Philippe Zaoui

TGF- β has been implicated as a major pathogenic factor in diabetic nephropathy. This randomized, double-blind, phase 2 study assessed whether modulating TGF- β 1 activity with a TGF- β 1–specific, humanized, neutralizing monoclonal antibody (TGF- β 1 mAb) is safe and more effective than placebo in slowing renal function loss in patients with diabetic nephropathy on chronic stable renin-angiotensin system inhibitor treatment. We randomized 416 patients aged ≥25 years with type 1 or type 2 diabetes, a serum creatinine (SCr) level of 1.3–3.3 mg/dl for women and 1.5–3.5 mg/dl for men (or eGFR of 20–60 ml/min per 1.73 m 2 ), and a 24-hour urine protein-to-creatinine ratio ≥800 mg/g to TGF- β 1 mAb (2-, 10-, or 50-mg monthly subcutaneous dosing for 12 months) or placebo. We assessed a change in SCr from baseline to 12 months as the primary efficacy variable. Although the Data Monitoring Committee did not identify safety issues, we terminated the trial 4 months early for futility on the basis of their recommendation. The placebo group had a mean±SD change in SCr from baseline to end of treatment of 0.33±0.67 mg/dl. Least squares mean percentage change in SCr from baseline to end of treatment did not differ between placebo (14%; 95% confidence interval [95% CI], 9.7% to 18.2%) and TGF- β 1 mAb treatments (20% [95% CI, 15.3% to 24.3%], 19% [95% CI, 14.2% to 23.0%], and 19% [95% CI, 14.0% to 23.3%] for 2-, 10-, and 50-mg doses, respectively). Thus, TGF- β 1 mAb added to renin-angiotensin system inhibitors did not slow progression of diabetic nephropathy.

Fifty-seven cases of Ig light chain-associated Fanconi syndrome (FS) have been reported so far, mostly as isolated reports. The pioneering work by Maldonado and associates (35), who reviewed the first 17 cases in 1975, led to the unifying concept that patients with FS and Bence Jones proteinuria have a special form of plasma cell dyscrasia characterized by slow progression of the tumor and by prominent crystal formation in proximal tubule cells, in the absence of myeloma casts in the distal tubule. We carefully reappraised these characteristics in a series of 11 patients. Ten renal biopsy specimens were available for electron microscopy, adding to the 15 previously reported cases with ultrastructural studies. Moreover, 10 of the kappa light chains could be entirely or partially sequenced and tested for their resistance to cathepsin B, a lysosomal protease present in proximal tubule cells. Our series showed an unexpected clinicopathologic heterogeneity. Seven patients presented with the typical clinical and pathologic features of FS and low-mass myeloma or monoclonal gammopathy of undetermined significance (MGUS), in keeping with Maldonado et al's description. Crystals in bone marrow cells were detected in patients of this group, only. Three patients who presented with full-blown FS exhibited, however, the characteristic features of myeloma cast nephropathy in the setting of high-mass myeloma. One patient of this group also had numerous crystals in proximal tubule cells. The eleventh patient had complete FS with MGUS, but no crystals in proximal tubule cells even after electron microscopy. Contrasting with the clinicopathologic heterogeneity, genetic and biochemical analyses of the light chains showed a striking homogeneity. First, they all were of the kappa type. Second, 8 of 9 belonged to the V kappa I variability subgroup, which indicates that FS light chains are related by the sequence of their variable regions. Third, the 8 V kappa I light chain sequences most likely originated from only 2 germline genes, LCO2/012 and LCO8/018. Fourth, all 5 LCO2/012-derived sequences presented an unusual hydrophobic or nonpolar residue at position 30. These sequence peculiarities may account for unusual physicochemical properties of the light chains including the resistance of their variable domain V kappa to proteolysis by cathepsin B, observed in 7 of 9 patients in our series, while light chains isolated from patients with myeloma cast nephropathy are completely digested. Resistance of V kappa to proteolysis in FS patients can explain the accumulation of the light chain in the endocytotic compartment of the proximal tubule cells, leading to impairment of proximal tubule functions.

BACKGROUND: Treatment of acute antibody-mediated rejection (AMR) is based on a combination of plasma exchange (PE), IVIg, corticosteroids (CS), and rituximab, but the place of rituximab is not clearly specified in the absence of randomized trials. METHODS: In this phase III, multicenter, double-blind, placebo-controlled trial, we randomly assigned patients with biopsy-proven AMR to receive rituximab (375 mg/m) or placebo at day 5. All patients received PE, IVIg, and CS. The primary endpoint was a composite of graft loss or no improvement in renal function at day 12. RESULTS: Among the 38 patients included, at 1 year, no deaths occurred, but 1 graft loss occurred in each group. The primary endpoint frequency was 52.6% (10/19) and 57.9% (11/19) in the rituximab and placebo groups, respectively (P = 0.744). Renal function improved in both groups, as soon as day 12 with no difference in serum creatinine level and proteinuria at 1, 3, 6, and 12 months. Supplementary administration of rituximab and total number of IVIg and PE treatments did not differ between the 2 groups. Both groups showed improved histological features of AMR and Banff scores at 1 and 6 months, with no significant difference between groups but with a trend in favor of the rituximab group. Both groups showed decreased mean fluorescence intensity of donor-specific antibodies as soon as day 12, with no significant difference between them but with a trend in favor of the rituximab group at 12 months. CONCLUSIONS: After 1 year of follow-up, we observed no additional effect of rituximab in patients receiving PE, IVIg, and CS for AMR. Nevertheless, our study was underpowered and important differences between groups may have been missed. Complementary trials with long-term follow-up are needed.