Manfred Wehrmann

The pathogenesis of chronic renal failure in diabetic nephropathy. Investigation of 488 cases of diabetic glomerulosclerosis.

Investigation of renal biopsy specimens from 488 patients with diabetic glomerulosclerosis (DGS) of varying severity revealed the following: 1) The severity of DGS increases with the duration of the diabetes. 2) As the severity of DGS increases, it is complicated with increasing frequency by exudative changes, which correspond in detail to hyperperfusion lesions described in the literature. 3) As the severity of DGS increases, the severity of arteriolosclerosis and the incidence of nephrotic syndrome increase significantly. 4) The 5- and 10-year renal survival rates are highest for those diabetic patients in whom the tubules and renal cortical interstitium are of normal appearance. These survival rates are diminished if any of the following are present at the time of biopsy: a) interstitial fibrosis; b) hyperperfusion lesions; c) nephrotic syndrome; d) elevation of the serum creatinine concentration to more than 1.3 mg%. 5) No significant correlation was found between renal survival rate and age, sex, or type of diabetes. 6) The inflammation of the renal interstitium seen in diabetes does not differ from that seen in chronic glomerulonephritis. Monocytes, macrophages, T lymphocytes, fibroblasts and fibrocytes play the major role in this inflammation. This inflammatory process is considered to represent not pyelonephritis, but rather an auto-immune process. In other words, it is proposed that the diabetic kidney fails not only as a result of non-specific glomerular lesions (hyperperfusion lesions) but also because of non-specific tubulointerstitial changes, whereas diabetic glomerulosclerosis alone does not lead to chronic renal failure.

Identification of Ectonucleotidases CD39 and CD73 in Innate Protection during Acute Lung Injury

Acute lung injury (ALI), such as that which occurs with mechanical ventilation, contributes to morbidity and mortality of critical illness. Nonetheless, in many instances, ALI resolves spontaneously through unknown mechanisms. Therefore, we hypothesized the presence of innate adaptive pathways to protect the lungs during mechanical ventilation. In this study, we used ventilator-induced lung injury as a model to identify endogenous mechanisms of lung protection. Initial in vitro studies revealed that supernatants from stretch-induced injury contained a stable factor which diminished endothelial leakage. This factor was subsequently identified as adenosine. Additional studies in vivo revealed prominent increases in pulmonary adenosine levels with mechanical ventilation. Because ectoapyrase (CD39) and ecto-5′-nucleotidase (CD73) are rate limiting for extracellular adenosine generation, we examined their contribution to ALI. In fact, both pulmonary CD39 and CD73 are induced by mechanical ventilation. Moreover, we observed pressure- and time-dependent increases in pulmonary edema and inflammation in ventilated cd39−/− mice. Similarly, pharmacological inhibition or targeted gene deletion of cd73 was associated with increased symptom severity of ventilator-induced ALI. Reconstitution of cd39−/− or cd73−/− mice with soluble apyrase or 5′-nucleotidase, respectively, reversed such increases. In addition, ALI was significantly attenuated and survival improved after i.p. treatment of wild-type mice with soluble apyrase or 5′-nucleotidase. Taken together, these data reveal a previously unrecognized role for CD39 and CD73 in lung protection and suggest treatment with their soluble compounds as a therapeutic strategy for noninfectious ALI.

Reliability of differentiating human coronary plaque morphology using contrast-enhanced multislice spiral computed tomography : A comparison with histology

Background: Initial clinical results indicate that multislice spiral computed tomography (MDCT) might be useful for the noninvasive characterization of human coronary plaque morphology by determining tissue density within the lesions. This seems to be of clinical relevance, because coronary artery disease might be detected at an early stage before calcifications occur and noncalcified plaques that may be more likely to rupture could also be visualized noninvasively. The aim of the present study was to evaluate the reliability of contrast-enhanced MDCT in differentiating human atherosclerotic coronary plaque morphology by comparing it with the histopathologic gold standard. Methods and Results: Twelve human hearts were scanned postmortem using an MDCT (Somatom Volume Zoom; Siemens, Forchheim, Germany) high-resolution computed tomography scanner to detect atherosclerotic coronary plaques. Density measurements were performed within detected plaque areas. The exact location of each plaque was marked at the surface of the heart to assure accurate histopathologic sectioning of these lesions. The plaques were classified according to a modified Stary classification. Seventeen plaques were identified by MDCT. Six plaques were histopathologically classified as lipid rich (Stary III/IV), 6 plaques as intermediate (Stary V), and 5 plaques as calcific (Stary VII). Lipid-rich plaques had a mean density on MDCT of 42 ± 22 Hounsfield units (HU), intermediate plaques had a mean density of 70 ± 21 HU, and calcific plaques had a mean density of 715 ± 328 HU. ANOVA analysis revealed a significant difference in plaque density between the 3 groups (P < 0.0001). Conclusions: The comparison with histopathology confirms that tissue density as determined by contrast-enhanced MDCT might be used to differentiate atherosclerotic plaque morphology.

Significance of Postglomerular Capillaries in the Pathogenesis of Chronic Renal Failure

Correlations between the relative volume of the intertubular capillaries in the renal cortex and the serum creatinine concentration in primary glomerulopathies, renal vasculopathies, and chronic interstitial nephritides are reported. In the mesangioproliferative glomerulonephritides, there are significant negative correlations between the number and area of the intertubular capillaries in the cortex and the serum creatinine concentration. In diabetic glomerulosclerosis, renal glomerular amyloidosis, decompensated benign nephrosclerosis, secondary malignant nephrosclerosis, and chronic interstitial nephritis, there is a significant negative correlation between the relative area of the intertubular capillaries and the serum creatinine concentration. Thus, in these diseases, there is progressive narrowing/ obliteration of the postglomerular capillaries which leads to a progressive decrease in glomerular filtration rate and thus to a rise in serum creatinine concentration.

IgA Nephritis: On the Importance of Morphological and Clinical Parameters in the Long-Term Prognosis of 239 Patients

This study is concerned with the correlation between tubulointerstitial changes (interstitial fibrosis, acute renal failure, and interstitial fibrosis with acute renal failure), glomerular changes (focal and segmental lesions, hyperperfusion lesions), vascular changes, clinical data at the time of biopsy (serum creatinine concentration, creatinine clearance, hematuria, proteinuria, and hypertension) and first symptoms (hematuria, proteinuria and hypertension) and the kidney survival rate in 239 patients with IgA nephritis without nephrotic syndrome. The morphological and clinical parameters were subjected to multivariate analysis in order to examine their significance with regard to the prognosis. The interstitial fibrosis was proven to be the most important morphological parameter, and the most important clinical parameters were the serum creatinine concentration and the creatinine clearance.

Smooth muscle cell proliferation and restenosis after stand alone coronary excimer laser angioplasty

It has been shown that coronary excimer laser angioplasty can remove atherosclerotic intracoronary tissue. Stand alone coronary excimer laser angioplasty was successfully performed in a 53 year old white man with 90% stenosis of the left anterior descending coronary artery and exertional angina (Canadian Cardiovascular Society class III). The lesion was reduced to a 30% residual stenosis with use of a 1.2 mm and subsequently a 1.8 mm diameter laser catheter. Early follow-up angiography 24 h later revealed persistent patency and unchanged lesion diameter of the target vessel. The patient was free of symptoms during the 2 month follow-up period, but died suddenly while playing in a tennis tournament 63 days after the procedure. Postmortem histologic examination revealed 80% restenosis at the lesion site without plaque disruption or thrombosis. Specific staining of the histologic specimen for smooth muscle cells using alpha-actin revealed significant smooth muscle cell proliferation at the site of coronary excimer laser angioplasty. However, most of the vessel narrowing appeared to be due to underlying fibrotic plaque as a result of insufficient tissue ablation. This was probably related to the size of the currently available catheters, which are too small to create a large channel.

The Consequences of Tubulo-Interstitial Changes for Renal Function in Glomerulopathies

In recent years it has become recognized to an increasing extent that a wide range of inflammatory and non-inflammatory glomerular diseases may be complicated with varying frequency by disease in the region of the post-glomerular intertubular capillaries. Thus we found additional disease of the tubulo-interstitial system in 4.0 – 69.5% of patients with the diseases listed in Table 1. Amongst these diseases, accompanying inflammation of the renal cortical interstitium occurs least often in endocapillary glomerulonephritis and most often in diabetic glomerulosclerosis. Amongst the glomerulonephritides, interstitial inflammation leading to fibrosis is observed most frequently in rapidly progressive glomerulonephritis and membranoproliferative glomerulonephritis. Interstitial inflammation is found relatively often in glomerular amyloidosis. As a result of investigations we have undertaken in the last three years, it has been possible to demonstrate that the character of the inflammatory interstitial changes that accompany glomerular diseases is always the same, no matter what the glomerulopathy may be. The cells most predominantly involved in the inflammatory process are T lymphocytes, macrophages, fibroblasts and fibrocytes. Thus dense foci of T lymphocytes and macrophages are seen not only in Table 1 Survey of the incidence of intertubular inflammation associated with interstitial fibrosis in various glomerulopathies. Various Glomerulopathies And The Occurrence Of Interstitial Inflammation And Interstitial Fibrosis Total Number Of Casas Cases With Interstitial Fibrosis (%) 1) Endocapillary GN 137 4.0 2) Minimal Changes With NS 470 8.5 3) Focal Sclerosing GN 469 34.1 4) Mesangioproliferative GN 805 23.0 a) Immunologically Negative GN 238 13.9 b) IgA Nephritis 369 23.3 c) Non-lgA Nephritis 198 33.3 5) Chronic Idiopathic Membranous GN 642 23.8 6) Membranoproliferative GN Type I 259 41.0 7) Rapidly Progressive GN 208 56.7 8) Perireticular Amyloidosis 443 48.0 9) Diabetic Glomerulosclerosis 406 69.5 mesangioproliferative glomerulonephritis, but also in the interstitial inflammation that complicates renal amyloidosis. The tubulo-interstitial inflammation of diabetic glomerulosclerosis is also characterized by T lymphocytes, macrophages, fibroblasts and fibrocytes.

The long-term prognosis of the primary glomerulonephritides. A morphological and clinical analysis of 1747 cases.

Long-term studies of all types of primary glomerulonephritis (GN) taking into consideration the major morphological and clinical findings revealed the following: 1) Endocapillary GN, post-streptococcal type has a very good prognosis when only glomerulitis is present. The prognosis is significantly worse if either interstitial inflammation with fibrosis or nephrotic syndrome (NS) is present at the time of the biopsy. 2) The prognosis of the various types of mesangioproliferative GN (IgA nephritis, non-IgA nephritis, and immunohistologically negative GN) is very good if there is only glomerulitis. The prognosis is worse for all three types when the renal cortical interstitium exhibits inflammation with fibrosis at the time of the biopsy, and is worst of all when both interstitial fibrosis (IF) and the signs of acute renal failure (ARF) are present. Of this group, the type in which there are negative immunohistological findings exhibits the best prognosis. No difference in prognosis is found between IgA nephritis and non-IgA nephritis. 3) Minimal changes GN with NS has a very good prognosis when the interstitium is not involved. The presence of interstitial inflammation and fibrosis worsens the prognosis significantly. 4) Focal sclerosing GN has a much poorer prognosis than minimal changes GN with NS, even when there is glomerulitis only (5- and 10-year renal survival rates (RSRs) of 90% and 67%, respectively). If interstitial inflammation and fibrosis are present, the prognosis is significantly worse (5- and 10-year RSRs of 84% and 55%, respectively). The prognosis is worst when both ARF and IF are present at the time of the biopsy (5- and 10-year RSRs of 56% and 46%, respectively). From the clinical side, the prognosis is significantly worse if, at the time of the biopsy, NS is present or the serum creatinine concentration is elevated to more than 1.3 mg%. 5) Chronic membranous GN has a better prognosis than focal sclerosing GN if glomerulitis only is present (5-year RSR, 88%; 10-year RSR, 77%). If the renal cortical interstitium is also involved (in the form of IF), the prognosis is significantly worse (5-year RSR, 65%; 10-year RSR, 38%). The prognosis in this disease, too, is worst when both ARF and IF are present at the time of the biopsy (5-year RSR, 38%; 10-year RSR, 25%). 6) Membranoproliferative GN has a worse prognosis than any of the types of GN so far mentioned (5-year RSR, 51%; 10-year RSR, 32%).(ABSTRACT TRUNCATED AT 400 WORDS)

Epigenetic combination therapy as a tumor-selective treatment approach for hepatocellular carcinoma.

Innovative epigenetic therapeutics comprise histone deacetylase inhibitors (HDAC‐I) and demethylating agents (DA). It was recently found that HDAC‐I compounds exhibit profound therapeutic activities against hepatocellular carcinoma (HCC). A comprehensive preclinical investigation was performed on the potential of a combined HDAC‐I/DA epigenetic regimen for the highly chemotherapy‐resistant HCC entity.

MRI Findings in Deep and Generalized Morphea (Localized Scleroderma)

OBJECTIVE Our objective was to describe the spectrum of MRI features in patients with deep and generalized morphea. CONCLUSION Imaging features of morphea are not specific and usually overlap with those of other disorders involving the skin, fascia, and musculature, such as some types of fasciitis, myositis, and so forth. Nevertheless, the imaging features of morphea reflect pathomorphologic changes of this rare disorder and enable a complete assessment of the disease extent, including depth of infiltration and disease activity.