Birt-Hogg-Dubé Syndrome and Hereditary Leiomyomatosis and Renal Cell Carcinoma Syndrome: An Effective Multidisciplinary Approach to Hereditary Renal Cancer Predisposing Syndromes

AimWe aimed to describe and analyse clinical features, characteristics, and adherence to surveillance guidelines in an Australian Birt-Hogg-Dubé syndrome (BHD) and hereditary leiomyomatosis and renal cell cancer (HLRCC) cohort.MethodsAll identified patients with a diagnosis of BHD or HLRCC at RBWH 01/01/2014-01/09/2019 were included (HREC/17/QRBW/276). All patients were initially assessed and counselled by a clinical geneticist and then referred to an adult nephrologist. Baseline and incidental clinical variables were extracted and analysed.ResultsFifty-seven patients were identified (28 BHD, 29 HLRCC) with a median age of 47 years. The median and cumulative follow-up were 1 and 99 years, respectively. Baseline renal MRI occurred in 40/57 patients, and 33/57 had regular MRI as per the national guidelines (eviQ). Of 18/57 without baseline imaging, nine were yet to have imaging, seven were lost follow-up, and two patients had logistic difficulties. RCC was diagnosed in 11/57 patients: two of 28 with BHD were diagnosed with RCC aged 73 and 77, both prior to commencement of surveillance. Nine of 29 patients with HLRCC were diagnosed with RCC (one of 29 during surveillance at 47 years of age) and eight of 29 prior to commencement of surveillance (11–55 years). Amongst BHD patients, cutaneous fibrofolliculomas were noted in 15 patients, lung cysts were detected in seven patients, spontaneous pneumothoraces in five patients, and parotid oncocytoma in two of 28. Amongst those with HLRCC, cutaneous leiomyomas were noted in 19/29, cutaneous leiomyosarcoma diagnosed in one of 29, and uterine fibroids in 13 female patients.ConclusionEvidence-based RCC screening in BHD and HLRCC cohort is feasible and able to identify incidental renal lesions. Multidisciplinary patient management enables expedited genetic counselling, diagnosis, longitudinal screening, and RCC management. The success of this clinical model warrants consideration of undertaking longitudinal screening of BHD and HLRCC patients by nephrologists.

A pilot study of preoperative nivolumab in high-risk nonmetastatic renal cell carcinoma.

323 Background: Immunotherapy improves survival in patients with advanced renal cell carcinoma (RCC), but has no established role for perioperative use in patients with localized RCC. Neoadjuvant immunotherapy is a promising strategy in several cancers, and may leverage the primary tumor as antigen source. Methods: We conducted a single institution pilot study of neoadjuvant nivolumab in patients with RCC undergoing nephrectomy with curative intent. Patients were eligible if their risk of metastatic recurrence within the first 12 years was >20% by an established nomogram. After confirmatory biopsy and renal MRI, patients were treated with standard dose nivolumab every 2 weeks for 4 treatments, with a follow-up renal MRI prior to nephrectomy. The primary end points of the study were safety and feasibility defined as being able to complete 3/4 treatments without surgical delay. We evaluated adverse events by CTCAE, surgical safety by Clavien-Dindo classification, and tumor radiographic response by RECIST 1.1. Results: Eighteen (11 men, 7 women; median age 60) were enrolled. All patients had clear cell RCC, median tumor size at baseline was 8.8cm (range 6.4-14.2cm). Median predicted 12-year probability of recurrence was 45% (range 25-71%). All received at least 1 dose of nivolumab; 16/18 patients completed all 4 doses. 17/18 (94%) patients completed at least 3 doses. No patient had notable delay in the timing of their nephrectomy. 4 patients had surgical complications per Clavien-Dindo classification, including 2 with grade 3a chylous ascites after lymphadenectomy. Two patients had nivolumab discontinued for immune-related adverse events, including grade 3 transaminitis and grade 2 arthralgias; a third patient developed grade 4 colitis 4 months after completing nivolumab. All patients had stable disease as the best response prior to surgery. Recurrence-free survival at 2 years was 0.74 (95%CI 0.45-0.90). We analyzed an additional 21 patients with metastatic RCC (20 ccRCC, 1 epithelioid AML) who subsequently had nephrectomy after standard immunotherapy. 15 patients had received ipilimumab+nivolumab, 6 received single-agent PD-1 or PD-L1 inhibitors. 3 (14%) patients achieved a near or complete pathologic response, including a patient with epithelioid AML. Analysis of radiologic and pathologic biomarkers of response are ongoing and will be presented at conference. Conclusions: In this pilot study, there were no new safety signals or delays in surgery with preoperative nivolumab. Neoadjuvant immunotherapy shows preliminary evidence of safety, feasibility and efficacy; biomarker studies may help identify individuals who may have a higher likelihood of response. Clinical trial information: NCT02595918 .

Quantitative Assessment of Renal Perfusion and Oxygenation by Invasive Probes: Basic Concepts

Renal tissue hypoperfusion and hypoxia are early key elements in the pathophysiology of acute kidney injury of various origins, and may also promote progression from acute injury to chronic kidney disease. Here we describe basic principles of methodology to quantify renal hemodynamics and tissue oxygenation by means of invasive probes in experimental animals. Advantages and disadvantages of the various methods are discussed in the context of the heterogeneity of renal tissue perfusion and oxygenation.This chapter is based upon work from the COST Action PARENCHIMA, a community-driven network funded by the European Cooperation in Science and Technology (COST) program of the European Union, which aims to improve the reproducibility and standardization of renal MRI biomarkers. This introduction chapter is complemented by a separate chapter describing the experimental procedure and data analysis.

Recommendations for Preclinical Renal MRI: A Comprehensive Open-Access Protocol Collection to Improve Training, Reproducibility, and Comparability of Studies

Renal MRI holds incredible promise for making a quantum leap in improving diagnosis and care of patients with a multitude of diseases, by moving beyond the limitations and restrictions of current routine clinical practice. Clinical and preclinical renal MRI is advancing with ever increasing rapidity, and yet, aside from a few examples of renal MRI in routine use, it is still not good enough. Several roadblocks are still delaying the pace of progress, particularly inefficient education of renal MR researchers, and lack of harmonization of approaches that limits the sharing of results among multiple research groups.Here we aim to address these limitations for preclinical renal MRI (predominantly in small animals), by providing a comprehensive collection of more than 40 publications that will serve as a foundational resource for preclinical renal MRI studies. This includes chapters describing the fundamental principles underlying a variety of renal MRI methods, step-by-step protocols for executing renal MRI studies, and detailed guides for data analysis. This collection will serve as a crucial part of a roadmap toward conducting renal MRI studies in a robust and reproducible way, that will promote the standardization and sharing of data.This chapter is based upon work from the COST Action PARENCHIMA, a community-driven network funded by the European Cooperation in Science and Technology (COST) program of the European Union, which aims to improve the reproducibility and standardization of renal MRI biomarkers.

Renal Diffusion-Weighted Imaging (DWI) for Apparent Diffusion Coefficient (ADC), Intravoxel Incoherent Motion (IVIM), and Diffusion Tensor Imaging (DTI): Basic Concepts

The specialized function of the kidney is reflected in its unique structure, characterized by juxtaposition of disorganized and ordered elements, including renal glomerula, capillaries, and tubules. The key role of the kidney in blood filtration, and changes in filtration rate and blood flow associated with pathological conditions, make it possible to investigate kidney function using the motion of water molecules in renal tissue. Diffusion-weighted imaging (DWI) is a versatile modality that sensitizes observable signal to water motion, and can inform on the complexity of the tissue microstructure. Several DWI acquisition strategies are available, as are different analysis strategies, and models that attempt to capture not only simple diffusion effects, but also perfusion, compartmentalization, and anisotropy. This chapter introduces the basic concepts of DWI alongside common acquisition schemes and models, and gives an overview of specific DWI applications for animal models of renal disease.This chapter is based upon work from the COST Action PARENCHIMA, a community-driven network funded by the European Cooperation in Science and Technology (COST) program of the European Union, which aims to improve the reproducibility and standardization of renal MRI biomarkers. This introduction chapter is complemented by two separate chapters describing the experimental procedure and data analysis.

Experimental Protocols for MRI Mapping of Renal T1

The water proton longitudinal relaxation time, T1, is a common and useful MR parameter in nephrology research. Here we provide three step-by-step T1-mapping protocols suitable for different types of nephrology research. Firstly, we provide a single-slice 2D saturation recovery protocol suitable for studies of global pathology, where whole-kidney coverage is unnecessary. Secondly, we provide an inversion recovery type imaging protocol that may be optimized for specific kidney disease applications. Finally, we also provide imaging protocol for small animal kidney imaging in a clinical scanner.This chapter is based upon work from the COST Action PARENCHIMA, a community-driven network funded by the European Cooperation in Science and Technology (COST) program of the European Union, which aims to improve the reproducibility and standardization of renal MRI biomarkers. This analysis protocol chapter is complemented by two separate chapters describing the basic concept and experimental procedure.

Ultrasound and Photoacoustic Imaging of the Kidney: Basic Concepts and Protocols

Noninvasive, robust, and reproducible methods to image kidneys are provided by different imaging modalities. A combination of modalities (multimodality) can give better insight into structure and function and to understand the physiology of the kidney. Magnetic resonance imaging can be complemented by a multimodal imaging approach to obtain additional information or include interventional procedures. In the clinic, renal ultrasound has been essential for the diagnosis and management of kidney disease and for the guidance of invasive procedures for a long time. Adapting ultrasound to preclinical requirements and for translational research, the combination with photoacoustic imaging expands the capabilities to obtain anatomical, functional, and molecular information from animal models. This chapter describes the basic concepts of how to image kidneys using different and most appropriate modalities.This chapter is based upon work from the COST Action PARENCHIMA, a community-driven network funded by the European Cooperation in Science and Technology (COST) program of the European Union, which aims to improve the reproducibility and standardization of renal MRI biomarkers. This introduction chapter is complemented by two separate chapters describing the experimental procedure and data analysis.

Sodium (23Na) MRI of the Kidney: Basic Concept

The handling of sodium by the renal system is a key indicator of renal function. Alterations in the corticomedullary distribution of sodium are considered important indicators of pathology in renal diseases. The derangement of sodium handling can be noninvasively imaged using sodium magnetic resonance imaging (23Na MRI), with data analysis allowing for the assessment of the corticomedullary sodium gradient. Here we introduce sodium imaging, describe the existing methods, and give an overview of preclinical sodium imaging applications to illustrate the utility and applicability of this technique for measuring renal sodium handling.This chapter is based upon work from the COST Action PARENCHIMA, a community-driven network funded by the European Cooperation in Science and Technology (COST) program of the European Union, which aims to improve the reproducibility and standardization of renal MRI biomarkers. This introduction chapter is complemented by two separate chapters describing the experimental procedure and data analysis.

Renal pH Imaging Using Chemical Exchange Saturation Transfer (CEST) MRI: Basic Concept

Magnetic Resonance Imaging (MRI) has been actively explored in the last several decades for assessing renal function by providing several physiological information, including glomerular filtration rate, renal plasma flow, tissue oxygenation and water diffusion. Within MRI, the developing field of chemical exchange saturation transfer (CEST) has potential to provide further functional information for diagnosing kidney diseases. Both endogenous produced molecules as well as exogenously administered CEST agents have been exploited for providing functional information related to kidney diseases in preclinical studies. In particular, CEST MRI has been exploited for assessing the acid-base homeostasis in the kidney and for monitoring pH changes in several disease models. This review summarizes several CEST MRI procedures for assessing kidney functionality and pH, for monitoring renal pH changes in different kidney injury models and for evaluating renal allograft rejection.This chapter is based upon work from the COST Action PARENCHIMA, a community-driven network funded by the European Cooperation in Science and Technology (COST) program of the European Union, which aims to improve the reproducibility and standardization of renal MRI biomarkers. This introduction chapter is complemented by two separate chapters describing the experimental procedure and data analysis.