Clinical presentations and molecular basis of complement C1r deficiency in a male African-American patient with systemic lupus erythematosus.

Homozygous deficiencies of early components for complement activation are among the strongest genetic risk factors for human systemic lupus erythematosus (SLE). Eleven cases of C1r deficiency are documented but this is the first report on the molecular basis of C1r deficiency. The proband is an African-American male who developed SLE at 3 months of age. He had a discoid lupus rash and diffuse proliferative glomerulonephritis. Serum complement analysis of the patient showed zero CH50 activity, undetectable C1r, and reduced levels of C1s, but highly elevated levels of complement C4, C2, and C1-inhibitor. The coding regions of the mutant C1R gene with 11 exons located at chromosome 12p13 were polymerase chain reaction (PCR)-amplified and sequenced to completion. DNA sequencing revealed a homozygous C→T mutation at nucleotide-6392 in exon 10 of the C1R gene, resulting in a nonsense mutation from Arg-380 (R380X). The patient's clinically normal mother was heterozygous for this mutation. A sequence-specific primer (SSP) PCR coupled with StuI-restriction fragment length polymorphism (RFLP) was developed to detect the novel mutation. Screening of 209 African-American SLE patients suggested that the R380X mutation is a rare causal variant. Mutations leading to early complement component deficiencies in SLE are mostly private variants with large effects.

Mitomycin-associated renal failure. Case report and review.

Renal failure due to mitomycin chemotherapy is a poorly appreciated entity often associated with microangiopathic hemolytic anemia. We describe a 45-year-old man in whom renal failure and anemia developed, without evidence of hemolysis, five months after beginning chemotherapy with mitomycin, fluorouracil, and doxorubicin hydrochloride. A biopsy specimen taken from the patient's kidney showed fibrin thrombi in two of 18 glomeruli and in several small arteries. The patient's condition required institution of maintenance dialysis. Similar reports from the literature are reviewed.

Evaluation of amphotericin B-cyclosporine interaction in the rat.

Although a significant interaction between cyclosporine and amphotericin-B (AmpB) has been observed clinically, these findings have not been duplicated in animal studies. A total of 64 male albino rats were used in single- and multiple-dose experiments with AmpB and CsA in the absence or presence of systemic Candida infection. No significant differences in glomerular filtration rate were found in rats given single i.v. doses of AmpB 1 mg/kg compared with AmpB and CsA. Furthermore, rats given i.p. AmpB 1 mg/kg and CsA 10 mg/kg daily for 10 days showed no significant differences in GFR compared with animals given CsA alone. Morphology and CsA whole-blood pharmacokinetics were not different between groups administered single-dose CsA, AmpB, or the combination; similarities also existed with multiple-dose studies. In an attempt to mimic the clinical setting, 2 groups of rats were administered i.p. CsA 10 mg/kg/day for 10 days followed by inoculation of Candida albicans. After 48 hr, a single i.v. dose of AmpB 1.0 mg/kg was associated with a 33% decline in GFR compared with those given sterile water (P less than 0.05). Systemic clearance of CsA was markedly reduced in candidiasis rats administered AmpB compared with controls given sterile water. A significant reduction in renal Candida colony-forming units was found in rats given CsA and AmpB compared with those administered CsA alone. These data suggest that the presence of systemic Candida highlights the interaction of CsA and AmpB in the rat model.

Proteinuria in cyclosporine-treated renal transplant recipients.

Of 704 renal transplant recipients receiving long-term cyclosporine immunosuppression, 71 patients experienced proteinuria greater than 1 g/24 hr beyond the first month posttransplant. Eight patients displayed transient proteinuria, defined as lasting less than 3 months. In most cases this condition was attributed to biopsy-proved acute rejection. The transient proteinuria cohort experienced good graft outcome--namely, 87.5% one-year and 52.5% five-year actuarial graft survivals, which was similar to that observed in patients without proteinuria. In contrast, 52.4% of the 63 patients with nontransient proteinuria experienced graft loss within a median time of 6.1 months. The one- and five-year actuarial graft survivals in patients with nontransient proteinuria were 75.3% and 37.5%, respectively. Among the 63 patients with nontransient proteinuria, histopathologic diagnosis included chronic rejection in 19, transplant glomerulopathy in 14, acute rejection in 9, glomerulonephritis (GN) in 7 including 2 cases of membranous GN, and nonspecific interstitial fibrosis in 10 cases. Despite the overall poor prognosis for graft survival among the entire cohort of patients with nontransient proteinuria, the seven with allograft GN maintained prolonged graft function. They showed an 83.3% five-year actuarial graft survival versus 31.2% in patients with other causes of proteinuria (P = 0.043). These results suggest that posttransplant proteinuria in CsA-treated renal transplant recipients arises primarily as a consequence of allograft rejection and portends a poor graft outcome.

Congenital mesoblastic nephroma: an immunohistochemical and lectin study.

Eight cases of congenital mesoblastic nephroma (CMN) were examined. Three CMNs were of the classical (typical) variant, two were cellular (atypical), and three showed a mixed pattern. A panel of nephron segment-specific tubular epithelial markers (the lectins Tetragonolobus purpureas, Phaseolus vulgaris erythroagglutinin, and Arachis hypogaea and antibodies to epithelial membrane antigen, cytokeratin, and Tamm-Horsfall protein) were used to differentiate epithelial structures within the tumor. Antibodies against vimentin, desmin, and muscle-specific actin were used as mesenchymal markers. A monoclonal antibody to the long (embryonic) form of polysialic acid (PSA) on the neural cell adhesion molecule was used as a putative renal oncodevelopmental marker. An antibody to proliferating cell nuclear antigen also was applied, which revealed increased proliferative rate in cellular CMNs. In addition to clearly entrapped native renal tubules, CMNs contain tubular structures with immature, dysplastic epithelium and occasional epithelial cell clusters embedded deep within the tumor. These immature tubules and clusters express distal nephron, including collecting duct markers and, occasionally, vimentin and PSA. We propose that these primitive tubules and epithelial structures may originate from the ureteric bud. An epithelial differentiation of the tumor cells also is possible. In one pure cellular CMN and two mixed CMNs the cellular component showed diffuse staining for PSA. The PSA (neural cell adhesion molecule) expression of the cellular component suggests that CMN may originate from the uninduced nephrogenic mesenchyme.

Pulmonary malignant fibrous histiocytoma. Light and electron microscopic studies of one case.

A malignant fibrous histiocytoma (MFH) arising in the lungs of a 51-year-old man was studied by light and electron microscopy. Features observed were identical to those of MFHs which occur in the skin and subcutaneous tissue and less commonly in other deep locations. By light microscopy, a storiform pattern with admixture of fibroblasts and histiocytes, as well as xanthomatous and giant cells, was noted. Undifferentiated tumor cells along with fibroblasts and histiocytes in different degrees of differentiation were identified ultrastructurally. These findings lend support to the concept that MFH is a sarcoma of primitive mesenchymal cell origin. The addition of the lung as another primary site for the development of this tumor is consistent with the view that MFHs may potentially arise in any part of the body.

Primary intratracheal neurilemoma.

We report a case in a 38-year-old white woman of a benign primary intratracheal neurilemoma that recurred 12 years after an initial endoscopic excision. Of the 12 intratracheal neurilemomas that have previously been reported, all occurred in white persons in an age range of 6 to 71 years and most were located in the lower trachea and produced symptoms of cough and wheezing.

Evaluation of chronic renal disease in heart transplant recipients: importance of pretransplantation native kidney histologic evaluation.

Although long-term use of cyclosporine has been implicated in the pathogenesis of arteriolar hyalinosis, interstitial fibrosis, and glomerulosclerosis observed in the native kidneys of heart transplant recipients, it is not clear that these histologic abnormalities are entirely specific for a drug-induced toxic nephropathy. The purpose of this study was to determine whether long-standing congestive heart failure, particularly when complicated by disease processes such as atherosclerosis and hypertension, may independently predispose to the development of similar renal histopathology. Records and specimens were selected from autopsy files for evaluation of clinical profiles and kidney histology in 16 patients who died of end-stage cardiomyopathy of varying causes without having recourse to heart transplantation. The study cohort consisted of 12 men and four women. Cardiomyopathies were the result of coronary artery disease in six patients and nonischemic causes in the other 10 patients. The mean age at the time of death was 53 +/- 3 years (range 28 to 74 years). Thirteen (81%) of 16 patients had a history of hypertension. Nadir serum creatinine concentrations during the month before death were 1.7 +/- 0.2 mg/dl (range 1.2 to 3.5 mg/dl). Interstitial fibrosis, tubular atrophy, and glomerulosclerosis were present in 15 (94%) of 16 patients. Arteriosclerosis and arteriolosclerosis were found in 13 (81%) of 16 and 14 (88%) of 16 patients, respectively. A nodular pattern of arteriolar hyalinosis was observed in two patients with ischemic disease.(ABSTRACT TRUNCATED AT 250 WORDS)

Intrathoracic extramedullary hematopoiesis: report of a case in a patient with sickle-cell disease-beta-thalassemia.

A case of paravertebral extramedullary hematopoiesis in a patient with sickle-cell anemia-beta-thalassemia is reported. Interesting aspects in this case, including the high level of Hb F and large number of nucleated erythrocytes in the peripheral blood, are discussed. Fifty-five cases of intrathoracic extramedullary hematopoiesis have been reported. Most of these cases occurred in patients with thalassemia or hereditary spherocytosis. Extramedullary hematopoiesis should be considered in the differential diagnosis of a posterior mediastinal mass in a patient who has chronic anemia or other syndromes associated with extramedullary hematopoiesis.

De novo hemolytic uremic syndrome in renal transplant recipients immunosuppressed with cyclosporine.

Three renal transplant recipients were studied who developed the hemolytic uremic syndrome (HUS) during cyclosporine (CsA) immunosuppression. All patients displayed characteristic findings including normocytic, normochromic anemia, thrombocytopenia, erythrocyte morphologic abnormalities, increased numbers of reticulocytes, bone marrow hyperplasia, and renal failure. The clinical studies support the diagnosis of an extrinsic hemolytic process. Renal biopsy specimens demonstrated fibrin deposition and glomerular thrombosis. The renal failure was not responsive to antirejection therapy. The first patient was converted to azathioprine and consequently had a gradual improvement in renal function. Failure to convert the second patient resulted in adequate immunosuppression and subsequent graft loss. The third patient's improvement corresponded with a moderate CsA dose reduction. The occurrence of HUS in these patients represents a de novo presentation after CsA immunosuppression. An analysis of these cases indicates that CsA should be discontinued if HUS persists after moderate dose reduction.

Correlation of radionuclide and ultrasound studies with biopsy findings for diagnosis of renal transplant rejection.

The diagnosis of early renal transplant rejection is of the utmost importance to the transplant recipient. Unfortunately, such a diagnosis is often extremely difficult to make. In an attempt to clarify this issue we retrospectively evaluated 35 patients with the presenting diagnosis of rejection for the correlation of comparable radionuclide (RN) and ultrasound (US) examinations with biopsy findings. In 21 patients with heavy interstitial mononuclear cell infiltration, 22 of 23 serial RN studies within forty-eight hours of biopsy were positive for rejection. Only 3 of 14 comparable US studies were positive for rejection. When examinations performed within approximately fourteen days were evaluated, 7 of 11 RN studies were positive for rejection, while 2 of 9 comparable US studies were positive for rejection. However, in 14 patients with mild or no interstitial cellular infiltration, only 6 of 13 RN studies were positive, while all 4 US examinations were negative. In the group evaluated at approximately two weeks, 2 of 6 RN studies were positive, while 0 of 5 US studies were positive. We conclude that the serial RN study is more sensitive than US examination for the diagnosis of acute rejection. US, however, proved valuable in the identification of transplant complications (i.e., fluid collections, ascites, and hydronephrosis).

Cyclosporine nephrotoxicity in the Fischer rat.

Male Fischer rats received daily intraperitoneal injections of cyclosporine (IV preparation containing CsA + cremophor) diluted in NaCl or in NaCl + cremophor. At the dose of 100 mg and 50 mg/kg/day the animals developed seizures, motor weakness and died at 4-7 days. Light microscopy at 7 days in these rats showed diffuse vacuolization of all segments of the proximal tubules which was very extensive in the outer stripe. At the dose of 25 mg and 15 mg/kg/day animals were free of symptoms and were sacrificed at day 15 for functional and histological studies. Light and electron microscopy showed cytoplasmic vacuolization in all segments of the proximal tubules. Crystal structures were observed in the experimental animals as well as in the control group that received cremophor + NaCl. The CsA blood levels were at the range of 134-236 ng/ml. Reduction of the glomerular filtration rate was observed in experimental animals as compared with the controls. We concluded that CsA is not the cause of an interstitial nephritis in the Fischer rats and that CsA is nephrotoxic to all segments of the proximal tubules. The cremophor is the cause of the crystal structures seen in the proximal tubules.

Renal glomerular and tubular abnormalities in glycogen storage disease type I.

Three children had renal histopathologic findings indicative of glycogen storage disease type I. Glomerular basement membrane (GBM) alterations were present in the three patients, particularly so in the two patients with proteinuria. Thickening, lamellation, and glycogen deposition were the characteristic alterations in the GBM. Glomerulosclerosis was prominent in one patient. We suggest that the GBM alteration is related to the glomerular sclerosis and that both are related to metabolic derangements of glycogen storage disease type I.

Intracytoplasmic lumina in a case of bilaterally multifocal renal oncocytomas.

We report a case of bilaterally multifocal renal oncocytomas in a patient with chronic renal disease and a long history of hypertension. Histologic study of the multiple oncocytic neoplasms with hematoxylin-eosin, periodic acid-Schiff, trichrome, and colloidal iron stains revealed novel, intracytoplasmic lumina, which were accentuated by immunoperoxidase staining with high-molecular-weight cytokeratin, epithelial membrane antigen, and Arachis hypogaea lectin. Ultrastructural studies demonstrated multiple microvilli lining the intracytoplasmic lumina. We also review the literature on bilaterally multifocal oncocytomas.

Bullous amyloidosis.

Amyloidosis may present with involvement of a variety of organ systems. Cutaneous involvement is a relatively common finding in patients with systemic amyloidosis. The occurrence of bullous skin lesions, however, is rare; only a few such cases have been previously reported. We describe a patient who presented with a subepidermal bullous skin disease initially thought to be bullous pemphigoid based on both clinical and histologic appearances. The patient subsequently developed the nephrotic syndrome. Biopsy specimens of the skin and kidney showed involvement of both organs with amyloid, and amyloid was later found in the spleen, heart, and nervous system. No subsequent evidence of myeloma was found in this patient. The clinical, histopathologic, immunofluorescent, and electron microscopic findings of systemic amyloidosis are discussed.

[Transurethral resection of the prostate: when?]. / La resezione transuretrale della prostata: quando?

Over a period of 5 years (from 1989 to 1993) 410 patients with benign prostatic hypertrophy (BPH) were treated by transurethral resection of the prostate (TURP). A retrospective study was conducted by the Authors to evaluate indications, surgical approaches and results. The Authors' experience is compared with literature reports.

Expression of the Wnt inhibitor Dickkopf-1 is required for the induction of neural markers in mouse embryonic stem cells differentiating in response to retinoic acid.

Cultured mouse D3 embryonic stem (ES) cells differentiating into embryoid bodies (EBs) expressed several Wnt isoforms, nearly all isotypes of the Wnt receptor Frizzled and the Wnt/Dickkopf (Dkk) co-receptor low-density lipoprotein receptor-related protein (LRP) type 5. A 4-day treatment with retinoic acid (RA), which promoted neural differentiation of EBs, substantially increased the expression of the Wnt antagonist Dkk-1, and induced the synthesis of the Wnt/Dkk-1 co-receptor LRP6. Recombinant Dkk-1 applied to EBs behaved like RA in inducing the expression of the neural markers nestin and distal-less homeobox gene (Dlx-2). Recombinant Dkk-1 was able to inhibit the Wnt pathway, as shown by a reduction in nuclear beta-catenin levels. Remarkably, the antisense- or small interfering RNA-induced knockdown of Dkk-1 largely reduced the expression of Dlx-2, and the neuronal marker beta-III tubulin in EBs exposed to RA. These data suggest that induction of Dkk-1 and the ensuing inhibition of the canonical Wnt pathway is required for neural differentiation of ES cells.