Christian S. Haas

Glomerular and renal vascular structural changes in α8 integrin-deficient mice

Integrins are matrix receptors that regulate cell-matrix interactions during development and in adult tissue. In the adult kidney, the alpha8 chain is specifically expressed in glomerular mesangial cells and vascular smooth muscle cells. alpha8-deficient (alpha8-/-) mice demonstrate reductions in renal mass, which can range from complete renal agenesis to the development of kidneys that are only slightly smaller than wild-type kidneys. No histologic abnormalities of these kidneys have been described. However, considering the prominent expression of alpha8 in glomeruli and renal vessels, it seemed unlikely that the kidneys of alpha8-/- mice would be completely normal. Therefore, the renal phenotype of adult alpha8-/- mice was investigated, for assessment of more subtle morphologic alterations in kidney tissue. alpha8-/- mice displayed a significant reduction in nephron number and an increase in glomerular volume, compared with wild-type control animals. Albuminuria was not different in wild-type and alpha8-/- mice. Quantitative morphologic analyses revealed that the glomeruli of alpha8-/- mice were hypercellular, with an increased number of mesangial cells, compared with wild-type mice. Mesangial matrix deposition (as demonstrated for collagen IV and the alpha8 ligand fibronectin) was expanded in alpha8-/- mice, compared with wild-type mice. Collagens I and III, which are not normally present in glomeruli, were detected in the glomeruli of alpha8-/- mice. Staining for other glomerular integrins demonstrated an increased abundance of the collagen receptor alpha2 integrin in alpha8-/- mice. The glomerular capillary length density was significantly greater in alpha8-/- mice than in wild-type mice. Cortical arterial vessel walls were not altered in alpha8-/- mice, but the capillaries of the peritubular network were widened. Despite the strong mesangial and vascular expression of alpha8, glomerular and renal vascular alterations in alpha8-/- mice were relatively mild. Only aged alpha8-/- mice demonstrated increased glomerular capillary widening, compared with control animals. The results suggest that the lack of alpha8 can be largely compensated for, at least in younger alpha8-/- mice. It is not yet clear whether the occurrence of collagens that are not normally present in glomeruli and the increased abundance of the collagen receptor alpha2 contribute to maintaining the glomerular structure in alpha8-/- mice. The compensatory mechanisms involved will be the subject of future research.

Characterization and outcome following Puumala virus infection: a retrospective analysis of 75 cases

BACKGROUND Infection with the Puumala virus (PUUV), which belongs to the Hantavirus family, is a common but often neglected cause of acute kidney injury (AKI) in endemic areas of Europe. The objective of the present study was to systematically analyse clinical presentation and renal outcomes following PUUV infection. METHODS In a retrospective study, we analysed data from 75 patients who were admitted to two large hospitals in Germany over an 8-year period and who tested positive for PUUV infection. Clinical and laboratory data were collected from patient files; creatinine levels before admission and during follow-up were obtained from phone calls. RESULTS Patients were between 16 and 82 years old (average +/- SD, 40.4 +/- 13.4) with a male to female ratio of 2.5:1. They showed a wide variety of clinical presentations with renal failure being the cause of admission in only 50%. AKI developed in 95% of patients who showed maximum creatinine levels of 4.3 +/- 0.3 mg/dl. Four patients required temporary dialysis, and one patient died from pulmonary complications. Thrombocytopaenia (137 +/- 11 x 10(3)/microl) was present in almost all cases, and elevated levels of lactate dehydrogenase (LDH) and C-reactive protein (CRP) were observed in 57 and 100% of patients, respectively. Urinalysis revealed mild to nephrotic proteinuria in 85%, which was often associated with haemoglobinuria. All patients showed full recovery of renal function and return to pre-existing normal serum creatinine levels. CONCLUSION In a majority of cases, PUUV infection results in thrombocytopenic AKI. Fever is a requirement for diagnosis, while elevated LDH and CRP values are also frequently observed. Overall, early renal outcomes were excellent.

Asymptomatic Sustained Ventricular Fibrillation in a Patient With Left Ventricular Assist Device

Optimal medical treatment, cardiac resynchronization, and the use of an implantable cardioverter defibrillator are established therapies of severe congestive heart failure. In refractory cases, left ventricular assist devices are more and more used not only as bridging to cardiac transplantation but also as destination therapy. Ventricular arrhythmias may represent a life-threatening condition and often result in clinical deterioration in patients with congestive heart failure. We report a case of asymptomatic sustained ventricular fibrillation with preserved hemodynamics caused by a nonpulsatile left ventricular assist device. Consecutive adequate but unsuccessful discharges of the implantable cardioverter defibrillator were the only sign of the usually fatal arrhythmia, prompting the patient to consult emergency services. Electrolyte supplementation and initiation of therapy with amiodarone followed by external defibrillation resulted in successful restoration of a stable cardiac rhythm after 3.5 hours.

Restricted expression of mouse GCMa/Gcm1 in kidney and thymus.

Mouse Glial Cells Missing a (mGCMa) belongs to a small family of transcription factors named after the prototypical GCM from Drosophila. mGCMa was expected to regulate gliogenesis, but instead found to be primarily expressed during development in trophoblasts of chorion and labyrinth. Its deletion causes abnormal placental labyrinth formation and results in embryonic lethality. Here we identify kidney and thymus as sites of mGCMa expression. In thymus, mGCMa is restricted to few small clusters of cells, in kidney to the S3 segment of proximal tubules. mGCMa expression is primarily postnatal, arguing for a role in organ function rather than organ development.

Angiopoietin 1 and 2 gene and protein expression is differentially regulated in acute anti-Thy1.1 glomerulonephritis

Capillary neoformation is important in repair of glomerular injury of various origins. VEGF was shown to be crucial for glomerular capillary repair in glomerulonephritis (GN). We reasoned that other angiogenic factors are likewise involved in glomerular capillary remodeling and found angiopoietin 1 and -2 (ANG1 and ANG2) mRNA to be upregulated in cDNA microarrays of microdissected glomeruli of anti-Thy1.1 GN of the rat. We then studied glomerular in situ gene and protein expression of ANG1 and ANG2 and their receptor Tie-2 in the course of anti-Thy1.1 GN, which was induced by injection of OX-7 antibody. Animals were perfusion fixed at days 6 and 12 after GN induction and compared with nonnephritic controls receiving PBS. Capillary damage and repair were quantitatively analyzed using stereological techniques. Gene and protein expression of ANG1 and ANG2 and their receptor Tie-2 was analyzed using real-time quantitative PCR from microdissected glomeruli, nonradioactive in situ hybridization, double immunofluorescence, and Western blot analysis. Glomerular capillarization assessed as length density was significantly lower at day 6 of anti-Thy1.1 GN than in controls; it was back to normal values at day 12. ANG1 and ANG2 gene expression was markedly upregulated at day 6 of the disease compared with controls. Protein expression of ANG1 and ANG2 was confined to podocytes and that of Tie-2 to endothelial cells. At day 12 of anti-Thy1.1 GN when capillary restoration was nearly completed, ANG1 and ANG2 gene expression returned to basal levels, whereas Tie-2 expression was still high. With the use of a combined molecular and in situ approach, the spatial and temporal gene and protein expression of the angiopoietins and their receptor was analyzed in anti-Thy1.1 GN. The results indicate that glomerular expression of ANG1 and ANG2 and Tie-2 is differentially regulated and may contribute to healing and endothelial cell stabilization in experimental GN.

Characterization of the renal phenotype in a mouse model of Marfan syndrome

The microfibrillar protein fibrillin-1 is expressed abundantly in the vasculature and the glomerulus of the kidney. Mutations in the fibrillin-1 gene lead to Marfan syndrome. The most common complication of this disease is aortic dilatation due to elastic deficiencies of the vascular wall. Several case reports describe glomerular disease in patients with Marfan syndrome, and fibrillin-1 has been implicated in nephrogenesis. To study the role of fibrillin-1 in renal development and function, we characterized the renal phenotype of fibrillin-1-underexpressing mice. Kidney histology was evaluated by means of morphometry and stereology. Relative kidney weights, daily urine excretion, urinary albumin excretion, serum and urinary creatinine, as well as serum urea were not different than wild-type mice. Glomerular number and renal capillarization were normal. The size of the renal filtration surface was comparable in wild-type and fibrillin-1-underexpressing mice. There was no indication for glomerular, renal vascular, or tubulointerstitial injury. However, glomerular volume and mesangial area were reduced. No changes in glomerular cell numbers were detected, but the cellular volume of mesangial cells was significantly lower in glomeruli of fibrillin-1-underexpressing mice. Thus, despite the high abundance of fibrillin-1 in glomeruli of wild-type animals, underexpression of fibrillin-1 did not lead to functional deficiencies of the glomerulus. Alterations in renal histology were only subtle with a reduced glomerular volume and mesangial area likely due to a reduced mesangial cell volume.

Hantavirus Infection: A Neglected Diagnosis in Thrombocytopenia and Fever?

Thrombocytopenia, fever, and acute renal failure are characteristic features of nephropathia epidemica, the predominant hantavirus infection in Europe. However, clinical presentation and blood cell counts may point to other disorders, such as a hematologic disease, particularly when impairment of renal function is not evident. This differential diagnosis often results in further extensive and unnecessary testing. We describe 3 patients with hantavirus infection with no renal failure, in whom a hematologic disorder was initially suspected. Serologic testing of hantavirus finally unraveled the mystery, and outcome of the patients was excellent. It is conceivable that similar cases often remain undiagnosed. Thus, testing for hantavirus should always be considered in cases of thrombocytopenia and fever of unknown origin, especially in areas endemic for the infection.

Effect of Endothelin Blockade on Early Cardiovascular Remodeling in the One-Clip-Two-Kidney Hypertension of the Rat

Background: In models of hypertension and of renal failure, pharmacological blockade of the ETA receptor has been shown to cause some inconsistent lowering of blood pressure (BP) and lesser left ventricular hypertrophy (LVH). The effects of ETA receptor blockade (ETA-RB) on vascular remodeling and their potential relation to BP lowering, have not been clarified. Design: The experimental study in male Sprague-Dawley rats was designed to compare four experimental groups: (1) sham-operated controls (sham); (2) untreated rats with one-clip-two-kidney (1C-2K) renovascular hypertension; (3) 1C-2K rats treated with the ACE inhibitor (ACE-i) trandolapril (0.3 mg/kg b.w./day), and (4) 1C-2K rats treated with the ETA-RB LU-135252 (50 mg/kg b.w./day). BP was measured weekly by tail plethysmography. After 3 weeks, animals were sacrificed and cardiac, aortic and mesenteric artery morphology was evaluated using morphometric and stereological techniques. Results: Systolic BP was significantly higher in 1C-2K rats compared to sham. BP was not significantly affected by ETA-RB, but was significantly lowered by the ACE-i. Despite no significant change in BP, ETA-RB treatment led to a significantly less volume density of the cardiac interstitium (sham 1.40 ± 0.18, 1C-2K 2.66 ± 0.56, 1C-2K + ACE-i 1.88 ± 0.38, 1C-2K + ETA-RB 2.15 ± 0.37%). In contrast, ETA-RB had no significant effect on left ventricular/body weight ratio (sham 2.85 ± 0.26, 1C-2K 2.96 ± 0.33, 1C-2K + ACE-i 2.54 ± 0.22 and 1C-2K + ETA-RB 3.15 ± 0.44 mg/g) or on wall thickness of intramyocardial arteries. Conclusions: The ETA-RB LU-135252 ameliorated the development of myocardial fibrosis in a short-term hyperreninemic normal salt model of experimental hypertension nearly as effectively as an ACE-i. This effect of LU-135252 is independent of systemic BP. In contrast to findings in other models, ETA receptor blockade had no significant effect on LVH or vascular remodeling. Only the ACE-i but not the ETA-RB prevented structural changes of small intramyocardial arteries and of the aorta.

Persistent left superior vena cava

A 76-year-old man with coronary artery disease and a history of aortocoronary bypass surgery seven years previously presented with symptomatic bradycardia and atrial fibrillation. After evaluation of the coronary status by cardiac catheterization, the decision was made to implant a ventricular rate responsive demand (VVIR) pacemaker. Positioning of the ventricular lead via the left subclavian vein was associated with problems while pushing the lead forward. Radiographic imaging with contrast media revealed the presence of a persistent left superior vena cava (PLSVC), with the pacemaker lead following the path of the additional vein. Using fluoroscopy, positioning of the pacemaker lead was completed without further problems. The chest x-ray performed after the procedure showed the left-sided path of the pacemaker’s lead (Figure 1), indicating the presence and path of the abnormal vein. PLSCV is the most common thoracic vein anomaly, occurring in approximately 0.5% of the normal population. It is often associated with a missing right superior vena cava or other cardiac anomalies (1), and can be detected by various methods, including echocardiography and magnetic resonance tomography (2). However, in the majority of cases, PLSCV is an incidental finding during diagnostic and therapeutic procedures (3,4). Therefore, physicians should be aware of this anomaly and the associated technical problems in this setting. Figure 1) Chest x-ray following ventricular rate responsive demand (VVIR) pacemaker implantation, showing a left-sided path of the lead (arrow)

Mystery or Misery? Primary Group A Streptococcal Peritonitis in Women: Case Report

Acute primary peritonitis in the absence of other comorbid conditions such as liver cirrhosis, immunosuppression, or nephrotic syndrome is a rare disorder in young adults. In women, ascending genital infections are thought to be a major pathogenic cause of this type of peritonitis. Pus was detected in the peritoneal cavity by abdominal paracentesis in a 27-year-old woman who had no predisposing features for severe peritonitis. Abdominal computed tomography showed perirectal edema. Laparotomy was performed, but no intra-abdominal focus of infection could be detected. The abdomen was irrigated via a subhepatic and retroperitoneal presacral approach, and broad-spectrum antibiotic therapy was started. Blood cultures revealed group A streptococci, usually a common cause of upper respiratory tract infections or erysipelas. Within a few days, the patient recovered completely and returned to normal life.