Not all proteinuria is created equal Andrew Beenken, … , Jonathan M. Barasch, Ali G. Gharavi J Clin Invest. 2020;130(1):74-76. https://doi.org/10.1172/JCI133250. Commentary Albuminuria acts as a marker of progressive chronic kidney disease and as an indicator for initiation of hypertension treatment via modulation of the renin-angiotensin-aldosterone system with angiotensin receptor blockers or angiotensin- converting enzyme inhibitors. However, the true significance of albuminuria has yet to be fully defined. Is it merely a marker of underlying pathophysiology, or does it play a causal role in the progression of kidney disease? The answer remains under debate. In this issue of the JCI, Bedin et al. used next-generation sequencing data to identify patients with chronic proteinuria who had biallelic variants in the cubilin gene (CUBN). Through investigation of these pathogenic mutations in CUBN, the authors have further illuminated the clinical implications of albuminuria. Find the latest version: https://jci.me/133250/pdf COMMENTARY The Journal of Clinical Investigation Not all proteinuria is created equal Andrew Beenken, Jonathan M. Barasch, and Ali G. Gharavi Division of Nephrology, Department of Medicine, Columbia University Vagelos College of Physicians and Surgeons, New York, New York, USA. recent low-resolution electron micros- copy data suggest that these C-terminal Albuminuria acts as a marker of progressive chronic kidney disease and as domains should cluster at the distal end of an indicator for initiation of hypertension treatment via modulation of the a 700-Å-long tree-like structure (7) where renin-angiotensin-aldosterone system with angiotensin receptor blockers or they are readily exposed to the urinary angiotensin-converting enzyme inhibitors. However, the true significance of filtrate and available to bind proteins. In albuminuria has yet to be fully defined. Is it merely a marker of underlying addition to albumin, it is possible that these pathophysiology, or does it play a causal role in the progression of kidney domains could bind other ligands of similar disease? The answer remains under debate. In this issue of the JCI, Bedin et size and isoelectric point (pI) such as vita- al. used next-generation sequencing data to identify patients with chronic min D–binding protein (DBP), which has a proteinuria who had biallelic variants in the cubilin gene (CUBN). Through close evolutionary relationship to albumin. investigation of these pathogenic mutations in CUBN, the authors have Varying proteinuric phenotypes have further illuminated the clinical implications of albuminuria. been reported in the literature, depending on which domains of cubilin are affected. Previously, a p.P1297L point mutation with- in the VitB12-IF binding site was observed Biallelic mutations related to (n = 2216 patients) of patients with chronic to lead to anemia without proteinuria. proteinuria proteinuria ranging from 0.5 to 2.5 g/d and Additionally, numerous variants causing The kidneys filter approximately 180 identified 39 patients who had biallelic global cubilin dysfunction have been docu- liters of plasma daily to balance the excre- variants in the CUBN gene. Interestingly, mented to cause IGS with both anemia and tion of water, acid, nitrogen, sodium, and the CUBN variants resulted in isolated pro- proteinuria that is inclusive of albumin as potassium with varying environmental teinuria without the megaloblastic anemia well as other cubilin ligands such as apoA-1, conditions. Larger proteins are retained typical of IGS, suggesting that there are transferrin, and DBP (8). Now, the study by in the plasma because of filtration bar- separate binding sites in cubilin for vita- Bedin et al. extends the known proteinuric riers in the glomeruli, but the kidney min B12–intrinsic factor (VitB12-IF) and phenotypes resulting from CUBN variants tubules must still capture up to 2.5 g/d of albumin. Cubilin is an enormous protein, to include isolated albumin-predominant low-molecular-weight (LMW) proteins a 460-kDa peripheral membrane glyco- proteinuria resulting from C-terminal that escape the glomerular barriers (1). protein with 27 putative ligand-binding mutations (4). Certainly, further analysis of Cubilin and megalin are located in the CUB domains (complement components urinary proteins from patients with CUBN apical membrane of the proximal tubule C1r/C1s, UEGF, and bone morphogenic variants is bound to delineate still more and are responsible for receptor-medi- protein-1) (5). Although biochemical and phenotypes of proteinuria. ated endocytosis of the filtered proteins structural methods have determined that The authors noted two interesting that leak through the glomerular barri- the binding site for VitB12-IF is CUB6–8 features of the patients in the studied ers. Biallelic mutations in megalin (LRP2) (6), the manner in which cubilin binds to cohorts: (a) despite experiencing chronic lead to Donnai-Barrow syndrome (DBS), other proteins including albumin is still proteinuria, these patients retained nor- characterized by LMW proteinuria and being investigated. mal estimated glomerular filtration rates abnormal neurological development (2), The patient cohorts in Bedin et al. (eGFRs), a standard assessment of renal whereas biallelic cubilin (CUBN) muta- offered an opportunity to genetically dis- function, which is consistent with prior tions can lead to another recessive disease, sect cubilin-albumin binding, and the studies reporting normal renal function in Imerslund-Gräsbeck syndrome (IGS), authors made the novel proposal that patients with IGS, and (b) the proteinuria which is characterized by LMW protein- CUB13 or CUB26 are potential albumin- they exhibited was albumin predominant, uria and megaloblastic anemia (3). binding domains due to their proximity with, on average, more than 60% of the In this issue of the JCI, Bedin et al. to Ca2+-coordinating motifs (4). CUB13 total proteinuria consisting of albumin (4). (4) analyzed next-generation sequenc- and CUB26 have not yet been structurally ing data from three different cohorts characterized at high resolution, although The impact of albuminuria on renal function Albuminuria is a predictor of negative clin- Related Article: p. 335 ical outcomes including the progression of renal disease, but the degree to which Conflict of interest: The authors have declared that no conflict of interest exists. Copyright: © 2020, American Society for Clinical Investigation. albuminuria can be used independently as Reference information: J Clin Invest. 2020;130(1):74–76. https://doi.org/10.1172/JCI133250. a surrogate therapeutic target is a matter of 74 jci.org Volume 130 Number 1 January 2020 The Journal of Clinical Investigation COMMENTARY ongoing discussion (9–12). Furthermore, er than 80 mL/min. Although the authors clinical practice that is essential for avoid- whether albuminuria causes progres- could not document an extended longi- ing unnecessary therapeutic or diagnostic sive chronic kidney disease (CKD) also tudinal follow-up of renal function mea- interventions. For instance, seven of the remains unknown. Causality has been sug- surements in their patients, their obser- patients in the Bedin et al. cohorts were gested by reductions in albuminuria asso- vation of normal or near-normal eGFRs in treated with ACEI/ARB therapy with- ciated with reduced CKD progression to patients with decades of exposure to albu- out benefit, and others underwent renal end-stage renal disease (ESRD) in several minuria is nonetheless intriguing. To fur- biopsies that were nondiagnostic (4). The different clinical trials that evaluated the ther investigate their findings, the authors importance of genetic screening to help treatment of CKD patients with angioten- conducted a meta-analysis of cohorts from exclude unnecessary therapy is even more sin-converting enzyme inhibitors (ACEIs) the CKDGen Consortium using CUBN pointed in situations in which steroid treat- or angiotensin receptor blockers (ARBs) variants previously associated with albu- ment is being considered, such as in cases (13–16). Notably, the Renoprotection of minuria in GWAS studies (24). Through of focal sclerosing glomerulosclerosis (or Optimal Antiproteinuric Doses (ROAD) this cross-sectional population-based in presumed cases of minimal change dis- trial showed a reduction in CKD progres- approach and using an additive model to ease in children. sion in nondiabetic proteinuric patients test for associations, the authors found an Ultimately, more longitudinal data will when renin-angiotensin-aldosterone sys- association of four different CUBN vari- be required to definitively establish that tem (RAAS) blockade was titrated to albu- ants with both albuminuria and a small but long-term, isolated albumin-predominant minuria targets (17), but the significance statistically significant increase in eGFR. proteinuria is truly benign. The diversity of those results has been disputed (10). Thus, in these patients with CUBN loss of proteinuria phenotypes that can occur So far, a reduction in albuminuria beyond of function and isolated chronic protein- in human disease and their subsequent, that achieved by ACEI/ARB monotherapy uria, the consequence of long-term albu- variable clinical consequences still remain has yet to show an effect on hard outcomes min exposure to the kidney tubules may to be fully appreciated. For instance, Bedin (18–22), raising the possibility that RAAS be benign. The authors reanalyzed their et al. draw a distinction between