HYDROchlorothiazide versus placebo to PROTECT polycystic kidney disease patients and improve their quality of life: study protocol and rationale for the HYDRO-PROTECT randomized controlled trial.

BACKGROUND: Autosomal dominant polycystic kidney disease (ADPKD) leads to progressive renal cyst formation and loss of kidney function in most patients. Vasopressin 2 receptor antagonists (V2RA) like tolvaptan are currently the only available renoprotective agents for rapidly progressive ADPKD. However, aquaretic side effects substantially limit their tolerability and therapeutic potential. In a preliminary clinical study, the addition of hydrochlorothiazide (HCT) to tolvaptan decreased 24-h urinary volume and appeared to increase renoprotective efficacy. The HYDRO-PROTECT study will investigate the long-term effect of co-treatment with HCT on tolvaptan efficacy (rate of kidney function decline) and tolerability (aquaresis and quality of life) in patients with ADPKD. METHODS: The HYDRO-PROTECT study is an investigator-initiated, multicenter, double-blind, placebo-controlled, randomized clinical trial. The study is powered to enroll 300 rapidly progressive patients with ADPKD aged ≥ 18 years, with an eGFR of > 25 mL/min/1.73 m2, and on stable treatment with the highest tolerated dose of tolvaptan in routine clinical care. Patients will be randomly assigned (1:1) to daily oral HCT 25 mg or matching placebo treatment for 156 weeks, in addition to standard care. OUTCOMES: The primary study outcome is the rate of kidney function decline (expressed as eGFR slope, in mL/min/1.73 m2 per year) in HCT versus placebo-treated patients, calculated by linear mixed model analysis using all available creatinine values from week 12 until the end of treatment. Secondary outcomes include changes in quality-of-life questionnaire scores (TIPS, ADPKD-UIS, EQ-5D-5L, SF-12) and changes in 24-h urine volume. CONCLUSION: The HYDRO-PROTECT study will demonstrate whether co-treatment with HCT can improve the renoprotective efficacy and tolerability of tolvaptan in patients with ADPKD.

Leukopenia in autosomal dominant polycystic kidney disease: a single-center cohort of kidney transplant candidates with post-transplantation follow-up.

Background: Autosomal dominant polycystic kidney disease (ADPKD) has occasionally been associated with lower peripheral white blood cell (WBC) counts. This study aimed to investigate the peripheral blood cell counts in a large cohort of kidney transplant recipients before and after kidney transplantation and its potential impact on post-transplant outcomes. Methods: This was a retrospective study with long-term follow-up data of 2090 patients who underwent a first kidney transplantation in the Leuven University Hospitals, of whom 392 had ADPKD. Results: In total, 2090 patients who underwent a first kidney transplantation in the Leuven University Hospitals were included, of whom 392 had ADPKD. Both pre- and post-transplantation, ADPKD patients had significantly lower total WBC counts, and more specifically lower neutrophil, lymphocyte and eosinophil counts compared with the non-ADPKD patients. This observation was independent of potential confounders such as level of inflammation, smoking habit, vitamins and pre-transplant medication. Overall survival and kidney transplant survival were significantly better in ADPKD vs non-ADPKD transplant recipients and a longer time to first infection was observed. However, no association between blood cell counts and outcome differences was found. Conclusions: In conclusion, this large single-center study reports a strong and independent association between ADPKD and lower peripheral WBC counts both before and after kidney transplantation. Considering the role of inflammation in disease progression, further investigation into the role of WBC in ADPKD is needed.

Standardized 4-point scoring scale of [18F]-FDG PET/CT imaging helps in the diagnosis of renal and hepatic cyst infections in patients with autosomal dominant polycystic kidney disease: a validation cohort.

Background: Autosomal dominant polycystic kidney disease (ADPKD) is prone to multiple complications, including cyst infection (CyI). 2-Deoxy-2-[18F]fluoro-d-glucose positron emission tomography/computed tomography ([18F]-FDG PET/CT) imaging has proved useful in the diagnosis of renal and hepatic CyI. A 4-point scale comparing the uptake of [18F]-FDG in the suspected infected cyst versus the hepatic physiological background has been recently proposed. We performed an independent validation of this semi-quantitative scoring system. Methods: All ADPKD patients hospitalized between January 2009 and November 2019 who underwent an [18F]-FDG PET/CT for suspected CyI were retrospectively identified using computer-based databases. Medical files were reviewed. CyI was conventionally defined by the combination of fever (≥38°C), abdominal pain, increased plasma C-reactive protein levels (≥70 mg/L), absence of any other cause of inflammation and favourable outcome after ≥21 days of antibiotics. [18F]-FDG uptake of the suspected CyI was evaluated using a 4-point scale comparing the uptake of [18F]-FDG around the infected cysts with the uptake in the hepatic parenchyma. Statistics were performed using SAS version 9.4. Results: Fifty-one [18F]-FDG PET/CT scans in 51 patients were included, of which 11 were cases of CyI. The agreement between the 4-point scale and the gold-standard criteria of CyI was significant [odds ratio of 6.03 for CyI in case of a score ≥3 (P = .014)]. The corresponding sensitivity, specificity, and positive and negative predictive values of [18F]-FDG PET/CT using the 4-point scale were 64% [Clopper-Pearson 95% confidence interval (CI) 30%-89%], 78% (95% CI 62%-89%), 44% (95% CI 20%-70%) and 89% (95% CI 73%-97%), respectively. Conclusions: Our independent validation cohort confirms the use of a semi-quantitative 4-point scoring system of [18F]-FDG PET/CT imaging in the diagnosis of CyI in patients with ADPKD. Considering its performance metrics with high specificity and negative predictive value, the scoring system is particularly useful to distinguish other causes of clinical inflammation than CyI and as such avoid unnecessarily long antibiotic treatment.

Low agreement between various eGFR formulae in pediatric and young adult ADPKD patients.

BACKGROUND: Young autosomal dominant polycystic kidney disease (ADPKD) patients are becoming the new target population for the development of new treatment options. Determination of a reliable equation for estimated glomerular filtration rate (eGFR) from early stages is needed with the promising potential interventional therapies. METHODS: Prospective and longitudinal study on a cohort of 68 genotyped ADPKD patients (age range 0-23 years) with long-term follow-up. Commonly used equations for eGFR were compared for their relative performance. RESULTS: The revised Schwartz formula (CKiD) showed a highly significant decline in eGFR with aging (- 3.31 mL/min/1.73 m2/year, P < 0.0001). The recently updated equation by the Schwartz group (CKiDU25) showed a smaller (- 0.90 mL/min/1.73 m2/year) but significant (P = 0.001) decline in eGFR with aging and also showed a significant sex difference (P < 0.0001), not observed by the other equations. In contrast, the full age spectrum (FAS) equations (FAS-SCr, FAS-CysC, and the combined) showed no age and sex dependency. The prevalence of hyperfiltration is highly dependent on the formula used, and the highest prevalence was observed with the CKiD Equation (35%). CONCLUSIONS: The most widely used methods to calculate eGFR in ADPKD children (CKiD and CKiDU25 equations) were associated with unexpected age or sex differences. The FAS equations were age- and sex-independent in our cohort. Hence, the switch from the CKiD to CKD-EPI equation at the transition from pediatric to adult care causes implausible jumps in eGFR, which could be misinterpreted. Having reliable methods to calculate eGFR is indispensable for clinical follow-up and clinical trials. A higher resolution version of the Graphical abstract is available as Supplementary information.

Risk Severity Model for Pediatric Autosomal Dominant Polycystic Kidney Disease Using 3D Ultrasound Volumetry.

BACKGROUND: Height-adjusted total kidney volume (htTKV) measured by imaging defined as Mayo Imaging Class (MIC) is a validated prognostic measure for autosomal dominant polycystic kidney disease (ADPKD) in adults to predict and stratify disease progression. However, no stratification tool is currently available in pediatric ADPKD. Because magnetic resonance imaging and computed tomography in children are difficult, we propose a novel 3D ultrasound-based pediatric Leuven Imaging Classification to complement the MIC. METHODS: A prospective study cohort of 74 patients with genotyped ADPKD (37 female) was followed longitudinally with ultrasound, including 3D ultrasound, and they underwent in total 247 3D ultrasound assessments, with patients' median age (interquartile range [IQR]) at diagnosis of 3 (IQR, 0-9) years and at first 3D ultrasound evaluation of 10 (5-14) years. First, data matching was done to the published MIC classification, followed by subsequent optimization of parameters and model type. RESULTS: PKD1 was confirmed in 70 patients (95%), PKD2 in three (4%), and glucosidase IIα unit only once (1%). Over these 247 evaluations, the median height was 143 (IQR, 122-166) cm and total kidney volume was 236 (IQR, 144-344) ml, leading to an htTKV of 161 (IQR, 117-208) ml/m. Applying the adult Mayo classification in children younger than 15 years strongly underestimated ADPKD severity, even with correction for height. We therefore optimized the model with our pediatric data and eventually validated it with data of young patients from Mayo Clinic and the Consortium for Radiologic Imaging Studies of Polycystic Kidney Disease used to establish the MIC. CONCLUSIONS: We proposed a five-level Leuven Imaging Classification ADPKD pediatric model as a novel classification tool on the basis of patients' age and 3D ultrasound-htTKV for reliable discrimination of childhood ADPKD severity.

Safety, Efficacy, and Predictors for Late Reintervention After Embolization of Renal Angiomyolipomas - Embolization renal angiomyolipoma.

PURPOSE: To retrospectively analyze the procedural and long-term clinical outcome of the selective embolization of renal angiomyolipoma. In addition, potential predictive factors for higher risk of late re-intervention were analyzed. METHODS: Retrospective monocentric study, including 34 consecutive patients, analyzing the safety, efficiency, and long-term clinical outcome of catheter-directed embolization of renal AML. Additionally, the difference in postembolization renal function between patients embolized in the acute and in the elective setting was analyzed. Secondly, we also evaluated whether volume/diameter of the AML and presence of intralesional aneurysms are risk factors for late re-intervention. RESULTS: Embolization of renal AML was performed to control volume (n = 21; 62 %) or to stop spontaneous hemorrhage (n = 13; 38 %) with angiographic success in all cases but was associated with renal abscess (n = 1) and pulmonary embolism (n = 1) without a significant difference in renal function before and after embolization (P = 0.513). Volume/diameter (P = 0.276/P = 0.21) and presence of aneurysms before embolization (P = 0.37) are not predictive for a higher risk of late re-intervention. CONCLUSION: Catheter-directed embolization is a safe and effective treatment modality for asymptomatic and bleeding renal AML, without a negative impact on renal function. Initial mass volume/diameter or presence/absence of intralesional aneurysms does not seem to be predictive for late re-intervention. KEY POINTS: · Complications related to renal angiomyolipoma embolization are rare.. · Embolization of angiomyolipoma will not reduce renal function.. · Initial volume or diameter of angiomyolipoma is not predictive for late re-intervention.. CITATION FORMAT: · Claesen E, Bonne L, Laenen A et al. Safety, Efficacy, and Predictors for Late Reintervention After Embolization of Renal Angiomyolipomas. Fortschr Röntgenstr 2023; 195: 319 - 325.

On Methods for the Measurement of the Apelin Receptor Ligand Apelin.

Apelin exists in many isoforms, both in the circulation and in specific tissues. Apelin peptides have a short half-life but preservation before measurement is scarcely studied. Reproducible mass spectrometry methods to specifically measure a broad range of apelinergic peptide isoforms are currently lacking. A sample protocol to conserve apelinergic peptides in the preanalytical phase and a high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) method to measure apelinergic isoforms was developed. Apelin was measured in plasma. For validation, human embryonic kidney (HEK) cells transfected with cDNA for preproapelin were used. Results were compared with a validated radioimmunoassay (RIA) method. Acidifying plasma to pH 2.5 improves post-sampling stability of apelin. HPLC-MS/MS was unable to detect apelin isoforms in plasma of healthy volunteers (n = 16) and chronic kidney disease patients (n = 4). RIA could detect apelin in concentrations between 71 and 263 fmol/l in 10 healthy volunteers. An optimized preanalytical protocol was developed. A sensitive and specific HPLC-MS/MS method failed to detect apelin in human plasma. Apelin-36 was detected in HEK cells transfected with cDNA for preproapelin. Currently, RIA with relatively selective antibodies is the best alternative for the measurement of apelin but novel sensitive and specific methods are needed.

Natural History of Bone Disease following Kidney Transplantation.

BACKGROUND: Knowledge of the effect of kidney transplantation on bone is limited and fragmentary. The aim of this study was to characterize the evolution of bone disease in the first post-transplant year. METHODS: We performed a prospective, observational cohort study in patients referred for kidney transplantation under a steroid-sparing immunosuppressive protocol. Bone phenotyping was done before, or at the time of, kidney transplantation, and repeated at 12 months post-transplant. The phenotyping included bone histomorphometry, bone densitometry by dual-energy x-ray absorptiometry, and biochemical parameters of bone and mineral metabolism. RESULTS: Paired data were obtained for 97 patients (median age 55 years; 72% male; 21% of patients had diabetes). Bone turnover remained normal or improved in the majority of patients (65%). Bone histomorphometry revealed decreases in bone resorption (eroded perimeter, mean 4.6% pre- to 2.3% post-transplant; P<0.001) and disordered bone formation (fibrosis, 27% pre- versus 2% post-transplant; P<0.001). Whereas bone mineralization was normal in all but one patient pretransplant, delayed mineralization was seen in 15% of patients at 1 year post-transplant. Hypophosphatemia was associated with deterioration in histomorphometric parameters of bone mineralization. Changes in bone mineral density were highly variable, ranging from -18% to +17% per year. Cumulative steroid dose was related to bone loss at the hip, whereas resolution of hyperparathyroidism was related to bone gain at both spine and hip. CONCLUSIONS: Changes in bone turnover, mineralization, and volume post-transplant are related both to steroid exposure and ongoing disturbances of mineral metabolism. Optimal control of mineral metabolism may be key to improving bone quality in kidney transplant recipients. CLINICAL TRIAL REGISTRY NAME AND REGISTRATION NUMBER: Evolution of Bone Histomorphometry and Vascular Calcification Before and After Renal Transplantation, NCT01886950.

Diagnostic Accuracy of Noninvasive Bone Turnover Markers in Renal Osteodystrophy.

RATIONALE & OBJECTIVE: Bone biopsy remains the gold standard for diagnosing renal osteodystrophy as comparable noninvasive alternatives have yet to be established. This study investigated the diagnostic accuracy of biochemical markers of skeletal remodeling to predict bone turnover. STUDY DESIGN: Cross-sectional retrospective diagnostic test study. SETTING & PARTICIPANTS: Patients with chronic kidney disease glomerular filtration rate categories 4-5, including patients treated with dialysis (G4-G5D) and kidney transplant recipients with successful transiliac bone biopsies. TESTS COMPARED: Bone turnover as determined by bone histomorphometry was compared with the following biochemical markers: full-length (amino acids 1-84) "biointact" parathyroid hormone (PTH), bone-specific alkaline phosphatase (BsAP), intact procollagen type I N-terminal propeptide (PINP), and tartrate-resistant acid phosphatase isoform 5b (TRAP5b). OUTCOME: Diagnostic performance was evaluated by area under the receiver operator characteristics curve (AUC), sensitivity, specificity, and negative and positive predictive values. Optimal diagnostic cutoffs were determined in an exploration cohort (n = 100) and validated in a separate cohort (n = 99). RESULTS: All biomarkers differed across categories of low 33 (17%), normal 109 (55%), and high 57 (29%) bone turnover. AUC values were in the range of 0.75-0.85. High negative predictive values (≥90%) were found for both high and low bone turnover, indicating the ability to rule out both conditions using the suggested biomarker cutoffs. The highest diagnostic performances were seen with combinations of biomarkers, with overall diagnostic accuracies of 90% for high turnover, and 78% for low turnover. Results were comparable for kidney transplant candidates and recipients in a sensitivity analysis. LIMITATIONS: The single-center approach and heterogeneity of the study cohort are main limitations of this study. CONCLUSIONS: We conclude that the diagnostic performance of biochemical markers of bone turnover is acceptable, with clinical utility in ruling out both high and low turnover bone disease.

The emerging role of the apelinergic system in kidney physiology and disease.

The apelinergic system (AS) is a novel pleiotropic system with an essential role in renal and cardiovascular physiology and disease, including water homeostasis and blood pressure regulation. It consists of two highly conserved peptide ligands, apelin and apela, and a G-protein-coupled apelin receptor. The two ligands have many isoforms and a short half-life and exert both similar and divergent effects. Vasopressin, apelin and their receptors colocalize in hypothalamic regions essential for body fluid homeostasis and interact at the central and renal levels to regulate water homeostasis and diuresis in inverse directions. In addition, the AS and renin-angiotensin system interact both systemically and in the kidney, with implications for the cardiovascular system. A role for the AS in diverse pathological states, including disorders of sodium and water balance, hypertension, heart failure, pre-eclampsia, acute kidney injury, sepsis and diabetic nephropathy, has recently been reported. Furthermore, several metabolically stable apelin analogues have been developed, with potential applications in diverse diseases. We review here what is currently known about the physiological functions of the AS, focusing on renal, cardiovascular and metabolic homeostasis, and the role of the AS in associated diseases. We also describe several hurdles and research opportunities worthy of the attention of the nephrology community.

AQP1 Promoter Variant, Water Transport, and Outcomes in Peritoneal Dialysis.

BACKGROUND: Variability in ultrafiltration influences prescriptions and outcomes in patients with kidney failure who are treated with peritoneal dialysis. Variants in AQP1, the gene that encodes the archetypal water channel aquaporin-1, may contribute to that variability. METHODS: We gathered clinical and genetic data from 1851 patients treated with peritoneal dialysis in seven cohorts to determine whether AQP1 variants were associated with peritoneal ultrafiltration and with a risk of the composite of death or technique failure (i.e., transfer to hemodialysis). We performed studies in cells, mouse models, and samples obtained from humans to characterize an AQP1 variant and investigate mitigation strategies. RESULTS: The common AQP1 promoter variant rs2075574 was associated with peritoneal ultrafiltration. Carriers of the TT genotype at rs2075574 (10 to 16% of patients) had a lower mean (±SD) net ultrafiltration level than carriers of the CC genotype (35 to 47% of patients), both in the discovery phase (506±237 ml vs. 626±283 ml, P = 0.007) and in the validation phase (368±603 ml vs. 563±641 ml, P = 0.003). After a mean follow-up of 944 days, 139 of 898 patients (15%) had died and 280 (31%) had been transferred to hemodialysis. TT carriers had a higher risk of the composite of death or technique failure than CC carriers (adjusted hazard ratio, 1.70; 95% confidence interval [CI], 1.24 to 2.33; P = 0.001), as well as a higher risk of death from any cause (24% vs. 15%, P = 0.03). In mechanistic studies, the rs2075574 risk variant was associated with decreases in AQP1 promoter activity, aquaporin-1 expression, and glucose-driven osmotic water transport. The use of a colloid osmotic agent mitigated the effects of the risk variant. CONCLUSIONS: A common variant in AQP1 was associated with decreased ultrafiltration and an increased risk of death or technique failure among patients treated with peritoneal dialysis. (Funded by the Swiss National Science Foundation and others.).

Strategies for asymmetrical triacetate dialyser heparin-free effective haemodialysis: the SAFE study.

BACKGROUND: In haemodialysis, maintaining patency of the extracorporeal circuit requires the use of anticoagulants. Although (low molecular weight) heparins are the mainstay, these are not well tolerated in all patients. Alternative approaches include saline infusion, citrate-containing dialysate, regional citrate anticoagulation or the use of heparin-coated membranes. Asymmetric cellulose triacetate (ATA) dialysers have a low degree of platelet contact activation and might be an alternative to heparin-coated dialysers. The aim of this study was to test the clotting propensity of ATA when used without systemic anticoagulation. METHODS: We performed a Phase II pilot study in maintenance dialysis patients. The 'Strategies for Asymmetrical Triacetate dialyzer heparin-Free Effective hemodialysis' (SAFE) study was a two-arm open-label crossover study. In Arm A, patients were dialysed using 1.9 m2 ATA membranes in combination with a citrate-containing dialysate (1 mM). In Arm B, the ATA membrane was combined with high-volume predilution haemodiafiltration (HDF) without any other anticoagulation. The primary endpoint was the success rate to complete 4 h of haemodialysis without preterm clotting. Secondary endpoints included time to clotting and measures of dialysis adequacy. RESULTS: We scheduled 240 dialysis sessions (120/arm) in 20 patients. Patients were randomized 1:1 to start with Arm A or B. All patients crossed to the other arm halfway through the study. A total of 232 (96.7%) study treatments were delivered. Overall, 23 clotting events occurred, 7 in Arm A and 16 in Arm B. The success rate in Arm A (ATA + citrate-containing dialysate) was 90.8/94.0% [intention to treat (ITT)/as treated]. The success rate in Arm B (ATA + predilution HDF) was 83.3/86.2% (ITT/as treated). Time to clotting was borderline significantly better in Arm A (Mantel-Cox log rank P = 0.05). CONCLUSION: ATA dialysers have a low clotting propensity and both predilution HDF and a citrate-containing dialysate resulted in high rates of completed dialysis sessions.

Patterns of renal osteodystrophy 1 year after kidney transplantation.

BACKGROUND: Renal osteodystrophy is considered common, but is not well characterized in contemporary kidney transplant recipients. This study reports extensively on bone phenotype by bone histomorphometry, bone densitometry and novel bone biomarkers 1 year after kidney transplantation. METHODS: A transiliac bone biopsy and dual-energy X-ray absorptiometry scans were performed in 141 unselected kidney transplant recipients in this observational cohort study. Blood and 24-h urine samples were collected simultaneously. RESULTS: The median age was 57 ± 11 years, 71% were men and all were of Caucasian ethnicity. Bone turnover was normal in 71% of patients, low in 26% and high in just four cases (3%). Hyperparathyroidism with hypercalcaemia was present in 13% of patients, of which only one had high bone turnover. Delayed bone mineralization was detected in 16% of patients, who were characterized by hyperparathyroidism (137 versus 53 ρg/mL), a higher fractional excretion of phosphate (40 versus 32%) and lower levels of phosphate (2.68 versus 3.18 mg/dL) and calcidiol (29 versus 37 ng/mL) compared with patients with normal bone mineralization. Osteoporosis was present in 15-46% of patients, with the highest prevalence at the distal skeleton. The proportion of osteoporotic patients was comparable across categories of bone turnover and mineralization. CONCLUSIONS: The majority of kidney transplant recipients, including patients with osteoporosis, have normal bone turnover at 1-year post-transplant. Low bone turnover is seen in a substantial subset, while high bone turnover is rare. Vitamin D deficiency and hypophosphataemia represent potential interventional targets to improve bone health post-transplant.

Static histomorphometry allows for a diagnosis of bone turnover in renal osteodystrophy in the absence of tetracycline labels.

A bone biopsy with prior tetracycline labeling is the gold standard to diagnose renal osteodystrophy. In cases of missing tetracycline labels, it is still paramount to gain clinically relevant information from the extracted bone sample, by evaluating the static histomorphometry. This study investigates the diagnostic performance of static histomorphometry for the evaluation of high and low bone turnover. Transiliac bone biopsies taken pre- or post- kidney transplantation, of sufficient quality for a full histomorphometric analysis were included (n = 205). The cohort was randomly split to provide separate exploration and validation subsets. Diagnostic performance was evaluated by area under the receiver operator characteristics curve (AUC). All histomorphometric parameters were significantly different across categories of low (24%), normal (60%), and high (16%) bone turnover, and all were significant predictors of both high and low bone turnover (AUC 0.71-0.84). Diagnostic performance was very good for high turnover, as a combination of static parameters resulted in negative and positive predictive values (NPV and PPV) of 80% and 96%, respectively. For low turnover, the combined model resulted in PPV of 71% and NPV of 82%. We conclude that in the absence of tetracycline labels, static histomorphometry provide an acceptable alternative for a diagnosis of bone turnover in renal osteodystrophy.

Enhanced MCP-1 Release in Early Autosomal Dominant Polycystic Kidney Disease.

INTRODUCTION: Autosomal dominant polycystic kidney disease (ADPKD) causes kidney failure typically in adulthood, but the disease starts in utero. Copeptin, epidermal growth factor (EGF), and monocyte chemoattractant protein-1 (MCP-1) are associated with severity and hold prognostic value in adults but remain unstudied in the early disease stage. Kidneys from adults with ADPKD exhibit macrophage infiltration, and a prominent role of MCP-1 secretion by tubular epithelial cells is suggested from rodent models. METHODS: In a cross-sectional study, plasma copeptin, urinary EGF, and urinary MCP-1 were evaluated in a pediatric ADPKD cohort and compared with age-, sex-, and body mass index (BMI)-matched healthy controls. MCP-1 was studied in mouse collecting duct cells, human proximal tubular cells, and fetal kidney tissue. RESULTS: Fifty-three genotyped ADPKD patients and 53 controls were included. The mean (SD) age was 10.4 (5.9) versus 10.5 (6.1) years (P = 0.543), and the estimated glomerular filtration rate (eGFR) was 122.7 (39.8) versus 114.5 (23.1) ml/min per 1.73 m2 (P = 0.177) in patients versus controls, respectively. Plasma copeptin and EGF secretion were comparable between groups. The median (interquartile range) urinary MCP-1 (pg/mg creatinine) was significantly higher in ADPKD patients (185.4 [213.8]) compared with controls (154.7 [98.0], P = 0.010). Human proximal tubular cells with a heterozygous PKD1 mutation and mouse collecting duct cells with a PKD1 knockout exhibited increased MCP-1 secretion. Human fetal ADPKD kidneys displayed prominent MCP-1 immunoreactivity and M2 macrophage infiltration. CONCLUSION: An increase in tubular MCP-1 secretion is an early event in ADPKD. MCP-1 is an early disease severity marker and a potential treatment target.

Cytopenia in autosomal dominant polycystic kidney disease (ADPKD): merely an association or a disease-related feature with prognostic implications?

Autosomal dominant polycystic kidney disease (ADPKD) is associated with distinct cytopenias in observational studies; the most consistent and strongest association is seen with alternations in the lymphocytic lineages. Although the underlying mechanism of these associations is unclear, it has been hypothesized to be secondary to sequestration of white blood cells in cystic organs, or related to the uremic environment in chronic kidney disease (CKD). However, since mutations in PKD1 or -2 affect several immunomodulating pathways, cytopenia may well be an unrecognized extrarenal manifestation of ADPKD. Furthermore, many important questions on the clinical implications of this finding and the effect on the disease course in these patients are unanswered. In this review article, we provide an overview of the current evidence on cytopenia in ADPKD and explore the underlying mechanisms of this association and its potential prognostic implications. Based on the current literature, we hypothesize that polycystin deficiency can disturb immune cell homeostasis and that cytopenia is thus an intrinsic feature of ADPKD, related to genetic factors. Taken together, these findings warrant further investigation to establish the exact etiology and role of cytopenia in patients with ADPKD.

Measures of Loop Diuretic Efficiency and Prognosis in Chronic Kidney Disease.

BACKGROUND: The evolution and prognostic impact of loop diuretic efficiency according to chronic kidney disease (CKD) severity is unclear. METHODS: This retrospective cohort study includes 783 CKD patients on oral loop diuretic therapy with a 24-h urine collection available. Acute kidney injury and history of renal replacement therapy were exclusion criteria. Patients were stratified according to Kidney Disease Improving Global Outcomes (KDIGO) glomerular filtration rate class. Loop diuretic efficiency was calculated as urine output, natriuresis, and chloruresis, each adjusted for loop diuretic dose, and compared among strata. Risk for onset of dialysis and all-cause mortality was evaluated. RESULTS: Loop diuretic efficiency metrics decreased from KDIGO class IIIB to IV in furosemide users and from KDIGO class IV to V with all loop diuretics (p value <0.05 for all comparisons). The correlation between loop diuretic efficiency and creatinine clearance was moderate at best (Spearman's ρ 0.298-0.436; p value <0.001 for all correlations). During median follow-up of 45 months, 457 patients died (58%) and 63 received kidney transplantation (8%), while dialysis was started before in 328 (42%). All loop diuretic efficiency metrics were significantly and independently associated with both the risk for dialysis and all-cause mortality. In KDIGO class IV/V patients, low loop diuretic efficiency (i.e., urine output adjusted for loop diuretic dose ≤1,000 mL) shortened median time to dialysis with 24 months and median time to all-cause mortality with 23 months. CONCLUSION: Low loop diuretic efficiency is independently associated with a shorter time to dialysis initiation and a higher risk for all-cause mortality in CKD.

Sevelamer Use in End-Stage Kidney Disease (ESKD) Patients Associates with Poor Vitamin K Status and High Levels of Gut-Derived Uremic Toxins: A Drug-Bug Interaction?

Gut microbial metabolism is not only an important source of uremic toxins but may also help to maintain the vitamin K stores of the host. We hypothesized that sevelamer therapy, a commonly used phosphate binder in patients with end-stage kidney disease (ESKD), associates with a disturbed gut microbial metabolism. Important representatives of gut-derived uremic toxins, including indoxyl sulfate (IndS), p-Cresyl sulfate (pCS), trimethylamine N-oxide (TMAO), phenylacetylglutamine (PAG) and non-phosphorylated, uncarboxylated matrix-Gla protein (dp-ucMGP; a marker of vitamin K status), were analyzed in blood samples from 423 patients (65% males, median age 54 years) with ESKD. Demographics and laboratory data were extracted from electronic files. Sevelamer users (n = 172, 41%) were characterized by higher phosphate, IndS, TMAO, PAG and dp-ucMGP levels compared to non-users. Sevelamer was significantly associated with increased IndS, PAG and dp-ucMGP levels, independent of age, sex, calcium-containing phosphate binder, cohort, phosphate, creatinine and dialysis vintage. High dp-ucMGP levels, reflecting vitamin K deficiency, were independently and positively associated with PAG and TMAO levels. Sevelamer therapy associates with an unfavorable gut microbial metabolism pattern. Although the observational design precludes causal inference, present findings implicate a disturbed microbial metabolism and vitamin K deficiency as potential trade-offs of sevelamer therapy.