Fouad T. Chebib

Vasopressin and disruption of calcium signalling in polycystic kidney disease

Autosomal dominant polycystic kidney disease (ADPKD) is the most common monogenic kidney disease and is responsible for 5–10% of cases of end-stage renal disease worldwide. ADPKD is characterized by the relentless development and growth of cysts, which cause progressive kidney enlargement associated with hypertension, pain, reduced quality of life and eventual kidney failure. Mutations in the PKD1 or PKD2 genes, which encode polycystin-1 (PC1) and polycystin-2 (PC2), respectively, cause ADPKD. However, neither the functions of these proteins nor the molecular mechanisms of ADPKD pathogenesis are well understood. Here, we review the literature that examines how reduced levels of functional PC1 or PC2 at the primary cilia and/or the endoplasmic reticulum directly disrupts intracellular calcium signalling and indirectly disrupts calcium-regulated cAMP and purinergic signalling. We propose a hypothetical model in which dysregulated metabolism of cAMP and purinergic signalling increases the sensitivity of principal cells in collecting ducts and of tubular epithelial cells in the distal nephron to the constant tonic action of vasopressin. The resulting magnified response to vasopressin further enhances the disruption of calcium signalling that is initiated by mutations in PC1 or PC2, and activates downstream signalling pathways that cause impaired tubulogenesis, increased cell proliferation, increased fluid secretion and interstitial inflammation.

Autosomal Dominant Polycystic Kidney Disease: Core Curriculum 2016.

Autosomal dominant polycystic kidney disease (ADPKD) is the most common monogenic kidney disease. It is characterized by relentless development of kidney cysts, hypertension, and eventually end-stage renal disease (ESRD). ADPKD is associated abdominal fullness and pain, cyst hemorrhage, nephrolithiasis, cyst infection, hematuria, and reduced quality of life, among other symptoms. The disease is a consequence of mutations in PKD1 or PKD2, encoding polycystin 1 and polycystin 2, respectively. Many recent advances have been made in understanding and managing ADPKD. This Core Curriculum outlines the different aspects of molecular genetics, pathophysiology, diagnosis, and management of kidney and extrarenal complications in ADPKD.

Effect of genotype on the severity and volume progression of polycystic liver disease in autosomal dominant polycystic kidney disease

BACKGROUND The autosomal dominant polycystic kidney disease (APDKD) genotype influences renal phenotype severity but its effect on polycystic liver disease (PLD) is unknown. Here we analyzed the influence of genotype on liver phenotype severity. METHODS Clinical data were retrieved from electronic records of patients who were mutation screened with the available liver imaging (n = 434). Liver volumes were measured by stereology (axial or coronal images) and adjusted to height (HtLV). RESULTS Among the patients included, 221 (50.9%) had truncating PKD1 (PKD1-T), 141 (32.5%) nontruncating PKD1 (PKD1-NT) and 72 (16.6%) PKD2 mutations. Compared with PKD1-NT and PKD2, patients with PKD1-T had greater height-adjusted total kidney volumes (799 versus 610 and 549 mL/m; P < 0.001). HtLV was not different (1042, 1095 and 1058 mL/m; P = 0.64) between the three groups, but females had greater HtLVs compared with males (1114 versus 1015 mL/m; P < 0.001). Annualized median liver growth rates were 1.68, 1.5 and 1.24% for PKD1-T, PKD1-NT and PKD2 mutations, respectively (P = 0.49), and remained unaffected by the ADPKD genotype when adjusted for age, gender and baseline HtLV. Females <48 years of age had higher annualized growth rates compared with those who were older (2.65 versus 0.09%; P < 0.001). After age 48 years, 58% of females with severe PLD had regression of HtLV, while HtLV continued to increase in males. CONCLUSIONS In contrast to the renal phenotype, the ADPKD genotype was not associated with the severity or growth rate of PLD in ADKPD patients. This finding, along with gender influence, indicates that modifiers beyond the disease gene significantly influence the liver phenotype.

Intravitreal Antivascular Endothelial Growth Factor Therapy May Induce Proteinuria and Antibody Mediated Injury in Renal Allografts.

Introduction Systemic adverse effects of intravenous antivascular endothelial growth factor (VEGF) therapy include: hypertension, proteinuria, renal failure, and thrombotic microangiopathy. Intravitreal therapy with these agents is generally believed to be safe. Methods We report 2 cases of renal transplant recipients who developed significant allograft dysfunction after the initiation of intravitreal anti-VEGF therapy. Results The first case is a 67-year-old man with polycystic kidney disease and recipient of a zero-antigen mismatch kidney allograft which developed worsening proteinuria over the first year after transplantation. At 4 months, a biopsy showed only minimal fibrosis and atrophy. At 1 year, an allograft biopsy showed phospholipase A 2 receptor–negative membranous nephropathy. The second patient was a 52-year-old man with tuberous sclerosis who was a recipient of a living related kidney allograft with diminished but stable graft function 16 years from transplantation. After the initiation of intravitreal anti-VEGF therapy, there was an escalating degree of proteinuria. Renal biopsy revealed acute and chronic antibody-mediated rejection with glomerular thrombi and transplant glomerulopathy. Conclusions These cases, although do not prove causality, point to the need for careful follow-up of renal transplant recipients undergoing intravitreal therapy with anti-VEGF agents. These locally administered agents may play a role in the development of proteinuria and modulate antibody-mediated phenomena. We recommend that in renal transplant recipients undergoing therapy with intravitreal anti-VEGF agents, proteinuria be checked monthly, and there should be a low threshold for performing a biopsy to evaluate for allograft injury.

Volume regression of native polycystic kidneys after renal transplantation

BACKGROUND The natural course of native kidneys after renal transplantation (RT) or dialysis in patients with autosomal dominant polycystic kidney disease (ADPKD) remains poorly understood. METHODS We measured the total volumes of native kidneys and liver in 78 and 68 ADPKD patients, respectively, who had pre-transplant (within 2 years) and at least one post-transplant computed tomography (CT)/magnetic resonance imaging (MRI); in 40 patients with at least two post-transplant but no pre-transplant CT/MRIs; in 9 patients on chronic hemodialysis with at least one CT/MRI before and after beginning dialysis; and in 5 patients who had no image before and more than one image after dialysis. The last imaging was used in patients with multiple studies. RESULTS Mean total kidney volume (TKV) ( ± SD) prior to transplantation was 3187 ± 1779 mL in the 78 patients who had imaging before and after transplantation and decreased by 20.2, 28.6, 38.3 and 45.8% after 0.5-1 (mean 0.7), 1-3 (1.8), 3-10 (5.7) and >10 (12.6) years, respectively. In the multivariable analysis, time on dialysis prior to RT and time from baseline to transplantation were negatively associated with reduction in TKV, whereas estimated glomerular filtration rate (eGFR) after transplantation and time from transplantation were positively associated with percent reduction in TKV. In the 40 patients with imaging only after transplantation, TKV decreased by 3.2 ± 16.3% between 7.2 ± 6.0 and 11.2 ± 6.8 years after transplantation (P < 0.001). TKV was 11.2 ± 35.6% higher (P = NS) after a follow-up of 3.4 ± 2.0 years in the 9 patients with imaging before and after initiation of hemodialysis and 3.4 ± 40.2% lower (P = NS) in the 5 patients with imaging between 2.0 ± 2.1 and 3.5 ± 3.6 years after initiation of hemodialysis. In the 68 patients with liver measurements, volume increased by 5.8 ± 17.9% between baseline and follow-up at 3.7 ± 3.8 years after transplantation (P = 0.009). CONCLUSIONS TKV of native polycystic kidneys decreases substantially after RT. The reduction occurs mainly during the early post-transplantation period and more slowly thereafter.

Native Nephrectomy in Renal Transplant Recipients with Autosomal Dominant Polycystic Kidney Disease.

Background Native nephrectomy (NNx) is often done in patients with autosomal-dominant polycystic kidney disease. Controversy exists concerning the need and timing of nephrectomy in transplant candidates. We hypothesize that posttransplant NNx does not negatively impact patient and graft survival. Methods Among 470 autosomal-dominant polycystic kidney disease transplant recipients included in the study, 114 (24.3%) underwent pretransplant (30.7%) or posttransplant (69.3%) NNx. Clinical data were retrieved from electronic records. Follow-up was until death, graft loss or June 2014. Perioperative complications were compared between the surgical techniques (open or laparoscopic) and between the pretransplant and posttransplant nephrectomy groups. The effect of nephrectomy on graft survival was analyzed as a time-dependent covariate when performed posttransplant. Results Mean age at transplant was 52.4 years, 53.8% were men, 93% white, 70% were from living donors, and 56.8% were preemptive. Nephrectomy was done laparoscopically in 31% and 86% in the pretransplant and posttransplant nephrectomy groups, respectively. Complications were less common in those who underwent nephrectomy posttransplant (26.6% vs 48%, P = 0.03) but were similar regardless of surgical technique (open, 33.3% vs laparoscopic, 33%; P = 0.66). Patient and graft survivals were similar between those who underwent pretransplant nephrectomy and the rest of the recipients. In the posttransplant nephrectomy group, nephrectomy did not affect patient (hazards ratio, 0.77; 95% confidence interval, 0.38-1.54; P = 0.45) or graft survival (hazards ratio, 1.0; 95% confidence interval, 0.57-1.76; P = 0.1). Conclusions Nephrectomy does not adversely affect patient or graft survival. Posttransplant nephrectomy is feasible when indicated without compromising long-term graft outcome and has fewer complications than pretransplant nephrectomy.

Long-Term Administration of Tolvaptan in Autosomal Dominant Polycystic Kidney Disease.

BACKGROUND AND OBJECTIVES In the 3-year Tolvaptan Efficacy and Safety in Management of ADPKD and Its Outcomes (TEMPO) 3:4 and 1-year Replicating Evidence of Preserved Renal Function: an Investigation of Tolvaptan Safety and Efficacy in ADPKD (REPRISE) trials, tolvaptan slowed the decline of eGFR in patients with autosomal dominant polycystic kidney disease at early and later stages of CKD, respectively. Our objective was to ascertain whether the reduction associated with the administration of tolvaptan is sustained, cumulative, and likely to delay the need for kidney replacement therapy. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS One hundred and twenty-eight patients with autosomal dominant polycystic kidney disease participated in clinical trials of tolvaptan at the Mayo Clinic. All had the opportunity to enroll into open-label extension studies. Twenty participated in short-term studies or received placebo only. The remaining 108 were analyzed for safety. Ninety seven patients treated with tolvaptan for ≥1 year (mean±SD, 4.6±2.8; range, 1.1-11.2) were analyzed for efficacy using three approaches: (1) comparison of eGFR slopes and outcome (33% reduction from baseline eGFR) to controls matched by sex, age, and baseline eGFR; (2) Stability of eGFR slopes with duration of follow-up; and (3) comparison of observed and predicted eGFRs at last follow-up. RESULTS Patients treated with tolvaptan had lower eGFR slopes from baseline (mean±SD, -2.20±2.18 ml/min per 1.73 m2 per year) and from month 1 (mean±SD, -1.97±2.44 ml/min per 1.73 m2 per year) compared with controls (mean±SD, -3.50±2.09 ml/min per 1.73 m2 per year; P<0.001), and lower risk of a 33% reduction in eGFR (risk ratio, 0.63; 95% confidence interval, 0.38 to 0.98 from baseline; risk ratio, 0.53; 95% confidence interval, 0.31 to 0.85 from month 1). Annualized eGFR slopes of patients treated with tolvaptan did not change during follow-up and differences between observed and predicted eGFRs at last follow-up increased with duration of treatment. CONCLUSIONS Follow-up for up to 11.2 years (average 4.6 years) showed a sustained reduction in the annual rate of eGFR decline in patients treated with tolvaptan compared with controls and an increasing separation of eGFR values over time between the two groups.

The Value of Genetic Testing in Polycystic Kidney Diseases Illustrated by a Family With PKD2 and COL4A1 Mutations

The diagnosis of autosomal dominant polycystic kidney disease (ADPKD) relies on imaging criteria in the setting of a positive familial history. Molecular analysis, seldom used in clinical practice, identifies a causative mutation in >90% of cases in the genes PKD1, PKD2, or rarely GANAB. We report the clinical and genetic dissection of a 7-generation pedigree, resulting in the diagnosis of 2 different cystic disorders. Using targeted next-generation sequencing of 65 candidate genes in a patient with an ADPKD-like phenotype who lacked the familial PKD2 mutation, we identified a COL4A1 mutation (p.Gln247*) and made the diagnosis of HANAC (hereditary angiopathy with nephropathy, aneurysms, and muscle cramps) syndrome. While 4 individuals had ADPKD-PKD2, various COL4A1-related phenotypes were identified in 5 patients, and 3 individuals with likely digenic PKD2/COL4A1 disease reached end-stage renal disease at around 50 years of age, significantly earlier than observed for either monogenic disorder. Thus, using targeted next-generation sequencing as part of the diagnostic approach in patients with cystic diseases provides differential diagnoses and identifies factors underlying disease variability. As specific therapies are rapidly developing for ADPKD, a precise etiologic diagnosis should be paramount for inclusion in therapeutic trials and optimal patient management.

The regulatory 1α subunit of protein kinase A modulates renal cystogenesis

The failure of the polycystins (PCs) to function in primary cilia is thought to be responsible for autosomal dominant polycystic kidney disease (ADPKD). Primary cilia integrate multiple cellular signaling pathways, including calcium, cAMP, Wnt, and Hedgehog, which control cell proliferation and differentiation. It has been proposed that mutated PCs result in reduced intracellular calcium, which in turn upregulates cAMP, protein kinase A (PKA) signaling, and subsequently other proliferative signaling pathways. However, the role of PKA in ADPKD has not been directly ascertained in vivo, although the expression of the main regulatory subunit of PKA in cilia and other compartments (PKA-RIα, encoded by PRKAR1A) is increased in a mouse model orthologous to ADPKD. Therefore, we generated a kidney-specific knockout of Prkar1a to examine the consequences of constitutive upregulation of PKA on wild-type and Pkd1 hypomorphic (Pkd1RC) backgrounds. Kidney-specific loss of Prkar1a induced renal cystic disease and markedly aggravated cystogenesis in the Pkd1RC models. In both settings, it was accompanied by upregulation of Src, Ras, MAPK/ERK, mTOR, CREB, STAT3, Pax2 and Wnt signaling. On the other hand, Gli3 repressor activity was enhanced, possibly contributing to hydronephrosis and impaired glomerulogenesis in some animals. To assess the relevance of these observations in humans we looked for and found evidence for kidney and liver cystic phenotypes in the Carney complex, a tumoral syndrome caused by mutations in PRKAR1A These observations expand our understanding of the pathogenesis of ADPKD and demonstrate the importance of PRKAR1A highlighting PKA as a therapeutic target in ADPKD.

Extrarenal Manifestations of Autosomal Dominant Polycystic Kidney Disease: Polycystic Liver Disease

Liver involvement is the most frequent extrarenal organ manifestation seen in autosomal dominant polycystic kidney disease (ADPKD). Most patients with polycystic liver disease (PLD) are asymptomatic and do not require interventions, but an important minority of individuals with symptomatic PLD can have challenging clinical problems resulting from massive hepatomegaly and its associated complications. These individuals can also experience a progressive decline in health status and quality of life. We discuss disease pathogenesis, prevalence, complications, and management. The current role of surgical interventions such as cyst fenestration, partial hepatectomy, liver transplantation, and recent advances in current and medical therapies is reviewed.