Real-World Scenario Improvements in Serum Phosphorus Levels and Pill Burden in Peritoneal Dialysis Patients Treated with Sucroferric Oxyhydroxide.

BACKGROUND: A database analysis was conducted to assess the effectiveness of sucroferric oxyhydroxide (SO) on lowering serum phosphorus and phosphate binder (PB) pill burden among adult peritoneal dialysis (PD) patients prescribed SO as part of routine care. METHODS: Adult PD patients (n = 258) prescribed SO through a renal pharmacy service were analyzed. Baseline was 3 months before SO prescription. SO-treated follow-up was for 6 months or until either a new PB was prescribed, SO was not refilled, PD modality changed, or patient was discharged. In-range serum phosphorus was defined as ≤5.5 mg/dL. RESULTS: At baseline, mean serum phosphorus was 6.59 mg/dL with 10 prescribed PB pills/day. The proportion of patients achieving in-range serum phosphorus increased by 72% from baseline to month 6. Prescribed PB pills/day decreased by 57% (10 at baseline to 4.3 at SO follow-up, p < 0.0001). The mean length of SO follow-up was 5.1 months; SO follow-up ended for 38, 27, and 50 patients at months 4, 5, and 6, respectively, due to no further PB fills, and for 10, 11, and 4 patients at months 4, 5, and 6, respectively, due to another PB prescribed. In patients with baseline serum phosphorus >5.5 mg/dL who achieved in-range serum phosphorus during SO follow-up for ≥1 quarter, a notable improvement in serum phosphorus (6.54 to 5.10 mg/dL, p < 0.0001) was observed, and there was a 53% reduction in PB pill burden (9.9 to 4.7, p < 0.0001). CONCLUSION: Among PD patients prescribed SO as part of routine care, improvements in serum phosphorus control and >50% reduction in PB pills/day were observed.

Bigenic mouse models of focal segmental glomerulosclerosis involving pairwise interaction of CD2AP, Fyn, and synaptopodin.

Focal segmental glomerulosclerosis (FSGS) is the most common primary glomerular diagnosis resulting in end-stage renal disease. Defects in several podocyte proteins have been implicated in the etiology of FSGS, including podocin, alpha-actinin-4, CD2-associated protein (CD2AP), and TRPC6. Despite our growing understanding of genes involved in the pathogenesis of focal segmental sclerosis, the vast majority of patients with this disease, even those with a familial linkage, lack a clear genetic diagnosis. Here, we tested whether combinations of genetic heterozygosity (bigenic heterozygosity) that alone do not result in clinical kidney disease could function together to enhance susceptibility to glomerular damage and FSGS. Combinations of Cd2ap heterozygosity and heterozygosity of either synaptopodin (Synpo) or Fyn proto-oncogene (Fyn) but not kin of IRRE like 1 (Neph1) resulted in spontaneous proteinuria and in FSGS-like glomerular damage. These genetic interactions were also reflected at a functional level, as we found that CD2AP associates with Fyn and Synpo but not with Neph1. This demonstrates that bigenic heterozygosity can lead to FSGS and suggests that combined mutations in 2 or multiple podocyte genes may be a common etiology for glomerular disease.

Albumin-associated free fatty acids induce macropinocytosis in podocytes.

Podocytes are specialized epithelial cells in the kidney glomerulus that play important structural and functional roles in maintaining the filtration barrier. Nephrotic syndrome results from a breakdown of the kidney filtration barrier and is associated with proteinuria, hyperlipidemia, and edema. Additionally, podocytes undergo changes in morphology and internalize plasma proteins in response to this disorder. Here, we used fluid-phase tracers in murine models and determined that podocytes actively internalize fluid from the plasma and that the rate of internalization is increased when the filtration barrier is disrupted. In cultured podocytes, the presence of free fatty acids (FFAs) associated with serum albumin stimulated macropinocytosis through a pathway that involves FFA receptors, the Gß/Gγ complex, and RAC1. Moreover, mice with elevated levels of plasma FFAs as the result of a high-fat diet were more susceptible to Adriamycin-induced proteinuria than were animals on standard chow. Together, these results support a model in which podocytes sense the disruption of the filtration barrier via FFAs bound to albumin and respond by enhancing fluid-phase uptake. The response to FFAs may function in the development of nephrotic syndrome by amplifying the effects of proteinuria.

Pathogenesis of nonimmune glomerulopathies.

Nonimmune glomerulopathies are an area of significant research. This review discusses the development of focal segmental glomerulosclerosis, with particular attention to the role of the podocyte in the initiation of glomerulosclerosis and the contribution to glomerulosclerosis from capillary hypertension and soluble factors such as transforming growth factor beta, platelet-derived growth factor, vascular endothelial growth factor, and angiotensin. The effects of these factors on endothelial and mesangial cells are also discussed. In addition, we review our current understanding of the slit diaphragm (a specialized cell junction found in the kidney), slit diaphragm-associated proteins (including nephrin, podocin, alpha-actinin-4, CD2-associated protein, and transient receptor potential channel 6), and the role of these proteins in glomerular disease. We also discuss the most recent research on the pathogenesis of collapsing glomerulosclerosis, human immunodeficiency virus associated nephropathy, Denys-Drash, diabetic nephropathy, Alport syndrome, and other diseases related to the interaction between the podocyte and the glomerular basement membrane.

CD2-associated protein (CD2AP) expression in podocytes rescues lethality of CD2AP deficiency.

Mice born without CD2-associated protein (CD2AP) develop renal failure and nephrotic syndrome about 4 weeks after birth and die around 6 weeks of age. Although CD2AP is widely expressed, the severity of the renal failure precludes a clear determination of the role of CD2AP in other tissues. Here we generated transgenic mice expressing CD2AP using a podocyte-specific promoter. Podocyte-specific expression of CD2AP prevented the development of proteinuria, demonstrating that the renal failure is solely due to loss of CD2AP in podocytes and not in other renal or in immune cells. CD2AP-deficient mice are long-lived and appear phenotypically normal. Histological analysis demonstrated testicular abnormalities that were age-related. CIN85, a paralog of CD2AP, is poorly expressed in both the podocyte and the basal seminiferous tubule, suggesting that the loss of CD2AP in specific tissues may be compensated for by CIN85.