The association between increased serum urate and hypertension has been a subject of intense controversy. Extracellular uric acid drives uric acid deposition in gout, kidney stones, and possibly vascular calcification. Mendelian randomization studies, however, indicate that serum urate is likely not the causal factor in hypertension although it does increase the risk for sudden cardiac death and diabetic vascular disease. Nevertheless, experimental evidence strongly suggests that an increase in intracellular urate is a key factor in the pathogenesis of primary hypertension. Pilot clinical trials show beneficial effect of lowering serum urate in hyperuricemic individuals who are young, hypertensive, and have preserved kidney function. Some evidence suggest that activation of the renin–angiotensin system (RAS) occurs in hyperuricemia and blocking the RAS may mimic the effects of xanthine oxidase inhibitors. A reduction in intracellular urate may be achieved by lowering serum urate concentration or by suppressing intracellular urate production with dietary measures that include reducing sugar, fructose, and salt intake. We suggest that these elements in the western diet may play a major role in the pathogenesis of primary hypertension. Studies are necessary to better define the interrelation between uric acid concentrations inside and outside the cell. In addition, large-scale clinical trials are needed to determine if extracellular and intracellular urate reduction can provide benefit hypertension and cardiometabolic disease.

Background Minimal Change Disease (MCD) in relapse is associated with increased podocyte CD80 expression and elevated urinary CD80 excretion, whereas focal segmental glomerulosclerosis (FSGS) has mild or absent CD80 podocyte expression and normal urinary CD80 excretion. Methods One patient with MCD, one patient with primary FSGS and three patients with recurrent FSGS after transplantation received CD80 blocking antibodies (abatacept or belatacept). Urinary CD80 and CTLA-4 were measured by ELISA. Glomeruli were stained for CD80. Results After abatacept, urinary CD80 became undetectable with concomitant transient resolution of proteinuria in the MCD patient. In contrast, proteinuria remained unchanged after abatacept or belatacept therapy in one patient with primary FSGS and in two recurrent FSGS subjects despite the presence of mild CD80 glomerular expression but normal urinary CD80 excretion. One patient with recurrent FSGS after transplantation had elevated urinary CD80 excretion immediately after surgery which fell spontaneously before abatacept. After Abatacept, his proteinuria remained unchanged for 5 days despite normal urinary CD80 excretion. Conclusion These observations are consistent with a role of podocyte CD80 in the development of proteinuria in MCD. In contrast, CD80 may not play a role in recurrent FSGS since urinary CD80 is only increased transiently after surgery and normalization of urinary CD80 did not result in resolution of proteinuria.

Background C3 glomerulopathy (C3G) defines a group of rare complement-mediated kidney diseases with a shared underlying pathophysiology: dysregulation of complement in the fluid phase and glomerular microenvironment. Dysregulation can be driven by autoantibodies to C3 and C5 convertases. Study Design Case series Setting & Participants 168 C3G patients (dense deposit disease, 68; C3 glumerulonephritis, 100) selected from our C3G bio-bank. Outcomes Patient-purified IgGs were tested for C4 nephritic factors (C4Nefs). These autoantibodies recognize C4b2a, the C3 convertase of the classical pathway of complement. Measurements C4Nefs were detected using a modified hemolytic assay. Results C4Nefs were identified in 5 patients, 4 of whom had C3 glomerulonephritis. The C4Nefs were associated with dysregulation of C3 and C5 convertases and they appear to stabilize these convertases in a dose-dependent manner. The C4Nefs also appear to protect C4b2a from decay mediated by soluble CR1 and C4 binding protein (C4BP). The stabilizing activity of the autoantibodies was further demonstrated by using heat treatment to inactivate complement. C4Nefs were not detected in 150 patients with another complement-mediated kidney disease, atypical hemolytic uremic syndrome. They were also absent in 300 apparently healthy controls. Limitations In addition to C4Nefs, two patients had positive findings for other autoantibodies: one patient also had autoantibodies to factor H; the other patient also had autoantibodies to C3bBb (C3Nefs). Conclusions The finding of C4Nefs in a small percentage of C3G patients highlights the challenge in identifying autoantibodies that drive complement dysregulation and underscores the complexity of the autoantibody repertoire that can be identified in these patients.

Background Minimal Change Disease (MCD) is characterized by increased urinary excretion of CD80, whereas Focal Segmental Glomerulosclerosis (FSGS) is associated with increased serum suPAR. The aim of the study was to assess whether the simultaneous measurement of urinary CD80 and serum suPAR helps differentiate MCD and FSGS. Methods Urine and sera were collected from patients with MCD in relapse or in remission, from FSGS patients with nephrotic syndrome, and from normal subjects. CD80 and suPAR were measured by ELISA. Results Urinary CD80 was significantly increased in MCD patients in relapse compared with those in remission, as well as with FSGS patients and control subjects. Serum suPAR levels were significantly higher in patients with FSGS when compared to MCD patients in relapse. Urinary suPAR showed a positive correlation with proteinuria in MCD in relapse and FSGS patients, whereas urinary CD80 correlated with proteinuria only in MCD patients in relapse. Conclusion Urinary CD80 is elevated in MCD patients in relapse compared to FSGS patients. In contrast, serum suPAR is significantly elevated in FSGS patients. The consistent pattern of these two biomarkers in MCD and FSGS suggests that these two conditions represent different entities rather than a continuum spectrum of one disease.

Minimal change disease (MCD) is the most common type of nephrotic syndrome in children and adolescents. The pathogenesis of proteinuria in this condition is currently being reassessed. Following the Shalhoub hypothesis, most efforts have been placed on identifying the putative circulating factor, but recent advancement in podocyte biology has focused attention on the molecular changes at the glomerular capillary wall, which could explain the mechanism of proteinuria in MCD. This report critically reviews current knowledge on the different postulated mechanisms at the glomerular capillary wall level for increased permeability to plasma proteins in MCD. The report helps describe the rationale behind novel therapies and suggests future targeted therapies for MCD.