Helen Liapis

ER stress has emerged as a signaling platform underlying the pathogenesis of various kidney diseases. Thus, there is an urgent need to develop ER stress biomarkers in the incipient stages of ER stress–mediated kidney disease, when a kidney biopsy is not yet clinically indicated, for early therapeutic intervention. Cysteine-rich with EGF-like domains 2 (CRELD2) is a newly identified protein that is induced and secreted under ER stress. For the first time to our knowledge, we demonstrate that CRELD2 can serve as a sensitive urinary biomarker for detecting ER stress in podocytes or renal tubular cells in murine models of podocyte ER stress–induced nephrotic syndrome and tunicamycin- or ischemia-reperfusion–induced acute kidney injury (AKI), respectively. Most importantly, urinary CRELD2 elevation occurs in patients with autosomal dominant tubulointerstitial kidney disease caused by UMOD mutations, a prototypical tubular ER stress disease. In addition, in pediatric patients undergoing cardiac surgery, detectable urine levels of CRELD2 within postoperative 6 hours strongly associate with severe AKI after surgery. In conclusion, our study has identified CRELD2 as a potentially novel urinary ER stress biomarker with potential utility in early diagnosis, risk stratification, treatment response monitoring, and directing of ER-targeted therapies in selected patient subgroups in the emerging era of precision nephrology.

Collapsing glomerulopathy (CGP) is a pattern of kidney injury seen on renal biopsy with multiple associations and etiologies. It is most commonly described in African-Americans and others with recent African ancestry. The disease is rapidly progressive and often presents with abrupt onset of renal failure and nephrotic-range proteinuria. Since its description 30 years ago, this entity has transformed from a morphologic diagnosis typically seen in the setting of HIV infection to a complicated diagnosis with numerous etiologies, many of which are associated with underlying apolipoprotein L1 (APOL1)-risk variants or other genetic disorders. We review the evolution of CGP, and its history and proposed pathomechanisms. We also present the disease spectrum from our experience with emphasis on recognizing the lesion, distinguishing from mimics and linking the histopathological pattern to a specific cause. Our understanding continues to evolve as clinicians and scientists work toward a more complete understanding of the molecular pathways of injury in this disease and how these might be disrupted for therapeutic purposes. Much still remains to be discovered in CGP as the molecular underpinnings leading to disease are still not completely understood and no effective treatment exists despite the high morbidity. Based on this rapid evolution, CGP is a modern template of how we diagnose and think about kidney disease. The story of CGP represents the current shift in nephrology and nephropathology from morphology-alone-based diagnosis to a comprehensive approach including molecular diagnostics. We believe this new, holistic approach will lead to pathogenesis-centered diagnoses that will help to individualize risk stratification and treatment protocols.

Castleman’s disease (CD) is an uncommon, heterogeneous lympho-proliferative disorder leading to high circulating levels of interleukin-6 (IL-6) and vascular endothelial growth factor (VEGF). Renal involvement has been only described in a limited number of small studies. Herein, we report a rare case of renal thrombotic microangiopathy (TMA) associated with CD and investigate the podocyte expression of VEGF in the renal biopsy prior to initiation of treatment. An 18-year-old male presented with fever, diarrhea, diffuse lymphadenopathy, ascites and acute kidney injury. Laboratory tests for hemolytic uremic syndrome and thrombotic thrombocytopenic purpura were negative. The kidney biopsy showed TMA. An excisional lymph node biopsy was consistent with CD, plasma cell variant. Immunofluorescence staining showed suppressed podocyte VEGF expression. Chemotherapy that inhibits production of inflammatory mediators including IL-6 and VEGF led to complete recovery of renal function. Our case illustrates a rare renal histological feature of CD. IL-6 and VEGF are postulated to suppress glomerular VEGF expression, thereby causing renal TMA. Therapy directed against these inflammatory mediators may have important therapeutic implications.