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 (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 . 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 (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 Related Article: p. 335 Albuminuria is a predictor of negative clin- 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 the albu- inhibition itself, rather than the associated data for one of the variants under a reces- min-predominant proteinuria resulting reductions in albuminuria, mediates the sive model and found a stronger associa- from CUBN mutations and the proteinuria clinical benefits. tion with albuminuria in homozygotes. It seen in LRP2 mutations that features a There are reasonable grounds to posit will be informative to reanalyze all these higher proportion of α1- and β2-microglob- a role for albuminuria in the pathogenesis GWAS data under a recessive model to ulins as well as a possible association with of proteinuric CKD. In vitro evidence has confirm an association with more severe reduced eGFR (4, 25). This phenotypic dis- shown that protein overload in proximal proteinuria in individuals carrying two of tinction is striking, given that megalin and tubule cells activates NF-κB signaling, these risk variants. In addition, the avail- cubilin associate in the apical membrane upregulates inflammation via monocyte ability of large data sets such as those from of the proximal tubule and are coreceptors chemotactic protein 1, and induces vaso- the UK Biobank will enable detection of for a large repertoire of proteins, including constriction via endothelin 1 (23), which associations of these variants with pheno- albumin. That loss of function of one or the together can contribute to the develop- types beyond albuminuria. other of these coreceptors results in differ- ment of tubulointerstitial disease. The ent patterns of proteinuria with differing in vivo evidence, however, does not fully Clinical implications clinical consequences is a remarkable fact support the hypotheses generated from That the proteinuria in the Bedin et al. that highlights how much there is yet to in vitro experiments. Humans with loss patient cohorts was albumin predominant discover about proteinuria and its physio- of function of megalin or cubilin have up yields important conclusions for practicing logical consequences. to 2.5 g/d of proteinuria (1), implying that nephrologists: all albuminuria is not of glo- the proximal tubule is chronically exposed merular origin, and isolated albuminuria Acknowledgments to gram quantities of albumin that must be may not be toxic to kidney function (4). AB is supported by NIH grants efficiently endocytosed by megalin-cubi- Albuminuria has long been recognized as a T32DK108741 and TL1TR001875. JMB is lin. This suggests at least that chronic hallmark of glomerular disease and indic- supported by NIH grants 1U54DK104309, albumin exposure in the proximal tubule ative of a compromised filtration barrier 2R01DK073462, and UG3 DK114926 and is insufficient for the development of tub- that has lost size and charge selectivity. by a Columbia Precision Medicine Pilot ulointerstitial disease. Although another genetic form of tubular Award. AGG is supported by NIH grants The proteinuric consequences of cubi- proteinuria, Dent disease, results in kid- U01 DK100876 and R01 DK080099. lin mutations have been well document- ney failure, interpretation is confounded ed (8), but Bedin et al. (4) went further to by concomitant hypercalciuria and neph- Address correspondence to: Ali G. Ghara- query the impact of albuminuria on renal rocalcinosis. Here, Bedin et al. show that vi, Division of Nephrology, Columbia Uni- function. Their 39 patients were primarily albuminuria can be associated with nor- versity Vagelos College of Physicians and children, but the age range encompassed mal renal function in the context of CUBN Surgeons, 1150 St. Nicholas Avenue, Russ newborns, teenagers, seven patients aged loss of function (4). Identifying genetic Berrie Pavilion 413, New York, New York 30 to 40 years, and one aged 66 years, all causes of renal disease that are intracta- 10032, USA. Phone: 212.851.4927; Email: of whom exhibited normal eGFRs of great- ble to medical therapy is a growing area of [email protected].

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