Tuberculosis in patients with systemic lupus erythematosus-a 37-year longitudinal survey-based study.

BACKGROUND: Infections are one of the most common causes of morbidity and mortality in patients with systemic lupus erythematosus (SLE). SLE patients have a higher risk of tuberculosis (TB) infection due to impaired immune defence. OBJECTIVES: To investigate the demographics, clinical characteristics and outcomes of patients with SLE and concomitant TB. METHODS: Medical records of SLE patients with TB who were admitted to Peking Union Medical College (PUMC) Hospital in 1983-2019 were retrospectively reviewed. Age- and sex-matched SLE inpatients without TB were randomly selected as controls. Clinical and laboratory features and treatment were analysed and compared, and subjects were followed up to assess their outcome. RESULTS: Of the 10 469 SLE inpatients, 249 (2.4%) were diagnosed with TB. Compared with controls, SLE/TB + patients exhibited higher frequency of prior haematologic, mucocutaneous and musculoskeletal system involvement, and prior treatment with potent glucocorticoid/immunosuppressive agents (GC/ISA). Arthritis and alopecia, positive T-SPOT.TB test and lymphocytopenia were more common in SLE/TB + patients. SLE/TB + patients with lupus before TB (SLE â†’ TB) had higher risk of miliary TB (22.8%) and intracranial TB (16.5%) than SLE/TB + patients with lupus after TB (TB â†’ SLE). SLE/TB + patients exhibited shorter long-term survival than SLE/TB- patients; those with poorer in-hospital outcomes had more severe lymphocytopenia and had received less treatment with ISAs. CONCLUSION: Systemic lupus erythematosus patients treated vigorously with GC/ISA should be alerted of increased risk of TB infection, especially miliary and intracranial TB. Positive T-SPOT.TB and lymphocytopenia served as discriminatory variables between SLE/TB + and SLE/TB- patients. Lymphocytopenia was associated with poorer outcomes in SLE/TB + patients.

The incidence and prevalence of systemic lupus erythematosus in Thrace, 2003-2014: A 12-year epidemiological study.

BACKGROUND: We estimated the prevalence and incidence, clinical features, treatment, and prognosis of systemic lupus erythematosus (SLE) patients in the Thrace region of Turkey. METHODS: We retrospectively evaluated 331 patients (307 female, 24 male, mean age 38.5 years) diagnosed with SLE between 2003 and 2014. Clinical features, treatments, and response to various treatment modalities were recorded. Our hospital has been the only tertiary referral center for rheumatological diseases for a mixed rural and urban population of 620,477 people (306,036 females, 314,411 males) for more than 16 years. RESULTS: The mean annual incidence of SLE was 4.44/100,000 (females, 8.4/100,000; males, 0.6/100,000). The overall prevalence of SLE was 51.7/100,000 (females, 97.7/100,000; males, 7/100,000). Major organ involvement was present in the following percentages: neurologic involvement: 20.1%; renal involvement: 28.2%; autoimmune hemolytic anemia: 9.6%; thrombocytopenia: 14.7%. Seventeen SLE patients (13 females, four males) died at a median follow-up of 48 months. The five-year survival was 94.5%, and the ten-year survival was 89.9%. According to Kaplan-Meier survival analysis, poor prognostic factors were: male gender (p = 0.015); smoking (p = 0.02); pleural involvement (p = 0.011); thrombocytopenia (p = 0.021); myocarditis (p = 0.028); renal involvement (p = 0.037); treatment with cyclophosphamide (p = 0.011); and an initial high SLEDAI score (>4) (p = 0.02). Lymphopenia at the time of diagnosis appeared as a favorable prognostic factor (p = 0.008). Cox regression analysis revealed myocarditis (OR: 20.4, p = 0.018) and age at diagnosis (OR: 1.11, p = 0.035) to be poor, and lymphopenia at the time of diagnosis to be good prognostic factors (OR:0.13, p = 0.031). CONCLUSIONS: The annual incidence and prevalence of SLE in the Thrace region of Turkey is lower than those reported in North America, however they are similar to those reported for European countries. Clinical manifestations appear to be milder, whereas survival was similar to those recorded in Western countries.

T cells as a therapeutic target in SLE.

Systemic lupus erythematosus (SLE) is a multisystem autoimmune disease characterized by a loss of tolerance to multiple endogenous antigens. SLE etiology remains largely unknown, despite recent insight into the immunopathogenesis of the disease. T cells are important in the development of the disease by amplifying the immune response and contributing to organ damage. Aberrant signaling, cytokine secretion, and tissue homing displayed by SLE T cells have been extensively studied and the underlying pathogenic molecular mechanisms are starting to be elucidated. T-cell-targeted treatments are being explored in SLE patients. This review is an update on the T-cell abnormalities and related therapeutic options in SLE.

A novel isoform of the orphan receptor RORγt suppresses IL-17 production in human T cells.

T helper (Th)17 cells constitute a distinct subset of CD4(+) helper T cells that is mainly characterized by abundant interleukin (IL)-17 production and is involved in the host defence against bacteria and fungi as well as in the pathogenesis of autoimmune diseases. The retinoic orphan receptor (ROR)γt directs the transcriptional activation of the IL17 gene. Here, we report the presence of a novel RORγt isoform, RORγt-Δ(5-8), which lacks the hinge-encoding exons 5-8 and represses potently IL17 and IL21 gene transcription. It thereby reduces the expression of multiple Th17-assigned cytokines. We propose that RORγt-Δ(5-8) acts as a dominant-negative regulator of RORγt-mediated gene regulation and the balance between the full-length RORγt and the novel repressor isoform may arbitrate IL-17 production in human T cells.

Biological properties and regulation of IL-10 related cytokines and their contribution to autoimmune disease and tissue injury.

The IL-10 cytokine family has nine members, four of which are located in the IL10 cluster on chromosome 1q32. These cytokines are the immune regulatory cytokine IL-10 itself, and the IL-20 subfamily members IL-19, IL-20, and IL-24. IL-10 instructs innate and adaptive immune responses and limits pro-inflammatory responses in order to prevent tissue damage. The IL-20 subfamily members are involved in host defense mechanisms, particularly from epithelial cells and seem essential for tissue integrity. Dysregulation of IL-10 family cytokines results in inflammation and autoimmune disease. Here, we discuss cellular source, gene regulation, and receptor complexes of cytokines in the IL10 cluster and their contribution to autoimmune disease and tissue damage.

Complement fragment C3d is colocalized within the lipid rafts of T cells and promotes cytokine production.

UNLABELLED: The complement system plays an important role in tissue inflammation and damage in SLE patients. High levels of C3d were detected on the surface of erythrocytes and lymphocytes of SLE patients. The objective of this study was to assess the functional consequences of C3d fragments deposited on the surface membrane of SLE T cells. METHODS: 46 SLE patients, 43 patients with other autoimmune diseases (OAD) and 33 healthy individuals (N) were enrolled in this study. T cells were isolated from peripheral blood and flow cytometry studies were conducted to assess the levels of C3d fragments, Ca++ influx responses and cytokine production. Confocal microscopy was used to study co-localized molecules. Student's t-test was performed to determine statistical significance among study groups. RESULTS: A significant percentage of the SLE T cells were found to be positive for C3d (13.58 ± 3.92%) when compared with normal T cells (4.52 ± 2.92%) (p < 0.0000547) and T cells from patients with other autoimmune diseases (6.31 ± 4.57%) (p < 0.00513). Peak Ca++ influx responses were significantly higher in C3d- SLE T cells compared with C3d+ SLE T cells (p < 0.011). C3d+ T cells produced significantly more IL-2, IFN-gamma, IL-4 and IL-17. In contrast to the increased production of IL-2 by the C3d+ T cells, the overall SLE T cell population produced less IL-2 when compared with T cells from normal individuals or patients with other autoimmune disease. The C3d fragments were found to be localized within the lipid rafts. CONCLUSION: C3d fragments are localized in the lipid rafts of SLE T cells and contribute to abnormal T cell function by modulating Ca++ influx responses and increased cytokine production.

IL-17-producing T cells in lupus nephritis.

Significant evidence implicates interleukin-17 (IL-17) in the pathogenesis of systemic lupus erythematosus (SLE), particularly in the development of tissue damage. IL-17 production and IL-17-producing CD4+ and CD3 + CD4-CD8- cells are increased in patients with SLE. IL-17-producing cells are present in the inflamed kidney tissues from patients with lupus nephritis. In lupus-prone mice, IL-17 production appears to be involved in the expression of disease pathology and pharmacologic or genetic manipulation of its production results in suppression of the disease. It becomes obvious that the use of biologics including humanized anti-IL-17 antibodies or decoy IL-17 receptors deserve clinical consideration. Similarly, the development of drugs that suppress the production of IL-17 is in order.

A systemic lupus erythematosus gene expression array in disease diagnosis and classification: a preliminary report.

Systemic lupus erythematosus (SLE) is a clinically heterogeneous disease diagnosed on the presence of a constellation of clinical and laboratory findings. At the pathogenetic level, multiple factors using diverse biochemical and molecular pathways have been recognized. Succinct recognition and classification of clinical disease subsets, as well as the availability of disease biomarkers, remains largely unsolved. Based on information produced by the present authors' and other laboratories, a lupus gene expression array consisting of 30 genes, previously claimed to contribute to aberrant function of T cells, was developed. An additional eight genes were included as controls. Peripheral blood was obtained from 10 patients (19 samples) with SLE and six patients with rheumatoid arthritis (RA) as well as 19 healthy controls. T cell mRNA was subjected to reverse transcription and PCR, and the gene expression levels were measured. Conventional statistical analysis was performed along with principal component analysis (PCA) to capture the contribution of all genes to disease diagnosis and clinical parameters. The lupus gene expression array faithfully informed on the expression levels of genes. The recorded changes in expression reflect those reported in the literature by using a relatively small (5 ml) amount of peripheral blood. PCA of gene expression levels placed SLE samples apart from normal and RA samples regardless of disease activity. Individual principal components tended to define specific disease manifestations such as arthritis and proteinuria. Thus, a lupus gene expression array based on genes previously claimed to contribute to immune pathogenesis of SLE may define the disease, and principal components of the expression of 30 genes may define patients with specific disease manifestations.

Interleukin-17 and systemic lupus erythematosus: current concepts.

The emerging role of interleukin (IL)-17 as a hallmark proinflammatory cytokine of the adaptive immune system, produced primarily by a new T helper cell subset termed 'Th17', has received considerable attention. Differentiation of Th17 cells is driven by the simultaneous presence of transforming growth factor-beta and certain inflammatory cytokines (e.g. IL-6, IL-21), and recent studies have shown that inflammation instigated by IL-17-producing cells is central to the development and pathogenesis of several human autoimmune diseases and animal models of autoimmunity. In this review, we focus on the information regarding IL-17 and systemic lupus erythematosus (SLE), a chronic autoimmune disease. The work that has explored the development and behaviour of IL-17-producing cells in SLE is discussed, and different mechanisms by which IL-17 could potentially augment inflammation and autoantibody production in the context of SLE are proposed.

Monoclonal antibody-directed radioimmunoassay detects cytochrome P-450 in human placenta and lymphocytes.

A multiplicity of cytochromes P-450 is responsible for the detoxification and activation of xenobiotics such as drugs and carcinogens. Individual differences in sensitivity to these agents may reside in the cytochrome P-450 phenotype. A monoclonal antibody-directed radioimmunoassay was developed that detects epitope-specific cytochromes P-450 in human placentas and peripheral lymphocytes. Placentas from women who smoked cigarettes contained greater amounts of cytochrome P-450 with the monoclonal antibody-specific epitope than placentas from nonsmokers. The amount of this cytochrome P-450 in human peripheral lymphocytes increased after treatment of the mitogenized lymphocytes with the cytochrome P-450 inducer benz[a]anthracene.

Heat shock factor-1 protein in heat shock factor-1 gene-transfected human epidermoid A431 cells requires phosphorylation before inducing heat shock protein-70 production.

Heat shock factor-1 (HSF1) is a transcriptional factor that binds to heat shock elements located on the promoter region of heat shock protein genes. The purpose of this study was to further investigate the regulation of the expression of the heat shock protein-70 (HSP-70) gene. The HSF1 gene was inserted into pCDNA3 plasmid and then transfected into human epidermoid A431 cells using the CaOP3 method. Control cells were transfected with vector alone. Expression of HSP-70, HSF1, and HSF2 genes and protein were determined. We found a significant increase in the expression of the HSF1 gene, but not HSP-70 and HSF2 genes, in the HSF1 gene-transfected cells. The amount of HSF1-heat shock element complex was significantly increased in both the nucleus and cytosol in HSF1 gene-transfected cells, indicating increased synthesis of HSF1. The amount of HSP-72 in these cells did not change. Therefore, overexpression of HSF1 protein failed to initiate transcription of the HSP-70 gene. Subsequently, we treated the cells with 1 microM PMA (a protein kinase C stimulator), and HSP-70 mRNA and protein were measured at 1 or 4 h of the treatment, respectively. The levels of both HSP-70 mRNA and HSP-72 protein were significantly increased in nontransfected and transfected cells; the levels of HSP-72 in HSF1 gene-transfected cells were greater than that found in the vector-transfected cells. The PMA-induced increase in HSP-72 protein peaked 8 h after treatment with PMA and returned to baseline levels at 72 h. This increase was blocked by a PKC inhibitor, staurosporine. After treatment with PMA, HSF1 translocated quickly from cytosol to nucleus. The results suggest that phosphorylation of newly synthesized HSF1 and possibly of other factors are necessary for the induction of HSP-72. Activation of PKC can cause phosphorylation of HSF1, which leads to an enhanced but transient increase in HSP-70 production.

B cells from patients with systemic lupus erythematosus display abnormal antigen receptor-mediated early signal transduction events.

To understand the molecular mechanisms that are responsible for the B cell overactivity that is observed in patients with SLE, we have conducted experiments in which the surface immunoglobulin (sIg)-mediated early cell signaling events were studied. The anti-sIgM-mediated free intracytoplasmic calcium ([Ca2+]i) responses were significantly higher in SLE B cells compared with responses of normal individuals and to those of patients with other systemic autoimmune rheumatic diseases. The anti-IgD mAb induced [Ca2+]i responses were also higher in lupus B cells than in controls. The magnitude of anti-sIgM-mediated Ca2+ release from intracellular stores was also increased in B cells from SLE patients compared with normal controls. The amount of inositol phosphate metabolites produced upon crosslinking of sIgM was slightly higher in patients with lupus than in normal controls, although the difference was not statistically significant. In contrast, the degree of anti-sIgM-induced protein tyrosine phosphorylation was obviously increased in lupus patients. Our study demonstrates clearly for the first time that SLE B cells exhibit aberrant early signal transduction events, including augmented calcium responses after crosslinking of the B cell receptor and increased antigen-receptor-mediated phosphorylation of protein tyrosine residues. Because the above abnormalities did not correlate with disease activity or treatment status, we propose that they may have pathogenic significance.

Altered pattern of TCR/CD3-mediated protein-tyrosyl phosphorylation in T cells from patients with systemic lupus erythematosus. Deficient expression of the T cell receptor zeta chain.

Cellular immunity aberrations in patients with SLE are underscored by the abnormal early Ag receptor-mediated lymphocyte signal transduction pathway. To further characterize the T cell receptor (TCR)/CD3-initiated signaling defects, we studied 22 patients with SLE, 12 patients with other systemic rheumatic diseases, and 14 normal donors. The early (1 min) TCR/CD3-mediated tyrosine phosphorylation of cellular proteins with a molecular size between 36 and 64 kD was increased in 15 of 21 SLE patients, compared to normal or disease control subjects. The deficiency or absence of a band with a molecular size of approximately 16 kD in the immunoblots of SLE patients led us to investigate the expression of the TCRzeta chain. In immunoblots using anti-zeta antibodies we found that 10 of 22 lupus patients tested lacked the expression of TCRzeta, which was always present in control subjects (P < 0.001). Flow cytometric studies using permeabilized cells confirmed the deficiency or absence of the TCRzeta chain in lupus T cells. Using Northern blots we found that for eight patients tested, the TCRzeta mRNA was missing in three, decreased in three, and apparently normal in two patients (P < 0.003), but was always present in control subjects. Reverse transcriptase-PCR verified Northern blot results. We conclude that TCRzeta chain expression is either decreased or absent in the majority of patients with SLE, but not in patients with other systemic rheumatic diseases, regardless of disease activity, treatment status, or clinical manifestations. The previously described increases in TCR-initiated Ca2+ responses and the herein described increases in TCR-induced protein tyrosine phosphorylation and deficient TCRzeta expression may represent intrinsic defects modulating lupus T cell function.

Dexamethasone inhibits human interleukin 2 but not interleukin 2 receptor gene expression in vitro at the level of nuclear transcription.

Glucocorticosteroids have an inhibitory effect on the expression of interleukin 2 (IL-2) and interleukin 2 receptor (IL-2R) genes. To determine the mechanisms of this inhibition, human T lymphocytes were stimulated with mitogens in the presence of dexamethasone. Nuclear transcription run-off assays showed that high doses of dexamethasone inhibited the transcription of the IL-2 gene but not that of the IL-2R gene. Post-transcriptionally, high doses of dexamethasone (10(-4) M) were required to inhibit IL-2R mRNA levels by 50%, whereas lower doses (10(-6) M) inhibited by greater than 70% the accumulation of IL-2 mRNA. IL-2 mRNA half-life decreased in the presence of dexamethasone (10(-6) M) by approximately 50%. At the protein product level, dexamethasone inhibited both IL-2 production, as well as cell surface and soluble forms of IL-2R. IL-2R gene expression was inhibited for at least 72 h after exposure of cells to dexamethasone. In the presence of exogenous IL-2, dexamethasone failed to exert a significant effect on the production of IL-2R protein. These data indicate that dexamethasone has a greater effect on the expression of the IL-2 gene than on the IL-2R gene. Dexamethasone both inhibits transcription of the IL-2 gene and decreases the stability of IL-2 mRNA. The effect of dexamethasone on the IL-2R gene is post-transcriptional and may result indirectly from decreased IL-2 production.

Monoclonal antibodies against complement 3 neoantigens for detection of immune complexes and complement activation. Relationship between immune complex levels, state of C3, and numbers of receptors for C3b.

C3-bearing immune complexes and C3 activation products were detected by using two monoclonal antibodies, one specific for a neoantigenic determinant on C3c and the other for C3d. To quantitate immune complexes, the anti-C3c or anti-C3d antibodies were fixed to microtiter plates and reacted with test plasma. The binding of C3-bearing immune complexes in this plasma was then measured with radioisotope- or enzyme-labeled anti-human IgG. To test for C3 breakdown products, solid-phase monoclonal antibody to the C3d neoantigen was reacted with EDTA-plasma samples, and fixed iC3b or C3d was measured with a polyclonal anti-C3 antibody. Patients with autoimmune diseases, such as systemic lupus erythematosus, rheumatoid arthritis, and Sjogren's syndrome, and paracoccidioidomycosis were found to contain immune complexes bearing C3b/iC3b or C3d. In most conditions, there were more C3d-containing immune complexes than C3b/iC3b. Although CR1 (C3b receptors) rapidly converted immune complex-bound iC3b to C3dg/C3d and lupus patients had reduced CR1, no correlation between the state of C3 on circulating immune complexes or levels of immune complexes and CR1 numbers was seen. However, levels of C3-fixing ICs correlated with levels of C3 activation products. This assay system with monoclonal antibodies to neoantigens expressed on activated, but not native, C3 provides sensitive and specific means for detecting and classifying C3-fixing immune complexes and for assessing C3 activation.

Gene therapy in systemic lupus erythematosus.

Despite the fact that the etiopathogenesis of systemic lupus erythematosus is largely unknown, key steps in the pathophysiology of the disease have been recognized and targeted using gene therapy techniques. In animal models of lupus, gene transfer has been used to block the action of pro-inflammatory cytokines and co-stimulatory molecules leading to clinical improvement. In humans, ex vivo experiments have shown the feasibility of gene transfer in live T cells and its potential for restoring normal phenotype in T cells from patients with lupus. Still in experimental phase, gene therapy in lupus promises to correct the aberrant immunological response without the numerous side-effects of the currently used immunosuppressant medications.

Heat shock protein 70 kDa: molecular biology, biochemistry, and physiology.

Heat shock proteins (HSPs) are detected in all cells, prokaryotic and eukaryotic. In vivo and in vitro studies have shown that various stressors transiently increase production of HSPs as protection against harmful insults. Increased levels of HSPs occur after environmental stresses, infection, normal physiological processes, and gene transfer. Although the mechanisms by which HSPs protect cells are not clearly understood, their expression can be modulated by cell signal transducers, such as changes in intracellular pH, cyclic AMP, Ca2+, Na+, inositol trisphosphate, protein kinase C, and protein phosphatases. Most of the HSPs interact with other proteins in cells and alter their function. These and other protein-protein interactions may mediate the little understood effects of HSPs on various cell functions. In this review, we focus on the structure of the HSP-70 family (HSP-70s), regulation of HSP-70 gene expression, their cytoprotective effects, and the possibility of regulating HSP-70 expression through modulation of signal transduction pathways. The clinical importance and therapeutic potential of HSPs are discussed.

Pituitary-adrenal responsiveness to corticotropin-releasing hormone in patients receiving chronic, alternate day glucocorticoid therapy.

We examined the responsiveness of the pituitary-adrenal axis to ovine corticotropin-releasing hormone (oCRH) in 14 women with systemic lupus erythematosus receiving chronic, alternate day glucocorticoid therapy with prednisone. Testing was done twice and in a random order (at 2000 h) on the day when the steroid was taken (12 h after the last dose) and on the day when no glucocorticoid was administered (36 h after the last dose). Plasma ACTH and cortisol responses were markedly blunted on the day of treatment and mildly blunted on the day off treatment compared to those in normal subjects. Altered metabolic clearance of exogenous oCRF was not responsible for this difference, since the plasma disappearance curves of immunoreactive oCRH were similar on both days. The degree of suppression was dependent on the dose of prednisone, and the amount of cortisol secreted during the oCRH test was directly proportional to the logarithm of the concurrent plasma ACTH level. Thus, the cortisol response to ACTH was normal in all patients. These data suggest that the blunting of responsiveness to oCRH on both days of testing represents prednisolone suppression of the corticotroph cell. Despite this, the adrenal glands retain normal responsiveness to ACTH, suggesting that moderate decreases in daily ACTH secretion are compatible with sustaining normal adrenal function. Hence, the site of the mild suppression of the hypothalamic-pituitary-adrenal axis during chronic, alternate day treatment with glucocorticoids is central, whereas the adrenal glands appear to remain functionally unaffected.

Dissociation between cortisol and adrenal androgen secretion in patients receiving alternate day prednisone therapy.

To evaluate the hypothesis that chronic, low dose, alternate day prednisone treatment may suppress adrenal androgen secretion without causing long term suppression of the hypothalamic-pituitary-adrenal axis we studied seven patients with systemic lupus erythematosus who had been taking low dose (5-20 mg), alternate day prednisone therapy for at least 1 yr. Basal and ovine CRH (oCRH)-stimulated plasma ACTH, cortisol, and adrenal androgen levels were measured 12 h (day on) and 36 h (day off) after the most recent dose of prednisone, and the results were compared to those in seven age- and sex-matched normal subjects. The patients' basal ACTH and cortisol levels did not differ significantly from those in the normal subjects on either the day on or the day off prednisone treatment. By contrast, their basal adrenal androgen levels were significantly decreased compared to those in normal subjects on both the day on and the day off prednisone (P less than 0.05). The patients' oCRH-stimulated ACTH and cortisol levels on the day off prednisone did not differ from normal levels, but were significantly blunted during the day on prednisone (P less than 0.05). In contrast, the patient's oCRH-stimulated adrenal androgen levels were significantly decreased during both the day off and the day on prednisone (P less than 0.05). These findings are consistent with the hypothesis that chronic alternate day prednisone therapy, at doses close to or below replacement, suppresses adrenal androgen levels without long term suppression of the hypothalamic-pituitary-adrenal axis. Based upon these findings, we postulate that an alternate day regimen of prednisone might maintain the benefits while reducing the risks of glucocorticoid therapy of adrenal hyperandrogenism.

Renal and metabolic complications of undifferentiated and lymphoblastic lymphomas.

The early metabolic events in 33 patients with non-Hodgkin lymphoma were analyzed in the present study. Twenty-three patients had Burkitt lymphoma, 3 had non-Burkitt undifferentiated lymphoma and 7 had lymphoblastic lymphoma. Eight patients developed azotemia prior to starting chemotherapy while five did so during the first treatment week. All the patients but two who developed azotemia had stage C or D disease. Serum LDH prior to chemotherapy correlated well with the stage of disease and predicted the serum levels of creatinine, uric acid and phosphorus in the post-treatment period. Surgical excision of the main tumor mass was associated with a low incidence of azotemia and other metabolic derangements. Hyperuricemia and occasionally obstruction were encountered as the causes of azotemia in the pre-treatment period. Hyperuricemia and/or hyperphosphatemia were presumed responsible for the development of azotemia in the post-chemotherapy period. Two patients were dialyzed for renal failure due to hyperuricemia and one for renal failure due to hyperphosphatemia which developed shortly after starting chemotherapy. The patterns of renal and metabolic disturbances observed during treatment of these patients were characterized by the following profiles: 1. Azotemia due to hyperuricemia prior to treatment. 2. Hyperuricemia without azotemia in the pre-treatment period with azotemia due to hyperphosphatemia in the post-treatment period. 3. Azotemia due to combined hyperphosphatemia and hyperuricemia developing gradually in post-treatment period. 4. Increased urine phosphorus excretion in both non-azotemic and azotemic patients.