Parathyroid carcinoma secondary to prolonged hyperplasia in chronic renal failure and in coeliac disease.

The presentation of parathyroid carcinoma in patients with chronic renal failure is rare, although with improvements in life expectancy associated with this condition there have now been 12 reported cases, including the first case we report here. It has been proposed that in these cases there has been a malignant transformation of benign parathyroid hyperplastic tissue. We also report the first case of parathyroid carcinoma associated with coeliac disease and suggest that the same mechanism may be responsible. We review the presentation, diagnosis, treatment and natural history of the disease.

Pulmonary artery sarcoma mimicking pulmonary embolism: successful surgical intervention.

Because of its rarity and the similarity of its presentation to that of pulmonary thromboembolic disease, the diagnosis of pulmonary artery sarcoma is often not considered early in patients presenting with recurrent or chronic pulmonary emboli. We present a case of pulmonary artery sarcoma that was treated as pulmonary embolism for 3 years before surgical resection was carried out. Two years after the resection the patient is well with no clinical or radiologic evidence of recurrent or metastatic disease.

Improved survival in lupus nephritis in the modern era (1979 - 1989).

We analysed outcome retrospectively in relation to treatment and disease stage in patients with systemic lupus erythematosus and glomerulonephritis, and compared these with similar patients referred to us during 1969 - 78, and other published series from the same period. Eighty two patients with lupus nephritis were referred during 1979 - 89. Of these, 73 were followed up for a mean of 58.1 (SD 34.5) months. The histological pattern in renal biopsies was WHO Class IV (diffuse proliferative glomerulonephritis) in 59% of patients. In the acute phase 43 patients received intravenous nethyl-prednisolone IG daily, for three days, in 25 accompanied by daily 4 litre plasma exchanges on 5 to 10 days. Twelve patients received induction therapy using oral cyclophosphamide during the acute phase, for 8 - 12 weeks only. Maintenance therapy was with oral prednisolone in all patients, accompanied by azathioprine in 84% of cases. Long- term cyclophosphamide was never used, neither intravenously nor orally. At 10 years actuarially calculated patient survival was 87% and survival of renal function 86% compared with 57% and 65% respectively in 1970 - 78 ([P < 0.01]). Survival was no different in patients with renal biopsies classified into the various WHO classes. In patients with Class IV biopsies, survival in those treated with prednisolone and azathioprine only was the same as that in those given intravenous methylprednisolone and/or plasma exchange as well. However, patients treated with methylprednisolone or plasma exchange tended to have more severe disease. At last followup, 24/82 patients were in complete remission, 23 had normal plasma creatinine concentrations but abnormal urine, ie proteinuria, haematuria, or both, 16 had abnormal urine and elevated plasma creatinine concentrations, and 9 had started renal replacement therapy. Eight patients had died. The survival of patients with lupus nephritis has improved in the past decade in patients with comparable severity of disease, and renal failure is no longer the principle cause of death. Results of maintenance treatment using azathioprine as adjunct to oral prednisolone in patients with severe nephritis are as good as those in series published elsewhere describing regular intravenous cyclophosphamide. No clear advantage was evident from the additional use of intravenous methylprednisolone and/or plasma exchange in the acute phase, in patients with WHO Class IV severe diffuse proliferative glomerulonephritis.

Improved survival in lupus nephritis in the modern era (1979 - 1989) using only oral corticosteroids and azathioprine as maintenance

The authors analysed outcome retrospectively in relation to treatment and disease stage in patients with systemic lupus erythematosus and glomerulonephritis; and compared these with similar patients referred to us during 1969 - 78; and other published series from the same period. Eighty two patients with lupus nephritis were referred during 1979 - 89. Of these; 73 were followed up for a mean of 58.1 (SD 34.5) months. The histological pattern in renal biopsies was WHO Class IV (diffuse proliferative glomerulonephritis) in 59 per cent of patients. In the acute phase 43 patients received intravenous nethyl-prednisolone IG daily; for three days; in 25 accompanied by daily 4 liter plasma exchanges on 5 to 10 days. Twelve patients received induction therapy using oral cyclophosphamide during the acute phase; for 8 - 12 weeks only. Maintenance therapy was with oral prednisolone in all patients; accompanied by azathioprine in 84 per cent of cases. Long term cyclophosphamide was never used; neither intravenously nor orally. At 10 years actuarially calculated patient survival was 87 per cent; and survival of renal function 86 per cent; compared with 57 per cent and 65 per cent respectively in 1970 - 78 (p less than 0.01). Survival was no different in patients with renal biopsies classified into the various WHO classes. In patients with Class IV biopsies; survival in those treated with prednisolone and azathioprine only was the same as that in those given intravenous methylprednisolone and/or plasma exchange as well. However; patients treated with methylprednisolone or plasma exchange tended to have more severe disease. At last followup; 24/82 patients were in complete remission; 23 had normal plasma creatinine concentrations but abnormal urine; ie proteinuria; heaematuria; or both; 16 had abnormal urine and elevated plasma creatinine concentrations; and 9 had started renal replacement therapy. Eight patients had died. The survival of patients with lupus nephritis has improved in the past decade in patients with comparable severity of disease; and renal failure is no longer the principle cause of death. Results of maintenance treatment using azathioprine as adjunct to oral prednisolone in patients with severe nephritis are as good as those in series published elsewhere describing regular intravenous cyclophosphamide. No clear advantage was evident from the additional use of intravenous methylprednisolone and/or plasma exchange in the acute phase; in patients with WHO Class IV severe diffuse proliferative glomerulonephritis

Immunohistochemical studies of the peritoneal membrane and infiltrating cells in normal subjects and in patients on CAPD.

We performed immunohistochemical studies on biopsies of the parietal peritoneal membrane of 33 subjects to investigate whether other cell populations, in addition to mononuclear cells free in the dialysate, might participate in the defense of the peritoneum against microbial invasion during CAPD. Leukocytes were found to concentrate in two areas: a submesothelial layer composed of elongated macrophages displaying activation and maturation markers, and perivascular, less mature macrophages closely associated with T cells and HLA-DR, ICAM-1 and VCAM-1 expressing endothelial cells. Normal mesothelial cells were found to express constitutively the transferrin receptor and the adhesion molecules ICAM-1 and VCAM-1 but not ELAM-1. There were no major differences between normal and uremic subjects, while peritoneal dialysis patients exhibited minor derangements of the submesothelial layer and slight up-regulation of the expression of HLA-DR on endothelial cells. Peritonitis was associated with increased submesothelial cellularity and, particularly, perivascular leukocyte infiltration accompanied by increased expression of HLA-DR and adhesion molecules. Besides mononuclear cells free in the dialysate, this study demonstrates the existence of two additional peritoneal membrane leukocyte populations: submesothelial macrophages, and perivascular macrophages and T cells. It also suggests the existence of a fourth population of intracavitary leukocytes adherent to mesothelial cells. Studies are now necessary to evaluate their exact role in the host defence against peritonitis during CAPD.

Sodium-lithium countertransport activity as a determinant of deterioration of glomerular function in IgA nephropathy.

We measured Na+/Li+ CT in 16 IgA nephropathy patients. Records were reviewed (mean observation period 5.5 years) for serial measurements of blood pressure (BP), urinary protein excretion, GFR (51Cr-EDTA) and plasma creatinine. Na+/Li+ CT correlated with the slope of the plot of GFR versus time (rs = -0.66, p = 0.005) systolic BP at diagnosis (rs = 0.62, p = 0.011) and both systolic and diastolic BP at the end of follow-up (rs = 0.69, p = 0.003, and rs = 0.56, p = 0.023). A diastolic blood pressure (DBP) > or = 95 mm Hg was associated with a faster rate of GFR decline (rate of change of GFR: -0.40 vs. -0.14 ml/min/month, p = 0.07; for DBP > or = 95 vs. < 95 mm Hg, respectively). In a multiple regression analysis with the rate of decline of GFR as dependent variable, Na+/Li+ CT emerged as a significant and independent determinant of the rate of fall of GFR (beta coefficient -1.56, SE beta 0.49, p = 0.006) and explained 52.7% of the variation in the GFR fall. Higher activities of Na+/Li+ CT are significantly associated with an increased rate of deterioration of renal function in IgA nephropathy; part of this effect could be mediated by higher blood pressure values.

A survey of degenerative arterial change in the capsule of the hip joint in different disease states.

Degenerative arterial disease does affect the ligamentum teres and the capsule of the hip joint. In this investigation, the frequency of these changes was investigated in four groups of patients with hip disease. It is concluded that the highest incidence of all of degenerative arterial disease is found in elderly patients with subcapital fractures and in young patients with avascular necrosis of the femoral head after renal transplantation. The significance of this finding needs to be investigated further.

ICAM-1 expression in renal disease.

AIM: To determine the role of intercellular adhesion molecule-1 (ICAM-1) in immune mediated damage in glomerulonephritis, and whether its expression correlates with disease activity. METHODS: Fifty three renal biopsy specimens from a range of non-immune renal disease and low grade and high grade glomerulonephritides were stained with ICAM-1. Positivity was assessed in the tubules. Tubular damage and accompanying interstitial inflammation were also noted. The ICAM-1 positivity in damaged and undamaged tubules was correlated with the three groups of renal disease. RESULTS: ICAM-1 positivity in undamaged tubules was observed in glomerulonephritis, and this showed a strong correlation with disease activity. In contrast, ICAM-1 positivity on damaged tubules correlated with evidence of chronic tubular damage, and was seen in a large proportion of cases, regardless of the underlying disease. There was no correlation between ICAM-1 positivity and a local lymphocytic infiltrate. CONCLUSION: ICAM-1 probably has an important role in the pathogenesis of glomerulonephritis. Its expression may be secondary to cytokines released by cells participating in the glomerular damage. As these cytokines also influence tubule function, tubular ICAM-1 expression may be a marker of the extent of tubular disturbance in glomerulonephritis.

Recurrence of focal segmental glomerulosclerosis in transplanted kidneys: analysis of incidence and risk factors in 59 allografts.

Fifty-nine allografts were placed in 43 patients with renal failure from focal segmental glomerulosclerosis (FSGS): 27 allografts were put into 16 children aged less than 15 years, and 32 allografts into 27 adolescents and adults. Recurrence of FSGS was noted histologically in 13 allografts, 10 in 8 children and 3 in adults. None of the 9 children and 24 adults who never developed an allograft nephrotic syndrome showed FSGS in their allograft biopsies. The age of onset was a strong risk factor for recurrence: recurrent FSGS developed in 8 of 16 children (50%) but only in 11% of adolescents and adults (3 of 27 patients). Although the time from apparent onset to renal replacement treatment was shorter in those with recurrence than those without in the children, there was no difference in the time spent on dialysis prior to transplantation. Mesangial prominence was observed in the original biopsy in 12 of 13 patients with recurrence, and recurrence rate was similar in living and cadaver donor allografts; class I MHC matching was similar in those with and without recurrence. Three allografts treated with cyclosporin A as well as 9 with azathioprine showed recurrence. Of 9 second or subsequent allografts placed in those with recurrence in the first allograft, only 3 showed further recurrence. In 3 re-grafted after 13, 11 and 5 years, normal function was seen.

Lupus nephritis: correlation of interstitial cells with glomerular function.

Mononuclear inflammatory cells were studied using monoclonal antibodies in the interstitium and glomeruli of 35 renal biopsy specimens from patients with lupus nephritis already taking immunosuppressants. The aims of this study were to assess the composition and significance of the infiltrate, and to assess correlations with immediate glomerular function and ability to predict the future course of the disease. The majority of interstitial cells were T lymphocytes and monocytes/macrophages. The number of interstitial CD4 + ve T helper/inducer lymphocytes was greater than that of CD8 + ve T cytotoxic/suppressor cells in only 19 out of 35 biopsies, the mean CD4:CD8 ratio being only 1.5 +/- 1.2. NK cells and B lymphocytes were a minor component only. Some expression of IL-2, transferrin and C3b receptors was seen on interstitial cells, but HLA-DR expressing cells were much in excess of controls and the numbers of tubular cells expressing HLA-DR was also increased. The number of interstitial T cells, CD4 + ve cells and monocytes/macrophages was highly correlated with the extent of chronic damage judged by optical microscopy. There was also an association between glomerular function at biopsy and numbers of interstitial T cells, CD8 + ve cells, monocytes/macrophages and DR expressing cells. Subsequent decline in renal function, however, was associated only with numbers of monocytes/macrophages and the rather small number of C3b receptor-positive cells. The presence of tubulointerstitial immune aggregates of Ig and/or C in 63% of patients was associated with greater numbers of NK cells. As previously described, the degree of renal function at biopsy correlated with a chronicity index based on optical microscopy. No correlations were found between numbers or types (mostly monocyte/macrophages) of intraglomerular leukocytes and clinical or biopsy features, except that more proliferative types showed greater leukocyte numbers. One hypothesis consistent with our findings is that interstitial T cells and monocytes may be important determinants of pathogenesis and progression of lupus nephritis. While several mechanisms may play an initial role, interstitial monocytes may be the major factor in chronic injury.

Immune mechanisms in idiopathic membranous nephropathy: the role of the interstitial infiltrates.

Mononuclear inflammatory cells in renal biopsies from 36 patients with membranous nephropathy (MN) were analyzed, using monoclonal antibodies. In the interstitium, monocytes/macrophages and T cells were the predominant cell types (210 +/- 27 and 171 +/- 25/mm2, respectively); in contrast, very few intraglomerular leucocytes, mostly macrophages (1.0 +/- 0.7 cell/glomerular cross-section), were found. Among the interstitial T-cell population, helper/inducer cells (CD4+) predominated (CD4:CD8 ratio, 2.2 +/- 1.5). Natural killer (NK) cells and B lymphocytes were a minor component of the interstitial infiltrates and were almost absent in the glomeruli. Significantly higher numbers of DR-expressing cells were found in the interstitium (322 +/- 20/mm2) than in controls (109 +/- 30), but tubular DR expression was similar to controls (17 +/- 12 mm2). The numbers of total leukocytes and their subsets CD4+, CD8+, monocytes/macrophages, and B cells all correlated with the degree of renal impairment at the time of biopsy, but surprisingly there was no correlation between interstitial cell numbers and the histological severity of tubulointerstitial lesions. Progressive renal impairment over 5 years was associated with many interstitial T cells and monocytes/macrophages in the initial biopsy. Our results suggest that interstitial mononuclear cells may be important determinants in the pathogenesis of MN. Both cellular and humoral immune mechanisms may play a major role in the initiation of the disease, whereas progression toward renal failure seems to be determined mainly by cell-mediated immunity.

Diagnosis of rejection in renal allograft biopsies using the presence of activated and proliferating cells.

Forty cyclosporine-treated renal allograft biopsies were stained with anti-Tac, a monoclonal antibody (MoAb) against interleukin 2 receptor (CD25), anti-transferrin receptor MoAb, and Ki67 MoAb (a proliferating cell marker), using a method of gold enhancement of the diaminobenzidine reaction product, in order to study the utility of these markers to differentiate rejection from other causes of graft dysfunction. Biopsies were selected on the basis of availability of sufficient frozen material and optical microscopy diagnosis, and only biopsies that showed acute cellular rejection and biopsies that did not show any sign of rejection (cyclosporine toxicity or a stable graft) were studied. In addition biopsies were stained with a panel of monoclonal antibodies reacting with CD45, CD3, CD4, CD8, EBM11 (a monocyte-macrophage marker), HLA-DR, DP, and DQ, using the usual indirect immunoperoxidase method. The clinical diagnosis (rejection versus no rejection) was made in ignorance of the biopsy findings. In 17 of 18 (94%) episodes of rejection, anti-Tac and anti-transferrin receptor-positive cells, and in 15 of 18 rejection episodes (83%), proliferating cells, were found in the interstitium. Anti-Tac-positive cells were never found in the 11 biopsies diagnosed as no rejection, and only in two a few anti-transferrin receptor-positive cells were present. The proportion of activated and proliferating cells in rejection episodes, expressed as the percentage of CD45-positive cells were: anti-Tac MoAb 4.1 +/- 2.9%, anti-transferrin receptor MoAb 6.9 +/- 3.9%, and Ki-67 MoAb 6.3 +/- 4.8%. There was a positive correlation between the total number of infiltrating cells and the number of cells stained with anti-Tac (r = 0.75, P less than 0.005), anti-transferrin receptor MoAb (r = 0.84, P less than 0.0001), and Ki-67 (r = 0.50, P less than 0.05). The episodes of rejection that took place when cyclosporine levels were high had fewer 1L-2R-bearing cells in the interstitium than those that took place when cyclosporine levels were low (r = 0.47, P less than 0.05). We conclude that during rejection the presence of activated and proliferating cells is a consistent finding, and that these markers could be useful in differentiating between rejection and other causes of graft dysfunction as well as in grading the severity of rejection.

The role of interstitial infiltrates in IgA nephropathy: a study with monoclonal antibodies.

The leucocyte subpopulations in the interstitium and the glomeruli in renal biopsies from 34 patients with IgA nephropathy were analysed using monoclonal antibodies and immunoperoxidase techniques. Monocyte/macrophages and T-cells constituted the predominant infiltrating cell type in the interstitium (278 +/- 24 and 269 +/- 37 cells/mm2 respectively). Few intraglomerular leucocytes were seen, the majority of them belonging to the monocyte/macrophage phenotype (1.1 +/- 0.1 cells/glomerular cross-section). CD4+ lymphocytes predominated among the interstitial and glomerular T-cell populations and the CD4:CD8 ratio was 2.1 +/- 1.1 and 2.4 +/- 1.5 respectively. Only small numbers of NK cells and B cells were found in the interstitium, and almost none in the glomeruli. In contrast, significantly increased numbers of DR-expressing interstitial cells were seen (487 +/- 29/mm2), whereas DR expression by the tubular cells was minimal (37 +/- 6/mm2). Numbers of total leukocytes and T-cells were well correlated with the degree of tubulointerstitial damage and there was a significant correlation between renal functional impairment at the time of biopsy and the numbers of interstitial T cells (P less than 0.05) and CD4+ T cells (P less than 0.01). In contrast, interstitial mononuclear cells did not correlate with subsequent progression of the disease over 2-3 years. However, a more rapid decline of renal function was associated with increased numbers of interstitial B cells. No association was found between intraglomerular cells and degree of renal impairment either at the time of biopsy or in the long term.(ABSTRACT TRUNCATED AT 250 WORDS)

An unusual local reaction to continuous subcutaneous infused terbutaline in unstable asthmatics.

Three out of nine unstable asthmatics whose asthma is subjectively and objectively better controlled on continuous subcutaneous terbutaline infusions (6-12 mg/24 hours) developed tender indurated subcutaneous swellings at the infusion site. In the two cases reported here in detail, histologically the lesions were areas of panniculitis and deep dermal collagen necrosis. Further investigation of the possible causative mechanism for these lesions--drug solution pH, osmolality, or impurities--suggests that impurities in the solution are the most likely cause.

Malignant hemangiopericytoma of the parapharyngeal space.

Hemangiopericytoma is a rare vascular neoplasm, occasionally occurring in the head and neck region. Diagnosis is made histologically, but even then, it is difficult to predict the behavior of the tumor in an individual patient. The patient described in this report presented with symptoms of parapharyngeal compression due to such a tumor. It is believed that malignant hemangiopericytoma has not been previously reported in this site.

Histopathological changes in cyclosporin-treated renal allografts biopsied at one and twelve months.

Forty-four renal allograft recipients were biopsied routinely one month and one year after transplantation. All patients received cyclosporin and prednisolone. Fifteen patients had at least one rejection episode, while 29 patients never underwent rejection. At one year there were no specific histological features that enabled these two groups to be distinguished. Between one month and one year, interstitial cellular infiltrate and vascular pathology regressed, and renal function steadily improved. Interstitial fibrosis, however, was either unchanged or mildly increased in all patients. There was no correlation between the amount of interstitial fibrosis at one year and either the total dose of cyclosporin or the mean concentration during the first 3 months. Our results suggest that trough, whole blood cyclosporin concentrations, at the upper level of the therapeutic range (800-200 ng/ml), may be safely tolerated during the first 3 months, with little evidence of chronic damage at one year. At one year maintenance doses of cyclosporin can be achieved that are associated with almost normal plasma creatinine concentrations and minimal tubular atrophy and interstitial fibrosis. We expect that such doses may be continued indefinitely.

Morphological differentiation between rejection and cyclosporin nephrotoxicity in renal allografts.

In a prospective study of renal dysfunction in 60 consecutive allograft recipients treated with cyclosporin and prednisolone routine renal biopsies at one week and one month after transplantation, as well as for all episodes of renal dysfunction, were performed. The one year graft survival of this group was 88%. In a retrospective clinical analysis of these patients 35 episodes of dysfunction due to rejection, defined by a response to antirejection treatment alone, and 30 episodes due to cyclosporin nephrotoxicity, defined by a response to reduction in cyclosporin dose alone, were identified. The morphological findings from these biopsies were compared with 20 samples from routine biopsies taken from patients with stable renal function. All patients diagnosed as having rejection had a diffuse, interstitial mononuclear cell infiltrate (32 of 35) or arteritis (19 of 35), or both. In contrast, focal mononuclear cell infiltrates were common in both patients with nephrotoxicity and those with stable function (17 of 30 and 14 of 20, respectively). There were no important differences between biopsies from those with nephrotoxicity and those with stable function, except that arteriolar hyalinosis was considerably more common in the nephrotoxic patients than in those with stable function. Many patients with stable function were, in retrospect, in a state of stable mild nephrotoxicity. In our experience rejection should only be diagnosed when there is at least a diffuse interstitial infiltrate or an arteritis. Focal mononuclear cell infiltrates do not denote rejection. The development of arteriolar lesions in the absence of rejection is indicative of nephrotoxicity.

Glomerular thrombi in renal allografts associated with cyclosporin treatment.

We have found glomerular capillary thrombi or afferent arteriolar thrombosis in eight renal biopsy specimens from seven renal allograft recipients. All patients were receiving cyclosporin and prednisolone. Biopsies were performed either routinely one and four weeks after transplantation or during periods of renal dysfunction. None of the patients whose biopsy material contained glomerular thrombi was considered, in retrospect, to have been undergoing rejection at the time of biopsy. Thrombi consisted of finely granular material partially obstructing glomerular capillaries. By light microscopy the staining characteristics of the thrombi were compatible with platelet-fibrin aggregates, and this was confirmed by immunoperoxidase examination. Such thrombi have not previously been seen in biopsy material from patients treated with prednisolone and azathioprine, except rarely associated with acute vascular injection. In none of these patients was there haematological evidence of the haemolytic uraemic syndrome as has been reported in bone marrow recipients treated with cyclosporin.

Acute tubular necrosis, caused by therapeutic doses of paracetamol?

Reversible acute renal failure of unknown cause occurred in two men after taking paracetamol in therapeutic doses. Tubular necrosis was present; liver function was normal. We postulate that these patients might have formed arylating metabolites of paracetamol within the kidney which bound to tubular cells causing necrosis. Such events may not be infrequent but are unrecognized because paracetamol is not regarded as nephrotoxic in standard dosage. We suggest that a detailed history in cases of acute renal failure should include direct enquiry as to the ingestion of paracetamol in order to collect information on this point.