Thrombotic microangiopathy and the antiphospholipid syndrome.

The antiphospholipid syndrome (APS) comprises the association between vascular thrombosis, including microthrombosis, pregnancy morbidity and the coexistence of anti-phospholipid antibodies. Thrombotic microangiopathy (TMA) can be one of the manifestations of the APS and may involve any organ. This feature of the APS is probably less recognized by clinical doctors than venous thrombosis and recurrent abortions. This case report presents a patient who developed a widespread TMA with renal failure, gastric mucosa ulceration, urinary bladder ulcerations and a finger necrosis as part of the APS.

Lymphomas diagnosed in Uganda during the HIV/AIDS pandemic.

BACKGROUND: There are numerous reports from different countries documenting a change in frequency and profile of lymphomas after the onset of the HIV/AIDS pandemic. In Uganda little is known concerning the distribution of lymphoma subtypes diagnosed at the Department of Pathology, Makerere University College of Health Sciences during this period. OBJECTIVE: To examine the frequency and diagnostic profile of lymphomas diagnosed in Uganda in the HIV/AIDS era. DESIGN: Retrospective study. SETTING: Department of Pathology, Makerere University College of Health Sciences, Kampala, Uganda. SUBJECTS: One thousand and thirteen patients diagnosed with lymphomas in the period 1980-1989. RESULTS: The most common type of non-Hodgkin lymphoma was Burkitt lymphoma (36%). The frequencies of lymphocytic and histiocytic types were 34.5% and 8.2% respectively. CONCLUSION: There was a decrease in histopathologically diagnosed lymphomas in Uganda in the period 1980-1989. Burkitt lymphoma continues to be the most common subtype diagnosed, some major lymphoma subtypes like T-cell and follicular lymphomas were not reported in the country in the HIV/AIDS era.

Organ-confined clear cell renal cell carcinoma: the prognostic impact of microvascular invasion, nuclear grade and tumour size.

The frequency of diagnosed and treated organ-confined renal cell carcinoma is increasing. The prognosis of this group of tumours is difficult to predict. The main purpose of this study was to examine the prognostic significance of microvascular invasion, tumour size and nuclear grade in a complete cohort of 76 consecutive patients with organ-confined clear cell renal cell carcinoma treated with radical nephrectomy. Patient ages ranged from 39 to 88 years (mean 66 years). Median follow-up was 10.2 years (range 0.1-19.4 years). The tumours were graded according to Fuhrman. Representative histological sections were stained for CD31, which decorates endothelial cells, in order to assess microvascular invasion (MVI). In univariate analysis, microvascular invasion (p<0.01), tumour size (TS) (p=0.01), TNM stage (p=0.01) and Fuhrman nuclear grade (p=0.02) were significant predictors of cancer-specific survival. Multivariate analysis, adjusted for age, revealed that microvascular invasion, tumour size and nuclear grade were independent covariates. According to our findings microvascular invasion is a strong independent prognostic predictor, and including this in the histopathology report should be considered together with nuclear grade and tumour size.

Focal and segmental glomerular sclerosis (FSGS) in a man and a woman with Fabry's disease.

We describe a man and a woman with Fabry's disease. Renal biopsies showed late and early stages respectively of focal and segmental glomerulosclerosis (FSGS) and vascular changes. Clinically the hemizygous patient had advanced renal disease with nephrotic range proteinuria and serum creatinine 122 micromol/l. The female carrier had minimal albuminuria, borderline GFR with a normal serum creatinine, acroparesthesias, moderate fatigue, tinnitus and headache accompanied by ischemic cerebral lesions. Enzyme replacement therapy (ERT) was initiated according to our Fabry protocol, partly due to the renal morphologic findings. We conclude that FSGS and vascular changes may be an early morphologic finding in Fabry's disease, even in patients with subtle albuminuria. The potential role of FSGS as a marker of progressive renal disease in some Fabry patients is discussed. As FSGS and vascular changes obviously may exist across a wide range of clinical presentations and have potential prognostic implications, we suggest that a renal biopsy should be performed prior to enzyme replacement therapy in all adult Fabry patients with proteinuria of various levels. Efforts should be made to develop a scoring system to evaluate potential histologic markers. Protocol biopsies may have therapeutic implications and may provide valuable information in the evaluation of start and dosing of ERT.

Role of angiotensin II under prolonged increased intraabdominal pressure (IAP) in pigs.

BACKGROUND: The aim of the study was to investigate the effect of the angiotensin II receptor antagonist losartan on renal hemodynamics and diuresis in pigs with increased intraabdominal pressure (IAP). METHODS: The IAP was maintained at 30 mmHg for 3 h by intraperitoneal instillation of Ringer's solution. Ten animals were treated with losartan; another 10 animals served as controls. Renal blood flow, hormones in renal vein blood, and diuresis were measured. RESULTS: In control animals, the renal vascular resistance increased renal blood flow remained constant, the blood concentration of aldosterone increased and the diuresis decreased during increased IAP. Losartan prevented the increase in vascular resistance and improved renal blood flow under increased IAP. It also prevented the rise in aldosterone concentration and increased the urine output to baseline level. CONCLUSION: Our results suggest that the renal vasoconstriction associated with increased IAP is due to increased production of angiotensin II. The oliguria associated with increased IAP is probably due, at least partly, to increased reabsorbtion of sodium and water in the renal tubuli caused by increased tissue concentration of aldosterone.

Renal histopathology and clinical course in 94 patients with Wegener's granulomatosis.

BACKGROUND: The main purpose of this study was to examine histopathological changes seen in renal biopsies from patients with Wegener's granulomatosis (WG) with varying degrees of renal involvement and to study possible correlations between the morphological variables and the severity of the disease. METHODS: Ninety-four patients with WG and active renal disease were included in this retrospective study. All patients had a percutaneous renal biopsy taken on their first admission to the hospital and 14 patients had a second biopsy. The patients were followed for a median of 42.5 months (range 0.5-184). RESULTS: Segmental necrotizing glomerulonephritis and extracapillary proliferation were present in 85.1 and 91.5% respectively. Of seven patients (7.4%) with normal serum creatinine and urinary protein excretion <0.5 g/day, all had crescents and six had segmental glomerular necrosis. Serum creatinine at biopsy correlated significantly with the percentage of glomeruli with crescents (rho=0.52, P=0.0004), with necrosis (rho=0.36, P=0.002) and with the percentage of normal glomeruli (rho=-0.55, P=0.0003). On a multivariate analysis, only the percentage of normal glomeruli was significantly associated with renal function and development of end-stage renal disease. In 14 second biopsies after a mean of 41.2 (+/-26) months, chronicity scores had increased significantly in 13 biopsies in spite of full immunosuppressive treatment. CONCLUSION: Although renal biopsy is of value in defining renal involvement in WG, it is of limited help in the early stage of the disease in predicting renal outcome for the individual patient. A follow-up biopsy can be useful in revealing the degree of activity and chronicity and hence be of importance for the choice of further therapy.

[Diagnostic transmission electron microscopy]. / Diagnostisk transmisjonselektronmikroskopi.

BACKGROUND: Transmission electron microscopy (TEM) is an important diagnostic tool in surgical pathology. MATERIAL AND METHODS: We give an overview, based on our own experience, of the application of TEM in diagnostic pathology. RESULTS: In spite of its potential for high-grade resolution, the actual use of TEM in diagnostic pathology is rather limited. TEM is mandatory in the examination of kidney and muscle biopsies and is often indicated when a metabolic disease is suspected. However, in many centres its importance in tumour pathology has declined because of the advances in the field of immunohistochemistry. TEM requires a great deal of resources and high levels of skills in tissue processing and diagnostic interpretation. INTERPRETATION: The TEM diagnosis must be integrated with light microscopical and, often, immunohistopathological findings, as well as with the clinical data. We therefore recommend close collaboration between the clinician and the laboratory with regard to biopsy indication, handling of samples, and the final diagnosis.

Wegener's granulomatosis: inflammatory cells and markers of repair and fibrosis in renal biopsies--a clinicopathological study.

OBJECTIVE: This study aimed to quantitate inflammatory cells in renal biopsies from patients with Wegener's granulomatosis (WG) and to identify cells participating in early fibrogenesis. The goal was to determine whether these cells correlated with the severity of renal disease and whether their presence had a bearing on renal prognosis. MATERIAL AND METHODS: Sixty-one patients with WG who had a renal biopsy taken at the time of diagnosis were included in the study. Immunostaining with monoclonal antibodies towards macrophages (CD68), T- and B-lymphocytes, alpha-smooth muscle actin (alpha-SMA) and vimentin was done. RESULTS: The dominating intraglomerular leucocytes were macrophages (29.9 +/- 15 cells/glomerular cross-section) and to a lesser extent T-cells (2.57 +/- 1.8 cells/glomerular cross-section). No B-lymphocytes were detected in the glomeruli. More than two-thirds of the T-cells were CD8+ (cytotoxic) cells. Macrophages and T-lymphocytes were distributed equally in the renal interstitium and were numerous around crescentic glomeruli. Glomerular and interstitial macrophages and interstitial T-cells correlated significantly with serum (S-) creatinine at the time of biopsy but not after 1 year. S-creatinine at the time of biopsy and after 1 year differed significantly among the three levels of interstitial alpha-SMA staining. S-creatinine at biopsy was highest when tubular vimentin staining was strongest, and tubular vimentin staining was strongest in patients with acute tubular damage. CONCLUSIONS: Evidence was found for a cellular type IV immune response in WG, with CD8+ T-lymphocytes and macrophages dominating the cellular infiltrate. The detection of interstitial alpha-SMA, probably staining myofibroblasts implicated in renal fibrogenesis, indicated a low glomerular filtration rate 1 year after renal biopsy.

Wegener's granulomatosis: clinical course in 108 patients with renal involvement.

BACKGROUND: The aim of this study was to evaluate the clinical course of patients with Wegener's granulomatosis and renal involvement, with special reference to relapse rate, renal and patient survival and morbidity from serious infections. METHODS: A retrospective analysis was carried out of 108 patients presenting with Wegener's granulomatosis and active renal disease in eight hospitals in Norway between 1988 and 1998. Multivariate analysis was used to investigate whether selected variables predicted relapse, renal and patient survival and serious infections. RESULTS: Median follow-up was 41.5 months. Twenty-two patients (20.4%) were admitted with a need for dialysis. Complete remission was obtained in 81.5% after a median of 4 months, and 54.7% relapsed after a median of 22. 5 months. Two- and five-year renal survival was 86 and 75%, respectively, and 22.8% developed end-stage renal disease (ESRD). Two- and five-year patient survival was 88 and 74%, respectively, and the cumulative mortality was 3.8 times higher than expected. The relative risk of relapse increased with the use of intravenous pulse cyclophosphamide compared with daily oral cyclophosphamide. Initial renal function predicted renal survival, and low serum albumin and high age at treatment start increased the mortality risk. Thirty one per cent of the patients were hospitalized for serious infections during follow-up. Old age increased the risk of having an infection. CONCLUSIONS: The current treatment of Wegener's granulomatosis does not prevent relapse, development of ESRD and serious treatment-induced infections in a considerable fraction of the patients. Alternative strategies for the management of this disease will be an important objective for further studies.

Changes in tonsillar tissue in early HIV-1 infection and during 3 years of antiretroviral therapy.

Tonsillar tissue from individuals in the early stages of HIV-1 infection was studied during the natural course of infection and during antiretroviral therapy with and without a protease inhibitor in order to investigate markers of clinical progression and evaluate the effects of therapy. Tonsillar biopsies and blood samples were collected at regular intervals during 3 years and clinical observations were noted. Tonsillar morphology was evaluated and the fragmentation of the follicular dendritic cell network was quantified by standardised follicular fragmentation rate (FR) analysis. Lymphocyte subsets were phenotyped by flow cytometry, and viral load was calculated by limiting dilution assay. The FRs were higher in the HIV-1-infected individuals than in the uninfected controls, although tonsillar tissue from both groups contained follicular fragmentation. During HIV-1 infection, the FR increased and the tonsillar CD4/CD8 ratio declined. During maximum viral suppression, FR approached that of controls while tonsillar T cell subsets and blood CD4 cell counts normalised. Even when virus suppression was incomplete, tonsillar improvements were observed in parallel with a resolution of the HIV-1-related dermatological disorders. However, persistent viral replication paralleled distortion of the tonsillar architecture. We suggest that a normalisation of the lymphoid tissue may have important functional and clinical implications in HIV-1 infection.

Microscopic polyangiitis diagnosed at hysterectomy.

A 78 year old female developed polyneuropathy, weight loss, malaise, and joint pain. Necrotizing vasculitis was diagnosed at hysterectomy, and later renal biopsy demonstrated focal segmental necrotizing glomerulonephritis. The pathological findings together with the presence of pANCA was consistent with a diagnosis of microscopic polyangiitis (MPA). This is the first clinical description of MPA with involvement of the uterus.

A novel syndrome of diabetes mellitus, renal dysfunction and genital malformation associated with a partial deletion of the pseudo-POU domain of hepatocyte nuclear factor-1beta.

Mutations in the homeodomain-containing transcription factor hepatocyte nuclear factor (HNF)-1beta are the cause of one form of maturity-onset diabetes of the young (MODY), type 5 (MODY5). We have studied a Norwegian family, N5, with a syndrome of mild diabetes, progressive non-diabetic renal disease and severe genital malformations. The sequence of the HNF-1beta gene ( TCF2 ) revealed a 75 bp deletion in exon 2 (409-483del) which would result in the synthesis of a protein lacking amino acids Arg137 to Lys161 (R137-K161del). This deletion is located in the pseudo-POU region of HNF-1beta, a region implicated in the specificity of DNA binding. Functional studies of R137-K161del HNF-1beta revealed that it could not bind an HNF-1 target sequence or stimulate transcription of a reporter gene indicating that this is a loss-of-function mutation. The R137-K161del allele co-segregated with diabetes and renal disease in pedigree N5. In addition, two of four female carriers with this mutation had vaginal aplasia and rudimentary uterus (Müllerian aplasia). These studies strongly suggest that heterozygous mutations in the HNF-1beta gene are associated with a syndrome characterized by MODY and severe, non-diabetic renal disease. Moreover, the presence of internal genital malformations in two females suggests that additional clinical features may be associated with HNF-1beta mutations.

Correlates of latent and productive HIV type-1 infection in tonsillar CD4(+) T cells.

Correlates of virus load and characteristics of virus-producing cells in tonsillar tissue were investigated. Our results suggest that when less than 1:100 tonsillar CD4(+) T cells from individuals infected with HIV type-1 (HIV-1) contain replication competent provirus, the level of CD4(+) T cells in tonsils is comparable to that observed in uninfected individuals. Virus load at or above this level was associated with low CD4 cell numbers in tonsillar tissue. Only a few percent of all infected T cells in tonsillar tissue were active virus producers, with minor differences observed between individuals. Plasma viremia was found to correlate with infectious virus load in tonsillar tissue. With less than 1:1,000 of CD4 cells in lymphoid tissues being involved in active virus production, direct cytopathic effect by HIV-1 on infected CD4 cells is unlikely to fully explain the immunodeficiency seen in AIDS.

Autoregulation of total and zonal glomerular filtration rate in spontaneously hypertensive rats with mesangiolysis.

In this study we tested the hypothesis that mesangial cells participate in autoregulation of the glomerular filtration rate (GFR) in normotensive and hypertensive rats. Mesangial cell lesions were induced by intravenous administration of antithymocyte (anti-Thy 1.1) antibodies in spontaneously hypertensive rats (SHR) and in Wistar-Kyoto rats (WKY). Normal murine serum was injected in control rats. Hemodynamic measurements were performed 24 h after the infusion of the anti-Thy 1.1 antibodies. Renal blood flow (RBF) was measured by a transit time flowmeter (Transonic) and the GFR was measured as the uptake of 125 iodine-labeled aprotinin ([125]I-Ap) by proximal tubular cells at the control renal arterial pressure and (131)I-Ap at a pressure reduction close to the lower pressure limit of RBF autoregulation. RBF was unaltered and the autoregulatory capability was maintained in SHR and WKY after mesangial cell lesions. Mesangiolysis significantly reduced the total GFR in normotensive, but not in hypertensive animals. The fractional compensation of the GFR was attenuated in the outer cortical layer (p<0.05) in normotensive WKY. In SHRs the fractional compensation of the GFR was impaired in all cortical layers after mesangiolysis, slightly more in the outer than in the inner cortex. We conclude that mesangial cells may contribute to the autoregulation of GFR in hypertensive rats, but to a lesser extent in normotensive rats.

Reduced CD4 cell counts in blood do not reflect CD4 cell depletion in tonsillar tissue in asymptomatic HIV-1 infection.

OBJECTIVE: To investigate whether the loss of CD4 cells seen in peripheral circulation of HIV-1-positive individuals reflects a similar depletion of CD4 cells from lymphoid tissue. DESIGN: CD4 and CD8 cells in tonsillar mononuclear cell suspensions were quantified relative to tonsillar B cells, as these were thought to remain numerically unchanged in the course of HIV infection. Results were related to the CD4 cell counts in blood and to the clinical status of the patients. METHODS: Blood samples and tonsillar tissue were obtained from 13 HIV-1-seropositive individuals and six seronegative controls. B cells and T-cell subsets in mononuclear cells were quantified using a three-colour flow cytometry protocol. Histological sections were morphologically classified and B-cell areas were quantified by morphometry. RESULTS: The B-cell fraction was confirmed to be relatively unchanged in asymptomatic HIV-1-seropositive individuals compared with controls. The tonsillar CD4 : B-cell ratios in asymptomatic individuals was similar to those seen in controls, whereas the CD4 : B-cell ratios in symptomatic HIV-1-infected individuals were greatly reduced. The tonsillar CD4 : CD8 cell ratios in HIV-1-infected individuals were much lower than those seen in controls, in the asymptomatic group due to a considerable expansion of the tonsillar CD8 cell subset, and in the symptomatic group also due to a loss of CD4 cells. CONCLUSIONS: We found no evidence of CD4 cell depletion in tonsillar tissue in asymptomatic HIV-1-infected individuals despite low CD4 cell counts in blood. Loss of CD4 cells from this lymphoid tissue seems to occur as a late-stage phenomenon correlated with the onset of clinical symptoms.

An immunohistochemical study of lysozyme in the skin of psoriatic patients.

The distribution of lysozyme was investigated in psoriatic skin lesions, perilesional skin and in skin from healthy controls, using the immunoperoxidase techniques avidin-biotin complex and alkaline phosphatase-anti alkaline phosphatase. Lysozyme was identified in polymorphonuclear leukocytes present in the Munro microabscesses and also occasionally in other parts of the skin, as shown by very strong cytoplasmic staining. Stratum corneum, stratum granulosum and stratum spinosum were weakly stained. In some cases positive staining along the dermal collagen bundles was demonstrated and is most likely to be related to the number of inflammatory cells in the papillary dermis. Psoriatic skin lesions stained significantly stronger for lysozyme than did perilesional skin (p < 0.0001), whereas skin from healthy controls stained weakly positive or was lysozyme negative. Lysozyme may be of some importance in the psoriatic disease process. By comparison the alkaline phosphatase-anti-alkaline phosphatase was found to be the most specific of the two techniques.

Renal effects of maintenance low-dose cyclosporin A treatment in psoriasis.

The renal effects of low-dose cyclosporin A (CsA) treatment in severe psoriasis was investigated in 10 patients treated with a mean CsA dose of 3.23 (range 1.94-4.10) mg/kg/day for 12 months. The psoriasis area and severity index was reduced by 63-76%. Ambulatory GFR (iothalamate-125I), ERPF (hippuran-131I), RVR and MAP were examined at 3-months intervals. A control renal biopsy was performed shortly before treatment start and a second biopsy was taken after 12 months of therapy. GFR was slightly but significantly reduced after 6 and 9 months; after 12 months the decrease was not significant (121.0 +/- 7.6 versus 115.2 +/- 7.8 ml/min/1.73M2, P > 0.10). After 12 months serum creatinine increased from 82 +/- 4 to 94 +/- 7 mumol/litre (P < 0.05), while an insignificant increase of ERPF was seen and FF decreased from 0.29 +/- 0.01 to 0.26 +/- 0.01 (P < 0.05). MAP remained unchanged. GFR and serum creatinine correlated significantly within each 3-month interval. A slight de novo interstitial fibrosis was seen in the second biopsy in 4 of 10 patients receiving a mean CsA dose of 3.2-4.1 mg/kg/day. In three of these patients a concomitant rise in serum creatinine was seen. In conclusion, low-dose CsA was associated with reversible fall in GFR and potentially progressive structural changes not always accompanied by corresponding functional alterations. One should consider reducing the daily dose of CsA to 3.0 mg/kg bodyweight or less in CsA therapy up to 1 year.

Is Helicobacter pylori the cause of dyspepsia?

OBJECTIVE: To determine the association between infection with Helicobacter pylori and dyspepsia. DESIGN: Cross sectional study of dyspeptic subjects and age and sex matched controls identified by a questionnaire survey of all inhabitants aged 20-69. (Endoscopy, histological examination, and microbiological examinations of biopsies from the gastric mucosa were performed blind.) SETTING: Population based survey in Sørreisa, Norway. SUBJECTS: All 782 dyspeptic subjects (excluding those with a previous history of peptic ulcer, gall stones or kidney stones, and coronary heart disease) and controls were offered an endoscopy, of whom 309 dyspeptic subjects and 310 controls attended. MAIN OUTCOME MEASURES: Prevalences of endoscopic and histological diagnoses and of cultures positive for H pylori. RESULTS: A high prevalence of positive cultures, increasing with age, was found in both dyspeptic subjects (48%) and non-dyspeptic controls (36%) (p = 0.004). Positive cultures in both dyspeptic subjects and controls were strongly associated with histological gastritis (70%, 95% confidence interval 65.5 to 85.3; 60%, 52.7 to 67.7, respectively) and peptic ulcer (92%, 61.5 to 99.8; 64.1, 9.4 to 99.2, respectively). Only 3% of subjects with a histologically non-inflamed gastric mucosa had this infection (dyspeptic subjects 2%, 0.2 to 7.0; controls 4%; 1.2 to 8.8). CONCLUSIONS: The relation between dyspeptic symptoms and H pylori is dubious; H pylori seems to have a pathogenetic role in gastritis and may be a contributing factor but not a cause of peptic ulcer.

A high-affinity folate binding protein in proximal tubule cells of human kidney.

High-affinity 3H-folate binding in solubilized brush border membranes of human kidney cortex display characteristics such as apparent positive cooperativity typical of specific folate binding. The folate binding activity and the activity of the brush border membrane-marker enzyme, gamma-glutamyltransferase, were eightfold higher in brush border membranes compared to crude kidney homogenate. Ultrogel AcA 44 chromatography revealed a major (Mr approximately 100 kDa) and a minor (Mr approximately 25 kDa) folate binding protein in brush border membranes. The large molecular size form may represent a membrane-derived hydrophobic folate binding protein inserted in Triton X-100 micelles. This notion was supported by the identical molecular weights of the 100 kDa and 25 kDa folate binding peaks determined by sodium dodecylsulfate polyacrylamide gel electrophoresis and immunoblotting. The folate binding protein in renal brush border membranes cross reacted with rabbit antibodies against 25 kDa human milk folate binding protein, and showed immunoprecipitation in the presence of these antibodies. Paraffin embedded sections of kidney cortex showed immunostaining of cells in the convoluted proximal tubules after exposure to rabbit antiserum (1:8000 dilution). Glomeruli and distal tubules showed no immunostaining.