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Glomerular injury may occur as a result of immune dysfunction in patients with remote lymphoplasmacytic neoplasms. Glomerular injury concurrent with direct infiltration of the kidney by lymphoplasmacytic neoplasms has been reported but is not extensively characterized. We identified 18 patients, all presenting with elevated serum creatinine and many with proteinuria, whose renal biopsies showed direct involvement of kidney by a variety of neoplasms, including chronic leukocytic leukemia/small lymphocytic lymphoma (n = 7), diffuse large B-cell lymphoma (n = 6), multiple myeloma (n = 4), or B-cell lymphoblastic lymphoma (n = 1). In 10 cases (55%), there was coexistent glomerular pathology: 5 of these cases, including glomerulonephritis with membranoproliferative glomerulonephritis-like pattern of injury (n = 4) and membranous nephropathy (n = 1), featured deposition of immune complexes; 2 demonstrated deposition of monoclonal immunoglobulin components: λ light chain amyloidosis (n = 1) and light chain deposition disease (n = 1); 2 showed minimal change disease; and, in 1 case, there was focal crescentic pauci-immune-type glomerulonephritis. In addition, 1 biopsy revealed diabetic nephropathy and 3 showed nonspecific ischemic changes. In the remaining 4 cases, there were no significant glomerular abnormalities. In 11 cases (61%), the diagnosis of lymphoproliferative disease was established following the kidney biopsy. Our study indicates that lymphoplasmacytic neoplasms may be first diagnosed in renal biopsies performed for evaluation of renal dysfunction with or without proteinuria. Concurrent glomerular injury may be a direct result of the lymphoplasmacytic disorder through a paraprotein deposition process resulting in amyloid or monoclonal immunoglobulin deposition disease, or may be caused indirectly through immune-mediated mechanisms, as in the cases of glomerulonephritis with membranoproliferative glomerulonephritis-like pattern of injury, membranous nephropathy, and possibly minimal change disease., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Podocytes are considered terminally differentiated cells in the mature kidney under normal conditions. In the face of injury, podocytes may proceed along several possible pathways, including dedifferentiation and proliferation, persistent cell cycle arrest, hypertrophy, apoptosis, or necrosis. There is mounting evidence that transdifferentiation into a dysregulated phenotype may also be a potential cell fate. We have previously reported that the transcript of SM22α, an actin-binding protein considered one of the earliest markers of smooth muscle differentiation, is upregulated nearly 70-fold in glomeruli of rats with passive Heymann nephritis (PHN). In contrast, the SM22α transcript is absent in normal adult rat glomeruli. The purpose of this study was to define SM22α's expression during kidney development and its role in glomerular diseases characterized by podocyte injury and proteinuria. During glomerulogenesis and podocyte differentiation, SM22α was expressed in glomeruli. This expression disappeared with glomerular maturation. Along with SM22α induction in PHN, confirmed at both mRNA and protein levels, SM22α was also induced across a broad range of proteinuric diseases, including experimental animal models (puromycin aminonucleoside nephropathy, adriamycin nephropathy, passive nephrotoxic nephritis, and diet-induced obesity) and human diseases (collapsing glomerulopathy, diabetic nephropathy, classic focal segmental glomerulosclerosis, IgA nephropathy, minimal-change disease, membranous nephropathy, and membranoproliferative glomerulonephritis). Crescentic glomerulonephritis was induced in SM22α +/+ and SM22α -/- mice by intraperitoneal injection of sheep anti-rabbit glomeruli antibody 12.5 mg/20 g body wt × 2 doses (n = 12-15/group), with mice euthanized at 7 and 14 days. Compared with SM22α -/- mice, SM22α +/+ mice demonstrated worse disease by histopathological parameters. In addition, there was greater apoptosis (cleaved caspase-3 immunostaining), fewer podocytes (Wilms' tumor-1 immunostaining), and less proliferation (Ki-67 immunostaining) in diseased SM22α +/+ mice. Furthermore, there was decreased activation of Erk1/2 in diseased SM22α +/+ mice. We conclude that the de novo expression of SM22α in glomerular epithelial cells affects the course of crescentic glomerulonephritis.

The histologic associations and clinical implications of peritubular capillary C4d staining from long-term renal allografts are unknown. We identified 99 renal transplant patients who underwent an allograft biopsy for renal dysfunction at least 10 yr after transplantation, 25 of whom were C4d-positive and 74 of whom were C4d-negative. The average time of the index biopsy from transplantation was 14 yr in both groups. Compared with C4d-negative patients, C4d-positive patients were younger at transplantation (29 +/- 13 versus 38 +/- 12 yr; P < 0.05) and were more likely to have received an allograft from a living donor (65 versus 35%; P < 0.001). C4d-positive patients had more inflammation, were more likely to have transplant glomerulopathy, and had worse graft outcome. The combined presence of C4d positivity, transplant glomerulopathy, and serum creatinine of >2.3 mg/dl at biopsy were very strong predictors of rapid graft loss. C4d alone did not independently predict graft loss. Retrospective staining of historical samples from C4d-positive patients demonstrated C4d deposition in the majority of cases. In summary, these data show that in long-term renal allografts, peritubular capillary staining for C4d occurs in approximately 25% of biopsies, can persist for many years after transplantation, and strongly predicts graft loss when combined with transplant glomerulopathy.

The glomerular microvasculature is particularly susceptible to injury in thrombotic microangiopathy, but the mechanisms by which this occurs are unclear. We report the cases of six patients who were treated with bevacizumab, a humanized monoclonal antibody against vascular endothelial growth factor (VEGF), in whom glomerular disease characteristic of thrombotic microangiopathy developed. To show that local reduction of VEGF within the kidney is sufficient to trigger the pathogenesis of thrombotic microangiopathy, we used conditional gene targeting to delete VEGF from renal podocytes in adult mice; this resulted in a profound thrombotic glomerular injury. These observations provide evidence that glomerular injury in patients who are treated with bevacizumab is probably due to direct targeting of VEGF by antiangiogenic therapy., (Copyright 2008 Massachusetts Medical Society.)

Fibrillary glomerulonephritis is a now widely recognized diagnostic entity, occurring in approximately 1% of native kidney biopsies in several large biopsy series obtained from Western countries. The distinctive features are infiltration of glomerular structures by randomly arranged fibrils similar in appearance but larger than amyloid fibrils and the lack of staining with histochemical dyes typically reactive with amyloid. It is widely but not universally recognized to be distinct from immunotactoid glomerulopathy, an entity characterized by glomerular deposits of immunoglobulin with substructural organization as microtubules and with clinical associations with lymphoplasmacytic disorders. The pathophysiologic basis for organization of the glomerular deposits as fibrils or microtubules in these entities remains obscure.

Nephrin is a podocyte adhesion molecule located at the slit diaphragm between adjacent glomerular epithelial cells. Mutations in the gene encoding nephrin result in the absence of nephrin or alterations in nephrin causing massive proteinuria in patients with congenital nephrotic syndrome. Given the importance of nephrin to the structural integrity of the glomerular filtration barrier, we postulated that it might also be altered in acquired forms of nephrotic syndrome (NS). To test this hypothesis, frozen kidney biopsy sections from 29 pediatric patients with acquired NS and 5 controls were examined for expression of nephrin. The pathological diagnoses were minimal change disease (MCNS) (19) and focal segmental glomerulosclerosis (FSGS) (10). To determine if nephrin expression differed between children and adults with NS, 10 adult patients and 3 controls were also examined. Nephrin expression was evaluated by immunoperoxidase staining with a monoclonal antibody against the extracellular FnIII portion of human nephrin. In all cases, nephrin expression was seen along the glomerular basement membrane in a finely granular/linear pattern. Expression of nephrin was similar to controls in all 19 patients with MCNS and all 10 patients with FSGS. Areas of sclerosis in patients with FSGS did not demonstrate nephrin expression. A distinctly granular pattern to nephrin expression was seen in adult patients with NS as well as controls. These findings suggest that an alteration in nephrin expression is not a feature of acquired forms of NS in childhood.