Proteinuria autoimmunity

Penicillamine onset may be seen in 1 to 3 months, and most responses occur within 6 months. Early adverse effects include skin rash, metallic taste, hypogeusia, stomatitis, anorexia, nausea, vomiting, and dyspepsia. Glomerulonephritis may occur, which manifests as proteinuria and hematuria. Penicillamine is usually reserved for patients who are resistant to other therapies because of the rare but potentially serious induction of autoimmune diseases (e.g., Goodpasture s syndrome, myasthenia gravis). 

Adverse reactions include alteration of taste perception in a high proportion of patients, drug fever, proteinuria and immune complex nephritis and an increased incidence of autoimmune diseases. Most feared are blood dyscrasias for which blood tests should be done regularly. 

Infrequent reactions to interferon therapy include proteinuria, renal toxicity, autoimmune disease, thyroid disease, ophthalmic toxicity, pulmonary dysfunction (pulmonary infiltrates, pneumonitis, and pneumonia), and cardiovascular effects (tachycardia, arrhythmia, hypotension, cardiomyopathy, and myocardial infarction). Rarely, the body may develop antibodies against interferons that inhibit their effectiveness. 

Proteinuric states are commonly accompanied by the fusion of podocyte foot processes. The assumption that this foot process fusion is only a nonspecific secondary response of podocytes to proteinuria has been recently challenged by the observation that foot process fusion may be caused by toxic or autoimmune damage to podocytes. 

Hypersensitivity reactions are frequent early in a course of penicillamine, with urticarial or maculopapular rashes, fever, and lymphadenopathy. Cross-allergy to penicillin can occur. In addition, the use of penicillamine can be complicated by a unique variety of often serious autoimmune reactions, involving the skin, kidneys, liver, lungs, muscles, or other organs. Proteinuria is found in more than 10% of patients and sometimes develops into the nephrotic syndrome. Pemphigus, myasthenia gravis, polymyositis, or a lupus-like syndrome occur in smaller percentages. 

Langworth et al. 1992b). There is limited information in humans that suggests that certain individuals may develop an autoimmune response when exposed to mercury. Deposition of IgG and complement C3 have been observed in the glomeruli of two workers with mercury-induced proteinuria (Tubbs et al. 

The interstitium of the kidney is also susceptible to injury from a variety of causes. Although acute interstitial nephritis is most commonly caused by medications (see Chap. 46), infections (e.g., streptococcal, leptospirosis, hantavirus, and human immimodeflciency virus), selected autoimmune disorders (systemic lupus erythematosus or mixed connective tissue disease) also may produce a similar syndrome. The presence of white blood cells (WBCs), WBC casts, and coarse granular casts in the urine aU suggest interstitial inflammation. The presence of eosinophUia and eosinophiluria also strongly suggest the presence of an interstitial nephritis. Occasionally low to moderate proteinuria can be seen on urinalysis. 

There is some evidence that human exposure to metallic Hg can induce an autoimmune response. Renal biopsies of two Hg-exposed workers who had developed proteinuria revealed deposits of IgG and complement C3 in the glomemli (Tubbs et al. 1982). Examination of 10 patients who complained of illnesses after they received dental amalgams found that 3 of them had antiglomemlar basement membrane antibodies, and 2 had elevated antinucleolar antibodies (Anneroth et al. 1992). In addition to those reports, Cardenas et al. (1993) reported high anti-DNA antibody titers in 8 of 44 workers from a chloralkali plant. No studies were located that evaluated autoimmunity in humans following exposure to organic forms of Hg. 

Penicillamine Suppresses T cells and circulating rheumatoid factor Proteinuria, hematotoxidty, autoimmune disease... 

Autoimmune-like phenomena in Brown Norway rats induced by mercuiy(II) chloride peak around day 10 after the last of five subcutaneous injections. After 20 days, immune alterations are mostly at control level, and the kidney effects (e.g. proteinuria) are clearly less than on day 10 (Aten et al., 1988). In addition, low-dose pretreatment of Brown Norway rats with mercuiy(II) chloride prevents development of adverse immunity (Szeto et al., 1999), and neonatal injection of mercury(II) chloride in Brown Norway rats renders them tolerant to mercury-induced (but not gold-induced) autoimmune phenomena (Field et al., 2000). These phenomena, transience of autoimmune effects as well as low-dose protection, are shown to be due at least in part to the development of regulatory immune cells. In the case of mercury(II) chloride, these cells have been identified as either IFN-y-producing CD8+CD45RC high regulatory T cells (Pelletier et al., 1990 Mathieson et al., 1991 Szeto et al., 1999 Field et al., 2003) or RT6.2+ T cells (Kosuda et al., 1994). In view of this, it is relevant to note that Lewis rats that produce predominantly CD8+ regulatory T cells ( suppressor T cells) in response to mercury(II) chloride are resistant to mercury-induced autoimmunity and instead display a polyclonal immunosuppressive response (Pelletier et al., 1987). Based on these differences in strain sensitivity, it is clear that susceptibility to mercury-induced autoimmune effects is dependent on MHC class II haplo-type (Aten et al., 1991). 

Tomita Y, Jyonouchi H, Engelman RW, Day NK, Good RA (1993) Preventive action of carotenoids on the development of lymphadenopathy and proteinuria in MRL-lpr/lpr mice. Autoimmunity, 16 95-102. 

An autoimmune response to mercury vapor, such as increased levels of serum IgE and antilaminin autoantibodies, deposition of IgG deposits in the renal glomeruli and proteinuria was observed in a susceptible strain of rats (Hua et al. 1993, Druet et al. 

Toxicity Adverse effects are common and may be severe. They include nephrotoxicity with proteinuria, pancytopenia, and autoimmune dysfunction, including lupus erythematosus and hemolytic anemia. 

Studies in our laboratory show that a basal diet composed of lipid exclusively from fish oil, instead of safflower oil, fed to autoimmune mice suppresses the progression of renal injury and prolongs survival. In MRL-/pr mice, the most aggressive model of lupus, a 20% fish oil diet suppresses the increase in proteinuria, the localization of immune complexes in the glomerulus and the development of renal pathology ". In the NZB x NZW mice with a less virulent form of this illness, a diet rich in fish oil can prevent renal injury when animals are started on it prior to the expression of renal disease and can arrest the progression and reduce mortality when treatment is delayed until the mice are mildly proteinuric ". These data suggest that a fish diet is not only prophylactically beneficial but also offers therapeutic promise. 

Several studies have reported that retinoids are effective for animal models of autoimmune diseases. Lupus nephritis is a major cause of mortality among systemic lupus erythematosus patients. ATRA inhibits IFN-y cytokine production from Thl and production and deposition to the kidneys of anti-DNA antibody IgG2a, and suppresses proteinuria and renal involvement in NZB/WFl mice, which are used as a lupus nephritis model (Nozaki et al. 2005). In an open clinical trial, seven patients with active lupus nephritis were treated with ATRA. As a result, four patients showed improvements in clinical symptoms and laboratory findings, including proteinuria and anti-dsDNA antibody levels. There were no adverse effects of ATRA therapy in any patient (Kinoshita et al. 2009). 

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