified based on CKD epidemiology collaboration (CKD-EPI) equation assessments of estimated glomerular filtration rate (eGFR). Blood levels of fibulin 1 and creatinine levels were analyzed. We measured brachial artery PWV (baPWV), augmentation index (AIx), and pulse pressure (PP) for the assessment of arterial stiffness and systolic and diastolic blood pressures (SBP and DBP, respectively). RESULTS: Fibulin 1 was significantly higher in the patient group (p < 0.001). SBP, DBP, MAP, PP, and baPWV levels were also significantly higher in the patient group. A statistically significant positive correlation was found between fibulin 1 and creatinine (r = 0.377, p = 0.001). No significant correlation was found between the fibulin 1 levels and age, SBP, DBP, MAP, baPWV, and AIx. CONCLUSIONS: Plasma concentrations of fibulin 1 increased in patients with ADPKD. Arterial stiffness measured by baPWV increased in patients with ADPKD, but it was not related to fibulin 1 levels.

Fibroblast growth factor 23 and soluble Klotho in patients with autosomal dominant polycystic kidney disease.

AIM: This study aimed to examine the roles of fibroblast growth factor 23 (FGF23) and soluble Klotho in phosphate metabolism in autosomal-dominant polycystic kidney disease (ADPKD) patients. METHODS: We measured these two factors and phosphate metabolism parameters in 80 patients with ADPKD and 53 patients with non-diabetic chronic kidney disease (CKD). RESULTS: The mean serum FGF23 level in the ADPKD group was significantly (twofold) higher than in the non-diabetic CKD patients, but the mean soluble Klotho level in the ADPKD group was significantly lower in the non-diabetic CKD group. The mean serum phosphate levels of the two groups were similar. The estimated glomerular filtration rate (eGFR) was approximately 45 mL/min per 1.73 m2 in both groups, and their serum vitamin D metabolite levels were in the normal range. CONCLUSION: The serum FGF23 levels were significantly higher and soluble Klotho levels significantly lower in the ADPKD group than in the non-diabetic CKD group matched for eGFR, and these findings may be associated with resistance of renal phosphate excretion.

Serum micro-rna profiles in patients with autosomal dominant polycystic kidney disease according to hypertension and renal function.

BACKGROUND: Autosomal dominant polycystic kidney disease (ADPKD) is a common hereditary disorder with unclear disease mechanism. Currently, overt hypertension and increased renal volume are the best predictors of renal function. In this study, we assessed the usefulness of selected circulating microRNAs (miRs) to predict disease progress in a cohort with ADPKD. METHODS: Eighty ADPKD patients (44.6 ± 12.7 years, 40% female, 65% hypertensive) and 50 healthy subjects (HS; 45.4 ± 12.7, 44% female) were enrolled in the study. Serum levels of 384 miRs were determined by Biomark Real Time PCR. Groups were compared using the limma method with multiple-testing correction as proposed by Smyth (corrected p < 0.01 considered significant). RESULTS: Comparing ADPKD to HS, we found significant differences in blood levels of 18 miRs (3 more and 15 less abundant). Of these, miR-3907, miR-92a-3p, miR-25-3p and miR-21-5p all rose while miR-1587 and miR-3911 decreased as renal function declined in both cross-sectional and longitudinal analysis. Using ROC analysis, an increased baseline miR-3907 in the circulation predicted a > 10% loss of GFR over the following 12 months (cut-off >2.2 AU, sensitivity 83%, specificity 78%, area 0.872 [95% CI: 0.790-0.953, p < 0.001]). Adjusting for age and starting CKD stage using multiple binary logistic regression analysis did not abrogate the predictive value. CONCLUSION: Increased copy numbers of miR-3907 in the circulation may predict ADPKD progression and suggest pathophysiological pathways worthy of further study.