Monoallelic IFT140 pathogenic variants are an important cause of the autosomal dominant polycystic kidney-spectrum phenotype.

Autosomal dominant polycystic kidney disease (ADPKD), characterized by progressive cyst formation/expansion, results in enlarged kidneys and often end stage kidney disease. ADPKD is genetically heterogeneous; PKD1 and PKD2 are the common loci (∼78% and ∼15% of families) and GANAB, DNAJB11, and ALG9 are minor genes. PKD is a ciliary-associated disease, a ciliopathy, and many syndromic ciliopathies have a PKD phenotype. In a multi-cohort/-site collaboration, we screened ADPKD-diagnosed families that were naive to genetic testing (n = 834) or for whom no PKD1 and PKD2 pathogenic variants had been identified (n = 381) with a PKD targeted next-generation sequencing panel (tNGS; n = 1,186) or whole-exome sequencing (WES; n = 29). We identified monoallelic IFT140 loss-of-function (LoF) variants in 12 multiplex families and 26 singletons (1.9% of naive families). IFT140 is a core component of the intraflagellar transport-complex A, responsible for retrograde ciliary trafficking and ciliary entry of membrane proteins; bi-allelic IFT140 variants cause the syndromic ciliopathy, short-rib thoracic dysplasia (SRTD9). The distinctive monoallelic phenotype is mild PKD with large cysts, limited kidney insufficiency, and few liver cysts. Analyses of the cystic kidney disease probands of Genomics England 100K showed that 2.1% had IFT140 LoF variants. Analysis of the UK Biobank cystic kidney disease group showed probands with IFT140 LoF variants as the third most common group, after PKD1 and PKD2. The proximity of IFT140 to PKD1 (∼0.5 Mb) in 16p13.3 can cause diagnostic confusion, and PKD1 variants could modify the IFT140 phenotype. Importantly, our studies link a ciliary structural protein to the ADPKD spectrum.

Distinct developmental reprogramming footprint of macrophages during acute kidney injury across species.

Acute kidney injury (AKI) is a common finding in hospitalized patients, particularly those who are critically ill. The development of AKI is associated with several adverse outcomes including mortality, morbidity, progression to chronic kidney disease, and an increase in healthcare expenditure. Despite the well-established negative impact of AKI and rigorous efforts to better define, identify, and implement targeted therapies, the overall approach to the treatment of AKI continues to principally encompass supportive measures. This enduring challenge is primarily due to the heterogeneous nature of insults that activate many independent and overlapping molecular pathways. Consequently, it is evident that the identification of common mechanisms that mediate the pathogenesis of AKI, independent of etiology and engaged pathophysiological pathways, is of paramount importance and could lead to the identification of novel therapeutic targets. To better distinguish the commonly modulated mechanisms of AKI, we explored the transcriptional characteristics of human kidney biopsies from patients with acute tubular necrosis (ATN), and acute interstitial nephritis (AIN) using a NanoString inflammation panel. Subsequently, we used publicly available single-cell transcriptional resources to better interpret the generated transcriptional findings. Our findings identify robust acute kidney injury (AKI-induced) developmental reprogramming of macrophages (MΦ) with the expansion of C1Q+, CD163+ MΦ that is independent of the etiology of AKI and conserved across mouse and human species. These results would expand the current understanding of the pathophysiology of AKI and potentially offer novel targets for additional studies to enhance the translational transition of AKI research.NEW & NOTEWORTHY Our findings identify robust acute kidney injury (AKI)-induced developmental reprogramming of macrophages (MΦ) with the expansion of C1Q+, CD163+ MΦ that is independent of the etiology of AKI and conserved across mouse and human species.

Accuracy and processing time of kidney volume measurement methods in rodents polycystic kidney disease models: superiority of semiautomated kidney segmentation.

Measurement of total kidney volume (TKV) using magnetic resonance imaging (MRI) is a valuable approach for monitoring disease progression in autosomal dominant polycystic kidney disease (PKD) and is becoming more common in preclinical studies using animal models. Manual contouring of kidney MRI areas [i.e., manual method (MM)] is a conventional, but time-consuming, way to determine TKV. We developed a template-based semiautomatic image segmentation method (SAM) and validated it in three commonly used PKD models: Cys1cpk/cpk mice, Pkd1RC/RC mice, and Pkhd1pck/pck rats (n = 10 per model). We compared SAM-based TKV with that obtained by clinical alternatives including the ellipsoid formula-based method (EM) using three kidney dimensions, the longest kidney length method (LM), and MM, which is considered the gold standard. Both SAM and EM presented high accuracy in TKV assessment in Cys1cpk/cpk mice [interclass correlation coefficient (ICC) ≥ 0.94]. SAM was superior to EM and LM in Pkd1RC/RC mice (ICC = 0.87, 0.74, and <0.10 for SAM, EM, and LM, respectively) and Pkhd1pck/pck rats (ICC = 0.59, <0.10, and <0.10, respectively). Also, SAM outperformed EM in processing time in Cys1cpk/cpk mice (3.6 ± 0.6 vs. 4.4 ± 0.7 min/kidney) and Pkd1RC/RC mice (3.1 ± 0.4 vs. 7.1 ± 2.6 min/kidney, both P < 0.001) but not in Pkhd1PCK/PCK rats (3.7 ± 0.8 vs. 3.2 ± 0.5 min/kidney). LM was the fastest (∼1 min) but correlated most poorly with MM-based TKV in all studied models. Processing times by MM were longer for Cys1cpk/cpk mice, Pkd1RC/RC mice, and Pkhd1pck.pck rats (66.1 ± 7.3, 38.3 ± 7.5, and 29.2 ± 3.5 min). In summary, SAM is a fast and accurate method to determine TKV in mouse and rat PKD models.NEW & NOTEWORTHY Total kidney volume (TKV) is a valuable readout in preclinical studies for autosomal dominant and autosomal recessive polycystic kidney diseases (ADPKD and ARPKD). Since conventional TKV assessment by manual contouring of kidney areas in all images is time-consuming, we developed a template-based semiautomatic image segmentation method (SAM) and validated it in three commonly used ADPKD and ARPKD models. SAM-based TKV measurements were fast, highly reproducible, and accurate across mouse and rat ARPKD and ADPKD models.

Utility of new image-derived biomarkers for autosomal dominant polycystic kidney disease prognosis using automated instance cyst segmentation.

New image-derived biomarkers for patients affected by autosomal dominant polycystic kidney disease are needed to improve current clinical management. The measurement of total kidney volume (TKV) provides critical information for clinicians to drive care decisions. However, patients with similar TKV may present with very different phenotypes, often requiring subjective decisions based on other factors (e.g., appearance of healthy kidney parenchyma, a few cysts contributing significantly to overall TKV, etc.). In this study, we describe a new technique to individually segment cysts and quantify biometric parameters including cyst volume, cyst number, parenchyma volume, and cyst parenchyma surface area. Using data from the Consortium for Radiologic Imaging Studies of Polycystic Kidney Disease (CRISP) study the utility of these new parameters was explored, both quantitatively as well as visually. Total cyst number and cyst parenchyma surface area showed superior prediction of the slope of estimated glomerular filtration rate decline, kidney failure and chronic kidney disease stages 3A, 3B, and 4, compared to TKV. In addition, presentations such as a few large cysts contributing significantly to overall kidney volume were shown to be much better stratified in terms of outcome predictions. Thus, these new image biomarkers, which can be obtained automatically, will have great utility in future studies and clinical care for patients affected by autosomal dominant polycystic kidney disease.

Prioritized polycystic kidney disease drug targets and repurposing candidates from pre-cystic and cystic mouse Pkd2 model gene expression reversion.

BACKGROUND: Autosomal dominant polycystic kidney disease (ADPKD) is one of the most prevalent monogenic human diseases. It is mostly caused by pathogenic variants in PKD1 or PKD2 genes that encode interacting transmembrane proteins polycystin-1 (PC1) and polycystin-2 (PC2). Among many pathogenic processes described in ADPKD, those associated with cAMP signaling, inflammation, and metabolic reprogramming appear to regulate the disease manifestations. Tolvaptan, a vasopressin receptor-2 antagonist that regulates cAMP pathway, is the only FDA-approved ADPKD therapeutic. Tolvaptan reduces renal cyst growth and kidney function loss, but it is not tolerated by many patients and is associated with idiosyncratic liver toxicity. Therefore, additional therapeutic options for ADPKD treatment are needed. METHODS: As drug repurposing of FDA-approved drug candidates can significantly decrease the time and cost associated with traditional drug discovery, we used the computational approach signature reversion to detect inversely related drug response gene expression signatures from the Library of Integrated Network-Based Cellular Signatures (LINCS) database and identified compounds predicted to reverse disease-associated transcriptomic signatures in three publicly available Pkd2 kidney transcriptomic data sets of mouse ADPKD models. We focused on a pre-cystic model for signature reversion, as it was less impacted by confounding secondary disease mechanisms in ADPKD, and then compared the resulting candidates' target differential expression in the two cystic mouse models. We further prioritized these drug candidates based on their known mechanism of action, FDA status, targets, and by functional enrichment analysis. RESULTS: With this in-silico approach, we prioritized 29 unique drug targets differentially expressed in Pkd2 ADPKD cystic models and 16 prioritized drug repurposing candidates that target them, including bromocriptine and mirtazapine, which can be further tested in-vitro and in-vivo. CONCLUSION: Collectively, these results indicate drug targets and repurposing candidates that may effectively treat pre-cystic as well as cystic ADPKD.

Venglustat, a Novel Glucosylceramide Synthase Inhibitor, in Patients at Risk of Rapidly Progressing ADPKD: Primary Results of a Double-Blind, Placebo-Controlled, Phase 2/3 Randomized Clinical Trial.

RATIONALE & OBJECTIVE: Autosomal dominant polycystic kidney disease (ADPKD) is characterized by the formation of multiple kidney cysts that leads to growth in total kidney volume (TKV) and progression to kidney failure. Venglustat is a glucosylceramide synthase inhibitor that has been shown to inhibit cyst growth and reduce kidney failure in preclinical models of ADPKD. STUDY DESIGN: STAGED-PKD was a 2-stage, multicenter, double-blind, randomized, placebo-controlled phase 2/3 study in adults with ADPKD at risk of rapidly progressive disease, who were selected based on Mayo Clinic imaging classification of ADPKD class 1C, 1D, or 1E and an estimated glomerular filtration rate (eGFR) of 30-89.9mL/min/1.73m2. SETTING & PARTICIPANTS: Enrollment included 236 and 242 patients in stages 1 and 2, respectively. INTERVENTIONS: In trial stage 1, the patients were randomized 1:1:1 to venglustat, 8mg; venglustat, 15mg; or placebo. In stage 2, the patients were randomized 1:1 to venglustat, 15mg (highest dose identified as safe and well tolerated in stage 1), or placebo. OUTCOMES: Primary end points were rate of change in TKV over 18 months in stage 1 and eGFR slope over 24 months in stage 2. Secondary end points were eGFR slope over 18 months (stage 1), rate of change in TKV (stage 2), and safety/tolerability, pain, and fatigue (stages 1 and 2). RESULTS: A prespecified interim futility analysis showed that venglustat treatment had no effect on the annualized rate of change in TKV over 18 months (stage 1) and had a faster rate of decline in eGFR slope over 24 months (stage 2). Due to this lack of efficacy, the study was terminated early. LIMITATIONS: The short follow-up period after the end of treatment and limited generalizability of the findings. CONCLUSIONS: In patients with rapidly progressing ADPKD, treatment with venglustat at either 8mg or 15mg showed no change in the rate of change in TKV and a faster rate of eGFR decline in STAGED-PKD despite a dose-dependent decrease in plasma glucosylceramide levels. FUNDING: This study was funded by Sanofi. TRIAL REGISTRATION: Registered at ClinicalTrials.gov with study number NCT03523728.

A Comprehensive Immune Cell Atlas of Cystic Kidney Disease Reveals the Involvement of Adaptive Immune Cells in Injury-Mediated Cyst Progression in Mice.

BACKGROUND: Inducible disruption of cilia-related genes in adult mice results in slowly progressive cystic disease, which can be greatly accelerated by renal injury. METHODS: To identify in an unbiased manner modifier cells that may be influencing the differential rate of cyst growth in injured versus non-injured cilia mutant kidneys at a time of similar cyst severity, we generated a single-cell atlas of cystic kidney disease. We conducted RNA-seq on 79,355 cells from control mice and adult-induced conditional Ift88 mice (hereafter referred to as cilia mutant mice) that were harvested approximately 7 months post-induction or 8 weeks post 30-minute unilateral ischemia reperfusion injury. RESULTS: Analyses of single-cell RNA-seq data of CD45+ immune cells revealed that adaptive immune cells differed more in cluster composition, cell proportion, and gene expression than cells of myeloid origin when comparing cystic models with one another and with non-cystic controls. Surprisingly, genetic deletion of adaptive immune cells significantly reduced injury-accelerated cystic disease but had no effect on cyst growth in non-injured cilia mutant mice, independent of the rate of cyst growth or underlying genetic mutation. Using NicheNet, we identified a list of candidate cell types and ligands that were enriched in injured cilia mutant mice compared with aged cilia mutant mice and non-cystic controls that may be responsible for the observed dependence on adaptive immune cells during injury-accelerated cystic disease. CONCLUSIONS: Collectively, these data highlight the diversity of immune cell involvement in cystic kidney disease.

Early infiltrating macrophage subtype correlates with late-stage phenotypic outcome in a mouse model of hepatorenal fibrocystic disease.

Hepatorenal fibrocystic disease (HRFCD) is a genetically inherited disorder related to primary cilia dysfunction in which patients display varying levels of fibrosis, bile duct expansion, and inflammation. In mouse models of HRFCD, the phenotype is greatly impacted by the genetic background in which the mutation is placed. Macrophages are a common factor associated with progression of HRFCD and are also strongly influenced by the genetic background. These data led us to hypothesize that macrophage subtypes that change in relation to the genetic background are responsible for the variable phenotypic outcomes in HRFCD. To test this hypothesis, we utilized a mouse model of HRFCD (Ift88Orpk mice) on the C57BL/6 and BALB/c inbred backgrounds that have well-documented differences in macrophage subtypes. Our analyses of infiltrating macrophage subtypes confirm that genetic strain influences the subtype of infiltrating macrophage present during normal postnatal liver development and in Ift88Orpk livers (Ly6clo in C57BL/6 vs Ly6chi in BALB/c). Each infiltrating macrophage subtype was similarly associated with a unique phenotypic outcome as analysis of liver tissue shows that C57BL/6 Ift88Orpk mice have increased bile duct expansion, but reduced levels of fibrosis compared to BALB/c Ift88Orpk livers. RNA sequencing data suggest that the ability to infiltrate macrophage subtypes to influence the phenotypic outcome may be due to unique ligand-receptor signaling between infiltrating macrophages and cilia dysfunctional biliary epithelium. To evaluate whether specific macrophage subtypes cause the observed phenotypic divergence, we analyzed the liver phenotype in BALB/c Ift88Orpk mice on a CCR2-/- background. Unexpectedly, the loss of Ly6chi macrophages, which were strongly enriched in BALB/c Ift88Orpk mice, did not significantly alter liver fibrosis. These data indicate that macrophage subtypes may correlate with HRFCD phenotypic outcome, but do not directly cause the pathology.

Mks6 mutations reveal tissue- and cell type-specific roles for the cilia transition zone.

The transition zone (TZ) is a domain at the base of the cilium that is involved in maintaining ciliary compartment-specific sensory and signaling activity by regulating cilia protein composition. Mutations in TZ proteins result in cilia dysfunction, often causing pleiotropic effects observed in a group of human diseases classified as ciliopathies. The purpose of this study is to describe the importance of the TZ component Meckel-Grüber syndrome 6 ( Mks6) in several organ systems and tissues regarding ciliogenesis and cilia maintenance using congenital and conditional mutant mouse models. Similar to MKS, congenital loss of Mks6 is embryonic lethal, displaying cilia loss and altered cytoskeletal microtubule modifications but only in specific cell types. Conditional Mks6 mutants have a variable cystic kidney phenotype along with severe retinal degeneration with mislocalization of phototransduction cascade proteins. However, other phenotypes, such as anosmia and obesity, which are typically associated with cilia and TZ dysfunction, were not evident. These data indicate that despite Mks6 being a core TZ component, it has tissue- or cell type-specific functions important for cilia formation and cilia sensory and signaling activities. Lewis, W. R., Bales, K. L., Revell, D. Z., Croyle, M. J., Engle, S. E., Song, C. J., Malarkey, E. B., Uytingco, C. R., Shan, D., Antonellis, P. J., Nagy, T. R., Kesterson, R. A., Mrug, M. M., Martens, J. R., Berbari, N. F., Gross, A. K., Yoder, B. K. Mks6 mutations reveal tissue- and cell type-specific roles for the cilia transition zone.

Single-Cell RNA Sequencing Identifies Candidate Renal Resident Macrophage Gene Expression Signatures across Species.

BACKGROUND: Resident macrophages regulate homeostatic and disease processes in multiple tissues, including the kidney. Despite having well defined markers to identify these cells in mice, technical limitations have prevented identification of a similar cell type across species. The inability to identify resident macrophage populations across species hinders the translation of data obtained from animal model to human patients. METHODS: As an entry point to determine novel markers that could identify resident macrophages across species, we performed single-cell RNA sequencing (scRNAseq) analysis of all T and B cell-negative CD45+ innate immune cells in mouse, rat, pig, and human kidney tissue. RESULTS: We identified genes with enriched expression in mouse renal resident macrophages that were also present in candidate resident macrophage populations across species. Using the scRNAseq data, we defined a novel set of possible cell surface markers (Cd74 and Cd81) for these candidate kidney resident macrophages. We confirmed, using parabiosis and flow cytometry, that these proteins are indeed enriched in mouse resident macrophages. Flow cytometry data also indicated the existence of a defined population of innate immune cells in rat and human kidney tissue that coexpress CD74 and CD81, suggesting the presence of renal resident macrophages in multiple species. CONCLUSIONS: Based on transcriptional signatures, our data indicate that there is a conserved population of innate immune cells across multiple species that have been defined as resident macrophages in the mouse. Further, we identified potential cell surface markers to allow for future identification and characterization of this candidate resident macrophage population in mouse, rat, and pig translational studies.

Tissue-Resident Macrophages Promote Renal Cystic Disease.

BACKGROUND: Mutations affecting cilia proteins have an established role in renal cyst formation. In mice, the rate of cystogenesis is influenced by the age at which cilia dysfunction occurs and whether the kidney has been injured. Disruption of cilia function before postnatal day 12-14 results in rapid cyst formation; however, cyst formation is slower when cilia dysfunction is induced after postnatal day 14. Rapid cyst formation can also be induced in conditional adult cilia mutant mice by introducing renal injury. Previous studies indicate that macrophages are involved in cyst formation, however the specific role and type of macrophages responsible has not been clarified. METHODS: We analyzed resident macrophage number and subtypes during postnatal renal maturation and after renal injury in control and conditional Ift88 cilia mutant mice. We also used a pharmacological inhibitor of resident macrophage proliferation and accumulation to determine the importance of these cells during rapid cyst formation. RESULTS: Our data show that renal resident macrophages undergo a phenotypic switch from R2b (CD11clo) to R2a (CD11chi) during postnatal renal maturation. The timing of this switch correlates with the period in which cyst formation transitions from rapid to slow following induction of cilia dysfunction. Renal injury induces the reaccumulation of juvenile-like R2b resident macrophages in cilia mutant mice and restores rapid cystogenesis. Loss of primary cilia in injured conditional Ift88 mice results in enhanced epithelial production of membrane-bound CSF1, a cytokine that promotes resident macrophage proliferation. Inhibiting CSF1/CSF1-receptor signaling with a CSF1R kinase inhibitor reduces resident macrophage proliferation, R2b resident macrophage accumulation, and renal cyst formation in two mouse models of cystic disease. CONCLUSIONS: These data uncover an important pathogenic role for resident macrophages during rapid cyst progression.

Heterozygous Pkhd1C642* mice develop cystic liver disease and proximal tubule ectasia that mimics radiographic signs of medullary sponge kidney.

Heterozygosity for human polycystic kidney and hepatic disease 1 ( PKHD1) mutations was recently associated with cystic liver disease and radiographic findings resembling medullary sponge kidney (MSK). However, the relevance of these associations has been tempered by a lack of cystic liver or renal disease in heterozygous mice carrying Pkhd1 gene trap or exon deletions. To determine whether heterozygosity for a smaller Pkhd1 defect can trigger cystic renal disease in mice, we generated and characterized mice with the predicted truncating Pkhd1C642* mutation in a region corresponding to the middle of exon 20 cluster of five truncating human mutations (between PKHD1G617fs and PKHD1G644*). Mouse heterozygotes or homozygotes for the Pkhd1C642* mutation did not have noticeable liver or renal abnormalities on magnetic resonance images during their first weeks of life. However, when aged to ~1.5 yr, the Pkhd1C642* heterozygotes developed prominent cystic liver changes; tissue analyses revealed biliary cysts and increased number of bile ducts without signs of congenital hepatic fibrosis-like portal field inflammation and fibrosis that was seen in Pkhd1C642* homozygotes. Interestingly, aged female Pkhd1C642* heterozygotes, as well as homozygotes, developed radiographic changes resembling MSK. However, these changes correspond to proximal tubule ectasia, not an MSK-associated collecting duct ectasia. In summary, by demonstrating that cystic liver and kidney abnormalities are triggered by heterozygosity for the Pkhd1C642* mutation, we provide important validation for relevant human association studies. Together, these investigations indicate that PKHD1 mutation heterozygosity (predicted frequency 1 in 70 individuals) is an important underlying cause of cystic liver disorders and MSK-like manifestations in a human population.

Truncating PKHD1 and PKD2 mutations alter energy metabolism.

Deficiency in polycystin 1 triggers specific changes in energy metabolism. To determine whether defects in other human cystoproteins have similar effects, we studied extracellular acidification and glucose metabolism in human embryonic kidney (HEK-293) cell lines with polycystic kidney and hepatic disease 1 ( PKHD1) and polycystic kidney disease (PKD) 2 ( PKD2) truncating defects along multiple sites of truncating mutations found in patients with autosomal recessive and dominant PKDs. While neither the PKHD1 or PKD2 gene mutations nor their position enhanced cell proliferation rate in our cell line models, truncating mutations in these genes progressively increased overall extracellular acidification over time ( P < 0.001 for PKHD1 and PKD2 mutations). PKHD1 mutations increased nonglycolytic acidification rate (1.19 vs. 1.03, P = 0.002), consistent with an increase in tricarboxylic acid cycle activity or breakdown of intracellular glycogen. In addition, they increased basal and ATP-linked oxygen consumption rates [7.59 vs. 5.42 ( P = 0.015) and 4.55 vs. 2.98 ( P = 0.004)]. The PKHD1 and PKD2 mutations also altered mitochondrial morphology, resembling the effects of polycystin 1 deficiency. Together, these data suggest that defects in major PKD genes trigger changes in mitochondrial energy metabolism. After validation in in vivo models, these initial observations would indicate potential benefits of targeting energy metabolism in the treatment of PKDs.

Long-term trajectory of kidney function in autosomal-dominant polycystic kidney disease.

Autosomal dominant polycystic kidney disease (ADPKD) is characterized by cyst and kidney growth, which is hypothesized to cause loss of functioning renal mass and eventually end-stage kidney disease. However, the time course of decline in glomerular filtration rate (GFR) is poorly defined. The Consortium for Radiologic Imaging Studies of Polycystic Kidney Disease study is a 14-year observational cohort study of 241 adults with ADPKD. As an estimate of the rate of kidney growth, participants were stratified into 5 subclasses based on baseline age and magnetic resonance imaging measurements of total kidney volume (TKV) according to the method of Irazabal. GFR trajectories spanning over four decades of life were reconstructed and fitted using mixed polynomial models, which were validated using data from the HALT-PKD study. GFR trajectories were nonlinear, with a period of relative stability in most participants, followed by accelerating decline. The shape and slope of these trajectories were strongly associated with baseline Irazabal class. Patients with PKD1 mutations had a steeper GFR decline than patients with PKD2 mutations or with no detected mutation, largely mediated by the effect of genotype on Irazabal class. Thus, GFR decline in ADPKD is nonlinear, and its trajectory throughout adulthood can be predicted from a single measurement of kidney volume. These models can be used for clinical prognostication, clinical trial design, and patient selection for clinical interventions. Our findings support a causal link between growth in kidney volume and GFR decline, adding support for the use of TKV as a surrogate endpoint in clinical trials.

A Practical Guide for Treatment of Rapidly Progressive ADPKD with Tolvaptan.

In the past, the treatment of autosomal dominant polycystic kidney disease (ADPKD) has been limited to the management of its symptoms and complications. Recently, the US Food and Drug Administration (FDA) approved tolvaptan as the first drug treatment to slow kidney function decline in adults at risk of rapidly progressing ADPKD. Full prescribing information approved by the FDA provides helpful guidelines but does not address practical questions that are being raised by nephrologists, internists, and general practitioners taking care of patients with ADPKD, and by the patients themselves. In this review, we provide practical guidance and discuss steps that require consideration before and after prescribing tolvaptan to patients with ADPKD to ensure that this treatment is implemented safely and effectively. These steps include confirmation of diagnosis; identification of rapidly progressive disease; implementation of basic renal protective measures; counseling of patients on potential benefits and harms; exclusions to use; education of patients on aquaresis and its expected consequences; initiation, titration, and optimization of tolvaptan treatment; prevention of aquaresis-related complications; evaluation and management of liver enzyme elevations; and monitoring of treatment efficacy. Our recommendations are made on the basis of published evidence and our collective experiences during the randomized, clinical trials and open-label extension studies of tolvaptan in ADPKD.

Casein kinase 1ε and 1α as novel players in polycystic kidney disease and mechanistic targets for (R)-roscovitine and (S)-CR8.

Following the discovery of (R)-roscovitine's beneficial effects in three polycystic kidney disease (PKD) mouse models, cyclin-dependent kinases (CDKs) inhibitors have been investigated as potential treatments. We have used various affinity chromatography approaches to identify the molecular targets of roscovitine and its more potent analog (S)-CR8 in human and murine polycystic kidneys. These methods revealed casein kinases 1 (CK1) as additional targets of the two drugs. CK1ε expression at the mRNA and protein levels is enhanced in polycystic kidneys of 11 different PKD mouse models as well as in human polycystic kidneys. A shift in the pattern of CK1α isoforms is observed in all PKD mouse models. Furthermore, the catalytic activities of both CK1ε and CK1α are increased in mouse polycystic kidneys. Inhibition of CK1ε and CK1α may thus contribute to the long-lasting attenuating effects of roscovitine and (S)-CR8 on cyst development. CDKs and CK1s may constitute a dual therapeutic target to develop kinase inhibitory PKD drug candidates.

Baseline total kidney volume and the rate of kidney growth are associated with chronic kidney disease progression in Autosomal Dominant Polycystic Kidney Disease.

Autosomal dominant polycystic kidney disease (ADPKD) is characterized by progressive enlargement of kidney cysts leading to chronic kidney disease (CKD) and end-stage renal disease (ESRD). Identification of an early biomarker that can predict progression of CKD is urgently needed. In an earlier Consortium for Radiologic Imaging Studies of Polycystic Kidney Disease (CRISP) study (a prospective, multicenter, observational analysis of 241 patients with ADPKD initiated in 2000), baseline height-adjusted total kidney volume (htTKV) was shown to be associated with development of CKD stage 3 after eight years of follow-up. Here we conducted an extended study and found that in a multivariable logistic regression model, baseline htTKV was shown to be a strong, independent predictor for the development of CKD after a median follow-up of 13 years. The odds ratio of reaching each CKD stage per 100 mL/m increment in htTKV was 1.38 (95% confidence interval 1.19-1.60) for stage 3, 1.42 (1.23-1.64) for stage 4, and 1.35 (1.18-1.55) for stage 5 or ESRD. Baseline htTKV was also associated with relative decreases in the glomerular filtration rate of 30%, and 57% or more. Moreover, the rate of change in htTKV was negatively correlated with the slope of the glomerular filtration rate. While ADPKD genotype was also associated with CKD outcomes, it was not an independent prognostic factor after adjusting for htTKV. Thus, baseline total kidney volume and the rate of kidney growth are strongly associated with the development of advanced stages of CKD. These findings support the use of total kidney volume as a prognostic and potentially monitoring biomarker in ADPKD.

Relationship between caffeine intake and autosomal dominant polycystic kidney disease progression: a retrospective analysis using the CRISP cohort.

BACKGROUND: Caffeine has been proposed, based on in vitro cultured cell studies, to accelerate progression of autosomal dominant polycystic kidney disease (ADPKD) by increasing kidney size. Since ADPKD patients are advised to minimize caffeine intake, we investigated the effect of caffeine on disease progression in the Consortium for Radiologic Imaging Studies of Polycystic Kidney Disease (CRISP), a prospective, observational cohort study. METHODS: Our study included 239 patients (mean age = 32.3 ± 8.9 ys; 188 caffeine consumers) with a median follow-up time of 12.5 years. Caffeine intake reported at baseline was dichotomized (any vs. none). Linear mixed models, unadjusted and adjusted for age, race, sex, BMI, smoking, hypertension, genetics and time, were used to model height-adjusted total kidney volume (htTKV) and iothalamate clearance (mGFR). Cox proportional hazards models and Kaplan-Meier plots examined the effect of caffeine on time to ESRD or death. RESULTS: Caffeine-by-time was statistically significant when modeling ln(htTKV) in unadjusted and adjusted models (p <  0.01) indicating that caffeine consumers had slightly faster kidney growth (by 0.6% per year), but htTKV remained smaller from baseline throughout the study. Caffeine consumption was not associated with a difference in mGFR, or in the time to ESRD or death (p > 0.05). Moreover the results were similar when outcomes were modeled as a function of caffeine dose. CONCLUSION: We conclude that caffeine does not have a significant detrimental effect on disease progression in ADPKD.

Image texture features predict renal function decline in patients with autosomal dominant polycystic kidney disease.

Magnetic resonance imaging (MRI) examinations provide high-resolution information about the anatomic structure of the kidneys and are used to measure total kidney volume (TKV) in patients with Autosomal Dominant Polycystic Kidney Disease (ADPKD). Height-adjusted TKV (HtTKV) has become the gold-standard imaging biomarker for ADPKD progression at early stages of the disease when estimated glomerular filtration rate (eGFR) is still normal. However, HtTKV does not take advantage of the wealth of information provided by MRI. Here we tested whether image texture features provide additional insights into the ADPKD kidney that may be used as complementary information to existing biomarkers. A retrospective cohort of 122 patients from the Consortium for Radiologic Imaging Studies of Polycystic Kidney Disease (CRISP) study was identified who had T2-weighted MRIs and eGFR values over 70 mL/min/1.73m2 at the time of their baseline scan. We computed nine distinct image texture features for each patient. The ability of each feature to predict subsequent progression to CKD stage 3A, 3B, and 30% reduction in eGFR at eight-year follow-up was assessed. A multiple linear regression model was developed incorporating age, baseline eGFR, HtTKV, and three image texture features identified by stability feature selection (Entropy, Correlation, and Energy). Including texture in a multiple linear regression model (predicting percent change in eGFR) improved Pearson correlation coefficient from -0.51 (using age, eGFR, and HtTKV) to -0.70 (adding texture). Thus, texture analysis offers an approach to refine ADPKD prognosis and should be further explored for its utility in individualized clinical decision making and outcome prediction.

Predicted Mutation Strength of Nontruncating PKD1 Mutations Aids Genotype-Phenotype Correlations in Autosomal Dominant Polycystic Kidney Disease.

Autosomal dominant polycystic kidney disease (ADPKD) often results in ESRD but with a highly variable course. Mutations to PKD1 or PKD2 cause ADPKD; both loci have high levels of allelic heterogeneity. We evaluated genotype-phenotype correlations in 1119 patients (945 families) from the HALT Progression of PKD Study and the Consortium of Radiologic Imaging Study of PKD Study. The population was defined as: 77.7% PKD1, 14.7% PKD2, and 7.6% with no mutation detected (NMD). Phenotypic end points were sex, eGFR, height-adjusted total kidney volume (htTKV), and liver cyst volume. Analysis of the eGFR and htTKV measures showed that the PKD1 group had more severe disease than the PKD2 group, whereas the NMD group had a PKD2-like phenotype. In both the PKD1 and PKD2 populations, men had more severe renal disease, but women had larger liver cyst volumes. Compared with nontruncating PKD1 mutations, truncating PKD1 mutations associated with lower eGFR, but the mutation groups were not differentiated by htTKV. PKD1 nontruncating mutations were evaluated for conservation and chemical change and subdivided into strong (mutation strength group 2 [MSG2]) and weak (MSG3) mutation groups. Analysis of eGFR and htTKV measures showed that patients with MSG3 but not MSG2 mutations had significantly milder disease than patients with truncating cases (MSG1), an association especially evident in extreme decile populations. Overall, we have quantified the contribution of genic and PKD1 allelic effects and sex to the ADPKD phenotype. Intrafamilial correlation analysis showed that other factors shared by families influence htTKV, with these additional genetic/environmental factors significantly affecting the ADPKD phenotype.