McNicholas, Bairbre

Drawing from basic knowledge of stem-cell biology, embryonic development, wound healing, and aging, regenerative medicine seeks to develop therapeutic strategies that complement or replace conventional treatments by actively repairing diseased tissue or generating new organs and tissues. Among the various clinical-translational strategies within the field of regenerative medicine, several can be broadly described as promoting disease resolution indirectly through local or systemic interactions with a patient’s cells, without permanently integrating or directly forming new primary tissue. In this review, we focus on such therapies, which we term disease-modulating regenerative therapies (DMRT), and on the extent to which they have been translated into the clinical arena in four distinct areas of nephrology: renovascular disease (RVD), sepsis-associated AKI (SA-AKI), diabetic kidney disease (DKD), and kidney transplantation (KTx). As we describe, the DMRT that has most consistently progressed to human clinical trials for these indications is mesenchymal stem/stromal cells (MSCs), which potently modulate ischemic, inflammatory, profibrotic, and immune-mediated tissue injury through diverse paracrine mechanisms. In KTx, several early-phase clinical trials have also tested the potential for ex vivo –expanded regulatory immune cell therapies to promote donor-specific tolerance and prevent or resolve allograft injury. Other promising DMRT, including adult stem/progenitor cells, stem cell–derived extracellular vesicles, and implantable hydrogels/biomaterials remain at varying preclinical stages of translation for these renal conditions. To date (2021), no DMRT has gained market approval for use in patients with RVD, SA-AKI, DKD, or KTx, and clinical trials demonstrating definitive, cost-effective patient benefits are needed. Nonetheless, exciting progress in understanding the disease-specific mechanisms of action of MSCs and other DMRT, coupled with increasing knowledge of the pathophysiologic basis for renal-tissue injury and the experience gained from pioneering early-phase clinical trials provide optimism that influential, regenerative treatments for diverse kidney diseases will emerge in the years ahead.

Objectives Pancreatic lesions in autosomal dominant polycystic kidney disease (ADPKD) are primarily cysts. They are increasingly recognized, with isolated reports of intraductal papillary mucinous neoplasia (IPMN). Methods Retrospective study to determine prevalence, number, size, and location of pancreatic abnormalities using abdominal magnetic resonance imaging (MRI) of genotyped ADPKD patients (seen February 1998 to October 2013) and compared with age- and sex-matched non-ADPKD controls. We evaluated presentation, investigation, and management of all IPMNs among individuals with ADPKD (January 1997 to December 2016). Results Abdominal MRIs were examined for 271 genotyped ADPKD patients. A pancreatic cyst lesion (PCL) was detected in 52 patients (19%; 95% confidence interval, 15%–23%). Thirty-seven (71%) had a solitary PCL; 15 (28%) had multiple. Pancreatic cyst lesion prevalence did not differ by genotype. Intraductal papillary mucinous neoplasia was detected in 1% of ADPKD cases. Among 12 IPMN patients (7 branch duct; 5 main duct or mixed type) monitored for about 140 months, 2 with main duct IPMNs required Whipple resection, and 1 patient died of complications from small-bowel obstruction after declining surgical intervention. Conclusions With MRI, PCLs were detected in 19% and IPMNs in 1% of 271 ADPKD patients with proven mutations, without difference across genotypes. Pancreatic cyst lesions were asymptomatic and remained stable in size.