Long-term effects of combination treatment with fludarabine and low-dose pulse cyclophosphamide in patients with lupus nephritis.

OBJECTIVES: To determine the safety and efficacy of a short course of fludarabine combined with cyclophoshamide in lupus nephritis. METHODS: A phase I/II open label pilot study. Thirteen patients with active proliferative lupus nephritis received monthly oral boluses of low-dose cyclophoshamide (0.5 gm/m(2) on day 1) and subcutaneous fludarabine (30 mg/m(2) on days 1-3) for 3-6 cycles. Concomitant prednisone was aggressively tapered from 0.5 mg/kg/day to a low-dose, alternate-day schedule. Patients were followed for at least 24 months after therapy. The primary outcome was the number of patients achieving renal remission defined as stable creatinine, proteinuria <1 gm/day and inactive urine sediment for at least 6 months. RESULTS: The study was terminated early because of bone marrow toxicity. Eleven patients who received at least three cycles were evaluated for efficacy. Ten patients improved markedly with seven patients achieving complete remission and three patients achieving partial remission. There were three serious haematological adverse events during the treatment with one death due to transfusion-associated graft vs host disease. Profound and prolonged CD4 (mean CD4: 98/microl at 7 months and 251/microl at 12 months) and CD20 lymphocytopenia was noted in most patients. Three patients developed Herpes zoster infections. CONCLUSIONS: A short course of low-dose fludarabine and cyclophoshamide can induce long-lasting remissions in patients with proliferative lupus nephritis, but severe myelosuppression limits its widespread use.

Membranous lupus nephritis.

Membranous lupus nephritis (MLN) represents about 20% of clinically significant renal disease in lupus. Few studies have addressed directly the pathogenesis of MLN. Our assumptions about the underlying mechanisms are based on the combination of extrapolations from idiopathic membranous nephritis (mainly from animal models) and proliferative lupus nephritis. Natural history studies of MLN suggest a relatively low rate of progression to end-stage renal disease but a high rate of significant comorbidities. Historical changes in the criteria for pathologic diagnosis and classification of membranous lupus nephropathy have precluded definitive descriptions of the natural history, prognosis and treatment of this disorder. Patients with membranous lupus nephropathy should be treated early with angiotensin antagonists to minimize proteinuria, as well as lifestyle changes and appropriate drugs to reduce attendant cardiovascular risk factors. In patients with protracted nephrotic syndrome, consideration should be given to immunosuppressive therapies, including corticosteroids, cyclosporine, mycophenolate and cyclophosphamide. Prospective controlled trials are clearly needed in order to establish solid clinical practice guidelines for use of these drugs and other experimental therapies currently under study in membranous lupus nephropathy.

Exogenous peptide and protein expression levels using retroviral vectors in human cells.

Pseudotyped retroviral vectors combine the advantages of broad host range, high expression, stable chromosomal integration, and ease of preparation. These vectors greatly facilitate delivery into mammalian cells of sequences encoding individual peptide inhibitors-including those with therapeutic utility-and inhibitor libraries. However, retroviral vectors vary in behavior, particularly with respect to expression levels in different cell lines. Expression level is especially important in transdominant experiments because the concentration of an inhibitor (for example, an expressed peptide) is one of the key determinants in the degree of complex formation between the inhibitor and its target. Thus, inhibitor concentration should have an impact on the expressivity and/or penetrance of an induced phenotype. Here, we compare several retroviral vectors and human cell lines for relative expression levels using a green fluorescent protein reporter. We show for a subset of these lines that cellular protein concentrations produced by single-copy vectors range up to about 2 microM. We also examine other variables that contribute to expression level, such as the nature of the expressed protein's carboxy terminus. Finally, we test the effect of increased concentration on phenotype with a nine-amino-acid peptide derived from the human papilloma virus protein E7 which overcomes E7-mediated cell growth.

Enzyme replacement therapy in Fabry disease: a randomized controlled trial.

CONTEXT: Fabry disease is a metabolic disorder without a specific treatment, caused by a deficiency of the lysosomal enzyme alpha-galactosidase A (alpha-gal A). Most patients experience debilitating neuropathic pain and premature mortality because of renal failure, cardiovascular disease, or cerebrovascular disease. OBJECTIVE: To evaluate the safety and efficacy of intravenous alpha-gal A for Fabry disease. DESIGN AND SETTING: Double-blind placebo-controlled trial conducted from December 1998 to August 1999 at the Clinical Research Center of the National Institutes of Health. PATIENTS: Twenty-six hemizygous male patients, aged 18 years or older, with Fabry disease that was confirmed by alpha-gal A assay. INTERVENTION: A dosage of 0.2 mg/kg of alpha-gal A, administered intravenously every other week (12 doses total). MAIN OUTCOME MEASURE: Effect of therapy on neuropathic pain while without neuropathic pain medications measured by question 3 of the Brief Pain Inventory (BPI). RESULTS: Mean (SE) BPI neuropathic pain severity score declined from 6.2 (0.46) to 4.3 (0.73) in patients treated with alpha-gal A vs no significant change in the placebo group (P =.02). Pain-related quality of life declined from 3.2 (0.55) to 2.1 (0.56) for patients receiving alpha-gal A vs 4.8 (0.59) to 4.2 (0.74) for placebo (P =.05). In the kidney, glomeruli with mesangial widening decreased by a mean of 12.5% for patients receiving alpha-gal vs a 16.5% increase for placebo (P =.01). Mean inulin clearance decreased by 6.2 mL/min for patients receiving alpha-gal A vs 19.5 mL/min for placebo (P =.19). Mean creatinine clearance increased by 2.1 mL/min (0.4 mL/s) for patients receiving alpha-gal A vs a decrease of 16.1 mL/min (0.3 mL/s) for placebo (P =.02). In patients treated with alpha-gal A, there was an approximately 50% reduction in plasma glycosphingolipid levels, a significant improvement in cardiac conduction, and a significant increase in body weight. CONCLUSION: Intravenous infusions of alpha-gal A are safe and have widespread therapeutic efficacy in Fabry disease.

New prospects for treatment of lupus nephritis.

Systemic lupus erythematosus (SLE) is envisioned to arise from hyperactivate helper T-cells that cause polyclonal B-cell secretion of pathogenic autoantibodies and formation of immune complexes which deposit in sites such as the kidney. The most widely used immunosuppressive drugs, notably corticosteroids and cyclophosphamide, are often criticized as being nonspecific. In fact, these agents may be effective in SLE and lupus nephritis because broad, rather than highly selective, effects are required to control the aberrant immune system. Nonetheless, these agents are not uniformly effective and are associated with substantial toxicities. The lack of universal efficacy raises the specter that lupus is a heterogeneous disorder with different etiopathogenesis in different subsets of patients (as in lupus-prone mice). Therapeutic prospects for the upcoming millennium include new forms and combinations of chemotherapeutic agents (mycophenolate and adenosine analogues), attempts to achieve immunological reconstitution using near-ablative chemotherapy (with or without bone marrow or stem cell rescue), monoclonal antibodies, and other inhibitors of T-cell costimulatory pathways (e.g., anti-CD154 and/or CTLA4-Ig). The prospect for gene therapy has already been realized in some animal models of SLE. In human SLE, the feasibility of gene therapy will depend on further definition of lupus-promoting genes and availability of methods to establish stable expression of potentially corrective genes.

Treatment of lupus nephritis.

Lupus nephritis is a prototype of immune complex-mediated glomerulonephritis. A broad range of clinical presentations and histological changes (proliferative, membranous, or both) are observed. Patients are at risk for progressive renal function deterioration as a result of the interaction of various active immunologic and chronic sclerosing mechanisms of kidney injury. Hypertension and hyperlipidemia contribute to morbidity and mortality. Monitoring serological parameters, urinary protein excretion rate and, especially, the urinary sediment facilitate the prompt recognition and treatment of this disorder. Kidney biopsy evaluation often clarifies the type, severity, and potential reversibility of the underlying renal lesions. Although contemporary immunosuppressive regimens for proliferative lupus nephritis have reduced the risk of end-stage renal failure, they are potentially toxic and not universally effective. Decisions regarding the intensity and duration of these treatments are difficult and are based on the severity of the disease, the initial response to therapy, and the risk for drug-induced toxicities. Studies are in progress to evaluate alternative regimens for proliferative lupus nephritis and membranous lupus nephropathy.

Methylprednisolone and cyclophosphamide, alone or in combination, in patients with lupus nephritis. A randomized, controlled trial.

BACKGROUND: Uncertainty exists about the efficacy and toxicity of bolus therapy with methylprednisolone or of the combination of methylprednisolone and cyclophosphamide in the treatment of lupus nephritis. OBJECTIVE: To determine 1) whether intensive bolus therapy with methylprednisolone is an adequate substitute for bolus therapy with cyclophosphamide and 2) whether the combination of methylprednisolone and cyclophosphamide is superior to bolus therapy with methylprednisolone or cyclophosphamide alone. DESIGN: Randomized, controlled trial with at least 5 years of follow-up. SETTING: Government referral-based research hospital. PATIENTS: 82 patients with lupus nephritis who had 10 or more erythrocytes per high-power field, cellular casts, proteinuria (> 1 g of protein per day), and a renal biopsy specimen that showed proliferative nephritis. INTERVENTIONS: Bolus therapy with methylprednisolone (1 g/m2 body surface area), given monthly for at least 1 year; bolus therapy with cyclophosphamide (0.5 to 1.0 g/m2 body surface area), given monthly for 6 months and then quarterly; or bolus therapy with both methylprednisolone and cyclophosphamide. MEASUREMENTS: 1) Renal remission (defined as < 10 dysmorphic erythrocytes per high-power field, the absence of cellular casts, and excretion of < 1 g of protein per day without doubling of the serum creatinine level), 2) prevention of doubling of the serum creatinine level, and 3) prevention of renal failure requiring dialysis. RESULTS: Renal remission occurred in 17 of 20 patients in the combination therapy group (85%), 13 of 21 patients in the cyclophosphamide group (62%), and 7 of 24 patients in the methylprednisolone group (29%) (P < 0.001). Twenty-eight patients (43%) did not achieve renal remission. By life-table analysis, the likelihood of remission during the study period was greater in the combination therapy group than in the methylprednisolone group (P = 0.028). Combination therapy and cyclophosphamide therapy were not statistically different. Adverse events were amenorrhea (seen in 41% of the cyclophosphamide group, 43% of the combination therapy group, and 7.4% of the methylprednisolone group), cervical dysplasia (seen in 11% of the cyclophosphamide group. 7.1% of the combination therapy group, and 0% of the methylprednisolone group), avascular necrosis (seen in 11% of the cyclophosphamide group, 18% of the combination therapy group, and 22% of the methylprednisolone group), herpes zoster (seen in 15% of the cyclophosphamide group, 21% of the combination therapy group, and 3.7% of the methylprednisolone group) and at least one infection (seen in 26% of the cyclophosphamide group. 32% of the combination therapy group, and 7.4% of the methylprednisolone group). CONCLUSIONS: Monthly bolus therapy with methylprednisolone was less effective than monthly bolus therapy with cyclophosphamide. A trend toward greater efficacy with combination therapy was seen.

Systemic lupus erythematosus: emerging concepts. Part 2: Dermatologic and joint disease, the antiphospholipid antibody syndrome, pregnancy and hormonal therapy, morbidity and mortality, and pathogenesis.

PURPOSE: To review 1) advances in the pathogenesis, diagnosis, and management of dermatologic and joint disease and the antiphospholipid antibody syndrome in patients with systemic lupus erythematosus; 2) controversies related to pregnancy and hormonal therapy and to morbidity and mortality in these patients; and 3) current views on the pathogenesis of systemic lupus erythematosus. DATA SOURCES AND STUDY SELECTION: Review of the English-language medical literature with emphasis on articles published within the last 5 years. More than 400 articles were reviewed. DATA SYNTHESIS: Despite considerable overlap, cutaneous lesions specific to lupus erythematosus may be divided into subsets with distinct clinical, histologic, and immunofluorescent features. A recent short-term, prospective, uncontrolled trial found hydroxychloroquine and retinoids to be of similar efficacy in the treatment of cutaneous lupus erythematosus. Optimal treatment for patients with lupus and the anticardiolipin antibody syndrome remains to be defined; uncontrolled, retrospective, and treatment-withdrawal studies suggest that warfarin may be more protective than aspirin. Whether pregnancy induces lupus flares has not yet been established; existing data suggest both that it does and that it does not. Oral contraceptive use and postmenopausal estrogen replacement therapy appear not to cause clinical deterioration in patients with lupus. Recent studies have documented a substantial improvement in the survival of patients with systemic lupus erythematosus; they found 5-year survival rates of 90% or more and 10-year survival rates of more than 80%. Most data suggest that systemic lupus erythematosus results from the activation of self-reactive T cells and B cells by genetic or environmental factors. CONCLUSIONS: The optimal treatment for dermatologic disease and the antiphospholipid antibody syndrome in patients with systemic lupus erythematosus remains unknown. Although mortality has decreased substantially, the morbidity related to the disease itself and to complications of therapy is still considerable. More studies are needed to further elucidate the effects of pregnancy on this condition and the pathogenetic mechanisms responsible for the development of this disease.

Systemic lupus erythematosus: emerging concepts. Part 1: Renal, neuropsychiatric, cardiovascular, pulmonary, and hematologic disease.

PURPOSE: To review advances and controversies in the diagnosis and management of systemic lupus erythematosus with visceral involvement (renal, neuropsychiatric, cardiopulmonary, and hematologic disease). DATA SOURCES AND STUDY SELECTION: Review of the English-language medical literature with emphasis on articles published in the last 5 years. More than 400 articles were reviewed. DATA SYNTHESIS: Recent debates pertaining to lupus nephritis have focused on the value of kidney biopsy data and the role of cytotoxic drug therapies. Many studies have shown that estimates of prognosis are enhanced by consideration of clinical, demographic, and histologic features. For patients with severe lupus nephritis, an extended course of pulse cyclophosphamide therapy is more effective than a 6-month course of pulse methylprednisolone therapy in preserving renal function. Adding a quarterly maintenance regimen to monthly pulse cyclophosphamide therapy reduces the rate of exacerbations. Plasmapheresis appears not to enhance the effectiveness of prednisone and daily oral cyclophosphamide. Small case series have shown pulses of cyclophosphamide to be beneficial in patients with lupus and neuropsychiatric disease refractory to glucocorticoid therapy, acute pulmonary disease (pneumonitis or hemorrhage), and thrombocytopenia. Patients with systemic lupus erythematosus have an increased prevalence of valvular and atherosclerotic heart disease, apparently because of factors related to the disease itself and to drug therapy. CONCLUSIONS: Cytotoxic agents are superior to glucocorticoid therapy for the treatment of proliferative lupus nephritis, but the optimal duration and intensity of cytotoxic therapy remain undefined. Definitive studies of the treatment of autoimmune thrombocytopenia and acute pulmonary disease and of the diagnosis and treatment of neuropsychiatric disease are not available.

High-risk features of lupus nephritis: importance of race and clinical and histological factors in 166 patients.

BACKGROUND: The pleomorphic nature of lupus nephritis has confounded efforts to refine estimates of prognosis. Consideration of interactions among prognostic factors may help to identify high-risk patients. METHODS: By univariate and multivariate survival analysis, race and attributes of severe active lupus nephritis were evaluated as potentially important prognostic factors in 166 patients upon entry into prospective therapeutic trials of lupus kidney disease. RESULTS: Black patients were significantly more likely than others to develop renal insufficiency. Cellular crescents emerged as the most predictive active pathological feature and interstitial fibrosis was the strongest chronic histological prognostic factor. Combinations of these morphological attributes identified particularly high-risk individuals. Patients with 50% or more cellular crescents and those with less extensive cellular crescents plus moderate to severe interstitial fibrosis were at markedly increased risk for doubling serum creatinine compared to those who lacked these histologic features (P < 0.0001). Azotaemia, anaemia, hypocomplementaemia, hypertension, tubular atrophy and glomerular sclerosis were also associated with an increased probability of renal function deterioration. Serum creatinine, haematocrit, race, and kidney pathology data emerged as independent predictors of renal insufficiency. Black patients in this study were more likely than the others to have high-risk histological features, including extensive cellular crescents (> or = 50%) and moderate to severe interstitial fibrosis, prior to randomization. CONCLUSIONS: Combinations of high-risk demographic, clinical and histological attributes identify patients at increased risk for progressive renal function deterioration. Several factors, including the severity of kidney biopsy findings, probably contribute to the poor prognosis of Black patients in this study population.

Predicting renal outcomes in severe lupus nephritis: contributions of clinical and histologic data.

Despite several years of intense investigation, there continues to be controversy about the value of clinical, demographic and histologic features in prediction of outcomes of lupus nephritis. In addition, contemporary treatments have reduced the risk of progressive renal injury and thus may have altered the prognostic significance of some of these factors. We have therefore re-examined the predictive value of variables previously associated with an increased risk of renal insufficiency by studying 65 patients with severe lupus nephritis treated with intensive regimens of intravenous pulse cyclophosphamide or methylprednisolone. Five clinical features at study entry were each associated with an increased probability of doubling the serum creatinine: age greater than 30 years, Black race, hematocrit less than 26%, serum creatinine greater than 2.4 mg/dl, and C3 complement less than 76 mg/dl. By multivariate survival analysis, serum creatinine, hematocrit and race emerged as the strongest set of independent clinical predictors; the other clinical and demographic factors, including age and C3 complement did not contribute significantly to outcome predictions in the context of these three variables. Renal biopsy evaluation offered additional prognostic information and showed that patients with severe active and chronic histologic changes were at increased risk for developing renal insufficiency. The combination of cellular crescents and interstitial fibrosis was particularly ominous. Outcome predictions based on the strongest clinical model (serum creatinine, hematocrit and race) were significantly enhanced by the addition of renal pathology data. Consideration of these prognostic factors may contribute to decisions regarding the type and intensity of immunosuppressive therapy for patients with lupus nephritis.

Gene targeting in normal somatic cells: inactivation of the interferon-gamma receptor in myoblasts.

Gene targeting in somatic cells represents a potentially powerful method for gene therapy, yet with the exception of pluripotent mouse embryonic stem (ES) cells, homologous recombination has not been reported for a well characterized, non-transformed mammalian cell. Applying a highly efficient strategy for targeting an integral membrane protein--the interferon gamma receptor--in ES cells, we have used homologous recombination to target a non-transformed somatic cell, the mouse myoblast, and to compare targeting efficiencies in these two cell types. Gene-targeted myoblasts display the properties of normal cells including normal morphology, ability to differentiate in vitro, stable diploid karyotype, inability to form colonies in soft agar and lack of tumorigenicity in nude mice.

Human immunodeficiency virus (HIV) and HIV infected cells in saliva and salivary glands of a patient with systemic lupus erythematosus.

A young woman with systemic lupus erythematosus (SLE) was infected with human immunodeficiency virus 1 (HIV-1) and about 6 years later developed persistent bilateral parotid gland enlargement. It was unclear whether this represented salivary gland involvement as a component of her SLE (secondary Sjögren's syndrome) or the initial clinical manifestation of her HIV-1 infection. HIV proviral DNA was found in individual salivary glandular secretions and in whole saliva. Additionally, cells positive for HIV RNA were isolated from whole saliva. A parotid gland biopsy revealed infiltrating lymphocytes containing large amounts of HIV RNA.

Renal toxicity of interleukin-2 administration in patients with metastatic renal cell cancer: effect of pre-therapy nephrectomy.

Systemic administration of interleukin-2 and lymphokine-activated killer cells is a new approach to the immunotherapy of advanced cancer. Metastatic renal cell cancer is one of the histological types of tumors particularly susceptible to this treatment approach although renal toxicity often is a dose-limiting side effect. We compared the renal functional changes observed during interleukin-2 therapy in 52 consecutive patients with advanced renal cancer to that of 83 consecutive patients with metastatic nonrenal cancer. Of the 52 patients with renal cancer 41 had recently undergone nephrectomy. The over-all peak serum creatinine values and the percentage increase of serum creatinine over baseline for all patients studied were significantly higher in cycle 2 of interleukin-2 therapy than in cycle 1: 3.8 +/- 0.2 versus 2.6 +/- 0.1 mg. per dl. and 241.7 +/- 16.5 versus 140.3 +/- 11.0 per cent, respectively. In patients with pre-therapy serum creatinine values of 0.4 to 0.9 mg. per dl. there were no significant differences in the mean peak serum creatinine nor in the percentage increase over baseline between renal and nonrenal cancer patients during cycle 1. In cycle 2 of therapy these values were higher in the renal cancer group (3.6 +/- 0.8 versus 2.4 +/- 0.2 mg. per dl. and 310.4 +/- 103.5 versus 214 +/- 30.4 per cent, respectively) but they did not reach statistical significance (P2 = 0.08 and 0.25, respectively). Renal and nonrenal cancer patients with pre-therapy serum creatinine levels of 1.0 to 1.4 mg. per dl. achieved similar high values in cycle 2 of interleukin-2 therapy (3.9 +/- 0.3 versus 3.9 +/- 0.4 mg. per dl. and 222.7 +/- 23.2 versus 248.7 +/- 33.5 per cent, respectively), although the initial increase (cycle 1) was higher in the renal cancer patients (3.3 +/- 0.3 versus 2.4 +/- 0.2 mg. per dl. and 172.3 +/- 25.9 versus 116.1 +/- 18.0 per cent, respectively). Baseline serum creatinine greater than or equal to 1.5 mg. per dl. was associated with an over-all higher peak serum creatinine and higher percentage increase of serum creatinine over baseline than that below 1.5 mg. per dl. baseline: 4.4 mg.per dl. and 171.1 +/- 36.3 per cent in cycle 1 and 6.5 +/- 0.7 mg. per dl. and 296.1 +/- 44.0 per cent in cycle 2, respectively (p less than 0.01). There was no association between peak serum creatinine and interval from nephrectomy to interleukin-2 therapy.(ABSTRACT TRUNCATED AT 400 WORDS)

Chronic dialysis in a patient with cystic fibrosis.

To our knowledge this is the first case reported in the literature of a patient with cystic fibrosis and end-stage renal disease, who was on dialysis for 2 years. We discuss here the possible mechanisms responsible for what has been called 'the cystic fibrosis nephropathy' and its consequences.

Evolution of ciclosporin nephrotoxicity in patients treated for autoimmune uveitis.

Among 73 patients treated with ciclosporin (CS) for autoimmune uveitis, a 50% elevation of serum creatinine was observed in 37% within 3 months of starting CS and in 25% after more than 6 months of relatively uncomplicated therapy. Sequential renal function and histologic evaluations were performed in 17 patients to further characterize the nephrotoxic effects of long-term CS therapy. Inulin clearance remained essentially unchanged in 12 patients despite CS dosage reductions in the majority. In 2 such patients, repeat renal biopsy specimens revealed evidence of progressive irreversible kidney injury even though renal function was stable. Inulin clearance decreased substantially in 3 patients; in 1 case a follow-up renal biopsy showed increased severity of chronic histologic change. For 2 patients, the inulin clearance more than doubled after CS dosage reduction; and in 1 of those cases, repeat renal biopsy showed no evidence of progressive renal scarring. Overall, the morphologic attributes of irreversible kidney injury (designated by a chronicity index including glomerular sclerosis, tubular atrophy and interstitial fibrosis) were increased in 3 of 6 follow-up renal biopsy specimens. Histologic alterations of renal arterioles, including hyaline change, were observed in all CS-treated patients. The hyaline change of arterioles was either extensive in the first renal biopsy specimen or became extensive in the second biopsy in the 3 cases manifesting an increased chronicity index on the follow-up renal biopsy. Thus, parenchymal injury can progress in some cases despite CS dosage reduction and stable renal function; renal arteriolar histologic change is a prominent finding in these patients. Patients that exhibit a substantial improvement in renal function after dosage reduction may experience a more favorable course.

Metabolic and renal effects of interleukin-2 immunotherapy for metastatic cancer.

The systemic administration of recombinant interleukin-2 (IL-2) either alone or in combination with lymphokine activated killer cells is a new approach to the immunotherapy of metastatic cancer in man. Renal toxicity is often a dose-limiting side effect of IL-2 administration. This prospective study of 17 consecutive patients receiving parenteral high dose IL-2 documents a reversible syndrome of hypotension, oliguria, fluid retention, azotemia and very low urinary excretion of sodium (median FeNa of 0.04%). The median nadir urinary uric acid to urinary creatinine ratio during IL-2 therapy was 0.2. This IL-2 regimen induces a reversible renal hypoperfusion syndrome (pre-renal azotemia) without evidence of acute uric acid nephropathy. Hypophosphatemia [median serum phosphorus of 1.9 mg/dl (0.61 mmol/l)] prompted further study of tubular function. Urinary excretions of phosphorus, calcium and magnesium were very low. Arterial blood gases revealed hyperventilation without alkalemia. The hypophosphatemia probably reflects increased utilization of inorganic phosphorus by rapidly proliferating lymphoid cells.

Lupus nephritis: association between serology and renal biopsy measures.

The relationship between serologic tests and renal histologic change over time was examined in 55 patients with lupus nephritis. After a median interval of 40 months on various immunosuppressive drug regimens, C3 complement levels were improved in 78% of patients and anti-DNA levels were improved in 85%. Comparison of initial and followup renal pathology showed that the activity index of the biopsy improved in 82%, while the chronicity index worsened in 71% of patients. Normalization of C3, but not anti-DNA levels, was associated with a lowering of the activity index on repeat biopsy. Prolonged depression of serum C3 levels was associated with a trend (p = 0.066) towards worsening of the chronicity index, but the change in chronicity index showed no relationship to the duration of elevated anti-DNA. Our studies indicate that abnormal levels of C3 complement are predictive of the degree of persistently active glomerular disease, but that duration of abnormal C3 or anti-DNA are less consistent predictors of the acquisition of chronic, irreversible renal lesions.

Effects of interleukin-2 on renal function in patients receiving immunotherapy for advanced cancer.

Adoptive transfer of autologous lymphokine-activated killer cells in conjunction with recombinant interleukin-2 in patients with advanced cancer has produced significant regression of metastatic disease in selected patients. We analyzed the effects of interleukin-2 regimens on renal function in 99 consecutive patients. Interleukin-2 therapy with or without lymphokine-activated killer cells was associated with varying degrees of hypotension, fluid retention, azotemia, oliguria, and low fractional sodium excretion. After the patients completed the interleukin-2 regimens, their renal function improved promptly. Renal function values returned to baseline levels within 7 days in 62% of patients, within 14 days in 84%, and within 30 days in 95%. Pretherapy serum creatinine values above 1.4 mg/dL predicted the severity of azotemia and prolonged duration of renal functional recovery, interleukin-2 therapeutic regimens induce prerenal azotemia. Careful selection of patients and early detection of adverse physiologic changes may alleviate the side effects of interleukin-2 therapy.

Severe glomerulonephritis with late emergence of classic Wegener's granulomatosis. Report of 4 cases and review of the literature.

We have analyzed an unusual group of 19 patients (15 previously reported) with Wegener's granulomatosis, who presented with severe glomerulonephritis and developed diagnostic respiratory lesions only after 4 to 78 months. Necrotizing glomerulonephritis, often with crescents, and rarely with vasculitis, was the predominant renal lesion. Wegener's granulomatosis was unsuspected initially, since systemic manifestations, such as fever, arthralgias, malaise, and even pulmonary hemorrhage, were nonspecific or transient, and because renal biopsy findings resembled those seen in microscopic polyarteritis or idiopathic crescentic nephritis. Despite therapy, usually with corticosteroids, only 4 patients maintained adequate renal function. Most patients were receiving chronic dialysis when respiratory involvement developed. Cavitary nodular pulmonary infiltrates were seen in 12 of the 17 patients with lung involvement, and otorhinological disease occurred in 10 patients. Arthralgias, fever, and cough, with or without hemoptysis, were common. Wegener's granulomatosis was diagnosed by lung biopsy in 15 cases and by nasal biopsy in 4. Specific treatment was required for the respiratory disease and was delayed in many patients, because of lack of awareness that Wegener's granulomatosis may present with primary glomerulonephritis and become active during chronic renal failure or dialysis. Nevertheless, all but 1 patient eventually responded to treatment, although 3 additional patients died of late complications.