Search

Purpose In selected ADPKD patients, a nephrectomy is required in the work-up for a kidney transplantation. Because the impact of this procedure is unknown, we investigated the effect of pre-transplantation nephrectomy on quality of life in this group. Methods In this retrospective cohort study all ADPKD patients, ≥ 18 years, who received a kidney transplantation in 2 ADPKD expertise centers between January 2000 and January 2016, were asked to participate. Quality of life was assessed using three validated questionnaires on three time points. Nephrectomy was performed in preparation for transplantation. Results Two hundred seventy-six ADPKD patients (53 ± 9 years, 56.2% male) were included. 98 patients (35.5%) underwent native nephrectomy in preparation for transplantation, of which 43 underwent bilateral nephrectomy. Pre-transplantation, ADPKD-IS scores were worse in the nephrectomy group vs. no-nephrectomy group (physical: 2.9 vs. 2.3, p p = 0.03; fatigue: 3.0 vs. 2.3, p = 0.01). Post-transplantation and post-nephrectomy, ADPKD-IS scores improved significantly in both groups, with a significantly higher improvement in the nephrectomy group. During follow-up, all scores were still better compared to pre-transplantation. Observed physical QoL (ADPKD-IS physical 1.3 vs. 1.7, p = 0.04; SF-36 physical 50.0 vs. 41.3, p = 0.03) was better post-transplantation after bilateral nephrectomy compared to unilateral nephrectomy. In retrospect, 19.7% of patients would have liked to undergo a nephrectomy, while the decision not to perform nephrectomy was made by the treating physician. Conclusion This study shows that pre-transplantation nephrectomy improves quality of life in selected ADPKD patients. Bilateral nephrectomy may be preferred, although the risk of additional complications should be weighted.

Introduction: There is no consensus if nor when a native nephrectomy should be performed in the workup for kidney transplantation in ADPKD patients. In our PKD Expertise Center, a restrictive approach is pursued in which nephrectomy is performed only in patients with severe complaints, i.e., in case of serious volume-related complaints, lack of space for the allograft, recurrent cyst infections, persistent cyst bleedings, or chronic refractory pain. We analyzed in a retrospective cohort study whether this approach is justified. Methods: All ADPKD patients who received kidney transplantation between January 2000 and January 2019 were reviewed. Patients were subdivided into three groups: no nephrectomy (no-Nx), nephrectomy performed before (pre-Tx), or after kidney transplantation (post-Tx). Simultaneous nephrectomy together with transplantation were not performed in our center. Results: 391 patients (54 ± 9 years, 55% male) were included. The majority of patients did not undergo a nephrectomy (n = 257, 65.7%). A nephrectomy was performed pre-Tx in 114 patients (29.2%). After Tx, nephrectomy was performed in only 30 patients (7.7%, median 4.4 years post-Tx). Surgery-related complication rates did not differ between both groups (38.3% pre-Tx vs. 27.0% post-Tx, p = 0.2), nor were there any differences in 10-year patient survival (74.4% pre-Tx vs. 80.7% post-Tx vs. 67.6% no-Nx, p = 0.4), as well as in 10-year death-censored graft survival (84.4% pre-Tx vs. 85.5% post-Tx vs. 90.0% no-Nx, p = 0.9). Conclusions: This study indicates that with a restrictive nephrectomy policy in the workup for kidney transplantation, only a part of ADPKD patients need a native nephrectomy.

Background Autosomal dominant polycystic kidney disease (ADPKD) is the most common inherited kidney disorder and a major cause of kidney failure worldwide. However, its impact on quality-of-life has not been systematically explored. Methods The CYSTic-QoL study was an observational study designed to study quality-of-life in adult European ADPKD patients with an estimated glomerular filtration rate (eGFR) ≥30 mL/min/1.73 m2. A total of 465 patients were recruited from six expert European centres with baseline data recorded, including health-related quality-of-life (HRQoL), incorporating a Kidney Disease QoL short form questionnaire (KDQoL-SF, version 1.3), magnetic resonance imaging (MRI) for total kidney volume (TKV) measurements and DNA for genotyping. The cohort was stratified by baseline eGFR, TKV or genotype and correlated with HRQoL scores. Bivariate and multivariate analyses were applied to examine the relationship between HRQoL and variables of interest. KDQoL-SF scores were calculated using an online tool provided by the RAND organization. For 36-item short form values, mean centre scores were normalized to their native populations. Results The mean age of participants was 43 years and 55% were female, with a mean eGFR of 77 mL/min/1.73 m2 and height-adjusted TKV (ht-TKV) of 849 mL/min; 66% had PKD1 pathogenic variants. ADPKD patients uniformly reported decreased general health and less energy, with the majority also experiencing poorer physical, mental or emotional health and limitations in social functioning. A total of 32.5% of participants experienced flank pain, which was significantly and negatively correlated with the majority of KDQoL-SF subscales by multivariate analysis. Higher ht-TKV and lower eGFR were negatively associated with decreased energy and poorer physical health, respectively, although not with flank pain. Conclusion ADPKD patients suffer from significantly decreased QoL in multiple domains, exacerbated particularly by chronic pain.

Purpose of review Patients with Autosomal Dominant Polycystic Kidney Disease (ADPKD) reach kidney failure at a median age of 58 years. There has been a strong interest in medical interventions to improve prognosis. With increasing understanding of the underlying pathophysiology, there is also a rationale for non-pharmaceutical interventions. However, these have received little attention. This review, therefore, focuses on dietary interventions in ADPKD. Recent findings Recent studies regarding salt, protein and water intake, caloric restriction, BMI, caffeine and alcohol are discussed in this review. In general, these studies suggest that advices do not need to be different from those in chronic kidney disease (CKD). On the basis of research in the general population and CKD, these advices will likely decrease cardiovascular morbidity and mortality. With respect to delaying ADPKD progression, evidence for salt restriction is growing. For increasing water intake and targeting glucose metabolism by intermittent fasting, preclinical studies are promising. Long-term randomized human intervention studies are, however, lacking. Summary In ADPKD, advices regarding dietary interventions can, in general, be the same as in CKD to decrease cardiovascular morbidity and mortality. Whether these interventions also delay disease progression needs further study.

Autosomal dominant polycystic kidney disease (ADPKD) is characterized by progressive cyst formation that ultimately leads to kidney failure in most patients. Approximately 10% of patients who receive kidney replacement therapy suffer from ADPKD. To date, a vasopressin V2 receptor antagonist (V2RA) is the only drug that has been proven to attenuate disease progression. However, aquaresis-related adverse events limit its widespread use. Data on the renoprotective effects of somatostatin analogues differ largely between studies and medications. This review discusses new drugs that are investigated in clinical trials to treat ADPKD, such as cystic fibrosis transmembrane conductance regulator (CFTR) modulators and micro RNA inhibitors, and drugs already marketed for other indications that are being investigated for off-label use in ADPKD, such as metformin. In addition, potential methods to improve the tolerability of V2RAs are discussed, as well as methods to select patients with (likely) rapid disease progression and issues regarding the translation of preclinical data into clinical practice. Since ADPKD is a complex disease with a high degree of interindividual heterogeneity, and the mechanisms involved in cyst growth also have important functions in various physiological processes, it may prove difficult to develop drugs that target cyst growth without causing major adverse events. This is especially important since long-standing treatment is necessary in this chronic disease. This review therefore also discusses approaches to targeted therapy to minimize systemic side effects. Hopefully, these developments will advance the treatment of ADPKD.

BACKGROUND AND AIMS In autosomal dominant polycystic kidney disease (ADPKD), the enlarged kidneys can cause clinical problems, for instance pain or gastro-intestinal complaints, recurrent infections, or cause a lack of space for a kidney transplant. In selected ADPKD patients, a nephrectomy is required in the work-up for a kidney transplantation. Currently, it is unknown how this procedure affects quality of life (QoL), nor how leaving both kidneys in situ influences wellbeing. The aim of this study was to investigate the impact of pretransplantation nephrectomy on quality of life in APDKD patients. METHOD In this retrospective cohort study all ADPKD patients, ≥18 years, who received a kidney transplantation in 2 ADPKD expertise centers in the Netherlands (UMC Groningen and UMC Leiden) between January 2000 and January 2016, were asked to participate. Of these two centers, one has a restrictive approach, wherein a unilateral procedure is only performed when strict indications are met, and one a proactive approach, wherein a bilateral procedure is performed routinely in the work-up for transplantation. Data were collected on patients characteristics, date of nephrectomy, date of kidney transplantation and QoL. QoL was assessed using validated questionnaires (the SF-36, PHQ-9 and ADPKD-Impact Score) on three different time points (12 months before transplantation, 12 months after transplantation and date of filling out the questionnaire). Patients were followed for at least 24 months after transplantation. RESULTS 321 ADPKD (61 ± 9 years, 57.9% male) patients were included. The minority of patients (n = 99, 30.8%) underwent native nephrectomy in preparation for transplantation, of which 43 patients (13.4%) underwent bilateral nephrectomy. Lack of space was the most common indication for nephrectomy (68.7%), followed by recurrent cyst infection (18.2%) and refractory pain complaints (9.1%). Age, sex and comorbidities did not differ before transplantation between patients who would later undergo a pretransplantation nephrectomy when compared to those who would not undergo this procedure, except for QoL. The SF-36 physical component score (PCS) and mental component score (MCS) were lower in the nephrectomy group vs. no nephrectomy group (33.8 versus 38.4, P = 0.003; 48.7 versus 51.7, P = 0.04, respectively). In addition, the PHQ-9 and ADPKD-IS were significantly lower in patients who would later undergo a pre-transplantation nephrectomy compared to patients who would not undergo this procedure (P = 0.01, P = 0.01, respectively). After transplantation the PCS and MCS improved significantly in both groups, with this improvement in PCS and MCS being significantly more in patients who had a pretransplant nephrectomy compared with those who did not have a nephrectomy (change in PCS 17.3, P CONCLUSION This study shows that ADPKD patients who underwent a pretransplantation nephrectomy experienced more complaints compared with patients without nephrectomy. After nephrectomy and transplantation, QoL significantly improved in these patients, resulting in a similar QoL level in all transplanted ADPKD patients on short as well as long-term follow-up. Bilateral nephrectomy had no additional benefit on QoL compared with unilateral nephrectomy. Together, this indicates that a restrictive approach, wherein a unilateral procedure is performed only when strict indications are met, may improve QoL in these patients and is therefore justified.

BACKGROUND AND AIMS In some patients with autosomal dominant polycystic kidney disease (ADPKD), one or both native kidneys are removed in the work-up for kidney transplantation. There is no consensus if and when a nephrectomy should be performed. Some centers advocate to routinely perform a (bilateral) nephrectomy to prevent complications associated with the native polycystic kidneys in the post-transplantation period. In our ADPKD expertise center, a restrictive approach is pursued: a nephrectomy is only performed in case of serious volume related complaints, lack of space for the allograft, recurrent cyst infections, persistent cyst bleedings or chronic invalidating pain. We analyzed in a retrospective study whether this approach is justified. METHOD All records of patients ≥18 years with ADPKD who received a kidney transplantation (Tx) in our ADPKD expertise center between January 2000 and January 2019 were reviewed. Data were collected on incidence, timing, indication and complications of nephrectomy, as well as on the kidney transplantation, graft function and mortality. Patients were subdivided into three groups: no nephrectomy (no-Nx), nephrectomy prior to (pre-Tx) or after kidney transplantation (post-Tx). Patients were followed for at least 12 months after transplantation. RESULTS About 391 ADPKD (54 ± 9 years, 55.2% male) patients were included. The majority of patients did not undergo a nephrectomy (n = 257, 65.7%). A unilateral nephrectomy was performed pre-Tx in 114 patients (29.2%), in most cases because of a lack of space (49.6%) or recurrent kidney cyst infection (28.1%). More male patients underwent a nephrectomy compared to women (65.7% versus 34.3%, P = 0.003). After Tx, nephrectomy was performed in only 30 patients (11%, median 4.4 years post-Tx), of which 10 were contralateral nephrectomies in patients who also had a nephrectomy pre-Tx. Most frequent indications for nephrectomy post-Tx were recurrent kidney cyst infection (51.4%) or severe pain (24.3%). Duration of nephrectomy was slightly longer when performed post-Tx (3.1 h post-Tx versus 2.6 h pre-Tx, P = 0.052). However, the median length of hospital admission was significantly shorter in these patients (6.0 days post-Tx versus 10.0 days pre-Tx, P CONCLUSION This study indicates that a minority of ADPKD patients require a native nephrectomy in the work-up for a kidney transplant. With a restrictive nephrectomy policy, only few patients need a nephrectomy after kidney transplantation for indications not foreseen before transplantation. Nephrectomy is a relatively safe procedure, even when performed in transplanted ADPKD patients where it did not result in more complications, graft failure or mortality. These data suggest that a restrictive nephrectomy policy in ADPKD is justified.

BACKGROUND AND OBJECTIVES: The vasopressin V2 receptor antagonist tolvaptan is the only drug that has been proven to be nephroprotective in autosomal dominant polycystic kidney disease (ADPKD). Tolvaptan also causes polyuria, limiting tolerability. We hypothesized that cotreatment with hydrochlorothiazide or metformin may ameliorate this side effect.DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We performed a clinical study and an animal study. In a randomized, controlled, double-blind, crossover trial, we included 13 tolvaptan-treated patients with ADPKD. Patients were treated for three 2-week periods with hydrochlorothiazide, metformin, or placebo in random order. Primary outcome was change in 24-hour urine volume. We also measured GFR and a range of metabolic and kidney injury markers.RESULTS: Patients (age 45±8 years, 54% women, measured GFR of 55±11 ml/min per 1.73 m2) had a baseline urine volume on tolvaptan of 6.9±1.4 L/24 h. Urine volume decreased to 5.1 L/24 h (PCONCLUSIONS: Both metformin and hydrochlorothiazide reduced tolvaptan-caused polyuria in a short-term study. Hydrochlorothiazide also reduced polyuria in a long-term animal model without negatively affecting nephroprotection.PODCAST: This article contains a podcast at https://www.asn-online.org/media/podcast/CJASN/2022_03_21_CJN11260821.mp3.

Urologic diseases can cause hematuria, but dysmorphic erythrocytes directs to a glomerular disease. The latter might occur isolated or in the presence of systemic complaints, proteinuria or kidney failure. These factors determine the differential diagnosis that ranges from an innocent IgA nephropathy to a fatal anti-glomerular basement membrane (GBM) nephritis.A 30-year old patient attended the outpatient clinic because of glomerular hematuria and normal kidney function with working diagnosis IgA nephropathy. Three months later he presented to the emergency department with a severe acute kidney injury duo to an anti-GBM nephritis. In retrospect, the anti-GBM titer was already high during the outpatient clinic phase, but due to the preserved kidney function, anti-GBM nephritis was not added to the differential diagnosis.Glomerular hematuria with a preserved kidney function could in a rare instance be caused by a subclinical anti-GBM nephritis. Follow-up of the kidney function and comprehensive laboratory testing - or even a kidney biopsy - could potentially lead to an early diagnosis of anti-GBM nephritis.

In this interdisciplinary volume, a team of classicists, historians, and archaeologists examines how the memory of the infamous emperor Nero was negotiated in different contexts and by different people during the ensuing Flavian age of imperial Rome. The contributions show different Flavian responses to Nero’s complicated legacy: while some aspects of his memory were reinforced, others were erased. Emphasizing the constant and diverse nature of this negotiation, this book proposes a nuanced interpretation of both the Flavian age itself and its relation to Nero’s Rome. By combining the study of these strategies with architectural approaches, archaeology, and memory studies, this volume offers a multifaceted picture of Roman civilization at a crucial turning point, and as such will have something to offer anyone interested in classics, (ancient) history, and archaeology.

On the basis of earlier observations, we evaluated the association between overweight and obesity and rapid progression of autosomal dominant polycystic kidney disease in participants in the Tolvaptan Efficacy and Safety in Management of Autosomal Dominant Polycystic Kidney Disease and Its Outcomes (TEMPO) 3:4 trial. More importantly, we also determined whether efficacy of tolvaptan was attenuated in individuals with baseline overweight or obesity.A total of 1312 study participants with relatively early-stage autosomal dominant polycystic kidney disease (mean eGFR 78±22 ml/min per 1.73 mIn fully adjusted models, higher BMI was associated with greater annual percent change in TKV (difference of 1.20 [95% confidence interval (95% CI), 0.85 to 1.55] per five-unit higher BMI). Overweight and obesity were associated with higher odds of annual percent change in TKV of ≥7% versus5% (overweight: odds ratio, 2.04 [95% CI, 1.45 to 2.87]; obese: odds ratio, 4.31 [95% CI, 2.83 to 6.57] versus normal weight). eGFR decline did not differ according to BMI (fully adjusted difference in decline of -0.95 [95% CI, -2.32 to 0.40] ml/min per 1.73 mOverweight and particularly obesity are strongly and independently associated with kidney growth, but not eGFR slope, in the TEMPO 3:4 trial, and tolvaptan efficacy is irrespective of BMI categorization.Tolvaptan Efficacy and Safety in Management of Autosomal Dominant Polycystic Kidney Disease and Its Outcomes (TEMPO) 3:4, NCT00428948.

Insomnia is very prevalent in psychiatry and is considered a transdiagnostic symptom of mental disorders. Yet, it is not only a consequence of a mental condition but may also exert detrimental effects on psychiatric symptom severity and therapeutic response; thus, adequate insomnia treatment is particularly important in psychiatric populations. The first choice of intervention is cognitive behavioral therapy for insomnia (CBT-I) as it is rather effective, also in the long run without side effects. It is offered in various forms, ranging from in-person therapy to internet-delivered applications. CBT-I protocols are typically developed for individuals with insomnia disorder without co-occurring conditions. For an optimal therapeutic outcome of CBT-I in individuals with comorbid mental disorders, adaptations of the protocol to tailor the treatment might be beneficial. Based on a literature search using major search engines (Embase; Medline; APA Psych Info; and Cochrane Reviews), this paper provides an overview of the effectiveness of the different CBT-I applications in individuals with diverse comorbid mental conditions and older adults and describes the functionality of CBT-I protocols that have been personalized to specific psychiatric populations, such as depression, substance abuse, and schizophrenia spectrum disorder. Finally, we discuss urgent needs for insomnia therapy targeted to improve both sleep and psychopathologies.

Background and Aims ADPKD is the most common inherited kidney disease in man, a major cause of end-stage renal disease and is a significant medical and economic burden worldwide. However, the impact of this major disease on the quality of life of patients with preserved kidney function has not been systematically explored. Method The CYSTic I study was an observational, prospective study designed to study the natural history of ADPKD in adult patients with preserved kidney function (eGFR ≥30 ml/min/1.73m2). 465 patients were recruited from six expert centres across Europe (Belgium, France, Italy, Netherlands, Spain and UK) with baseline data recorded including HR-QoL (Health-Related Quality of Life) incorporating a Kidney Disease QOL short form questionnaire (KDQoL-SF v1.3), MRI for Total Kidney Volume (TKV) and DNA for genotyping. The cohort was stratified by baseline eGFR, Ht-TKV or genotype and correlated with HR-QOL scores. Bivariate and multivariate analyses were applied to examine the relationship between HRQoL and variables of interest. KDQoL-SF scores were calculated using an online tool provided by the Rand organisation. Results Mean age of the participants was 44 years, 54.6% were female with a mean eGFR of 77ml/min/1.73m2 and Ht-TKV of 849ml/m. 72.3% had PKD1 mutations. 32.5% of participants reported flank pain that was not significantly correlated with eGFR, Ht-TKV or genotype. Of all the variables examined, flank pain showed significant negative associations with the highest number of KDQoL-SF subscale scores assessed (12/20). Conclusion Our results indicate that flank pain is common, likely to be under-reported in routine care but has a major negative impact on patient-reported quality of life.

Background and Aims Autosomal dominant polycystic kidney disease (ADPKD) is an inherited kidney disease characterized by development and growth of cysts leading to loss of kidney function. In patients with ADPKD, fibrosis has been associated with the expansion of cysts and with an increased rate of progression to end-stage kidney disease (ESKD). Fibrosis is characterized by an imbalanced turnover of extracellular matrix (ECM) components such as collagens. Existing biomarkers of ADPKD have limited prognostic ability and the ECM can be a source of novel biomarkers of disease progression. In the current study, we investigated the cross-sectional association of collagen biomarkers with markers of disease severity in patients with ADPKD. Method Collagen type I, III and VI formation as well as collagen type III degradation were assessed with the PRO-C1, PRO-C3, PRO-C6 and C3M enzyme-linked immunosorbent assays (ELISAs). The four biomarkers were measured in serum from 311 patients with ADPKD from the DIPAK-1 (NCT01616927) study at baseline. Biomarker levels were compared with levels in serum of 38 healthy controls matched for sex and age. The difference between the ADPKD and the control group was assessed by Kruskal-Wallis test. The association of the collagen biomarkers with kidney function (eGFR) and height adjusted total kidney volume (htTKV) was assessed with uni- and multivariate regression analysis. Data was log-transformed if appropriate. Results Biomarker levels in the ADPKD patients (age, median (IQR): 49 (43-54) years; sex: 53% female) were compared with levels in matched healthy controls (age, median (IQR): 49 (43-56) years; sex: 53% female). In patients with ADPKD both PRO-C3 and PRO-C6 levels were increased compared to healthy controls (ADPKD vs controls, PRO-C3 median (IQR): 12.8 (10.5-15.8) vs 8.4 (7.5-10.1) ng/mL; P Conclusion While biomarkers of tubulointerstitial fibrosis (PRO-C3 and PRO-C6) were elevated in circulation in ADPKD patients, possibly reflecting an elevated fibrosis activity in the kidneys, levels of collagen type I formation (PRO-C1) were lower, possibly reflecting a suppressed bone turnover previously observed in patients with ADPKD. Both PRO-C3 and PRO-C6 showed an independent association with eGFR, but not with htTKV, when adjusting for known determinants of disease severity. Such biomarkers deserve further investigation in this patient population, especially concerning their prognostic abilities, as fibrosis is acknowledged as a driving force in progression to ESKD.

Background. Patients on kidney replacement therapy comprise a vulnerable population and may be at increased risk of death from coronavirus disease 2019 (COVID-19). Currently, only limited data are available on outcomes in this patient population. Methods. We set up the ERACODA (European Renal Association COVID-19 Database) database, which is specifically designed to prospectively collect detailed data on kidney transplant and dialysis patients with COVID-19. For this analysis, patients were included who presented between 1 February and 1 May 2020 and had complete information available on the primary outcome parameter, 28-day mortality. Results. Of the 1073 patients enrolled, 305 (28%) were kidney transplant and 768 (72%) dialysis patients with a mean age of 60 ± 13 and 67 ± 14 years, respectively. The 28-day probability of death was 21.3% [95% confidence interval (95% CI) 14.3–30.2%] in kidney transplant and 25.0% (95% CI 20.2–30.0%) in dialysis patients. Mortality was primarily associated with advanced age in kidney transplant patients, and with age and frailty in dialysis patients. After adjusting for sex, age and frailty, in-hospital mortality did not significantly differ between transplant and dialysis patients [hazard ratio (HR) 0.81, 95% CI 0.59–1.10, P = 0.18]. In the subset of dialysis patients who were a candidate for transplantation (n = 148), 8 patients died within 28 days, as compared with 7 deaths in 23 patients who underwent a kidney transplantation Conclusions. The 28-day case-fatality rate is high in patients on kidney replacement therapy with COVID-19 and is primarily driven by the risk factors age and frailty. Furthermore, in the first year after kidney transplantation, patients may be at increased risk of COVID-19-related mortality as compared with dialysis patients on the waiting list for transplantation. This information is important in guiding clinical decision-making, and for informing the public and healthcare authorities on the COVID-19-related mortality risk in kidney transplant and dialysis patients.

Background and Aims Recently, we performed a large randomized-controlled trial to assess the effects of the somatostatin analogue lanreotide on kidney function and kidney and liver volume in autosomal dominant polycystic kidney disease (ADPKD), the DIPAK-1 trial. Lanreotide had no effect on rate of kidney function decline, but slowed kidney and especially liver growth and is used for this indication in clinical practice1,2. A higher incidence of gallstones has been suggested with lanreotide use, but the exact size and implications of this problem are unknown. Therefore, we systematically studied the incidence of gallstones with lanreotide in ADPKD patients. Method In the DIPAK-1 trial, 305 ADPKD patients (age 18-60 years and eGFR 30-60 ml/1.73m2/min) were randomized to lanreotide or standard of care. MRIs were performed at baseline and end of study (120 weeks). For this post-hoc study, patients with a medical history of cholecystectomy (n=7) or absence of a MRI at the end of study (n=28) were excluded. For the remaining study population (n=270), all MRIs were assessed for presence of gallstones by two trained investigators blinded for study treatment and study period and in case of disagreeing results, an abdominal radiologist was consulted for a final assessment. For patients with gallstones additional follow up after the end of the trial was obtained. Results In 2 baseline and 8 end-of -study MRIs, it was not possible to identify the gallbladder, due to multiple adjacent liver cysts. Of the remaining 260 patients (age 48.5 years, female 49.6%, eGFR 50.0 ml/min/1.73m2), 14 patients (5,4%) had gallstones at baseline, of whom 5 were randomized to lanreotide and 9 to standard care. At the end of study, 32 patients (12,3%) had gallstones, of whom 21 patients had received lanreotide and 11 standard care. During the 120 week lasting study, new gallstones occurred in 17 out of 128 patients receiving lanreotide (13.3%) and 3 out of 132 patients receiving standard care (2.3%), rendering an adjusted Odds Ratio for gallstone formation with lanreotide use of 6.9 (95% Confidence Interval 1.9-24.7) p Of the 32 patients with gallstones at the end of study, seven experienced gallstone-associated complications. Three experienced a biliary pancreatitis (1 during and 2 after the study). Another one had signs of a chronic pancreatitis as accidental finding on imaging during the study, without having had symptoms. Furthermore, another 3 patients underwent a cholecystectomy for symptomatic gallstones after the study. Importantly, all patients with gallstone-associated complications were part of the subgroup of patients that developed de novo gallstones during lanreotide use in the study. Conclusion Lanreotide increases the risk of gallstone formation in ADPKD sevenfold. Gallstones were associated with severe complications, most occurring after the end of the trial. The benefit of somatostatin analogues to reduce kidney and liver size in ADPKD should therefore be weighed against the higher incidence of these adverse events, and patients and doctors should be aware of the risk of (symptomatic) gallstones with use of these drugs.

Introduction Predicting disease progression in autosomal dominant polycystic kidney disease (ADPKD) patients poses a challenge, especially in early stage disease when renal function is not yet affected. The ongoing formation and growth of cysts causes the urine concentrating capacity to decrease from early on in the disease. We therefore hypothesized that the easy and inexpensive to measure urine-to-plasma urea ratio (UPU ratio), which is assumed to be surrogate for maximal urine concentrating capacity, can be used as marker to predict disease progression in ADPKD. Methods The UPU ratio was calculated by dividing urea concentration in a fasting morning spot urine sample by plasma urea concentration adjusted for plasma creatinine concentration. First, we validated the UPU ratio in 30 ADPKD patients who underwent a prolonged water deprivation test to measure the maximal urine concentrating capacity. Thereafter, the association of the UPU ratio with renal outcome was evaluated in 583 ADPKD patients participating in the DIPAK observational cohort (inclusion criteria: age>18 years, eGFR >15 mL/min/1.73m2, no concomitant diseases affecting eGFR, without V2 receptor antagonist prescription). Kidney function was assessed as eGFR by the creatinine based CKD-EPI formula, height adjusted total kidney volume (htTKV) by MRI and copeptin (surrogate for vasopressin) by ELISA. Results In the water deprivation test participants (n=30), the UPU ratio was strongly correlated with maximal urine concentrating capacity (R = 0.67, p40% during follow-up (adjusted Hazard Ratio per SD = 1.39, p = 0.007). Limiting the aforementioned analyses to the subgroup of patients with relative early stage disease (n=122, age 60 mL/min/1.73m2) rendered essentially similar results, with an adjusted β for UPU ratio in the final model of 0.33 (p = 0.04). In this subgroup with a limited number of events (n=10), Cox survival analysis did not reach formal significance (adjusted HR per SD: 2.67, p = 0.055). Conclusion The UPU ratio, which is calculated from routine laboratory measurements, predicts renal prognosis in ADPKD in addition to other, more laborious to measure and expensive risk markers. Notably, this marker of urine concentrating capacity also shows promise in early-stage disease.

Background and Aims The vasopressin V2 receptor antagonist tolvaptan is the first drug that was proven to ameliorate kidney function decline in ADPKD. Blockade of the vasopressin V2 receptor, however, also results in nephrogenic diabetes insipidus (NDI), with an associated polyuria of on average 6 to 8 L/24h, limiting its clinical use. Hydrochlorothiazide (HCT) is an established treatment in NDI of other origins, but is unclear whether it is also efficacious in tolvaptan-caused NDI. Importantly, the combination of HCT and tolvaptan could cause electrolyte disturbances, and HCT treatment could theoretically increase vasopressin, which might accelerate ADPKD disease progression. Recently, metformin has been shown to ameliorate aquaresis in an animal model of NDI, but has never been investigated for this indication in humans. We aimed to investigate efficacy and safety of hydrochlorothiazide and metformin treatment to ameliorate the aquaretic side-effects of tolvaptan. Method This is an investigator driven, double-blind, randomized, controlled cross-over trial. ADPKD patients (Ravine criteria) were eligible for inclusion if they were 18-55 years of age, had an eGFR ≥ 30 mL/min/1.73m2 and were treated with a stable dose of tolvaptan. Patients were treated for three 2 week-periods with hydrochlorothiazide (HCT) 25 mg (12.5 mg in the first week), metformin 2000 mg (1000 mg in the first week) or placebo (half dose in the first week), in random order. Primary outcome was change in 24-hour urine volume (average of 2 collections) compared to baseline. Key secondary outcomes were measured GFR (mGFR), plasma copeptin (the stable precursor of vasopressin), quality of life and electrolytes. Results All 13 patients that were included were able to complete every treatment period in the trial. Their mean age was 45±8 years, 54% was female and mGFR was 55±11 mL/min/1.73m2 (Table). 85% of participants used the maximum tolvaptan dose (90/30 mg). At baseline urine volume was 6.9±1.4 L/24h. On HCT treatment urine volume decreased with -25±13% (p Conclusion This is the first study to show that metformin can ameliorate aquaresis in NDI, and that HCT improves tolvaptan-caused NDI. Both treatments were well tolerated and safe during short-term use. The fact that copeptin is not increased by metformin, and even decreased by HCT suggests that these treatments will not negatively impact renoprotection by tolvaptan. These data provide an evidence base to test metformin and especially HCT in a real life setting to improve aquaresis and tolerability in patients with tolvaptan induced NDI. BaselineHCTPlaceboMetforminAbsolute urine volume (L/24h)6.95.1**6.35.4**Change in urine volume (%)0-25**-8-22**Creatinine excretion (mmol/24h)15.815.416.115.7Osmolar excretion (mOsm/24h)104410201013947*mGFR (mL/min/1.73m2)5551**5554SBP (mmHg)125117**122120Plasma copeptin (pmol/L)2520**2628Plasma sodium (mmol/L)141139141140Plasma potassium (mmol/L)3.83.6*3.94.0Plasma urea (mmol/L)7.08.6**6.97.2QoL ImprovedN/A7 (58%)2 (17%)1 (8%)Results in n=13 ADPKD patients on highest tolerated tolvaptan dose*P

Item does not contain fulltext 14 p.

Contains fulltext : 225147.pdf (Publisher’s version ) (Open Access) In autosomal dominant polycystic kidney disease (ADPKD), there are only scarce data on the effect of salt and protein intake on disease progression. Here we studied association of these dietary factors with the rate of disease progression in ADPKD and what the mediating factors are by analyzing an observational cohort of 589 patients with ADPKD. Salt and protein intake were estimated from 24-hour urine samples and the plasma copeptin concentration measured as a surrogate for vasopressin. The association of dietary intake with annual change in the estimated glomerular filtration rate (eGFR) and height adjusted total kidney volume (htTKV) growth was analyzed with mixed models. In case of significant associations, mediation analyses were performed to elucidate potential mechanisms. These patients (59% female) had a mean baseline age of 47, eGFR 64 mL/min/1.73m(2) and the median htTKV was 880 mL. The mean estimated salt intake was 9.1 g/day and protein intake 84 g/day. During a median follow-up of 4.0 years, eGFR was assessed a median of six times and 24-hour urine was collected a median of five times. Salt intake was significantly associated with annual change in eGFR of -0.11 (95% confidence interval 0.20 - -0.02] mL/min/1.73m(2)) per gram of salt, whereas protein intake was not (-0.00001 [-0.01 - 0.01] mL/min/1.73m(2)) per gram of protein). The effect of salt intake on eGFR slope was significantly mediated by plasma copeptin (crude analysis: 77% mediation, and, adjusted analysis: 45% mediation), but not by systolic blood pressure. Thus, higher salt, but not higher protein intake may be detrimental in ADPKD. The substantial mediation by plasma copeptin suggests that this effect is primarily a consequence of a salt-induced rise in vasopressin.

Background In autosomal dominant polycystic kidney disease (ADPKD), hypertension is prevalent and cardiovascular events are the main cause of death. Thiazide diuretics are often prescribed as second-line antihypertensives, on top of renin–angiotensin–aldosterone system (RAAS) blockade. There is a concern, however, that diuretics may increase vasopressin concentration and RAAS activity, thereby worsening disease progression in ADPKD. We aimed to investigate the validity of these suggestions. Methods We analysed an observational cohort of 533 ADPKD patients. Plasma copeptin (surrogate for vasopressin), aldosterone and renin were measured by enzyme-linked immunosorbent assay and radioimmunoassay, respectively. Linear mixed models were used to assess the association of thiazide use with estimated glomerular filtration rate (eGFR) decline and Cox proportional hazards models for the association with the composite kidney endpoint of incident end-stage kidney disease, 40% eGFR decline or death. Results A total of 23% of participants (n = 125) used thiazide diuretics at baseline. Compared with non-users, thiazide users were older, a larger proportion was male, they had lower eGFRs and similar blood pressure under more antihypertensives. Plasma copeptin was higher, but this difference disappeared after adjustment for age and sex. Both renin and aldosterone were higher in thiazide users. There was no difference between thiazide users and non-users in the rate of eGFR decline {difference −0.35 mL/min/1.73 m2 per year [95% confidence interval (CI) −0.83 to –0.14], P = 0.2} during 3.9 years of follow-up (interquartile range 2.5–4.9). This did not change after adjustment for potential confounders [difference final model: 0.08 mL/min/1.73 m2 per year [95% CI −0.46 to –0.62], P = 0.8). In the crude model, thiazide use was associated with a higher incidence of the composite kidney endpoint [hazard ratio (HR) 1.53 (95% CI 1.05–2.23), P = 0.03]. However, this association lost significance after adjustment for age and sex and remained unassociated after adjustment for additional confounders [final model: HR 0.80 (95% CI 0.50–1.29), P = 0.4]. Conclusions These data do not show that thiazide diuretics have a detrimental effect on the rate of disease progression in ADPKD and suggest that these drugs can be prescribed as second-line antihypertensives.

Tolvaptan, a vasopressin V2 receptor antagonist, has been shown to reduce the rates of growth in total kidney volume (TKV) and renal function loss in ADPKD patients, but also leads to polyuria because of its aquaretic effect. Prolonged polyuria can result in ureter dilatation with consequently renal function loss. Therefore, we aimed to investigate the effect of tolvaptan-induced polyuria on ureter diameter in ADPKD patients.70 ADPKD patients were included (51 were randomized to tolvaptan and 19 to placebo). At baseline and after 3 years of treatment renal function was measured (mGFR) and MRI was performed to measure TKV and ureter diameter at the levels of renal pelvis and fifth lumbar vertebral body (L5).In these patients [65.7 % male, age 41 +/- 9 years, mGFR 74 +/- 27 mL/min/1.73 m(2) and TKV 1.92 (1.27-2.67) L], no differences were found between tolvaptan and placebo-treated patients in 24-h urine volume at baseline (2.5 vs. 2.5 L, p = 0.8), nor in ureter diameter at renal pelvis and L5 (4.0 vs. 4.2 mm, p = 0.4 and 3.0 vs. 3.1 mm, p = 0.3). After 3 years of treatment 24-h urine volume was higher in tolvaptan-treated patients when compared to placebo (4.7 vs. 2.3 L, p Tolvaptan-induced polyuria did not lead to an increase in ureter diameter, suggesting that tolvaptan is a safe therapy from a urological point of view.

RATIONALE & OBJECTIVE: The vasopressin V2 receptor antagonist (V2RA) tolvaptan is the first drug that has been shown to slow the rate of kidney function decline in patients with autosomal dominant polycystic kidney disease (ADPKD). However, V2RAs also cause polyuria, with urine output that averages 6L/d. We assessed determinants of urine volume in patients with ADPKD using V2RAs because such information may help develop strategies to improve V2RA tolerability.STUDY DESIGN: Clinical trial of patients with ADPKD studied at baseline, after 3 weeks of V2RA treatment (tolvaptan, 90/30mg, in the last week), and after a 3-week washout period.SETTING & PARTICIPANTS: The trial included patients with ADPKD with a wide range of kidney function (measured glomerular filtration rates [mGFRs]; range, 18-148mL/min/1.73m2).INTERVENTION: Tolvaptan treatment for 3 weeks.OUTCOMES: 24-hour urine volume.ANALYTICAL APPROACH: Multivariable regression analysis with stepwise backward elimination was performed both during and without V2RA treatment to evaluate the influence of 24-hour osmolar excretion, mGFR, and total kidney volume on associations between tolvaptan and urine volume.RESULTS: Included were 27 patients (48% men, aged 46±9.8 years with mGFRs of 61±35mL/min/1.73m2). V2RA treatment caused a median increase in urine volume of 128% (interquartile range, 75%-202%), to 5,930±1,790mL. 24-hour osmolar excretion was strongly associated with 24-hour urine volume (standardized β = 0.73; P < 0.001). During V2RA use, no independent associations were detected between 24-hour urine volume and mGFR, total kidney volume, or V2RA concentration.LIMITATIONS: Limited sample size, no standardized diets.CONCLUSIONS: Osmolar excretion is the major determinant of urine volume in patients taking V2RAs as a consequence of the inability to concentrate urine. Restriction of osmolar intake may therefore limit V2RA-induced polyuria, giving patients more control over the aquaretic side effects and improving the tolerability of these drugs.

Contains fulltext : 209004.pdf (Publisher’s version ) (Open Access)

BACKGROUND: The TEMPO 3:4 Trial results suggested that tolvaptan had no effect compared with placebo on albuminuria in autosomal-dominant polycystic kidney disease (ADPKD) patients. However, the use of categorical 'albuminuria events' may have resulted in a loss of sensitivity to detect changes. The aim of this study is to investigate the effects of tolvaptan on albuminuria as a continuous variable. METHODS: Post hoc analysis of a 3-year prospective, blinded randomized controlled trial, including 1375 ADPKD patients. Albuminuria was measured in a spot morning urine sample prior to tolvaptan dosing and expressed as albumin-to-creatinine ratio (ACR). RESULTS: Baseline median (interquartile range) ACR was 3.2 (1.7-7.1) mg/mmol. Of note, 47.9% of ADPKD patients had normal, 48.7% moderately increased and 3.4% severely increased ACR. Subjects with higher baseline ACR had higher blood pressure and total kidney volume (TKV) and lower estimated glomerular filtration rate (eGFR). During follow-up, higher baseline ACR was associated with more rapid eGFR loss (P < 0.0001 for trend), but not with rate of growth in TKV. During the 3-year trial, ACR rose in placebo- and decreased in tolvaptan-treated patients (+0.23 versus -0.40 mg/mmol). The difference ACR increased over time, reaching a maximum of 24% at Month 36 (P < 0.001). At that time only a minor difference in blood pressure was observed (mean arterial pressure -1.9 mmHg for tolvaptan). The decrease in ACR was similar in all subgroups investigated, and remained after withdrawal of study drug. The beneficial effect of tolvaptan on TKV growth and eGFR loss was stronger in patients with higher baseline ACR. CONCLUSIONS: In ADPKD, higher baseline albuminuria was associated with more eGFR loss. Tolvaptan decreased albuminuria compared with placebo, independent of blood pressure. Treatment efficacy of tolvaptan on changes in TKV and eGFR was more readily detected in patients with higher albuminuria.

The epidermal growth factor receptor (EGFR) pathway has a critical role in renal development, tissue repair and electrolyte handling. Numerous studies have reported an association between dysregulation of this pathway and the initiation and progression of various chronic kidney diseases such as diabetic nephropathy, chronic allograft nephropathy and polycystic kidney disease through the promotion of renal cell proliferation, fibrosis and inflammation. In the oncological setting, compounds that target the EGFR pathway are already in clinical use or have been evaluated in clinical trials; in the renal setting, therapeutic interventions targeting this pathway by decreasing ligand availability with disintegrin and metalloproteinase inhibitors or with ligand-neutralizing antibodies, or by inhibiting receptor activation with tyrosine kinase inhibitors or monoclonal antibodies are only just starting to be explored in animal models of chronic kidney disease and in patients with autosomal dominant polycystic kidney disease. In this Review we focus on the role of the EGFR signalling pathway in the kidney under physiological conditions and during the pathophysiology of chronic kidney diseases and explore the clinical potential of interventions in this pathway to treat chronic renal diseases.

BackgroundUrinary excretion of alpha-1-microglobulin and beta-2-microglobulin reflects tubular damage and predicts outcome in patients with idiopathic membranous nephropathy with reasonable accuracy. Urinary kidney injury molecule-1 and neutrophil gelatinase-associated lipocalin are novel biomarkers of tubular damage. We investigated if these markers could improve prediction of outcome in idiopathic membranous nephropathy.MethodsWe measured kidney injury molecule-1 and neutrophil gelatinase-associated lipocalin in urine samples from patients with idiopathic membranous nephropathy, who had nephrotic proteinuria and normal renal function. Excretion of alpha-1-microglobulin and beta-2-microglobulin had been measured previously. Progression was defined as a serum creatinine rise >30%, a rise in serum creatinine to an absolute value of ≥135 µmol/L, or a clinical decision to start immunosuppressive therapy. Remission was defined as proteinuria 50% reduction from baseline.ResultsSixty-nine patients were included. Median follow-up was 35 months (interquartile range 18–63 months). Progression occurred in 30 patients (44%), and spontaneous remission in 36 (52%). Kidney injury molecule-1 and neutrophil gelatinase-associated lipocalin excretion rates were significantly correlated with each other, and with alpha-1-microglobulin and beta-2-microglobulin. The areas under the receiver operating characteristic curves for progression were 0.75 (0.62–0.87) for kidney injury molecule-1 and 0.74 (0.62–0.87) for neutrophil gelatinase-associated lipocalin. In multivariate analysis with either alpha-1-microglobulin and beta-2-microglobulin, kidney injury molecule-1 and neutrophil gelatinase-associated lipocalin did not independently predict outcome.ConclusionKidney injury molecule-1 and neutrophil gelatinase-associated lipocalin excretion rates correlated with excretion rates of other tubular damage markers and predicted outcome in patients with idiopathic membranous nephropathy. They did not add prognostic value compared to measurement of either alpha-1-microglobulin or beta-2-microglobulin.

Background: In autosomal dominant polycystic kidney disease, renoprotective treatment with a vasopressin V2 receptor antagonist (V2RA) is given in a fixed dose (FD). Disease progression and drug habituation could diminish treatment efficacy. We investigated whether the renoprotective effect of the V2RA can be improved by dose titration of the V2RA aiming to maintain aquaresis at a high level. Methods: The V2RA OPC-31260 was administered to Pkd1-deletion mice in an FD (0.1%) or in a titrated dose (TD, up to 0.8% when drinking volume dropped). Total kidney weight (TKW) and cyst ratio were investigated and compared to non-treated Pkd1-deletion mice. Treatment was started early or late (21 or 42 days postnatal). Results: Water intake was significantly higher throughout the experiment in the TD compared to the FD group. FD treatment that was initiated early reduced TKW and cyst ratio but lost its renoprotective effect later during the experiment. In contrast, TD treatment was able to maintain the renoprotective effect. TD treatment, however, was also associated with a higher early termination rate in comparison with FD treatment. Late start of treatment (FD or TD) did not show a renoprotective effect. Conclusions: Titration of a V2RA aimed to maintain aquaresis at a high level showed a better renoprotective effect compared to FD administration. However, this treatment regimen was poorly tolerated and did not overcome treatment unresponsiveness when started later in the disease.

BACKGROUND The prevalence of chronic kidney disease (CKD) is increasing worldwide. The identification of factors contributing to its progression is important for designing preventive measures. Previous studies have suggested that chronically high vasopressin is deleterious to renal function. Here, we evaluated the association of plasma copeptin, a surrogate of vasopressin, with the incidence of CKD in the general population. METHODS We studied 3 European cohorts: DESIR (n = 5,047; France), MDCS-CC (n = 3,643; Sweden), and PREVEND (n = 7,684; the Netherlands). Median follow-up was 8.5, 16.5, and 11.3 years, respectively. Pooled data were analyzed at an individual level for 4 endpoints during follow-up: incidence of stage 3 CKD (estimated glomerular filtration rate [eGFR] < 60 ml/min/1.73 m2); the KDIGO criterion "certain drop in eGFR"; rapid kidney function decline (eGFR slope steeper than -3 ml/min/1.73 m2/yr); and incidence of microalbuminuria. RESULTS The upper tertile of plasma copeptin was significantly and independently associated with a 49% higher risk for stage 3 CKD (P < 0.0001); a 64% higher risk for kidney function decline, as defined by the KDIGO criterion (P < 0.0001); a 79% higher risk for rapid kidney function decline (P < 0.0001); and a 24% higher risk for microalbuminuria (P = 0.008). CONCLUSIONS High copeptin levels are associated with the development and the progression of CKD in the general population. Intervention studies are needed to assess the potential beneficial effect on kidney health in the general population of reducing vasopressin secretion or action. FUNDING INSERM and Danone Research Centre for Specialized Nutrition.