Cyclosporine-associated nephropathy in patients with heart and bone marrow transplants.

The morphology of kidneys from heart (n = 55) and bone marrow (n = 112) transplant recipients treated either with cyclosporine (CSA) or conventional immunosuppression was investigated at autopsy. The major findings were: In the bone marrow transplant recipients glomerular collapse, tubular atrophy, interstitial fibrosis, striped form, CSA-associated arteriolopathy and thrombi in glomeruli and/or arterioles were more often found in the CSA group as compared to conventional immunosuppression. In the heart transplant recipients glomerular collapse and obsolescence, tubular atrophy and intimal fibrosis in arteries were more frequent in the CSA group. Vascular interstitial toxicity known to be associated with CSA treatment from renal transplant patients was found in 54% (25% severe) of the bone marrow and 19.5% (9.7% severe) of the the heart transplant recipients. The prevalence of vascular interstitial toxicity in bone marrow versus heart transplant recipients is possibly due to higher CSA dosage and pretreatment with cytostatic drugs and irradiation. Analyses of the lesions from early stages to the full picture of vascular interstitial toxicity suggests that CSA causes a form of thrombotic microangiopathy with focal glomerular and/or arteriolar thrombosis followed by typical CSA-associated arteriolopathy which results in interstitial fibrosis with tubular atrophy.

Cytomegalovirus and kidney.

This study was conceived to identify specific morphological characteristics associated with cytomegalovirus (CMV) infection of the kidney. 33 patients with manifest CMV infection at autopsy and 32 biopsies of kidney transplants with active or inactive CMV infection were studied. In 8 patients of the autopsy group a CMV infection of the kidney was detected (CMV cells in 3 cases, positive viral tissue culture in 4 cases, positive in-situ hybridization in one case), which was associated with severe dissemination into different organs. In situ hybridization was not superior to ordinary light microscopy in the detection of CMV cells. The biopsies were screened for the presence of glomerulopathy. No association of glomerulopathy with CMV could be found by light microscopy, whereas a significant correlation of glomerulopathy with vascular rejection was demonstrated. No differences as to the incidence of glomerulopathy were found, when non-transplant patients with manifest CMV infection at autopsy were compared with matched controls. With active infection electron microscopy revealed no osmiophilic deposits, but in immunofluorescence tiny IgG deposits were identified within the glomeruli (p less than 0.01). IgM or C3 deposition in the glomeruli was not specifically associated with either CMV infection or vascular rejection. Thus morphological identification of CMV infection of the kidney is difficult, necessitating the detection of CMV cells, positive viral tissue culture or positive in-situ hybridization. Glomerulopathy in light microscopy is associated with vascular rejection and is therefore termed transplant glomerulitis. Tiny IgG deposits may be indicative of CMV infection, although these are not always present.

[Analgesic nephropathy]. / Die Analgetika-Nephropathie.

Analgesic nephropathy, its morphology, development and pathogenesis are described. The earliest analgesic-caused lesion is capillary sclerosis of the urinary tract mucosa. Later focal necroses can be found in the papillae surrounding the collecting ducts. Foci of necrosis progress and become confluent, resulting in complete papillary necrosis. Later renal cortical lesions develop due to retained areas of papillary necrosis. The cortical changes include chronic interstitial nephritis with cortical atrophy in the suprapapillary region as well as hypertrophy of the columnae Bertini with segmental, focal glomerulosclerosis. The analgesic-related lesions are the result of toxic damage to endothelial, tubular and interstitial cells. Analgesic-induced kidney and urinary tract changes are quite specific. Frequent complications include hypertension, pyelonephritis, hydro- or pyonephrosis and urinary tract tumors. The clinical picture is characterized by the consequences of distal tubular damage: impairment of urine concentrating capacity, acidosis, electrolyte loss. Analgesic nephropathy is an example of an absolutely preventable drug induced nephropathy. It is the most important single manifestation of the analgesic syndrome. It is recommended that prescriptions for mixed analgesics (multi-component analgesics) should be made obligatory. Monocomponent analgesics could be sold over-the-counter.

Capillary sclerosis of the urinary tract and analgesic nephropathy.

Morphology, frequency and significance of capillary sclerosis (CS) in the ureter and electron microscopic findings in early papillary necrosis are described. CS of the urinary tract is characterized by a thickening of the basement membrane of capillaries lying just underneath the urothelium. The basement membrane changes can be demonstrated by PAS, Sudan stain and autofluorescence with equal reliability. By electron microscopy the thickened basement membranes exhibit a tree ring like pattern permeated by lipid vacuoles. CS is most often present in the renal pelvis and the ureter and only in particularly severe cases also in the urinary bladder. The most severe CS is found in the proximal and middle third of the ureter. In a prospective autopsy study CS was found in 3.5% of autopsies of adults and in 83% of clinically recognized phenacetin abusers. Since there is no association with other renal or metabolic diseases, CS can be considered as specific for phenacetin abuse. This finding is further substantiated by a significant correlation between the degree of severity of capillary sclerosis and the daily dose of phenacetin in grams. In about half of the patients with known analgesic abuse but without CS, possible causes for the lack of CS can be identified, of which the most important is regression of CS after stopping the abuse. Electron microscopic studies of early papillary necrosis show the same BM changes as in the ureter in peritubular capillaries, loops of Henle and similar BM alterations in the collecting ducts. The morphologic findings in the ureter and in the renal papilla suggest that CS in papillary necrosis are the consequence of a toxic damage of endothelial and in the kidney of endothelial and epithelial cells.

Chronic interstitial nephritis in Whipple's disease.

Report is given on a 68-year-old man who suffered primarily from progressive weight loss and repeated episodes of fever and arthralgia. Later, liver dysfunction and renal insufficiency developed. Liver and kidney biopsies disclosed granulomatous hepatitis and nephritis. Because of the morphologic and clinical findings, the diagnosis of Boeck's disease was made. Shortly before death, diarrhea developed. Autopsy revealed a massive systemic involvement in Whipple's disease proven by light and electron microscopy and immunofluorescence. Tuberculoid and epitheloid cell granulomas and isolated giant cells were found in addition to the biopsy findings in skeleton muscles, the small intestine, lymphnodes and bronchi. At autopsy, the kidney showed chronic interstitial nephritis. The literature of kidney involvement in Whipple's disease is reviewed. This is the first case with granulomatous interstitial nephritis and chronic renal insufficiency in an inadequately treated Whipple's disease.

[Phenacetin abuse VI: autopsy statistics with special reference to extrarenal findings]. / Phenacetinabusus VI: eine Autopsiestatistik unter besonderer Berücksichtigung extrarenaler Befunde.

Aim of the study is to evaluate whether gastric ulcer, hypertension, myocardial infarction etc. form part of the analgesic syndrome in Switzerland. About 160 autopsies of phenacetin abusers and an appropriate number of non-abusers were systematically evaluated. 18% of phenacetin abusers have gastric ulcers. Thus, gastric ulcers are more frequent in phenacetin abusers than in non-abusers and are probably the consequence of the admixture of salicylates in several compound analgesics. A low body weight (body index 1), which--together with the brownish pigmentation of the skin--contributes to premature aging, is also part of the analgesic syndrome. 50-70% (clinical/pathological findings) of phenacetin abusers are hypertensive. Hypertension is more frequent in phenacetin abusers than in controls but is less likely to be due to the analgesic abuse itself than to analgesic nephropathy. Myocardial infarctions are found in 32% of phenacetin abusers (males 50%, females 20%). Myocardial infarction is not markedly more frequent in phenacetin abusers than in non-abusers. Thromboembolic diseases are clearly increased in controls. Splenomegaly does not, on the basis of autopsy findings, form part of the analgesic syndrome.

[Phenacetin abuse V: number of phenacetin abusers in Basel autopsy material 1978-1980. Results of a prospective study]. / Phenacetinabusus V: Häufigkeit der Phenacetinabuser im Basler Autopsiegut 1978-1980. Ergebnisse einer prospektiven studie.

Between 1978-1890 the incidence of analgesic (phenacetin) abuse in autopsies of adult inhabitants of Basle was 3.87%. Only 2.3% of these were known abusers. The incidence of abuse varied considerably in different age groups, with a maximum of 16% in women in the age group 50-59 years. The sex distribution was male/female 1:1.93. It can therefore be assumed that 1500-3000 inhabitants of Basle actively abuse or abused phenacetin containing analgesics. Extension of the prescription requirement to all salicylate and paracetamol containing analgesics is accordingly recommended.

The challenge of education and training in pathology--the Basle response.

The aim of pregraduate teaching is to form young physicians who are masters in theart of observation and of biological reasoning, two faculties for which pathology is particularly suitable as a teaching instrument. In Basle we teach general pathology in the 3rd year in lecturesand in coordinated histology courses which are programmed. Thus, the student following his booklet with sketches, works up some slides, each step guided by questions which he has to answer in order to go on. In the 4th year the same schedule is followed for special pathology, which in the 6th year is applied at autopsy demonstrations. At these demonstrations a clinician first discusses the clinical history with the students thus preparing the questions which the pathologist has to answer by demonstrating his findings on color television. In other courses the students receive the clinical data and a week later a real clinico-pathological conference is held. Finally pathology is taught in small groups with fresh and formalin-fixed specimens. A great number of audiovisual courses are at the disposition of the students. We use them exclusively for repetition and not for initial teaching. The most important thing for a young pathologist is to learn how to work up biopsies including the knowledge where to find necessary help in the literature, an understandingof the clinical problems, and the precise final diagnois. In doing autopsies he must be able to understand and answer the clinical questions as well as to see the scientific problems. The programme spans 5 years including 1 in clinical work. During the 4 years in pathology the young pathologist, according to a schedule, rotates from one specialist to the other working up the biopsies under supervision. The attendance of several slide seminars organized by the society of pathology is compulsory. The young pathologist does about 300 autopsies and learns how to work up autopsies of junior colleagues. For self-education we prepared audiovisual courses with microscopic sets of slides. The main point in postgraduate education is the conviction of all permanent members of a department that teaching is one of our most important tasks, since with a thorough education of the next generation we are significantly helping to produce better pathologists.

Renal disease in essential mixed cryoglobulinaemia. Long-term follow-up of 44 patients.

The mode of presentation of renal disease in 44 patients with essential mixed cryoglobulinaemia (EMC) was: acute renal failure (two patients), acute nephritic syndrome (six patients), nephrotic syndrome (eight patients), proteinuria and/or haematuria (28 patients). Renal biopsy, performed in 35 patients showed proliferative lesions in 33, while only minimal glomerular changes were seen in the remaining two. Immunofluorescence studies showed: IgG (85 per cent), IgA (36 per cent), IgM (90 per cent), C3 (90 per cent), C1q (47 per cent), and C4 (33 per cent) deposits, mainly located in subendothelial position. On electron microscopy, crystalloid structure of deposits and monocyte infiltration of capillary loops were the outstanding feature. The survival rate was 75 per cent at 10 years from the onset of clinical symptoms. Thirty-nine patients were followed for three to 146 months (mean 53.8). Twelve patients died, cardiovascular disease and infection being the commonest cause of death. Thirteen patients showed acute renal failure of acute nephritis syndrome: nine recovered completely, whereas the remaining four died during the acute renal episode. Three patients developed chronic renal failure, but only one period required chronic dialysis. The ominous significance of renal impairment in EMC should therefore be revaluated. The high prevalence of hypertension (28/44 patients) which was refractory to treatment in six, may be important to the clinical outcome.

Acute renal failure in idiopathic nephrotic syndrome.

In 4 adults with idiopathic nephrotic syndrome an acute renal failure with prolonged anuria has been observed. At renal histology 1 patient showed minimal glomerular changes and 3 showed focal glomerulosclerosis. No vascular abnormalities were seen. In all cases severe tubular lesions with casts and cell debris in the lumina were observed. In 2 patients renal function improved after 3 and 6 months, respectively; the remaining 2 died after several months from the onset of acute renal failure being still anuric. Although the pathogenesis of this complication is unknown, tubular obstruction by proteinaceous casts and vasoconstriction may play an important role. The prognosis of this complication is severe, but the possibility of spontaneous recovery even after protracted anuria cannot be ruled out.

Immunothrombocytopenia and IgA nephritis.

A 32 year old female patient demonstrates the rare combination of a typical IgA nephritis and familial immunothrombocytopenia. Although this association may be purely fortuitous, our observation adds a new facet to a spectrum of reports on (familial) "thromborenal syndromes". The pathogenesis of the IgA nephritis has not yet been clarified. However, since IgA deposits are found relatively frequently in the mesangium in a number of diverse underlying diseases, there might be common etiological factors. In view of this possibility more attention should be directed to the investigation of IgA associated diseases.

Nephronophthisis (medullary cystic disease of the kidney). A study using electron microscopy, immunofluorescence, and a review of the morphological findings.

Light and electron microscopic as well as immunofluorescent findings in kidney biopsies of 9 patients suffering from nephronophthisis are reported. The lightmicroscopic picture is unspecific except the cysts at the cortico-medullary junction which are present in 70% of cases. The immunofluorescent findings are either negative or unspecifically positive. On electron microscopy, the tubular basement membranes exhibit characteristic but not specific changes, i.e. homogeneous thickening, splitting, reticulation, thinning, complete loss, granular disintegration and collapse. These findings suggest that the "Anlageschwäche" of the nephron especially of the tubular basement membrane may be the primary lesion in nephronophthisis.

Kidney disease.

The diagnostic highlights under electron microscopy in hereditary nephropathies and glomerulonephritides are reviewed: Alport's syndrome--lamellation, fragmentation and reticulation of glomerular basement membrane; benign essential (familial) hematuria--glomerular basement membrane thinning; nail patella syndrome--moth eaten holes and collagen like fibrils in glomeruli; nephronophthisis--thickening, thinning, reticulation and loss of tubular basement membrane; intramembranous and epimembranous glomerulonephritis--unequivocal diagnosis in early and late stages; extracapillary glomerulonephritis--exact classification of the basic type of glomerulonephritis; segmental focal sclerosing glomerulonephritis--unequivocal diagnosis of early stages and differentiation from other forms of glomerulonephritis or other nephropathies; Schönlein-Henoch's syndrome--scanty subepithelial deposits encases by a thin lamella of lamina densa; SLE--deciphering mixed forms of glomerulonephritis and demonstration of virus-like tubular structures in endothelium, so-called organized deposits, interstitial immunocomplex nephritis; mixed IgG/IgM cryoglobulinaemia--crystalloid structure of deposits; IgA nephritis--unequivocal demonstration of mesangial deposits; congenital nephrotic syndrome--irregularity of glomerular basement membrane and finally amyloidosis--unequivocal diagnosis. It is concluded that electron microscopy contributes information of clinical relevance in 30% of cases. Thus, electron microscopy should be used (in addition to light microscopy and immunofluorescence), whenever a renal biopsy specimen is to be critically evaluated.

[Phanacetin abuse III. Malignant urinary tract tumors in phenacetin abuse in Basle 1963-1977]. / Phenacetinabusus III. Maligne Harnwegtumoren bei Phenacetinabusus in Basel 1963-1977.

In 442 inhabitants of Basel 451 malignant tumors of the lower urinary tract were found at autopsy or biopsy from 1963 to 1977. 69/442 patients were abusers of phenacetin containing analgesics. Carcinomas and sarcomas of the lower urinary tract were nearly 13 times as frequent in abusers as in non-abusers. Carcinomas of the renal pelvis were 77 times, carcinomas of the ureter 89 times and those of the urinary bladder 7 times as frequent among abusers. The differences in incidence of malignant tumors are statistically highly significant for all localizations and for multiple carcinomas as well, even if smokers are excluded. "Phenacetin tumors" occurred in younger patients and were more common in women than in non-abusers. They were ofen, though not always, accompanied by analgesic nephropathy. Comparison with other etiological factors such as aromatic amines or thorotrast demonstrated that phenacetin abuse is of greatest importance. The significance of smoking cannot be established unequivocally. Because of the occurrence of a large number of malignant tumors in phenacetin abusers it is very important to prohibit by legislation the use of phenacetin or paracetamol containing analgesics without medical prescription. In addition, these drugs should be replaced by other analgesic compounds.