IgG4-related disease is a recently recognized multi-organ disorder characterized by high levels of serum IgG4 and dense infiltration of IgG4-positive cells into several organs. Although the pancreas was the first organ recognized to be affected by IgG4-related disorder in the syndrome of autoimmune pancreatitis, we present here clinico-pathological features of 23 patients diagnosed as having renal parenchymal lesions. These injuries were associated with a high level of serum IgG4 and abundant IgG4-positive plasma cell infiltration into the renal interstitium with fibrosis. In all patients, tubulointerstitial nephritis was the major finding. Although 14 of the 23 patients did not have any pancreatic lesions, their clinicopathological features were quite uniform and similar to those shown in autoimmune pancreatitis. These included predominance in middle-aged to elderly men, frequent association with IgG4-related conditions in other organs, high levels of serum IgG and IgG4, a high frequency of hypocomplementemia, a high serum IgE level, a patchy and diffuse lesion distribution, a swirling fibrosis in the renal pathology, and a good response to corticosteroids. Thus, we suggest that renal parenchymal lesions actually develop in association with IgG4-related disease, for which we propose the term 'IgG4-related tubulointerstitial nephritis.'

We completed the cDNA cloning and sequencing of gp330, the major kidney glomerular antigen for rat Heymann nephritis. However, gp330 differs from these proteins in (i) the cysteine-rich repeat arrangements found in the extreme extraceilular N-and C-terminal regions, (ii) the distribution pattern of cysteine residues in the YWTD spacer regions, (Mi") the location of the RX(K/R)R consensus recognition sequence offurin, a precursor processing endoprotease, and (iv) the length and rutrof the cytoplasmic tail. We suggest the name megaliln (from Greek mega) for gp330, the largest plasma membrane proti Identified so far in vertebrates. The cloned cDNA will be useful for studies on the physiological functions of gp330/megalin and for determining its role in Heymann nephritis.

Angiotensin II content in the kidney is much higher than in the plasma, and it increases more in kidney diseases through an uncertain mechanism. Because the kidney abundantly expresses angiotensinogen mRNA, transcriptional dysregulation of angiotensinogen within the kidney is one potential cause of increased renal angiotensin II in the setting of disease. Here, we observed that kidney-specific angiotensinogen knockout mice had levels of renal angiotensinogen protein and angiotensin II that were similar to those levels of control mice. In contrast, liver-specific knockout of angiotensinogen nearly abolished plasma and renal angiotensinogen protein and renal tissue angiotensin II. Immunohistochemical analysis in mosaic proximal tubules of megalin knockout mice revealed that angiotensinogen protein was incorporated selectively in megalin-intact cells of the proximal tubule, indicating that the proximal tubule reabsorbs filtered angiotensinogen through megalin. Disruption of the filtration barrier in a transgenic mouse model of podocyte-selective injury increased renal angiotensin II content and markedly increased both tubular and urinary angiotensinogen protein without an increase in renal renin activity, supporting the dependency of renal angiotensin II generation on filtered angiotensinogen. Taken together, these data suggest that liverderived angiotensinogen is the primary source of renal angiotensinogen protein and angiotensin II. Furthermore, an abnormal increase in the permeability of the glomerular capillary wall to angiotensinogen, which characterizes proteinuric kidney diseases, enhances the synthesis of renal angiotensin II. CKDs are often progressive and involve cardiovascular diseases. Pharmacological intervention of angiotensin II (AII) is the only currently available therapeutic clinical measure with proven effectiveness in protecting the kidney from progressive loss of renal function in CKD. However, in these conditions, circulating AII is typically not elevated. Of note, AII content in renal tissues is markedly higher than content in the circulation, and it is regulated in a manner distinct from circulating AII. 1-3 These findings have formed the currently prevailing notion that the kidney in and of itself is furnished with a full set of components necessary for de novo AII synthesis. In support of this notion, studies have shown that renal AII is elevated in hypertension and

Nephrotoxicity induced by antimicrobial or anticancer drugs is a serious clinical problem. Megalin, an endocytic receptor expressed at the apical membranes of proximal tubules, mediates the nephrotoxicity of aminoglycosides and colistin, key antimicrobials for multidrug-resistant organisms. The mechanisms underlying the nephrotoxicity induced by vancomycin, an antimicrobial for methicillin-resistant , and cisplatin, an important anticancer drug, are unknown, although the nephrotoxicity of these drugs and gentamicin, an aminoglycoside, is suppressed experimentally with cilastatin. In the clinical setting, cilastatin has been used safely to suppress dehydropeptidase-I-mediated renal metabolism of imipenem, a carbapenem antimicrobial, and thereby limit tubular injury. Here, we tested the hypothesis that cilastatin also blocks megalin-mediated uptake of vancomycin, cisplatin, colistin, and aminoglycosides, thereby limiting the nephrotoxicity of these drugs. Quartz crystal microbalance analysis showed that megalin also binds vancomycin and cisplatin and that cilastatin competes with megalin for binding to gentamicin, colistin, vancomycin, and cisplatin. In kidney-specific mosaic megalin knockout mice treated with colistin, vancomycin, or cisplatin, the megalin-replete proximal tubule epithelial cells exhibited signs of injury, whereas the megalin-deficient cells did not. Furthermore, concomitant cilastatin administration suppressed colistin-induced nephrotoxicity in C57BL/6J mice. Notably, cilastatin did not inhibit the antibacterial activity of gentamicin, colistin, or vancomycin, just as cilastatin did not affect the anticancer activity of cisplatin in previous studies. In conclusion, megalin blockade with cilastatin efficiently suppresses the nephrotoxicity induced by gentamicin, colistin, vancomycin, or cisplatin. Cilastatin may be a promising agent for inhibiting various forms of drug-induced nephrotoxicity mediated megalin in the clinical setting.

Aims/objectiveNephropathy, a major complication of diabetes, is the leading cause of end-stage renal disease. Recent studies have demonstrated that podocyte injury is involved in the onset of and progression to renal insufficiency. Here, we describe a novel, highly sensitive ELISA for detecting urinary podocalyxin, a glycoconjugate on the podocyte apical surface that indicates podocyte injury, particularly in the early phase of diabetic nephropathy.MethodsUrine samples from patients with glomerular diseases (n = 142) and type 2 diabetes (n = 71) were used to quantify urinary podocalyxin by ELISA. Urine samples were obtained from 69 healthy controls for whom laboratory data were within normal values. Podocalyxin was detected in urine by immunofluorescence, immunoelectron microscopy and western blotting.ResultsMorphologically, urinary podocalyxin was present as a vesicular structure; western blotting showed it as a positive band at 165–170 kDa. Levels of urinary podocalyxin were elevated in patients with various glomerular diseases and patients with diabetes. In patients with diabetes, urinary podocalyxin was higher than the cut-off value in 53.8% patients at the normoalbuminuric stage, 64.7% at the microalbuminuric stage and 66.7% at the macroalbuminuric stage. Positive correlations were observed between urinary podocalyxin levels and HbA1c, urinary β2 microglobulin, α1 microglobulin and urinary N-acetyl-β-d-glucosaminidase, although urinary podocalyxin levels were not correlated with other laboratory markers such as blood pressure, lipid level, serum creatinine, estimated GFR or proteinuria.Conclusions/interpretationUrinary podocalyxin may be a useful biomarker for detecting early podocyte injury in patients with diabetes.Electronic supplementary materialThe online version of this article (doi:10.1007/s00125-012-2661-7) contains peer-reviewed but unedited supplementary material, which is available to authorised users.