Only a few cases of various glomerulonephropathies have been reported in patients with polycythemia vera. We report the case of a 72-year-old female with polycythemia vera in whom renal biopsy examination showed membranoproliferative glomerulonephritis (MPGN)-like lesion and glomerular expression of plasmalemmal vesicle-associated protein-1 (PV-1), a marker of glomerular capillary remodeling after injury. Prior to admission to our hospital for nephrotic syndrome, she had received hydroxyurea and phlebotomy. On admission, she was hypertensive with pretibial edema, hepatosplenomegaly, massive proteinuria (6.14 g/day), low serum albumin (2.9 g/dl), high fibrinogen, fibrin/fibrinogen degradation products and thrombomodulin levels, but with normal serum creatinine and complement levels. Microscopic examination of a renal biopsy demonstrated MPGN-like features with double contour and mesangial interposition. Electron microscopy showed subendothelial deposits, platelets attached to glomerular capillary walls and fibrin deposition. Immunofluorescence study identified IgM deposition along part of the capillary wall and mesangium. CD42b-positive platelets and megakaryocytes were detected in glomerular capillaries, accompanied with increased expression of platelet-derived growth factor receptor b and thrombomodulin in the mesangium and glomerular capillary, respectively. PV-1 was expressed along the glomerular capillary. Anti-platelet and anticoagulant combination therapy, together with the use of anti-hypertensive agents and hydroxyurea, resulted in improvement of the nephrotic syndrome. The findings suggested that activated platelets, enhanced coagulation state and endothelial damage may contribute to glomerulonephropathy associated with polycythemia vera.

The link between the nephrotic syndrome (NS) and malignancy was first described in 1922. In solid tumors, the NS is most often due to membranous glomerulonephropathy, whereas in common hematological malignancies, minimal-change disease predominates. Focal segmental glomerulosclerosis (FSGS) is among the least frequently reported renal lesion associated with malignancy.We report a case of the simultaneous diagnoses of FSGS and Hodgkin's lymphoma, and review the literature on various nephrotic glomerulonephropathies associated with common leukemia and lymphoma.Although nephrotic glomerulonephropathies rarely occur in association with acute leukemia, they have often been described in chronic lymphocytic leukemia (CLL). Membranoproliferative glomerulonephropathy and membranous glomerulonephropathy are the most common lesions observed in CLL. Nephrotic glomerulonephropathies have also been well documented among patients with lymphomas, in particular, Hodgkin's lymphoma. While minimal-change disease is most commonly found in association with Hodgkin's lymphoma, more diverse and complex renal lesions are associated with non-Hodgkin's lymphoma. FSGS remains a rare association with hematological malignancies.Nephrotic glomerulonephropathies are not only linked to solid-organ tumors, but also to hematological malignancies. A thorough evaluation, including a physical examination for lymphadenopathy and organomegaly, as well as a hematological evaluation, must be performed in all patients presenting with nephrotic glomerulonephropathies.

The experimental data and the study on human renal tissue in patients with glomerulonephropathies indicate that monocyte chemoattractant protein-1 (MCP-1) plays a main role in progression of inflammatory processes in kidney diseases. Monocytes/macrophages are multifunctional cells that may regulate matrix accumulation by producing transforming growth factor beta-1 (TGF-beta-1), which plays an important role in the progression of renal diseases. The present study was undertaken to evaluate the relationships between the immunoexpression of MCP-1, the number of CD68-positive cells, the immunoexpression of TGF-beta-1 and the extent of renal fibrosis as well serum creatinine level in patients with lupus nephritis. Using immunohistochemistry we analyzed the expression of MCP-1, TGF-beta-1 and the number of CD68+ cells in renal biopsy specimens in 17 patients with IV class of lupus nephritis and in 10 normal kidneys. Statistical analysis revealed significant increase in the tubulointerstitial MCP-beta immunostaining in lupus nephritis as compared to normal controls. In lupus nephritis the amount of glomerular and interstitial CD68+ cells was higher than in control group. None of the control sections have evidence of glomerular or tubulointerstitial immunoexpression of TGF-beta-1. In patients with lupus nephritis TGF-beta-1 was detected in the renal tubular epithelial cells and the interstitium, and to a lesser extent within glomeruli. The tubulointerstitial MCP-1 immunoexpression was significantly correlated with monocyte/macrophage interstitial infiltrates, the immunoexpression of TGF-beta-1 in tubuli and interstitium as well as serum creatinine. Moreover, the tubulointerstitial immunoexpression of TGF-beta-1 was significantly positively correlated with renal interstitial cortical volume and serum creatinine in patients with lupus nephritis. In summary, these data suggest that in lupus nephritis MCP-1 may play a role in modulating interstitial inflammatory process and in tubulointerstitial renal damage via TGF-beta-1 pathway.

For years, anti-Leishmania immunoglobulin G (IgG) antibodies have been detected in the sera of dogs living in areas of leishmaniasis endemicity. They have also been found in the aqueous humor and cerebrospinal fluid. In contrast, a review of the literature failed to identify the detection of anti-Leishmania antibodies in urine samples from dogs with leishmaniasis. Ninety-five dog urine samples were examined for the presence of anti-Leishmania antibodies by using a protein A enzyme-linked immunosorbent assay (ELISA). Twenty additional urine samples were collected from healthy dogs as controls. An IgG2 ELISA was performed on 26 urine samples found positive by the protein A ELISA. Twenty-three urine samples found positive to anti-Leishmania antibodies were tested for the local production of anti-Leishmania antibodies in the urinary tract by means of the urine antibody coefficient. Ten urine samples (and the corresponding serum samples) were compared by Western blot (WB) analysis. Thirty-five out of the 95 urine samples were found positive, 57 were found negative, and 3 were found inconclusive for antibody detection by the protein A ELISA. A high correlation between protein A and IgG2 levels was found in positive urine samples. Anti-Leishmania antibodies were present in the urine of dogs that had leishmaniasis, urinary protein/creatinine (U P/C) ratios of greater than one, and normal urinary sediment. A statistically significant correlation was observed between the U P/C ratios and the levels of anti-Leishmania antibodies in positive urine samples. In general, WB analysis and the urine antibody coefficient suggested that the presence of anti-Leishmania antibodies in urine was the consequence of an impairment of filtration of the glomerular barrier. However, in some dogs, WB analysis could be interpreted as suggesting that the presence of anti-Leishmania antibodies was caused, to a lesser extent, by local antibody production in the urinary tract. Antibody detection in urine could be a noninvasive method for leishmaniasis diagnosis and prognosis in dogs with glomerulonephropathies.

Membranoproliferative glomerulonephritis, with or without cryoglobulinemia, and membranous glomerulonephritis are the best characterized glomerulonephropathies associated with hepatitis C virus (HCV) infection. Other more unusual patterns of glomerular injury, including IgA nephropathy, focal segmental glomerulosclerosis, crescentic glomerulonephritis, fibrillary glomerulonephritis, immunotactoid glomerulopathy, and thrombotic microangiopathy, have also been associated with HCV infection, but primarily on an anecdotal basis. It remains uncertain whether the patterns of glomerular injury seen in HCV infected patients, particularly the unusual patterns, represent a disease process specifically related to HCV infection or whether they represent nonspecific patterns of injury due to other causes that happen to occur in HCV-infected patients. We examine this issue by reviewing the epidemiological and pathological evidence in the literature that either supports or refutes a specific relationship between HCV and the pattern of glomerular injury. We also include our experience with 31 HCV-infected patients. In addition, the pathogenesis of HCV-associated glomerulonephropathies is discussed with an emphasis on the significance of detecting HCV in renal biopsies by reverse transcriptase-polymerase chain reaction.

We have previously shown a biochemical interaction between fibronectin (Fn) and polymeric immunoglobulins (Igs), that we localized to the fourth and fifth N-terminal type I repeats (4F1.5F1) in Fn and the Fc portion of IgG. Therefore, we hypothesized that Fn, as a constituent of the extracellular matrix (ECM) may directly bind circulating immune complexes (ICs) causing their deposition, thereby contributing to the pathogenesis of IC diseases. As an in vitro paradigm to test this idea, we have generated Fn-containing ECMs from varied cells in culture and demonstrated a saturable dose-dependent binding of aggregated (agg) IgG, as a prototype of ICs, as well as the binding of both heat and cold aggregated purified type I cryoglobulins (CGs) to these ECMs. No binding was observed to ECMs (Matrigel) that do not contain Fn. Characteristic of our previous findings, polymeric but not monomeric IgG bound to the acellular Fn-containing ECMs. To further demonstrate the specificity of the interaction and implicate matrix Fn in the binding of aggIgG, complete inhibition of binding of aggIgG to Fn was achieved by blocking Fn on the ECMs with anti-Fn antiserum and by preincubation of the Ig aggregates with anti-human IgG antibodies. By competing the binding interaction with fluid phase Fn and the Ig-binding site on Fn, 4F(1).5F(1), 70% inhibition was obtained. Additional experiments performed with purified CGs show that an identical dose-dependent increase in Fn binding occurred using both preformed and forming cryoprecipitates suggesting that Fn does not confer cryoprecipitation of CGs and that the specific association of Fn with cryoprecipitates probably results from their polymeric configuration. Our results support the notion that Fn, as it exits in expanding ECMs characteristic of glomerulonephropathies and rheumatoid synovial disease, specifically interacts with complexed/polymeric Igs, thereby perpetuating IC deposition and playing a role in the pathogenesis of IC diseases.

Monocyte chemoattractant protein-1 (MCP-1) is a specific chemokine to recruit and activate monocytes from the circulation to inflammatory site. In diabetic nephropathy, similar to other glomerulonephropathies, infiltration and activation of monocytes/macrophages in glomerulus have been implicated in the development of glomerular injury. The aim of the present study was to examine a possible relationship of MCP-1 with diabetic nephropathy and to investigate the role of glycated albumin (Gly-Alb) as well as high concentration of glucose (HG) on MCP-1 production by cultured human mesangial cells.MCP-1 in serum or urine and urinary albumin (Alb) as well as several clinical parameters such as plasma glucose, serum Gly-Alb, and hemoglobin A1c (HbA1c) were measured after overnight fasting in 16 control subjects and 54 diabetic patients. The relationships between the levels of urinary Alb and urinary or serum MCP-1 and also between the values of respective clinical parameter and urinary MCP-1 levels were analyzed. Next, using cultured human mesangial cells, we investigated the role of Gly-Alb and/or HG on the gene and protein expression of MCP-1.Urinary levels (ng/g creatinine), but not serum levels, of MCP-1 increased in accordance with the extent of albuminuria. In all subjects, there were significant correlations between the urinary levels of Alb and MCP-1 (r = 0.746, P < 0.0001) and between the levels of serum Gly-Alb and urinary MCP-1 (r = 0.475, P < 0.0001). In cultured human mesangial cells, the gene and protein expression of MCP-1 was dose and time dependently up-regulated by Gly-Alb. HG slightly but significantly stimulated MCP-1 expression. The combination of Gly-Alb and HG showed the greatest stimulation in more than an additive manner on MCP-1 production.This study suggests that facilitated MCP-1 production by mesangial cells in diabetic milieu contributes to the initiation and progression of diabetic nephropathy.

The pathogenetic concept of renal hyperperfusion and hyperfiltration in inducing glomerular pathology and disease progression documented in the renal ablation model in experimental animals to mimic renal disease with reduced nephron mass has recently been challenged. In contrast to the above, the intrarenal hemodynamic study in a variety of chronic glomerulonephropathies reveals a unique characteristic of renal hypoperfusion rather than hyperperfusion. This is associated with an elevated renal arteriolar resistance and reductions in renal plasma flow and peritubular capillary blood flow. The magnitude of reduction in peritubular capillary blood flow is inversely proportional to the degree of tubulointerstitial disease and tubular dysfunction. A progressive reduction in the vascular space due to nonvascular expansion with disease progression supports the concept of hypoperfusion of a whole kidney as well as a single nephron. In accordance with the renal ablation model and early diabetes mellitus, a similar hypoperfusion pattern is also subsequently observed in the chronic stage of renal ablation model in animals and late diabetic nephropathy. The disparity between the hyperperfusion and hypoperfusion in inducing renal disease progression can be enlightened by the Noble Truth of Lord Buddha stating "The Middle Tract is The Balance of Nature". Further support of this conceptual view of renal hypoperfusion as a determinant of tubulointerstitial disease and disease progression is in accordance with the therapeutic benefit with an enhanced-renal-perfusion formula per se in a variety of chronic glomerulonephropathies.

It has been demonstrated that cultured mesangial cells (MC) express latent transforming growth factor (TGF)-beta binding protein (LTBP) mRNA, and that LTBP might be essential for the extracellular matrix (ECM) accumulation stimulated by TGF-beta in cultured MC. We performed a study to test the pathophysiological role of LTBP in mesangial ECM accumulation in human glomerulonephropathies. The expression of LTBP in 64 renal biopsies of patients with renal diseases was examined by immunohistochemical staining with the specific antibody raised against human LTBP. The biopsy specimens were divided into three groups: Group 1, IgA nephropathy; Group 2, IgA negative mesangial proliferative glomerulonephritis, which mainly consisted of diabetic nephropathy and lupus nephritis; and Group 3, non-proliferative nephropathy, which consisted of minimal change and membranous nephropathy. Immunohistochemical staining of LTBP was significantly detected in mesangial/paramesangial area of glomerulus in Group 1, but not observed in Group 2 or Group 3. The intensity of staining was well related to the grade of mesangial ECM accumulation in Group 1. These findings suggest that the LTBP-TGF-beta complex may play a pivotal role in ECM accumulation in IgA nephropathy, and that modification of LTBP-ECM interaction might provide a new therapeutic strategy against the progression of glomerulosclerosis.

A glomerular endothelial function with its hemodynamic impact is proposed to determine disease progression. In the clinical settings associated with an intact endothelial function, such as minimal-change steroid-sensitive nephrosis, the early phase of diabetes mellitus and the early stage of an experimental model of renal ablation in animals, it was observed that adequate renal perfusion correlates with the intact structure and function of the nephron with no evidence of disease progression. In contrast, the clinical settings associated with endothelial dysfunction, such as chronic glomerulonephropathy, the late stage of diabetes mellitus and a renal ablation model in animals, are usually associated with a reduction in renal perfusion. The magnitude of renal hypoperfusion observed in all forms of chronic glomerulonephropathies is proportional to the degree of clinical severity. A progressive pattern of renal hypoperfusion is uniquely observed when disease severity progresses. In this context, a new therapeutic maneuver aiming to improve renal perfusion is proposed for treating glomerulonephropathy with disease progression and preventing it from developing to end-stage renal disease.