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Angiotensin-converting enzyme (ACE) inhibitors ameliorate the progression of renal disease. In combination with vitamin D receptor activators, they provide additional benefits. In the present study, uremic (U) rats were treated as follows: U+vehicle (UC), U+enalapril (UE; 25 mg/l in drinking water), U+paricalcitol (UP; 0.8 μg/kg ip, 3 × wk), or U+enalapril+paricalcitol (UEP). Despite hypertension in UP rats, proteinuria decreased by 32% vs. UC rats. Enalapril alone, or in combination with paricalcitol, further decreased proteinuria (≈70%). Glomerulosclerosis and interstitial infiltration increased in UC rats. Paricalcitol and enalapril inhibited this. The increase in cardiac atrial natriuretic peptide (ANP) seen in UC rats was significantly decreased by paricalcitol. Enalapril produced a more dramatic reduction in ANP. Renal oxidative stress plays a critical role in inflammation and progression of sclerosis. The marked increase in p22(phox), a subunit of NADPH oxidase, and decrease in endothelial nitric oxide synthase were inhibited in all treated groups. Cotreatment with both compounds inhibited the uremia-induced increase in proinflammatory inducible nitric oxide synthase (iNOS) and glutathione peroxidase activity better than either compound alone. Glutathione reductase was also increased in UE and UP rats vs. UC. Kidney 4-hydroxynonenal was significantly increased in the UC group compared with the normal group. Combined treatment with both compounds significantly blunted this increase, P < 0.05, while either compound alone had no effect. Additionally, the expression of Mn-SOD was increased and CuZn-SOD decreased by uremia. This was ameliorated in all treatment groups. Cotreatment with enalapril and paricalcitol had an additive effect in increasing CuZn-SOD expression. In conclusion, like enalapril, paricalcitol alone can improve proteinuria, glomerulosclerosis, and interstitial infiltration and reduce renal oxidative stress. The effects of paricalcitol may be amplified when an ACE inhibitor is added since cotreatment with both compounds seems to have an additive effect on ameliorating uremia-induced changes in iNOS and CuZn-SOD expression, peroxidase activity, and renal histomorphometry.

Transplantation therapy for human diabetes is limited by the toxicity of immunosuppressive drugs. If toxicity can be minimized, there will still be a shortage of human donor organs. Xenotransplantation of porcine islets is a strategy to overcome supply problems. Xenotransplantation in mesentery of pig pancreatic primordia obtained very early during organogenesis [embryonic day 28 (E28)] is a way to obviate the need for immunosuppression in rats or rhesus macaques and to enable engraftment of a cell component originating from porcine islets implanted beneath the renal capsule of rats. Here, we show engraftment in the kidney of insulin and porcine proinsulin mRNA-expressing cells following implantation of porcine islets beneath the renal capsule of diabetic rhesus macaques transplanted previously with E28 pig pancreatic primordia in mesentery. Donor cell engraftment is confirmed using fluorescent in situ hybridization (FISH) for the porcine X chromosome and is supported by glucose-stimulated insulin release in vitro. Cells from islets do not engraft in the kidney without prior transplantation of E28 pig pancreatic primordia in mesentery. This is the first report of engraftment following transplantation of porcine islets in non-immunosuppressed, immune-competent non-human primates. The data are consistent with tolerance to a cell component of porcine islets induced by previous transplantation of E28 pig pancreatic primordia.

Podocyte injury has been suggested to have a pivotal role in the pathogenesis of diabetic glomerulopathy. To glean insights into molecular mechanisms underlying diabetic podocyte injury, we generated temporal global gene transcript profiles of podocytes exposed to high glucose for a time interval of 1 or 2 weeks using microarrays. A number of genes were altered at both 1 and 2 weeks of glucose exposure compared with controls grown under normal glucose. These included extracellular matrix modulators, cell cycle regulators, extracellular transduction signals and membrane transport proteins. Novel genes that were altered at both 1 and 2 weeks of high-glucose exposure included neutrophil gelatinase-associated lipocalin (LCN2 or NGAL, decreased by 3.2-fold at 1 week and by 7.2-fold at 2 weeks), endothelial lipase (EL, increased by 3.6-fold at 1 week and 3.9-fold at 2 week) and UDP-glucuronosyltransferase 8 (UGT8, increased by 3.9-fold at 1 week and 5.0-fold at 2 weeks). To further validate these results, we used real-time PCR from independent podocyte cultures, immunohistochemistry in renal biopsies and immunoblotting on urine specimens from diabetic patients. A more detailed time course revealed changes in LCN2 and EL mRNA levels as early as 6 hours and in UGT8 mRNA level at 12 hours post high-glucose exposure. EL immunohistochemistry on human tissues showed markedly increased expression in glomeruli, and immunoblotting readily detected EL in a subset of urine samples from diabetic nephropathy patients. In addition to previously implicated roles of these genes in ischemic or oxidative stress, our results further support their importance in hyperglycemic podocyte stress and possibly diabetic glomerulopathy pathogenesis and diagnosis in humans.

Mutant forms of TRPC6 can activate NFAT-dependent transcription in vitro via calcium influx and activation of calcineurin. The same TRPC6 mutants can cause FSGS, but whether this involves an NFAT-dependent mechanism is unknown. Here, we generated mice that allow conditional induction of NFATc1. Mice with NFAT activation in nascent podocytes in utero developed proteinuria and glomerulosclerosis postnatally, resembling FSGS. NFAT activation in adult mice also caused progressive proteinuria and FSGS. Ultrastructural studies revealed podocyte foot process effacement and deposition of extracellular matrix. NFAT activation did not initially affect expression of podocin, synaptopodin, and nephrin but reduced their expression as glomerular injury progressed. In contrast, we observed upregulation of Wnt6 and Fzd9 in the mutant glomeruli before the onset of significant proteinuria, suggesting a potential role for Wnt signaling in the pathogenesis of NFAT-induced podocyte injury and FSGS. These results provide in vivo evidence for the involvement of NFAT signaling in podocytes, proteinuria, and glomerulosclerosis. Furthermore, this study suggests that NFAT activation may be a key intermediate step in the pathogenesis of mutant TRPC6-mediated FSGS and that suppression of NFAT activity may contribute to the antiproteinuric effects of calcineurin inhibitors.

Transplantation therapy for human diabetes is limited by the toxicity of immunosuppressive drugs. However, even if toxicity can be minimalized, there will still be a shortage of human donor organs. Xenotransplantation of porcine islets may be a strategy to overcome these supply problems. Xenotransplantation in mesentery of pig pancreatic primordia obtained very early during organogenesis [embryonic day 28 (E28)] can obviate the need for immune suppression in rats or rhesus macaques. Here, in rats transplanted previously with E28 pig pancreatic primordia in the mesentery, we show normalization of glucose tolerance in nonimmune-suppressed streptozotocin-diabetic LEW rats and insulin and porcine proinsulin mRNA-expressing cell engraftment in the kidney following implantation of porcine islets beneath the renal capsule. Donor cell engraftment was confirmed using fluorescent in situ hybridization for the porcine X chromosome and electron microscopy. In contrast, cells from islets did not engraft in the kidney without prior transplantation of E28 pig pancreatic primordia in the mesentery. This is the first report of prolonged engraftment and sustained normalization of glucose tolerance following transplantation of porcine islets in nonimmune-suppressed, immune-competent rodents. The data are consistent with tolerance induction to a cell component of porcine islets induced by previous transplantation of E28 pig pancreatic primordia.

Cardiovascular complications are the leading cause of death in patients with chronic kidney disease (CKD). Traditional causes such as diabetes, smoking, aging and hypertension do not fully explain the high rate of morbidity from cardiovascular disease seen in these patients. The renin-angiotensin-aldosterone system (RAAS) regulates extracellular volume homeostasis, which contributes to blood pressure stability. Overactivity of this system is involved in the pathophysiology of cardio-renal disease. New evidence suggests that vitamin D receptor activators (VDRAs) have a suppressive effect on the RAAS; however, VDRAs also have anti-inflammatory and anti-fibrotic effects. We have demonstrated that paricalcitol, a VDRA, ameliorates left ventricular hypertrophy (LVH) in uremic rats by up-regulating the VDR, decreasing myocardial PCNA and also decreasing myocardial oxidative stress. Thus, paricalcitol can suppress the progression of LVH, myocardial and perivascular fibrosis and myocardial arterial vessel thickness presumably by up-regulating the VDR. Paricalcitol may prove to have a substantial beneficial effect on cardiac disease and its outcome in patients with CKD. Prospective randomized studies in CKD patients are necessary to confirm these results., (Copyright (c) 2010 Elsevier Ltd. All rights reserved.)

The formation of proximal nephron segments requires canonical Notch2 signaling, but other functions of Notch signaling during renal development are incompletely understood. Here, we report that proximal tubules forming with reduced Notch signaling, resulting from delayed conditional inactivation of Notch1 and/or Notch2, are prone to cyst formation and tubular epithelial stratification. Conditional inactivation of the DNA binding factor RBP-J, which mediates Notch signaling, also resulted in multiple congenital cysts arising from the proximal tubule. Moreover, a few stratified foci/microadenomas containing hyperproliferative cells, resembling precursors of papillary renal cell carcinoma, formed in these proximal tubules. Epithelial stratification correlated neither with reduced expression of the transcriptional regulator of ciliary proteins TCF2/HNF1beta nor with loss of apical-basal polarity. Instead, Notch signaling helped to restrict the orientation of epithelial mitotic spindles to a plane parallel to the basement membrane during nephron elongation. In the absence of Notch, random spindle orientation may explain the epithelial stratification and cyst formation. Furthermore, post hoc analysis of human class 1 papillary renal cell carcinoma revealed reduced Notch activity in these tumors, resulting from abundant expression of a potent inhibitor of canonical Notch signaling, KyoT3/FHL1B. In summary, these data suggest that canonical Notch signaling maintains the alignment of cell division in the proximal tubules during nephrogenesis and that perturbations in Notch signaling may lead to cystic renal disease and tumorigenesis.

The role of axial structures, especially the notochord, in metanephric kidney development has not been directly examined. Here, we showed that disruption of the notochord and floor plate by diphtheria toxin (DTA)-mediated cell ablation did not disrupt nephrogenesis, but resulted in kidney fusions, resembling horseshoe kidneys in humans. Axial disruptions led to more medially positioned metanephric mesenchyme (MM) in midgestation. However, neither axial disruption nor the ensuing positional shift of the MM affected the formation of nephrons and other structures within the kidney. Response to Shh signaling was greatly reduced in midline cell populations in the mutants. To further ascertain the molecular mechanism underlying these abnormalities, we specifically inactivated Shh in the notochord and floor plate. We found that depleting the axial source of Shh was sufficient to cause kidney fusion, even in the presence of the notochord. These results suggested that the notochord is dispensable for nephrogenesis but required for the correct positioning of the metanephric kidney. Axial Shh signal appears to be critical in conferring the effects of axial structures on kidney positioning along the mediolateral axis. These studies also provide insights into the pathogenesis of horseshoe kidneys and how congenital kidney defects can be caused by signals outside the renal primordia., (Copyright (c) 2010 Elsevier Inc. All rights reserved.)

Introduction: Laparoscopic partial nephrectomy has emerged as a standard of care for small renal masses. Nevertheless, there remains concern over the potential for irreversible insult to the kidney as a result of exposure to warm ischemia. We aim to investigate the utility of selective segmental arterial clamping as a means to reduce the potential for ischemic damage to a solitary kidney during laparoscopic partial nephrectomy utilizing a porcine model., Materials and Methods: A total of 20 domestic swine were randomized into four equal groups. Each subject underwent laparoscopic radical nephrectomy to create the condition of a solitary kidney. On the contralateral side, a laparoscopic lower pole partial nephrectomy was performed, employing either selective or nonselective vascular clamping for either 60 or 90 minutes. Postoperatively, clinical status and serial serum studies were closely monitored for 1 week., Results: There were no intraoperative complications. The 90-minute nonselective clamping produced devastating effects, resulting in rapid deterioration into florid renal failure within 72 hours. The 60-minute nonselective clamping group experienced modest but significant rises in both blood urea nitrogen and creatinine. Both 60- and 90-minute selective clamping groups performed well, with no significant rises in creatinine over a 7-day period, and no instances of renal failure., Conclusions: Selective arterial clamping is a safe and feasible means of vascular control during laparoscopic partial nephrectomy. In the porcine model, selective clamping appears to improve functional outcomes during prolonged periods of warm ischemic insult. Prospective evaluation of the technique in humans is necessary to determine if selective arterial control confers long-term functional benefits in patients with limited renal reserve.

In the K/BxN mouse model of rheumatoid arthritis, autoantibodies specific for glucose-6-phosphate isomerase (GPI) can transfer joint-specific inflammation to most strains of normal mice. Binding of GPI and autoantibody to the joint surface is a prerequisite for joint-specific inflammation. However, how GPI localizes to the joint remains unclear. We show that glycosaminoglycans (GAGs) are the high affinity (83 nm) joint receptors for GPI. The binding affinity and structural differences between mouse paw/ankle GAGs and elbows/knee GAGs correlated with the distal to proximal disease severity in these joints. We found that cartilage surface GPI binding was greatly reduced by either chondroitinase ABC or beta-glucuronidase treatment. We also identified several inhibitors that inhibit both GPI/GAG interaction and GPI enzymatic activities, which suggests that the GPI GAG-binding domain overlaps with the active site of GPI enzyme. Our studies raise the possibility that GAGs are the receptors for other autoantigens involved in joint-specific inflammatory responses.

Podocyte loss in adults leads to glomerulosclerosis. However, the impact of podocyte loss on glomerulogenesis and the development of the kidney as a whole has not been directly studied. Here, we used a podocyte-specific Cre transgene to direct the production of diphtheria toxin (DTA) inside podocytes during nephrogenesis. Affected podocytes underwent translational arrest and apoptosis, leading to oliguria, proteinuria, hematuria, interstitial hemorrhage, and perinatal death. Glomerular cell-cell interactions were disrupted, even before overt podocyte apoptosis. VEGF production by podocytes was greatly decreased, and this was associated with reduced endothelial fenestration and altered glomerular vascular architecture. In addition to these glomerular anomalies, embryonic podocyte ablation also led to structural changes and increased apoptosis in proximal tubules. The collecting ducts, however, only showed molecular changes that are likely an indirect effect of the greatly reduced urine flow. Although podocyte loss significantly impacted the development and maintenance of the vasculature both inside and outside the glomerulus, our results suggest that there is a lack of long-range signaling from deep-seated, mature glomeruli to the differentiating cells in the outer nephrogenic zone. This study illustrates the tight integration of various cell types in the developing kidney and shows that the impact of podocyte loss during development is much greater than that in adults. This study also shows the specificity and effectiveness of a genetically controlled podocyte ablation system in mice where the additional readily available tools can further expand its applications.

Background: Pediatric heart transplant recipients with a positive complement-dependent cytotoxic (CDC) donor-recipient crossmatch are at high risk for rejection. We sought to correlate the pattern of C3d and C4d myocardial capillary deposition and pericapillary macrophage infiltration, possible markers of antibody-mediated rejection, to clinical evidence of rejection in these patients., Methods: Were studied 15 pre-sensitized pediatric patients who had 21 rejection episodes, as defined by International Society for Heart and Lung Transplantation (ISHLT) biopsy Grade >or=2R and/or the development of abnormal left ventricular (LV) function at >1 week after transplant. Archived paraffin-embedded endomyocardial biopsies (n = 74) from these patients were subjected to immunoperoxidase staining for C3d, C4d and CD68 in duplicate. Positive and negative controls were included for each assay., Results: C3d deposition was present in 74 of 74 (100%) specimens. C4d deposition was present in 6 of 74 (8%) biopsies from 4 patients. Biopsies with C4d deposition had ISHLT Grade >or=2R cellular infiltration in 5 of 6 specimens. Pericapillary macrophage infiltration, defined as positive staining for CD68, was found in 34 of 74 (46%) biopsies, and was associated with ISHLT Grade >or=2R in 10 of 34 (29%)., Conclusions: C3d deposition was universally present after heart transplantation with a CDC(+) donor/recipient crossmatch. C4d deposition and pericapillary macrophage infiltration were found with some, but not all, episodes of rejection. Further study is needed to understand the significance of the presence of complement fragments and pericapillary macrophage infiltration in these endomyocardial biopsies.

Molecular and genetic studies in the last 2 decades have shed new light on the understanding of congenital and infantile nephrotic syndrome (NS). Glomerular pathology may appear as minimal change disease, focal segmental glomerulosclerosis, or diffuse mesangial sclerosis, glomerular diseases now recognized as podocyte injuries and in part caused by altered podocyte genes. Even though genetic mutations are not implicated in all infants with NS, the study of familial disease and congenital NS reveals that proteinuria is in many patients due to specific gene mutations. The most common mutations are in 4 genes, 3 of which are podocyte genes: NPHS1 (Finnish nephropathy), NPHS2 (podocin-induced focal segmental glomerulosclerosis), WT1 (diffuse mesangial sclerosis), and LAMB2 (Pierson syndrome). Furthermore, these studies have improved our understanding of steroid-resistant NS in older children, particularly girls, in whom proteinuria may be due to WT1 mutations. Availability of molecular genetic testing and antibodies to specific gene products are closing the gap between histopathology of pediatric glomerular disease and molecular genetic diagnosis. Recognition of NS variants, which may be reversible (eg, mitochondrial mutations, viral disease), is important. This review discusses the most common entities and the differential diagnosis of pediatric NS from the pathologist's point of view, with an emphasis on congenital (<3 months) and infantile (3 months to 1 year) NS in light of molecular and genetic studies.

Background: Autosomal dominant polycystic kidney disease (ADPKD) is a common disease with several known extrarenal manifestations, although no known pulmonary features. The formation of renal cysts in ADPKD has been attributed to dysfunction of primary cilia and the primary cilia-related proteins polycystin-1 (in 85% of cases) and polycystin-2 in renal epithelial cells. The goals of this study were to characterize the normal expression of polycystin-1 in the motile cilia of airway epithelial cells and to evaluate lung structure in ADPKD patients., Methods: Airway epithelium from non-ADPKD patients was immunostained to localize polycystin-1 expression, and lung tissue from ADPKD patients was examined for pathologic changes. CT scans from ADPKD patients (n = 95) and a control group of non-ADPKD chronic kidney disease patients (n = 95) were retrospectively reviewed for the presence of bronchiectasis using defined criteria., Results: Immunostaining revealed polycystin-1 expression in the motile cilia of non-ADPKD airway epithelial cells. Lung tissue from one of five available ADPKD patient autopsies revealed histologic changes of bronchiectasis. Review of CT scans revealed a threefold-increased prevalence of bronchiectasis in the ADPKD group compared to the control group (37% vs 13%, p = 0.002)., Conclusions: ADPKD patients demonstrate an increased prevalence of radiographic bronchiectasis, a previously unrecognized manifestation of the disease. This association suggests that patients with primary cilia-associated diseases may be at risk for airway disease.

Light-chain deposition disease (LCDD) of the kidney is defined as deposition of monotypic light chains (LC) within glomerular (GBM) and tubular (TBM) basement membranes. The morphologic features of pure renal LCDD have been presented only in case reports or small series. The aim of this study was to perform a comprehensive evaluation of the light (LM), immunofluorescence (IF), and electron microscopic (EM) features of pure renal LCDD in a large series of biopsies. Out of 46 cases assembled, 42 had multiple myeloma, 2 had monoclonal gammopathy of unknown significance, and in 2 patients no lymphoproliferative disease was identified. The most common LM lesion of LCDD, nodular glomerulosclerosis, was present in only 14 (30%) cases. GBM and/or TBM thickening was found in 3 (6%), mild to moderate mesangial matrix increase in 12 (23%), and unremarkable glomeruli and tubules were seen in 15 (32%) cases. Forty-two had IF and 40 (92%) showed characteristic linear LC immunoreactivity (24 kappa, 16 lambda) along GBM and/or TBM. Among 39 cases in which IF and EM was available, 25 (64%) were positive by both. Two (6%) were negative by IF, but had deposits by EM. In 12 (30%) with immunoreactivity to LC (4 kappa, 8 lambda), no deposits were identified ultrastructurally. This study shows heterogeneous LM lesions in pure LCDD cases. LM alone may be suspicious but not diagnostic of LCDD. Immunofluorescence is more sensitive than EM for detection of LC for the definitive diagnosis of LCDD. This study supports the importance of utilizing kappa and lambda stains in the routine IF panel for diagnosis of LCDD.

Epstein-Barr virus (EBV) hepatitis is an uncommon, almost always self-limited disease in immunocompetent patients. Accurate diagnosis is imperative for appropriate clinical management. The aim of this study was to compare 3 available methods for EBV detection on routinely processed liver biopsies to determine their effectiveness in aiding the diagnosis. In 6 of the 8 cases of EBV hepatitis, EBV was detected by both polymerase chain reaction (PCR) for EBV DNA and in situ hybridization (ISH) for EBV early RNA (EBER). EBV was detected by PCR only in 1 case, and by ISH only in another. EBER-positive cells detected by ISH were typically few and individually distributed in the portal tracts and sinusoids. Immunohistochemical staining for EBV latent membrane proteins was negative in all 8 cases. Five cases of chronic hepatitis C used as negative controls were negative by all 3 detection methods for EBV. These data indicate that PCR and ISH are equally sensitive in detecting EBV in routinely processed liver biopsies. The ready implementation of ISH in pathology laboratories makes it a useful ancillary tool in confirming the diagnosis of EBV hepatitis in equivocal cases. However, EBER-positive cells can be sparse and easily overlooked. Immunohistochemistry for EBV latent membrane proteins apparently has no utility in the diagnosis of EBV hepatitis.

Congenital renal dysplasia (RD) is a major cause of renal failure in the pediatric population. Although molecular and genetic aspects of RD have been studied in animal models, limited studies have been done in human RD primarily due to lack of available material. To identify novel genes that are associated with RD and normal kidney development, we performed microarray analysis on total RNA extracted from age-matched fetal kidneys of normal and RD patients. In midgestational RD kidneys, we found 180 upregulated and 104 downregulated transcripts compared with normal kidneys. Among the increased transcripts in the dysplastic kidneys were matrix-degrading enzymes (MMP7, MMP19, TIMP1), inflammation- and immunity-related genes, and growth factors. Expression of genes known to be essential for normal kidney development, such as WT1, BMP7, renin, angiotensin receptor 2 (AGTR2), SAL-like 1 (SALL1) and glypican 3 (GPC3), were decreased in dysplastic kidneys. Expression of selected gene products (BMP7, renin, and MMP7) was further confirmed in parallel sections and in several normal and human dysplastic kidneys, supporting the role of these genes as putative RD biomarkers. These results are among the first to reveal disrupted expression profiles during gestation in human RD patients.

Monotherapy with angiotensin-converting enzyme inhibitors has been shown to be beneficial in suppressing the progression of experimentally induced kidney diseases. Whether such therapy provides additional benefits when combined with vitamin D or an analog of vitamin D has not been established. Rats were made uremic by 5/6 nephrectomy and treated as follows: Uremic + vehicle (UC), uremic + enalapril (30 mg/L in drinking water; E), uremic + paricalcitol (19-nor; 0.8 microg/kg, three times a week), and uremic + enalapril + paricalcitol (E + 19-nor). A group of normal rats served as control (NC). BP was significantly elevated in the UC and 19-nor groups compared with the NC group but was indistinguishable from normal in the E and E + 19-nor groups. The decrease in creatinine clearance and the increase in the excretion of urinary protein that were observed in the UC group were ameliorated by the use of E alone or by E + 19-nor (P < 0.05 versus UC). The glomerulosclerotic index was significantly decreased in both the 19-nor (P < 0.01) and E + 19-nor groups (P < 0.01) compared with the UC group. Tubulointerstitial volume was significantly decreased in both the E (P < 0.05) and E + 19-nor groups (P < 0.01) compared with the UC group. Both macrophage infiltration (ED-1-positive cells) and production of the chemokine monocyte chemoattractant protein-1 were significantly blunted in E + 19-nor compared with E group. TGF-beta1 mRNA and protein expression were increased in the UC group (mRNA: 23.7-fold; protein: 29.1-fold versus NC). These increases were significantly blunted in the 19-nor group (mRNA: 7.1-fold; protein: 8.0-fold versus NC) and virtually normalized in the E + 19-nor group (protein: 0.8-fold versus NC). Phosphorylation of Smad2 was also elevated in the UC group (7.6-fold versus NC) but less so in the 19-nor-treated rats (5.5-fold versus NC). When rats were treated with E + 19-nor, the phosphorylation of Smad2 was normal (1.1-fold versus NC). Thus, 19-nor can suppress the progression of renal insufficiency via mediation of the TGF-beta signaling pathway, and this effect is amplified when BP is controlled via renin-angiotensin system blockade.

There are few data on morphology of light-chain deposition disease (LCDD) of kidney with coexistent light-chain cast nephropathy (LCCN). Here, the authors report the morphology in 23 cases of LCDD and LCCN. They retrospectively evaluated 23 renal biopsies with light (LM), immunofluorescence (IF), and electron microscopy (EM). Twenty-one patients had myeloma, 1 had a monoclonal gammopathy, and in 1 no illness was found. Nodular glomerulosclerosis, the LM lesion suggestive of LCDD, was noted in only 3 of 23 cases. Glomeruli were unremarkable in 16 (69%) cases. The diagnostic casts of LCCN were seen in all biopsies. Linear light chain (LC) immunoreactivity was observed in 23 (100%) cases (18 kappa, 5 lambda); GBM + TBM in 13, TBM only in 7, GBM only in 1, TBM and interstitium in 1, GBM, TBM and mesangium in 1. Casts were positive with same LC in all cases (100%). Fifteen cases (65%) showed granular electron-dense deposits; GBM only in 5, TBM only in 5, GBM and TBM in 4, mesangium in 1. In 8 patients without EM deposits, the diagnosis of LCDD was rendered by IF. Fifteen (65%) had deposits detectable by IF and EM, 8 (37%) had deposits with IF only. LCCN dominated the LM findings in all patients. There were minimal or no glomerular changes by LM. This study shows the lack of characteristic LM findings of LCDD in combined cases of LCDD and LCCN and emphasizes the difficulty for-definitive diagnosis-without IF and EM.

Many molecules have been implicated in kidney development, often based on experimental animal studies with organ cultures and cell lines. There are very few studies, however, that have directly addressed equivalent living human embryonic tissues. We generated renal mesenchymal cell lines from normal human metanephroi and used a microarray strategy to define changes in gene expression after stimulation with growth factors which enhance nephrogenesis in rodents. Changes were observed in 1) genes modulating diverse general cellular processes, such as matrix metalloproteinase 1 and stanniocalcin 1; 2) genes previously implicated in organogenesis e.g., sprouty 4 and midline 1; and 3) genes involved in blood vessel growth, including angiopoietin 1 and 4. Expression of these same genes was subsequently confirmed in vivo. Our novel data have identified several previously unhighlighted genes that may be implicated in differentiation programs within early human nephrogenesis.

Aberrant immune responses underwrite lupus glomerulonephritis and may contribute to glomerular cell proliferation and inflammation. Recent studies provide evidence that apoptotic immune cells may initiate immune events leading to tissue damage. Nucleosomes within apoptotic particles are recognized by B cells and other antigen presenting cells and represent the most likely inciting antigen for autoantibody production. Some of these antibodies are nephritogenic depending on fine structural composition and antigen recognition in the circulation or on renal cells. Deficient complement components contribute to reduced clearance of circulating and native kidney apoptotic cells. This review summarizes current concepts in lupus immune pathogenesis and attempts to bridge immunology to pathology of lupus glomerulonephritis.

Pancreas or pancreatic islet transplantation in humans is limited by organ availability, and success of the latter is negatively impacted upon by tissue loss post-transplantation and limited potential for expansion of beta cells. A way to overcome the supply and expansion problems is to xenotransplant embryonic tissue. Previously, we have shown that beta cells originating from embryonic day (E) 28 (E28) pig pancreatic primordia transplanted into the mesentery of streptozotocin-diabetic (type 1) Lewis rats engraft without the need for host immune-suppression and normalize glucose tolerance. Here we show long-term engraftment of pig beta cells within liver, pancreas and mesenteric lymph nodes post-transplantation of E28 pig pancreatic primordia into diabetic ZDF rats, a model for type 2 diabetes. Porcine insulin is present in circulation after an oral glucose load. Glucose tolerance is normalized in transplanted ZDF hosts and insulin sensitivity restored in formerly diabetic ZDF males. Release of porcine insulin in vitro from tissue originating in transplanted rats occurs within 1 min of glucose stimulation characteristic of first-phase secretion from beta cells. Of potential importance for application of this transplantation technology to treatment of type 2 diabetes in humans and confirmatory of our previous findings in Lewis rats, no host immunosuppression is required for engraftment of E28 pig pancreatic primordia.

Background: The loss of renal function in chronic kidney disease (CKD) patients leads to a variety of metabolic disturbances that promote the development of secondary hyperparathyroidism (SH) and bone disease. One of these alterations, hyperphosphatemia, is a persistent problem in patients with CKD and is an important factor in the development and severity of SH as well as coronary artery and cardiac valve calcification. To help control serum phosphorus (P), phosphate binders are used to minimize intestinal absorption of P in these patients. Since the use of aluminum- and calcium-based phosphate binders can result in severe side effects, other phosphate binders have been proposed. One of these is lanthanum (La) carbonate., Methods: Since there is some controversy as to the degree La is absorbed by the intestine, whether it is deposited in tissues, and what effect its prolonged use would have in patients with chronic renal failure, we studied normal and uremic rats fed a control diet or a diet with La carbonate (1.5% elemental La) for 45, 90, or 110 days., Results: As expected, plasma creatinine increased after the induction of uremia and continued to increase with time. At 45 and 90 days, dietary La produced a reduction in plasma P in normal rats (N + La) [45 days: 3.15 +/- 0.35 vs. normal control (NC) 4.41 +/- 0.15 mg/dL, P < 0.01; 90 days: 3.20 +/- 0.30 vs. 4.09 +/- 0.15 mg/dL, P < 0.05], but not at 110 days. Plasma P was initially lower (45 days) in both groups of La-treated rats (U + La: 3.47 +/- 0.28 vs. UC: 4.91 +/- 0.27 mg/dL, P < 0.01), but was not at 90 and 110 days. Whole blood La content was not increased in rats fed the La diet and is, therefore, not a good indicator of the La content of tissue. La was increased in kidney, femur, and especially liver in normal and uremic rats fed the La diet. Uremia markedly enhanced tissue accumulation of La (liver, 110 days: N + La: 849 +/- 152 vs. U + La: 2676 +/- 479 ng/g wet wt, P < 0.01), which increased in a time-dependent manner. The increase in La in the liver of normal rats was 44-fold compared to control and 98-fold in the liver of uremic rats compared to uremic control., Conclusion: La accumulates in tissues, most strikingly in the liver, and renal failure accelerates the accumulation. While this was a relatively short-term study, La accumulation increased in a time-dependent manner. The effect of long-term La treatment on patients with chronic renal insufficiency needs to be evaluated.

Embryonic day (E) 28 (E28) pig pancreatic anlagen (PPA) transplanted into the omentum of non-immunosuppressed steptozotocin-diabetic Lewis rats normalize levels of circulating glucose within 2-4 weeks. Following transplantation formerly diabetic rats have porcine insulin, but no rat insulin detectable in circulation. At 3 weeks post-E28 PPA transplantation, bits of insulin-positive tissue are observed amidst host omental fat, but by 6 weeks only individual alpha and beta cells remain. In contrast, E35 PPA transplantation does not normalize glucose and 6 weeks post-implantation of E35 PPA transplanted tissue is rejected. In contrast to E28 PPA, no trace of implanted renal tissue is detectable post implantation of E28 pig renal anlagen (PRA) in non-immunosuppressed non-diabetic rats or in streptozocin-diabetic rats previously transplanted with E28 PPA. In the latter, normoglycemia is maintained post-PRA transplantation. We conclude that normalization of glucose levels following transplantation of PPA into non-immunosuppressed Lewis rats depends on obtaining the anlagen before E35 and that prior successful engraftment of E28 PPA as reflected by normalization of glucose, does not permit successful engraftment of E28 PRA.

Background: Hypereosinophilic syndrome (HES), defined as persistent marked eosinophilia of unknown origin complicated by end organ damage, is thought to be due to activation of eosinophils and release of substances that are toxic to various cells and tissues. An association between hypereosinophilia and kidney damage is not well documented., Methods: We describe two patients with the HES, acute renal failure, and thrombocytopenic hemolytic anemia. Renal biopsy pathology and immunohistochemistry for activated eosinophils were performed., Results: Renal biopsy revealed glomerular thrombosis, proliferative arteritis, and glomerular and tubulointerstitial eosinophil infiltrates. Ultrastructurally, subendothelial glomerular fibrin deposits and numerous luminal platelets characteristic of thrombotic microangiopathy (TMA) were present. Abundant degranulated eosinophils were localized in glomeruli and the interstitium. Immunofluorescence with specific antibody to eosinophil granule major basic protein (MBP) showed striking extracellular MBP deposition within glomeruli, a marker of eosinophil degranulation. Both patients developed TMA. High-dose glucocorticoids achieved sustained decrease of blood eosinophils and improvement of renal function., Conclusion: To our knowledge these are the first documented cases of TMA associated with HES. We propose that products released from degranulated eosinophils caused endothelial injury and microvascular thrombosis. Recognition of this serious renal complication associated with blood eosinophilia should prompt early diagnosis and treatment.

Background: Hemolytic uremic syndrome (HUS) is a rare coagulation disorder characterized by microangiopathic hemolytic anemia, thrombocytopenia and acute uremia. Reports have described this fatal syndrome in association with cytotoxic agents. To our knowledge, no case reports of HUS in ovarian cancer patients receiving treatment with combination gemcitabine and pegylated liposomal doxorubicin (PLD) have been reported., Case Reports: Three patients with recurrent ovarian carcinoma each developed profound hypertension and peripheral edema while receiving combination gemcitabine and PLD. The first patient had rapid hemolysis, thrombocytopenia, renal failure and respiratory distress. The other patients experienced slowly progressive renal failure and mild hematologic abnormalities. Two of the three patients had favorable outcomes., Conclusion: The reported incidence of gemcitabine-induced HUS is rare. Clinicians should suspect HUS if blood pressure elevation or peripheral edema develop.

Antiphospholipid syndrome (APS) is an autoimmune disease. Less than 1% of patients with APS present with life-threatening catastrophic APS (CAPS). We report here a case of CAPS in a young girl with cardiac, gastrointestinal and renal involvement. Although the management was complicated, the outcome was better than expected. We suggest that CAPS be included in the differential diagnosis of acute renal failure in children with multi-organ involvement and prolonged phospholipid-dependent coagulation time and promptly treated with immunomodulating agents and anticoagulants.

Background: Matrilysin, a secreted matrix metalloproteinase and target gene of Wnt signaling, functions in epithelial repair and host defense, but no role in renal injury has been described., Methods: Matrilysin expression was assessed in human kidney specimens by immunohistochemistry, and in experimental renal injury in mice by immunohistochemistry, Northern blotting, and RNase protection assays (RPA). A relationship to Wnt4, which is also induced in renal injury, was determined by RPA and in situ hybridization., Results: Matrilysin was not detected in the normal human renal tubular epithelium by immunohistochemistry. However, prominent staining was detected in sections from autosomal-dominant polycystic kidney disease in the cyst lining epithelium, atrophic tubules, and cyst micropolyps, and from hydronephrosis in dilated and atrophic tubules. Matrilysin expression was also induced by acute folic acid nephropathy and unilateral ureteral obstruction (UUO) in the mouse, and expression increased as acute injury progressed to tubulointerstitial fibrosis. Matrilysin staining was primarily localized to epithelium of distal tubule/collecting duct origin in both human and murine renal disease. Wnt signaling can induce matrilysin expression, and we found that the pattern of matrilysin expression during progression of renal fibrosis in the mouse after UUO or folic acid nephropathy, and in the jck model of murine polycystic kidney disease, closely paralleled that of Wnt4., Conclusion: These observations suggest that matrilysin may have a role in renal tubular injury and progression of tubulointerstitial fibrosis, and that Wnt4 may regulate matrilysin expression in the kidney.

Congenital renal arteriovenous malformations (AVM) are very rare abnormal communications between arteries and veins. These lesions are almost always unilateral, predominantly in the right kidney, and usually asymptomatic until adulthood. We present a unique case of bilateral renal AVM in a 10-year-old white boy who developed renal failure requiring renal transplantation. Microscopic sections of an atrophic right and a slightly larger left kidney with tortuous and dilated hilar vessels showed elaborate derangement of arteries and veins insinuating between lobules. Glomeruli were diffusely enlarged with increased number of capillary loops. Glomerular basement membrane reduplication and fibrinoid necrosis was focally noted. Electron microscopy demonstrated absence of electron-dense deposits or mesangial interposition excluding membranoproliferative glomerulonephritis. We believe that the glomerular lesions are secondary to congenital renal arteriovenous malformation. To our knowledge, bilateral arteriovenous malformation in infancy is not previously described.

Postradiation sarcomas are rare, and the most commonly reported ones are malignant fibrous histiocytoma, osteosarcoma, angiosarcoma, fibrosarcoma, malignant peripheral nerve sheath tumor, and high-grade pleomorphic sarcoma, not otherwise specified. There are a few case reports of postradiation rhabdomyosarcomas following treatment of retinoblastoma, breast cancer, endometrial adenocarcinoma, and Hodgkin's disease. Secondary neoplasms following radiation and surgical treatment of rectal adenocarcinomas have not been reported in the English literature. We report a case of pleomorphic rhabdomyosarcoma of the anterior abdominal wall following treatment of rectal carcinoma, and we review the literature.

Background: In chronic renal failure (CRF), hyperphosphatemia and an elevated calcium-phosphate product are associated with vascular calcification and increased cardiovascular morbidity and mortality. Previous data have demonstrated that 3-month treatment of uremic rats with sevelamer was associated with less nephrocalcinosis compared to calcium carbonate (CaCO3), despite similar control of serum phosphorus, calcium-phosphorus product (Ca x P product), and secondary hyperparathyroidism. There was no evidence of aortic calcification after 3 months of uremia (J Am Soc Nephrol 13:2299-2308, 2002). The present studies explore the influence of sevelamer and CaCO3 on cardiovascular and kidney calcifications in long-term experimental uremia over 6 months., Methods: Normal and 5/6 nephrectomized rats (U) were fed a high phosphorus (HP) diet for 6 months. Two phosphate binders, CaCO3 and sevelamer, were administered and their influence on hyperphosphatemia, secondary hyperparathyroidism, kidney/myocardial/aortic calcification, and renal function was compared., Results: All uremic rats began the study with the same degree of renal failure. Sevelamer was as effective as CaCO3 in reducing serum phosphorus, Ca x P product, and attenuating secondary hyperparathyroidism. Despite similar serum cholesterol levels, rats in the U-HP + sevelamer group had markedly lower calcium deposition in the myocardium and aorta (myocardium, 72 +/- 4 microg/g wet tissue; aorta, 736 +/- 156 microg/g wet tissue) compared to rats in either the U-HP + CaCO3 group (myocardium, 179 +/- 48, P < 0.05; aorta, 1308 +/- 343, P < 0.05) or the U-HP group (myocardium, 98 +/- 10, NS; aorta, 2150 +/- 447, P < 0.05). Dual immunohistochemical analysis for calcium and endothelial cell markers demonstrated that myocardial calcium deposition was intravascular within capillaries. Furthermore, calcium deposition in the kidney of uremic rats treated with sevelamer (582 +/- 111 microg/g wet tissue) was lower than that found in uremic rats treated with CaCO3 (1196 +/- 180 microg/g wet tissue). Sevelamer-treated rats had less deterioration in renal function with an associated lower serum creatinine, higher creatinine clearance, and less proteinuria. There was no difference in overall mortality between the three experimental groups., Conclusion: In long-term experimental CRF, in addition to controlling serum phosphorus and secondary hyperparathyroidism as efficiently as CaCO3, treatment with the phosphate-binder sevelamer attenuates vascular and kidney calcification.

To determine whether embryonic pancreatic anlagen transplanted to an intraperitoneal site in adult hosts grow, differentiate, and function, we implanted pancreas from embryonic day (E) 12.5 Lewis rat embryos into the omentum of adult Lewis rats or C57Bl/6J mice. E12.5 pancreatic anlagen were relatively undifferentiated except for the presence of condensing tubuloacinar cords. By 2 weeks after implantation, pancreatic anlagen transplanted into rats had enlarged and differentiated such that islets of Langerhans that stained positive for insulin could be delineated. Continued differentiation, as reflected by the presence of "ductal" islets connected to the duct epithelium, was observed at 6 weeks after implantation. At 15 weeks after implantation, "mature" islets had separated from the ducts. Electron microscopy showed eccentric dense bodies within clear vacuoles consistent with insulin granules. Little or no acinar tissue was present in developed anlagen. Within 5 weeks of pancreatic anlagen transplantation, levels of glucose in rats rendered diabetic by an injection of streptozotocin were normalized compared with levels in nontransplanted diabetic controls. Rat pancreatic anlagen underwent growth and development in the peritoneum of C57Bl/61 mice that received costimulatory blocking agents but not in the absence of costimulatory blockade. We concluded that whole E12.5 pancreatic anlagen undergo growth, differentiation, and function after intraperitoneal placement. Implantation of the embryonic pancreas, a "cellular" transplant, is followed by selective differentiation of islet compared with acinar components.

Background: Bone morphogenic protein-7 (BMP-7), an essential developmental renal morphogen, is a secreted differentiation factor of the adult collecting duct. It activates receptors in the collecting duct, distal nephron, proximal tubule, and glomerulus. BMP-7 is therapeutic in tubulointerstitial nephritis raising the question of broader efficacy in chronic kidney disease (CKD)., Methods: Diabetes was induced in 200 g rats by a single dose of streptozotocin. After 16 weeks, glomerular hypertrophy and proteinuria were established, and therapy with BMP-7 (10, 30, or 100 microg/kg intravenously twice a week), enalapril (20 mg/kg), or vehicle was begun and continued until 32 weeks. Kidney weight, glomerular filtration rate (GFR), urine albumin excretion, blood pressure, pathology, and BMP-7 expression were measured., Results: Diabetic vehicle-treated rats developed renal insufficiency by 32 weeks (GFR, 0.34 +/- 0.02 mL/min/100 g body weight vs. 0.55 +/- 0.02 in normal). In the diabetic BMP-7 high-dose-treated rats, GFR was preserved (0.70 +/- 0.08, P < 0.01 vs. vehicle), and higher than diabetic enalapril-treated rats (0.58 +/- 0.06). Kidney weights of vehicle-treated animals were not affected, but were reduced in all of the treatment groups (P < 0.001). Proteinuria was reversed to normal by BMP-7 in a dose-dependent manner. The reduction in proteinuria by the intermediate dose of BMP-7 was similar to the effect of enalapril therapy. Glomerular area and interstitial volume were significantly decreased in the BMP-7 and enalapril-treated animals. Glomerular sclerosis was prevented by BMP-7 therapy more effectively than by enalapril. Enalapril controlled hypertension throughout the course of therapy while BMP-7 did not affect blood pressure until the final 4 weeks of therapy. Diabetic vehicle-treated rats lost BMP-7 expression in the kidney. BMP-7 and enalapril therapy restored BMP-7 expression at high levels., Conclusion: BMP-7 partially reversed diabetic-induced kidney hypertrophy, restoring GFR, urine albumin excretion, and glomerular histology toward normal. Restoration of BMP-7 expression was associated with a successful repair reaction and a reversal of the ill-fated injury response.

This study assessed the incidence of cytomegalovirus (CMV) disease and associated outcomes after oral ganciclovir prophylaxis in renal transplantation. A retrospective analysis was performed of all adult renal transplant recipients at a single transplant center transplanted between August 16, 1996, and December 31, 2000. CMV disease prophylaxis included ganciclovir 1000 mg orally thrice daily prescribed for 90 d in D-/R+ cases and 180 d in D+/R- and D+/R+ cases. Forty (9.1%) of 470 patients studied were diagnosed with CMV disease, which varied significantly by CMV serostatus and number of HLA-DR matches. The highest incidence of disease, 26.2%, was in D+/R- patients with zero HLA-DR matches. Five-year graft survival was 56.8% with CMV disease compared with 79.1% without (P < 0.001). Five-year graft survival with CMV disease was 75.9% with one or two HLA-DR matches versus 16.2% with zero HLA-DR matches (P < 0.001). CMV remains an important factor in long-term graft survival after oral ganciclovir prophylaxis. However, we have observed that the adverse impact of CMV disease on graft survival is apparent only in patients with zero HLA-DR matches. These results call for the development of new CMV disease prophylaxis and treatment strategies in patients with zero HLA-DR matches. In addition, organ allocation policies discouraging combining CMV-seropositive donors and zero HLA-DR matches may be worth consideration.

Congenital obstructive nephropathy is a common disease affecting fetuses and young children. The kidney shows profound morphologic and functional changes. The physiologic developmental kidney program is disturbed in the most advanced cases, arguing for altered temporal/spatial expression of genes which control normal nephrogenesis. Major regulators of mesenchymal-epithelial transformation and collecting duct and tubular development such as WT1 and Sall1 are decreased with obstruction. Additional candidate genes include GDNF/cRET, LIM1 and Pax2. Excessive apoptosis is an undisputed mechanism in these processes, mediated by decreased expression of apoptosis inhibiting genes (Bcl-2, HGF, IGF, BMP7), and overexpression of pro-apoptotic genes like Bax and TGF-beta. Renin and AT2R implicated in renal vascular development are decreased. Numerous extracellular matrix genes including Matrilysin are altered. The emerging theories of the biology of congenital obstructive nephropathy suggest new targets for therapeutic interventions with profound implications for these children., (Copyright 2003 S. Karger AG, Basel)

Purpose: Some patients with multicystic dysplasia experience hypertension in infancy which can be clinically improved with simple nephrectomy. Little is known of the role of renin in multicystic dysplasia and therefore, we studied renin expression in nonhypertensive multicystic dysplasia and compared it with hypertensive multicystic dysplasia. Additionally, global gene transcript profiles were studied in nonhypertensive multicystic dysplasia., Materials and Methods: Tissue from 12 patients with multicystic dysplasia without hypertension and 2 patients with hypertensive multicystic dysplasia were compared to normal metanephric mid-term and neonatal kidneys. Renin expression was studied by immunohistochemistry. CD-68, a marker for macrophages, was applied to slides previously stained with renin. GeneChip (Affymetrix, Southern Oaks, California) microarray analysis was performed using total RNA from 2 nonhypertensive multicystic dysplastic kidneys and normal newborn kidney as control., Results: Strong renin staining was present in arteries and arterioles in normal early metanephric kidneys and concentrated in juxtaglomerular cells in neonatal kidneys. Renin was variably decreased in arterioles in multicystic dysplasia and was ectopically expressed in interstitial cells. Renin positive interstitial cells co-expressed CD-68 antigen identifying these cells as macrophages. Ectopic renin production was more pronounced in hypertensive multicystic dysplasia. GeneChip hybridization showed a 60 to 200-fold decrease in expression of renin transcript in multicystic dysplasia relative to normal kidney, concordant with immunohistochemical results. Altered expression of several other candidate transcripts was also identified., Conclusions: Dramatic renin decrease in multicystic dysplasia suggests that it may participate in the development of dysplastic vessels. Pronounced ectopic renin expression by macrophages in multicystic dysplasia associated with hypertension may be linked to hypertension in multicystic dysplasia. Several other candidate genes whose altered expression may be associated with the pathophysiology of multicystic dysplasia provide intriguing molecular targets for future study.

The control of serum phosphorus (P) and calcium-phosphate (Ca x P) product is critical to the prevention of ectopic calcification in chronic renal failure (CRF). Whereas calcium (Ca) salts, the most commonly used phosphate binders, markedly increase serum Ca and positive Ca balance, the new calcium- and aluminum-free phosphate binder, sevelamer hydrochloride (RenaGel), reduces serum P without altering serum Ca in hemodialysis patients. Using an experimental model of CRF, these studies compare sevelamer and calcium carbonate (CaCO(3)) in the control of serum P, secondary hyperparathyroidism (SH), and ectopic calcifications. 5/6 nephrectomized rats underwent one of the following treatments for 3 mo: uremic + high-P diet (U-HP); UHP + 3% CaCO(3) (U-HP+C); UHP + 3% sevelamer (U-HP+S). Sevelamer treatment controlled serum P independent of increases in serum Ca, thus reducing serum Ca x P product and further deterioration of renal function, as indicated by the highest creatinine clearances. Sevelamer was as effective as CaCO(3) in the control of high-P-induced SH, as shown by similar serum PTH levels, parathyroid (PT) gland weight, and markers of PT hyperplasia. Also, both P binders elicited similar efficacy in reducing the myocardial and hepatic calcifications induced by uremia. However, sevelamer caused a dramatic reduction of renal Ca deposition (29.8 +/- 8.6 micro g/g wet tissue) compared with both U-HP (175.5 +/- 45.7 micro g/g wet tissue, P < 0.01) and the U-HP+C (58.9 +/- 13.7 micro g/g wet tissue, P < 0.04). Histochemical analyses using Von Kossa and Alizarin red S staining of kidney sections confirmed these findings. The high number of foci of calcification in the kidney of uremic controls (108 +/- 25) was reduced to 33.0 +/- 11.3 by CaCO(3) and decreased even further with sevelamer (16.4 +/- 8.9, P < 0.02 versus CaCO(3)). Importantly, the degree of tubulointerstitial fibrosis was also markedly lower in U-HP+S (5%) compared with either U-HP+C (30%) or U-HP (50%). It is concluded that in experimental CRF in rats, despite a similar control of serum P and SH, sevelamer is more effective than CaCO(3) in preventing renal Ca deposition and tubulointerstitial fibrosis, including better preservation of renal function. These findings cannot be extrapolated to human disease, and further studies in patients are necessary to determine the benefits of either P binder.

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.

Diabetic glomerulopathy is a well-recognized consequence of both type I and type II diabetes. Occasionally, pathologic diagnosis may be challenging for the pathologist. These circumstances include atypical light microscopy or diabetic change with a second superimposed glomerulopathy (dual disease). We have compiled a selection of 12 renal biopsies from diabetic patients that show either an unusual pattern of nephropathy or "dual disease," as well as 2 cases in which the patient had no history of diabetes but had renal biopsies exhibiting changes consistent with diabetic nephropathy. The salient diagnostic features are discussed. To accurately assess these biopsies, immunofluorescence and electron microscopy become essential, and a broadened differential diagnosis must be considered.

Recent genetic studies indicate that Alport syndrome and thin glomerular basement membrane disease (TMD) may both be due to COL4A3, COL4A4, and COL4A5 mutations, but there is continuing uncertainty concerning the diagnosis and management of patients without classic family history and symptoms. We examined kidney pathology and collagen alpha 3 to alpha 5(IV) expression in a series of 16 patients who presented with overlapping signs between TMD and Alport nephritis. All patients presented with hematuria, and 11 also had proteinuria, of whom 5 had nephrotic range proteinuria. Only 9 had family history of hematuria. In 9 of 16 (60%) we found premature glomerulosclerosis in the renal biopsies. Three of 16 had predominantly wide, lamellated glomerullar basement membranes (GBM), and in these, alpha 3 to alpha 5(IV) was absent in glomeruli or skin, diagnostic of Alport nephritis. One patient (12) had a very wide GBM with intramembranous lucencies but no lamellation. Skin biopsy was collagen alpha 5(IV) positive. Nine of 16 patients had predominantly thin GBM by electron microscopy, and 3 had thin and slightly lamellated GBM. Collagen alpha 3 to alpha 5(IV) expression in the kidney or skin biopsy was present in all of the latter 12 patients. Three patients had end-stage renal disease, 7 patients had hypertension, and 1 patient had chronic renal failure. We found that of the 16 patients with presumed TMD, 3 had X-linked Alport nephritis, 2 appeared to have autosomal recessive Alport nephritis, and the remaining patients had either an Alport or a TMD variant. The latter had histologic and/or clinical evidence of progressive renal disease, including premature glomerulosclerosis, hypertension, sustained proteinuria, and either thin or slight GBM lamellation focally, and preserved alpha 3 to alpha 5(IV) expression. These patients have a TMD variant, but an Alport variant with a potentially transmissible severe defect different from benign hematuria cannot be excluded., (Copyright 2002, Elsevier Science (USA). All rights reserved.)

To delineate the roles of O(2) and vascular endothelial growth factor (VEGF) in the process of angiogenesis from the embryonic aorta, we cultured mouse embryonic aorta explants (thoracic level to lateral vessels supplying the mesonephros and metanephros) in a three-dimensional type I collagen gel matrix. During 8 days of culture under 5% O(2), but not room air, the addition of VEGF to explants stimulated the formation of CD31-positive, Flk-1-positive, Gs-IB(4)-positive structures in a concentration-dependent manner. Electron microscopy showed the structures to be capillary-like. VEGF-induced capillary-like structure formation was inhibited by sequestration of VEGF via addition of soluble Flt-1 fusion protein or anti-VEGF antibodies. Expression of Flk-1, but not Flt-1, was increased in embryonic aorta cultured under 5% O(2) relative to room air. Our data suggest that low O(2) upregulates Flk-1 expression in embryonic aorta in vitro and renders it more responsive to VEGF.

Malignant peripheral nerve sheath tumors (MPNSTs) are diagnostically challenging neoplasms for which sensitive and specific immunohistochemical markers are lacking. Although limited to date, previous studies have suggested that NF1 (17q), NF2 (22q), p16 (9p), and EGFR (7p) alterations may be involved in MPNST tumorigenesis. To determine whether specific genetic changes differentiate between MPNST and morphologically similar neoplasms, we assessed these chromosomal regions in 22 MPNSTs (9 NF1-associated, 13 sporadic), 13 plexiform neurofibromas, 5 cellular schwannomas, 8 synovial sarcomas, 6 fibrosarcomas, and 13 hemangiopericytomas by 2-color FISH. NF1 deletions, often in the form of monosomy 17, were found in MPNSTs (76%). neurofibromas (31%), hemangiopericytomas (17%), and fibrosarcomas (17%), but not in synovial sarcomas or cellular schwannomas. NF1 losses were encountered more frequently in MPNSTs versus other sarcomas (p < 0.001), as were p16 homozygous deletions (45% vs 0%; p < 0.001), EGFR amplifications (26% vs 0%; p = 0.006), and polysomies for either chromosomes 7 (53% vs 12%; p = 0.003) or 22 (50% vs 4%; p < 0.001). Hemizygous or homozygous p16 deletions were detected in 75% of MPNSTs, but not in benign nerve sheath tumors (p < 0.001). Thus, FISH analysis identifies relatively specific genetic patterns that may be useful in selected cases, for which the differential diagnosis includes low- or high-grade MPNST.

This study discusses the differential diagnosis of atypical postinfectious glomerulonephritis (PIGN) which may mimic a great variety of glomerular diseases. These include mild mesangial and/or endocapillary glomerulonephritis (GN) focal segmental glomerulosclerosis (FSGS) with diffuse IgM mesangial deposits, crescentic GN with C3 hump-like deposits, focal mesangiocapillary GN superimposed on endocapillary pattern, membranous GN with diffuse exudative changes, crescentic GN with microabscesses, and postinfectious glomerulonephritis with anti-GBM linear deposits.

We report a case of a 57-year-old woman who was diagnosed with a systemic AA amyloidosis associated with a pleomorphic sarcoma of the spleen. Although the association and causality between chronic inflammatory states and systemic AA amyloidosis have been well established, the evidence linking solid malignancies to reactive AA amyloidosis is scarce. Our patient had a significant systemic amyloid deposition including biopsy-proven renal and cardiac AA amyloidosis. Subsequent evaluation uncovered the presence of a large splenic mass, which was treated by splenectomy. Histologically the splenic tumor was classified as pleomorphic sarcoma. The removal of the tumor resulted in a marked decline in proteinuria, stable renal and cardiac functions, and symptomatic improvement at 1-year follow-up. Based on the noted improvements, we speculate that the pleomorphic sarcoma of the spleen caused secondary amyloidosis in our case. Stromal tumors, although rare, may be associated with and should be considered in the differential diagnosis of the cause of AA amyloidosis., (Copyright 2002 by the National Kidney Foundation, Inc.)