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BACKGROUND AND AIM: To determine risk factors for incident chronic kidney disease (CKD) in a large population-based cohort. METHODS: This prospective opt-in population-based cohort study is based on the 45 and Up Study, where New South Wales residents aged ≥45 years were randomly sampled from the Services Australia database and agreed to complete the 45 and Up Study baseline questionnaire and have their responses linked to their health data in routinely collected databases. The primary outcome was the development of incident CKD, defined as eGFR

Examination of the blood of 40 patients with leukaemic reticuloendotheliosis (LRE) revealed a drastic reduction in monocyte numbers (mean 74/microliter) when compared to a normal group of 33 (mean 442/microliter). Repeated blood studies in 8 LRE patients were made over periods of 2 months to 5 years and monocytopenia was observed to be a persistent phenomenon. Similarly, tissues from 29 patients showed an overall decrease in numbers of monocytes/ histiocytes when compared with those of 73 control subjects. Skin window examinations in all 11 patients so studied showed marked reduction or absence of monocyte response to inflammation. 2 exceptional cases to this trend are noted. In one, circulating monocyte levels remained normal over a 14-month period while examinations of blood and marrow in this case showed few hairy cells. In another case, severe and persistent monocyte deficiency was noted during a 2-year period of unsuccessful treatment. When he eventually responded to low dose chlorambucil and his Hb rose from 40-140 g/l and WBC became normal, the number of circulating monocytes also became normal.

Human serum contains two related isoforms of TRACP: TRACP 5a and TRACP 5b. Serum TRACP 5a protein is increased in about one third of rheumatoid arthritis (RA) sera. This study was undertaken to examine the significance of serum TRACP isoforms 5a and 5b as disease markers of inflammation and bone destruction in RA. One hundred eighteen patients were recruited including 50 with RA (25 with nodules), 26 with osteoarthritis (OA), and 42 with other rheumatic diseases. Twenty-six healthy adults served as controls. Serum TRACP 5a activity, TRACP 5a protein, and TRACP 5b activity were determined by in-house immunoassays. C-reactive protein (CRP) was determined by in-house immunoassay using commercial antibodies and CRP. Other commercial markers included bone-specific alkaline phosphatase (BALP), C-telopeptides of type-I collagen (ICTP), cartilage glycoprotein-39 (YKL-40), and IgM rheumatoid factors (IgM-RF). Mean TRACP 5a protein was significantly elevated only in RA compared with healthy controls and other disease groups. TRACP 5a protein correlated significantly only with IgM-RF in RA. Among RA patients, mean TRACP 5a protein and IgM RF were significantly higher in nodule formers. In contrast, TRACP 5b activity was slightly elevated in RA and correlated with BALP, ICTP, and YKL-40 but not with IgM-RF or CRP. Mean TRACP 5b activity was no different in RA patients with or without nodules. TRACP isoforms could be useful disease markers in RA; TRACP 5a protein may be a measure of systemic inflammatory macrophage burden and disease severity. TRACP 5b activity is a marker for osteoclast number and perhaps local or systemic bone destruction.

The association between elevated serum type 5 TRACP activity and metabolic bone diseases has been recognized for many years. However, serum type 5 TRACP exists as two related isoforms: 5a and 5b. Only isoform 5b is osteoclast-derived; the origin and significance of isoform 5a has hardly been explored. We have used simultaneous immunoassays for type-5 TRACP activity and total type-5 TRACP protein in conjunction with non-denaturing gel electrophoresis and column chromatography to investigate the nature and significance of TRACP isoforms 5a and 5b in end-stage renal disease (ESRD) and rheumatoid arthritis (RA). Our studies have shown that TRACP activity and protein are elevated in approximately 50% of sera from ESRD patients, which is caused by osteoclastic isoform 5b. We have also shown that total TRACP protein, but not TRACP activity, is elevated in approximately 30% of sera from RA patients, which is caused by non-osteoclastic isoform 5a. When macrophages or dendritic cells (DC) were cultured in vitro, abundant TRACP 5a was secreted into the culture medium, whereas TRACP 5b was retained intracellularly by both cell types. This implicates macrophages and DC as potential sources of elevated TRACP 5a in RA. Because TRACP isoform expression may be disease-specific, it is important to be able to distinguish TRACP 5a from 5b. There are four criteria by which to do so: (1) TRACP 5a bears sialic acid residues while TRACP 5b does not; (2) the pH optimum for TRACP 5a is 5.2 while that for TRACP 5b is 5.8; (3) the specific activity of TRACP 5a is significantly lower than that of TRACP 5b; and (4) TRACP 5a is as an uncleaved polypeptide, whereas TRACP 5b is a proteolytically nicked disulfide-linked "heterodimer." The differences in biochemical properties and disease-specific expression of TRACP isoforms 5a and 5b suggest that they are regulated differently and perform separate functions in a tissue-specific manner.

Fine-needle aspiration (FNA) of the lymph node was done in five patients with histiocytic necrotizing lymphadenitis (Kikuchi's disease). In four patients, the aspirates were found to have many small and large atypical lymphocytes, some reactive, phagocytic histiocytes, and intense extracellular debris. Neutrophils, plasma cells, or multinucleated giant cells were not seen. These cytologic findings were considered diagnostic for Kikuchi's disease. In one patient, the aspirate did not show significant histiocytosis or tissue necrosis and was considered nondiagnostic. In patients with both typical clinical features and characteristic cytologic findings in the lymph node aspirates, FNA of the lymph node alone will suffice for diagnosis. In those patients with typical clinical features but nondiagnostic findings in the FNA aspirates, the diagnosis of Kikuchi's disease may have to be established either on repeated nodal FNA or on lymph node biopsy.

The human prostatic acid phosphatase is a specific marker for the prostatic epithelial cells. By using an immunoperoxidase staining method for this enzyme, it is possible both to identify the prostatic epithelial cells and to recognize the prostatic origin of metastatic lesions of prostate cancer. Of the tissues containing prostatic epithelial cells from 120 patients, positive staining reaction was detected in 114 (95%), and negative in 6. In nonprostatic tissues from 242 patients, weak but positive staining reaction was detected in 8 (3.3%), including tissues from one renal cell carcinoma and 7 breast carcinomas. Of 27 patients in whom tumor tissues were tested at a time when tumor origin was unknown, the staining reaction was positive in 14 patients later found to have prostate cancer. It was negative in 6 patients with nonprostatic carcinoma and 7 patients with carcinoma of unknown primary. Although this immunohistochemical technique for prostatic acid phosphatase appears promising in diagnosing metastatic prostate cancer, its clinical significance and limitations remain unclear, and there are considerable technical problems yet to be solved. These problems are best approached by joint collaborative efforts of the various investigators interested in prostate cancer.

An immunohistochemical method for detecting prostatic acid phosphatase is described for the diagnosis of metastatic prostatic carcinoma. The specific antiserum against prostatic acid phosphatase was prepared from rabbit by injection of acid phosphatase purified from seminal fluid. This method gives a selective staining of the cytoplasm of the glandular epithelial cells of prostatic tissue specimens on paraffin section. Most of the non-prostatic tissues were negative except for occasional weak staining in granulocytes, islet cells of pancreas, parietal cells of stomach, tubular epithelial cells of kidney, and liver cells. Also examined were 50 consecutive cases of metastatic tumor involving the bone marrow and 5 cases of metastatic prostatic carcinoma involving the lymph node or lung. All 20 cases with prostatic primary lesion showed positive staining. All other cases were negative, except 5 of the 14 cases of metastatic breast carcinoma in women showing weakly positive results. The method is fairly specific for identification of metastatic prostatic carcinoma. Occasional positive staining in breast tumor needs further study to establish whether the staining is due to the same isoenzyme or to certain cross immunoreactivity.

Systemic mast cells disease (SMCD) is an uncommon disorder that constitutes approximately 10% of all mastocytoses. Diagnosis requires a substantial degree of clinical suspicion, which may not be present if characteristic skin lesions of urticaria pigmentosa are not observed. Lack of well-defined histopathologic features for the disease have delayed or prevented the diagnosis of SMCD. An initial diagnosis of "myeloproliferative disorder," chronic granulocytic leukemia, or myelofibrosis is frequently made. Study of the clinical and pathologic features of 26 cases of SMCD indicated that affected patients are generally middle aged and may have had urticaria pigmentosa for many years. Gastrointestinal symptoms are common, and splenomegaly and hepatomegaly along with radiographic evidence of generalized bone disease are usually noted. Hematologic factors are highly variable. Characteristic histopathologic features of SMCD are described for bone marrow, lymph nodes, liver, and spleen. The authors consider tissue fixation and staining methods to help identify mast cell lesions.

Six patients with lymphomatous lesions primarily involving the pulmonary parenchyma were studied. In these patients, both the history and physical findings were vague and minimal. The laboratory findings also were nonspecific, although the findings of large multiple lesions in the lungs and pleural adhesion or effusion were more consistent with lymphoma. Histologic examination revealed lymphocytic infiltration of the pulmonary parenchyma in all six patients and presence of germinal or growth centers in some areas of the lesions in four. The hilar or mediastinal lymph nodes were not involved in five patients so examined. Immunocytochemical study of cytoplasmic immunoglobulin revealed monoclonal lymphocytic proliferation in five patients and negative staining in one patient. Clinical, histologic, or immunohistochemical studies alone may not be sufficient to detect all of the lymphomatous lesions. The combined use of all of these parameters is more advantageous for accurate diagnosis of these lesions. Treatment is surgical resection. Radiotherapy or chemotherapy are used when residual disease is present after surgery. Three patients died of disseminated lymphoma 96, 42, and 8 months after diagnosis, respectively, and three patients are still alive at 18, 24, and 4 months, respectively.

Recognition of disseminated adenocarcinomas potentially responsive to current treatment programs is an important objective in the management of cancer patients. Metastatic adenocarcinoma of the prostate gland is a malignant entity which often can be palliated effectively by hormonally based therapeutic strategies. In cases of metastatic prostate cancer presenting with typical clinical features, the correct diagnosis can be readily achieved, but in patients with less obvious presentations the diagnosis of prostatic carcinoma may be overlooked. In the current report, a group of elderly men presenting with a clinical syndrome resembling either metastatic primary adenocarcinoma of the lung or primary adenocarcinoma of the lung coexisting with prostate cancer were found in fact to have metastatic prostatic carcinoma as their sole disease process. In each case, cytologic characterization of clinically involved tissue specimens by the prostate specific antigen and prostatic acid phosphatase immunohistochemical markers enabled clinical investigators to arrive at the correct diagnosis. Other clinical features, such as a positive bone scan and an enlarged prostate gland on physical exam and/or radiographic studies were noted to be present in these patients. All the patients in the current series responded to hormonal treatment regimens once the diagnosis of metastatic prostate cancer had been established. In elderly male patients presenting with what appears to be primary adenocarcinoma of the lung, the diagnosis of metastatic prostate cancer should be considered and when necessary evaluated by the use of appropriate clinical and immunohistochemical studies.

Diagnosis of central nervous system (CNS) non-Hodgkin's lymphomas may be difficult despite the use of sophisticated scans and routine cytologic methods. The use of an immunoalkaline phosphatase technique to examine cerebrospinal fluid (CSF) containing many mononuclear cells is described. Monoclonal proliferations of B-lymphocytes were demonstrated in six patients with neurologic abnormalities, whose clinical findings and subsequent clinical courses were those of lymphoma. The diagnosis of CNS lymphoma could not be made, despite multiple diagnostic procedures, until the immunocytochemical studies were performed. In three other patients, a lymphoproliferative disorder was suspected; however, examination of CSF showed many T-lymphocytes but no monoclonal B-lymphocytes, consistent with a reactive lymphocytosis. The subsequent clinical courses of these patients have shown no evidence of CNS lymphoma. Immunocytochemical studies of CSF lymphocytes are useful in differentiating benign from malignant proliferations.

DiGuglielmo syndrome is usually considered an idiopathic disorder occurring sporadically. A family in which DiGuglielmo syndrome occurred in 4 of 11 siblings is reported. A fifth sibling has developed unexplained marrow hypoplasia. Serial morphologic and cytochemical studies, supplemented by cytogenetic studies, documented the evolution of disease. Cytogenetic and environmental investigations did not explain this clustering of blood dyscrasias although a genetic predisposition to marrow damage by environmental factors cannot be excluded. The natural history of the disease in this sibship may consist of initial reactive changes in the marrow with subsequent progression to myelodysplasia with sideroblastosis and, finally, to DiGuglielmo syndrome.

A clinical and hematopathologic review of 66 patients with systemic mast cell disease (SMCD) was undertaken to investigate the frequency and the clinical significance of associated hematologic disorders. Twenty-two patients were found to have a second hematologic disorder, 19 of which involved the myeloid cells (ten dysmyelopoietic syndromes, five myeloproliferative disorders, three acute nonlymphocytic leukemias, and one chronic neutropenia), and three of which involved the lymphoid cells (three malignant lymphomas). A chromosome analysis of the bone marrow revealed abnormalities characteristic of neoplastic myeloid disorders in four patients. Five-year survival for patients with hematologic disorders was 28% compared with 61% for other SMCD patients (P = 0.004). Patients with hematologic disorders differed significantly from other SMCD patients in that they were about 7 years older (P = 0.039), and they presented more commonly with anemia (P less than 0.001) and constitutional symptoms (P = 0.007). These patients also had less frequent skin symptoms (P = 0.003) and urticaria pigmentosa (P = 0.018). By definition, patients with hematologic disorders had a greater percent of hematopoiesis (P less than 0.001) and decreased fat cells (P = 0.011) on bone marrow biopsies. A multivariate model demonstrated that the following independent variables were associated with the presence of hematologic disorders: low hemoglobin (P = 0.001), the absence of hepatomegaly (P = 0.016), high leukocyte count (P = 0.021), and the presence of pathologic fractures (P = 0.051). The frequent coexistence of SMCD with dysplastic and neoplastic disorders of myeloid cells is consistent with the concept that SMCD itself is a disorder of myeloid cells and that the mast cell may be myeloid in origin.

Nineteen patients with hairy cell leukemia were studied in order to define the hepatic changes in this disease and to correlate the morphologic changes in the liver with the clinical and biochemical findings. Although only eight of the patients had hepatomegaly, all 19 had microscopic mononuclear cell infiltration in the sinusoids or the portal areas or both. The severity of mononuclear infiltration in the liver correlated poorly with the size of the liver or spleen, the biochemical changes, or number of hairy cells in the blood. Abnormal serum biochemical values were present occasionally and were usually due to associated diseases or to complications of this disease. Elevated serum alkaline phosphatase activity was noted in four patients; three of them bad granulomatous lesions in the liver. Unless the characteristic “clear cell” pattern is seen, the hepatic mononuclear cell infiltration may not be diagnostic of hairy cell leukemia and, in many instances, may not even be suggestive of neoplasia. A new technique for demonstrating tartrate-resistant acid phosphatase activity in methacrylate-embedded sections was developed, which allowed identification of hairy cells in the liver biopsy specimens of all five patients so studied. The authors concluded that liver involvement is common in this disease.

Immunoelectron microscopic studies were done on prostatic tissues obtained from patients with benign hyperplasia. Rabbit IgG-peroxidase conjugate against purified human prostatic acid phosphatase band 2 (HPAP-2) was used for studies. Under the light microscope, the columnar secretory epithelia of prostatic glands showed different intensity and distribution of immunostaining whereas the basal cells were unstained. Under the electron microscope, the secretory epithelial cells often showed electron-dense reaction product in the Golgi apparatus and secretory vesicles and vacuoles, and only sparingly in the cisternae of nuclear envelope and rough ER. Sometimes, fusion of secretory vacuolar membrane and plasma membrane and discharge of the vacuolar contents into the extracellular space were noted. The surfaces of microvilli at the apical portion of the columnar epithelia and the lumen of the glandular acini always showed reaction product. These findings suggest that HPAP-2 may be synthesized in the rough ER and transported to the Golgi apparatus where it is concentrated and transferred to the secretory vesicles and vacuoles. HPAP-2 is finally discharged into the extracellular spaces through exocytosis, a secretory mechanism similar to that of other secretory proteins.