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

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

Management of delivery of a fetus with autosomal recessive polycystic kidney disease: a case report of abdominal dystocia and review of the literature

Background Autosomal recessive renal polycystic kidney disease occurs in 1 in 20,000 live births. It is caused by mutations in both alleles of the PKHD1 gene. Management of delivery in cases of suspected autosomal recessive renal polycystic kidney disease is rarely discussed, and literature concerning abdominal dystocia is extremely scarce. We present a case of a patient with autosomal recessive renal polycystic kidney disease whose delivery was complicated by abdominal dystocia, and we discuss the factors that determined the route and timing of delivery. Case presentation A 23-year-old Caucasian woman, G2 P0, with a prior unremarkable pregnancy was referred to our tertiary center at 31 weeks of gestation because of severe oligoamnios (amniotic fluid index = 2) and hyperechogenic, dedifferentiated, and enlarged fetal kidneys. She had no other genitourinary anomaly. Fetal magnetic resonance imaging showed enlarged, hypersignal kidneys and severe pulmonary hypoplasia. We had a high suspicion of autosomal recessive renal polycystic kidney disease, and after discussion with our multidisciplinary team, the parents opted for conservative care. Ultrasound performed at 35 weeks of gestation showed a fetal estimated weight of 3550 g and an abdominal circumference of 377 mm, both above the 90th percentile. Because of the very rapid kidney growth and suspected risk of abdominal dystocia, we proposed induction of labor at 36 weeks of gestation after corticosteroid administration for fetal lung maturation. Vaginal delivery was complicated by abdominal dystocia, which resolved by continuing expulsive efforts and gentle fetal traction. A 3300-g (P50–90) male infant was born with Apgar scores of 1-7-7 at 1, 5, and 10 minutes, respectively, and arterial and venous umbilical cord pH values of 7.23–7.33. Continuous peritoneal dialysis was started at day 2 of life because of anuria. Currently, the infant is 1 year old and is waiting for kidney transplant that should be performed once he reaches 10 kg. Molecular analysis of PKHD1 performed on deoxyribonucleic acid (DNA) from the umbilical cord confirmed autosomal recessive renal polycystic kidney disease. Conclusions Management of delivery in cases of suspected autosomal recessive renal polycystic kidney disease needs to be discussed because of the risk of abdominal dystocia. The route and timing of delivery depend on the size of the fetal abdominal circumference and the gestational age. The rate of kidney growth must also be taken into account.

The expression of somatostatin receptor 2 decreases during cyst growth in mice with polycystic kidney disease

Autosomal dominant polycystic kidney disease (ADPKD) is characterized by progressive renal cyst formation and expansion. Several clinical trials show that somatostatin analogs halt cyst growth and progression of ADPKD by inhibiting adenosine 3′,5′-cyclic monophosphate (cAMP) signaling. However, two studies suggest that the effect of the somatostatin analog octreotide on kidney growth during the first year of treatment is reduced in the subsequent follow-ups and the kidney enlargement resumes. We hypothesize that this biphasic change in kidney growth during octreotide treatment may be due to changes in somatostatin receptor 2 (SSTR2) expression. Here we analyzed the expression of renal SSTR2 in various polycystic kidney disease (PKD) mouse models in which PKD1 gene expression was disrupted on postnatal day 10 or 18 by tamoxifen. Using immunohistochemical analysis, we showed that the distribution of SSTR2 in murine kidneys is mainly in distal tubules and collecting ducts. In addition, in both PKD models, we observed a significant decrease in SSTR2 expression in epithelia of dilated tubules and cystic epithelia in mice with end stage of PKD compared to wild-type mice. These findings were further confirmed by quantitative PCR (qPCR) on mRNA levels of SSTR2. In conclusion, our data show that SSTR2 expression levels are reduced during kidney cyst growth, which may suggest reduced efficacy in long-term treatment with somatostatin analogs. Impact statement Somatostatin (SST) analogs have been shown to halt cyst growth and progression of autosomal dominant polycystic kidney disease by several clinical trials. However, two studies suggest that the effect of the SST analog octreotide on kidney growth during the first year of treatment is reduced in the subsequent follow-ups and the kidney enlargement resumes. This biphasic change in kidney growth during octreotide treatment may be partially explained by alterations in SSTR2 expression. Here, we found that SSTR2 is mainly expressed in distal tubules and collecting ducts in murine kidneys, and the expression of SSTR2 decreases during cyst growth in two PKD mouse models. Our data may thus provide possible explanations for the lack of efficacy in long-term treatment with SST analogs.

Histological evaluation of kidney development in young rats after a surgery and management of wound with fibrin glue

Aim. The subject of this study is evaluation of histological hallmarks of kidney growth in rats after a surgery and subsequent management of the wound with fibrin glue. Material and Methods. Sixty-five Wistar rats underwent a surgical procedure resulting in parenchymal injury by incision followed by an application of fibrin glue. Kidneys have been examined and evaluated histologically after 4 weeks (group I) and 26 weeks (group II) after the surgery Results. When fibrin glue was used, in both groups, regular anastomoses of the wound edges of the kidney after surgery were noted. Histological features of kidney growth (renal glomeruli, renal tubules and blood vessels) were observed in the parenchyma and in the postoperative scar. In the second group kidneys grew on average by 3.5mm in the longitudinal section and by 1.89 in the cross section. In this group, the number of renal glomeruli nearly doubled. Glomeruli and tubules were also found in the postoperative scar.