DDR1-deficient mice show localized subepithelial GBM thickening with focal loss of slit diaphragms and proteinuria

BACKGROUND: Type IV collagen in basement membranes is a ligand for the receptor tyrosine kinase discoidin domain receptor 1 (DDR1). DDR1 is expressed in renal cells and regulates cell adhesion and proliferation ex vivo. The interaction between type IV collagen and cell surface receptors is believed important for normal renal function as well as significant in chronic renal diseases and we therefore analyzed mice with a targeted deletion of DDR1. METHODS: Homozygous DDR1 knockout mice were compared to heterozygous and wild-type animals. The quantitative and qualitative amount of proteinuria was measured by urine-microelectrophoresis. Structural changes of the kidneys were determined by immunohistochemistry, light microscopy, and electron microscopy. RESULTS: Compared to heterozygous littermates, adult DDR1 knockout mice showed a selective middle- to high-molecular proteinuria of up to 0.3 g/L and urinary acanthocytes. There was no evidence of uremia with no change in serum urea in the first 9 months of age. Little apparent change in renal morphology was detected using light microscopy. However, electron microscopy showed a localized, subepithelial, mushroom-like isodense thickening of the glomerular basement membrane (GBM). Within these areas, a focal loss of the podocytic slit diaphragms occurred. CONCLUSION: The loss of cell-matrix communication in DDR1-deficient podocytes appears to result in excess synthesis of basement membrane proteins leading to disturbed anchorage of foot processes and disruption of the slit diaphragm. Our data suggest that the interaction between type IV collagen and DDR1 plays an important role in maintaining the structural integrity of the GBM.     

Morphometric study of glomerular slit diaphragms fixed by rapid-freezing and freeze-substitution.

The widths of slit diaphragms in rat glomeruli were quantitatively measured on electron micrographs obtained by the rapid-freezing and freeze-substitution (FS) fixation method and compared to those prepared by conventional chemical fixation procedures, such as tannic acid, glutaraldehyde and osmium tetroxide (TGO) or glutaraldehyde and osmium tetroxide (GO) fixation. When fixed by FS using 2% osmium tetroxide, glomerular slit diaphragms had widths of 33.8 +/- 3.6 nm, but when fixed by TGO or GO they had widths of 47.0 +/- 4.3 and 48.7 +/- 5.5 nm, respectively. The width of slit diaphragms was significantly narrower after cryofixation than after conventional TGO or GO fixation (P less than 0.001). Similarly, the distance between neighboring foot processes at 50 nm from slit diaphragms was significantly narrower after cryofixation (P less than 0.001). The widths were 98.6 +/- 17.1 nm after TGO fixation, 122.0 +/- 29.3 nm after GO fixation and only 54.8 +/- 18.7 nm after FS fixation. These foot processes were significantly broader after FS fixation. The foot processes were 179.2 +/- 59.4 nm in breadth after TGO fixation (P less than 0.001), 188.8 +/- 78.2 nm after GO fixation (P less than 0.01) and 235.1 +/- 87.2 nm after FS fixation. These results suggest that the cytoplasm of foot processes shrinks when the tissue is prepared by conventional chemical fixation methods, and that the broadening of slit diaphragms is an artifact separation of the margins of adjacent foot processes due to shrinkage. We propose that TGO fixation alters the structure of slit diaphragms by causing them to shrink.     

Proapoptotic Fas ligand is expressed by normal kidney tubular epithelium and injured glomeruli

Fas ligand (FasL) is a cell membrane cytokine that can promote apoptosis through activation of Fas receptors. Fas receptor activation induces glomerular cell apoptosis in vivo and participates in tubular cell death during acute renal failure. However, there is little information on the expression of FasL in the kidney. This study reports that FasL mRNA and protein are present in normal mouse and rat kidney. In situ hybridization and immunohistochemistry showed that proximal tubular epithelium is the main site of FasL expression in the normal kidney. In addition, increased total kidney FasL mRNA and de novo FasL protein expression by glomerular cells were observed in two different models of glomerular injury : rat immune-complex proliferative glumerulonephritis and murine lupus nephritis. Both full-length and soluble FasL were increased in the kidneys of the mice with nephritis. Cultured murine proximal tubular epithelial MCT cells and primary cultures of murine tubular epithelial cells expressed FasL mRNA and protein. Tubular epithelium-derived FasL induced apoptosis in Fassensitive lymphoid cell lines but not in Fas-resistant lymphoid cell lines. By contrast, MCT cells grown in the presence of the survival factors of serum were resistant to FasL, and only became partially sensitive to apoptosis induced by high concentrations (100 ng/ml) of FasL upon serum deprivation. However, MCT cells stimulated with inflammatory mediators (tumor necrosis factor-alpha, interferon-gamma, and lipopolysaccharide) increased cell surface Fas expression and were sensitized to apoptosis induced by FasL (FasL 55 +/- 5% versus control 8.3 +/- 4.1% apoptotic cells at 24 h, P < 0.05). Cytokine-primed primary cultures of tubular epithelial cells also acquired sensitivity to FasL-induced apoptosis. These results suggest that FasL expression by intrinsic renal cells may play a role in cell homeostasis in the normal kidney and during renal injury.     

Lymphoepithelial cysts and cystic lymphangiomas: Underrecognized benign cystic lesions of the pancreas

AIM: To identify their diagnostic and prognostic clinical characteristics in a large series.METHODS: Retrospective review of clinicopathologic and imaging characteristics of patients diagnosed with lymphoepithelial cysts and cystic lymphangiomas of the pancreas at Massachusetts General Hospital.RESULTS: Twelve patients were identified between 1/1/1997 and 8/1/2007. Their median age was 55.5 years(range 19-78 years), and 6 were females. The le-sion was incidentally discovered in half of the patients.Contrast enhanced computed tomography demonstrat-ed that the cysts had thin walls, without calcifications, pancreatic duct dilation or pancreatic parenchyma inva-sion. Endoscopic ultrasound with fine needle aspiration(EUS/FNA) confirmed the diagnosis of a lymphoepithe-lial cyst in 3 patients, one of whom was spared an op-eration and continues to do well after 6 years. Eleven patients had a resection: 3 pancreaticoduodenecto-mies, 7 distal pancreatectomies, and 1 enucleation. The median size of the cysts was 3 cm(range 2-20 cm). At a median follow-up of 57 mo no recurrences or other pancreas-related conditions occurred.CONCLUSION: Lymphoepithelial cysts and cystic lymphangiomas of the pancreas can be diagnosed with a combination of contrast-enhanced computed tomog-raphy scans and EUS/FNA. If the lesion is asymptom-atic, an operation might be avoided.     

Intraabdominal cystic lesions - the differentation of mesenteric cysts and cystic lymphangioma]

Mesenteric cysts and cystic lymphangioma are rare intraabdominal lesions. In our clinic, during one year, two young women with these intraabdominal cysts underwent operation because of unspecific abdominal pain. Despite preoperative imaging the final diagnosis of a cystic lymphangioma and a mesenteric chylous cyst was made not before surgery. The postoperative course was uneventful.Problems of diagnostic, differential diagnosis and therapy are presented and differences in etiology, histology and location are discussed.     

Congenital cystic lesions of the bronchi and lungs

A consecutive series of 18 patients with bronchogenic or congenital lung cysts confirmed by operation or postmortem examination is reviewed. Thirteen patients had bronchogenic cyst, and 6 of them were symptomatic: 4 patients had acute or chronic infections and 2 had respiratory distress with hyperinflation of one lung. All 5 patients with congenital lung cyst had symptoms of chronic or repeated respiratory infections. Seventeen patients had operations for removal of their cyst; complications occurred in 6 patients, and there was 1 operative death. One patient died of acute respiratory insufficiency without having had an operation.     

Parathyroid hormone-related protein as a renal regulating factor. From vessels to glomeruli and tubular epithelium.

Parathyroid hormone (PTH) and PTH-related protein (PTHrP) produce similar biological effects through the PTH/PTHrP receptor. Less is known about the physiological role of PTHrP, which was first identified as the agent of the humoral hypercalcemia of malignancy. Despite the widespread production of PTHrP in healthy individuals, the concentration of the protein is below the detectable limit of current assays, suggesting that PTHrP normally functions locally in an autocrine or paracrine manner. Thus, some differences in their biological activities have been described and they may be related to the presence of different receptors. In this regard, a second receptor that binds selectively to PTH has also been found. Recent studies have demonstrated the expression of both PTH/PTHrP receptor and protein in the renal glomeruli. Moreover, there are convincing data that support a direct role of PTH and PTHrP in modulating renal blood flow and glomerular filtration rate. This multifunctional protein, PTHrP, also has a proliferative effect on both glomerular mesangial cells and tubular epithelial cells. Increases in the expression of PTHrP have been observed in several experimental models of nephropathies, suggesting that PTHrP upregulation is a common event associated with the mechanism of renal injury and repair.     

Non-neoplastic cystic and cystic-like lesions of the pancreas: may mimic pancreatic cystic neoplasms

BACKGROUND: Cystic lesions of the pancreas consist of a broad range of pathological entities. With the exception of the pancreatic pseudocyst, these are usually caused by pancreatic cystic neoplasms. Non-neoplastic pancreatic cystic and cystic-like lesions are extremely rare. In the present article, the surgical experience with these unusual entities over a 14-year period is reported. METHODS: Between 1991 and 2004, all patients who underwent surgical exploration for a cystic lesion of the pancreas were retrospectively reviewed. Patients with a pancreatic pseudocyst were excluded. There were 106 patients of whom 8 (7.5%) had a final pathological diagnosis consistent with a non-neoplastic pancreatic cystic or cystic-like lesion, including 3 patients with a benign epithelial cyst, 2 with a pancreatic abscess (one tuberculous and one foreign body), 2 with mucous retention cysts and 1 with a mucinous non-neoplastic cyst. These eight patients are the focus of this study. RESULTS: There were six female and two male patients with a median age of 61.5 years (range, 41-71 years). All the patients were of Asian origin including seven Chinese and one Indian. Four of the patients were asymptomatic and their pancreatic cysts were discovered incidentally on radiological imaging for other indications. All the patients underwent preoperative radiological investigations, including ultrasonography, computed tomography or magnetic resonance imaging, which showed a cystic lesion of the pancreas. Three patients, all of whom were symptomatic, were diagnosed preoperatively with a malignant cystic neoplasm on the basis of radiological imaging. Two patients were eventually found to have a pancreatic abscess, one tuberculous and the other, secondary to foreign body perforation. The third patient was found on final histology to have chronic pancreatitis with retention cysts. The remaining five patients had a preoperative diagnosis of an indeterminate cyst; on pathological examination, they were found to have a benign epithelial (congenital) cyst (n = 3), retention cyst (n = 1) and mucinous non-neoplastic cyst (n = 1). At a median follow up of 20 months (range, 3-34 months), none of the patients had any evidence of recurrent disease. CONCLUSION: Non-neoplastic cystic and cystic-like lesions of the pancreas are rare causes of pancreatic cystic lesions that are generally benign and do not require surgery when asymptomatic. However, despite advances in diagnostic investigations such as endoscopic ultrasound with fluid aspirate and magnetic resonance imaging, the preoperative diagnosis remains unreliable. Hence, the challenge for all clinicians is to recognize these lesions preoperatively and to avoid 'unnecessary' surgery.     

Natural course and outcome of cystic lesions in the pancreas

Background

The number of patients identified with cysts of the pancreas is increasing. The current study was undertaken to assess the natural course and malignant potential of pancreatic cysts.

Methods

From 1995 to 2008, radiology records were reviewed for the presence of cystic lesions of the pancreas (CLP) characteristics, patient demographics, and follow-up.

Results

Eighty-two patients met the study inclusion criteria, with a mean age at time of diagnosis of 64.4 ± 16.7 years. Mean cyst size was 1.36 ± 1.05 cm, with 75.6% of patients having a solitary cyst. Thirteen patients underwent surgery. Operative intervention was statistically related to symptomatic, loculated cysts with the presence of calcifications (all P <.05). Malignancy was statistically related to symptomatic (P <.05), loculated cysts (P <.01), and male gender (P <.05).

Conclusions

Our data show that most pancreatic cysts found on radiographic imaging are asymptomatic, solitary, and small and can be followed safely radiographically.     

Remodeling of renal interstitial and tubular lesions in pancreas transplant recipients

Tubular atrophy and interstitial fibrosis, important in progression of renal diseases, including diabetic (D) and cyclosporine-induced (CSA) nephropathy, have been considered irreversible. Normoglycemia for 10 years following pancreas transplantation alone (PTA) reversed D glomerulopathy lesions. This study quantified tubular, interstitial, and arteriolar parameters in PTA recipients. Kidney function studies and biopsies were performed in eight non-uremic type I D patients (pts) at 5 and 10 years after PTA. Renal biopsies were analyzed by morphometric analysis. All pts were normoglycemic and insulin independent and received CSA during the study. Cortical interstitial volume fraction was increased at 5 years (0.31+/-0.07 vs normal 0.15+/-0.02, P<0.01) and decreased at 10 years post-PTA (0.23+/-0.03, P<0.02 vs 5 years). There was a reduction in the volume fraction of interstitial collagen and cells per cortical tissue, measured using electron microscopy, from 5 (0.126+/-0.061 and 0.103+/-0.026, respectively) to 10 years (0.079+/-0.031, P<0.05, and 0.074+/-0.018, P<0.05, respectively). The volume fraction of tubules which were atrophic (AT) was abnormal at 5 years (0.160+/-0.090) and decreased from 5 to 10 years (0.044+/-0.034, P<0.02), apparently due to AT reabsorption. The index of arteriolar hyalinosis did not change during the study (1.30+/-0.22 and 1.34+/-0.33 at 5 and 10 years, respectively, nonsignificant). This study demonstrates, for the first time in humans, that interstitial expansion is reversible and that atrophic tubules can be reabsorbed. In contrast, there was no improvement in the arteriolar lesions. Whether this is due to long-term normoglycemia, reduction of CSA dose or other mechanisms is unclear.     

Neuroendoscopic transventricular surgery for suprasellar cystic mass lesions such as cystic craniopharyngioma and Rathke cleft cyst

Cystic mass lesions in the suprasellar cistern are often associated with neurological deficits, cognitive disorders, and endocrinological impairments. Many surgical approaches are available to treat these mass lesions, but are technically difficult and cannot remove the lesion completely without risking damage to neurological and endocrinological functions due to the proximity to the surrounding structures. Neuroendoscopic transventricular surgery was performed using a ventricular fiberscope for three patients with craniopharyngiomas and two patients with Rathke cleft cysts, with gamma knife radiosurgery for craniopharyngiomas. The endoscopic transventricular approach is safe and minimally invasive for congenital benign suprasellar cystic lesions, especially arachnoid cysts.     

Laparoscopic management of benign solid and cystic lesions of the liver

OBJECTIVE: The authors present their experience in the laparoscopic management of benign liver disease. The aim of the study is to analyze technical feasibility and evaluate immediate and long-term outcome. SUMMARY BACKGROUND DATA: Indications for the laparoscopic management of varied abdominal conditions have evolved. Although the minimally invasive treatment of liver cysts has been reported, the laparoscopic approach to other liver lesions remains undefined. METHODS: Between September 1990 and October 1997, 43 patients underwent laparoscopic liver surgery. There were two groups of benign lesions: cysts (n = 31) and solid tumors (n = 12). Indications were solitary giant liver cysts (n = 16), polycystic liver disease (n = 9), hydatid cyst (n = 6), focal nodular hyperplasia (n = 3), and adenoma (n = 9). Only solid tumors, hydatid cysts, and patients with polycystic disease and large dominant cysts located in anterior liver segments were included. All giant solitary liver cysts were considered for laparoscopy. Patients with cholangitis, cirrhosis, and significant cardiac disease were excluded. Data were collected prospectively. RESULTS: The procedures were completed laparoscopically in 40 patients. Median size was 4 cm for solid nodules and 14 cm for solitary liver cysts. Conversion occurred in three patients (7%), for bleeding (n = 2) and impingement of a solid tumor on the inferior vena cava (n = 1). The median operative time was 179 minutes. All solitary liver cysts were fenestrated in less than 1 hour. There were no deaths. Complications occurred in 6 cases (14.1%). Two hemorrhagic and two infectious complications were noted after management of hydatid cysts. There were no complications after resection of solid tumors. Three patients received transfusions (7%). The median length of stay was 4.7 days. Median follow-up was 30 months. There was no recurrence of solitary liver or hydatid cysts. One patient with polycystic disease had symptomatic recurrent cysts at 6 months requiring laparotomy. CONCLUSION: Laparoscopic liver surgery can be accomplished safely in selected patients with small benign solid tumors located in the anterior liver segments and giant solitary cysts. The laparoscopic management of polycystic liver disease should be reserved for patients with a limited number of large, anteriorly located cysts. Hydatid disease is best treated through an open approach.     

The nature and course of cystic pancreatic lesions diagnosed by ultrasound

To determine the nature and course of cystic pancreatic lesions, we reviewed the records of 93 patients who were followed up with serial ultrasound until resolution occurred or definitive therapy was given. Initially, 105 cystic lesions were seen. Single cysts occurred in 83 patients and multiple cysts in ten. Eight patients had two cysts and two patients had three. Twenty-one patients had a single ultrasound examination and 72 had two or more examinations. Spontaneous resolution occurred in 29 of (28%) 105 cysts in 24 patients. In 46 patients, 53 pseudocysts were found at operation or autopsy. Five patients had pancreatic abscesses. Two patients became unavailable for follow-up and three refused surgery. The results of one examination were false negative. Twelve patients had false-positive ultrasound results. Factors influencing the likelihood of spontaneous resolution included initial cyst size, subsequent increase in size, multiple cysts, and the presence of calcifications. This study confirms the usefulness of serial ultrasound scans in determining the nature and necessity for treatment of cystic lesions of the pancreas.     

Clinical and pathology features of IgA nephropathy with active tubular interstitial lesions

Objective To investigate the clinical and pathological characteristics of IgA nephropathy (IgAN) in association with active tubular interstitial lesions. Methods 148 patients who were diagnosed as IgAN by renal biopsy and admitted to Zhejiang Provincial People's Hospital from March 2014 to December 2014 were enrolled. They were divided into IgAN with active tubular interstitial lesions group (IgAN-ATIL group, 23 patients) and IgAN without active tubular interstitial lesions group (control group, 125 patients). Clinical and pathological characteristics were retrospectively analyzed. Multivariate logistic regression analysis was used to analyze the influence factors. Results The prevalence of ATIL in 148 IgAN patients was 15.5%. IgAN-ATIL group showed an older average age and more higher proportion of medication history (antibiotics, diuretics, nonsteroidal anti-inflammatory drugs, etc) than those in control group. There were significant differences in Alb, eGFR, Scr, BUN, 24-hour urinary protein quantity, urinary NGAL and urinary RBC count between two groups (P＜0.05, respectively). A moderate of tubulointerstitial lesions of IgAN-ATIL group was shown, while the control group was mainly mild lesions. Multivariate logistic regression analysis showed that age, medication history and the urinary NGAL level were independent risk factors of IgAN-ATIL. Conclusions IgAN patients with active tubular interstitial lesions had more severe clinical manifestations and chronic interstitial lesions. The age, medication history (antibiotics, diuretics, nonsteroidal anti-inflammatory drugs, etc) and the urinary NGAL level were independent risk factors of IgAN-ATIL.     

Medullary cystic disease and tubular basement membrane changes: clinicopathological characteristics of four patients

We describe herein the clinicopathological characteristics of four members of a family in which about half of the generation was affected by chronic renal failure after middle age. The inheritance was considered to be an autosomal dominant pattern. Clinically, neither sensorineural deafness nor ocular abnormalities were evident. In addition, there was neither hypokalemia nor hypercalcemia causing deterioration of renal function. Radiological examination revealed no cystic formation in the kidneys in any patients, although in two of them the examination was performed at the time of endstage renal disease. Histological examination showed chronic tubulo-interstitial damage with periglomerular fibrosis. On electron microscopy, characteristic but nonspecific thickening and lamination of tubular basement membrane were noted in all patients, while glomerular basement membrane was unremarkable in all patients. These findings suggest that our patients had medullary cystic disease. Demonstration of lamination and thickening of the tubular basement membrane by electron microscopy may be useful for the diagnosis of medullary cystic disease with undetectable cyst formation. Received: December 1, 1999 / Accepted: October 16, 2000