John Klassen

Illness intrusiveness and quality of life in end-stage renal disease: comparison and stability across treatment modalities.

Investigated the degree to which chronic, life-threatening illness and its treatment interfere with continued involvements in valued activities and interests--that is, illness intrusiveness--and its impact on quality of life in end-stage renal disease. Data were collected on two occasions separated by a lag of 6 weeks. Mixed analyses of variance indicated that life domains were affected differentially across treatments. Perceived illness intrusiveness correlated significantly with treatment time requirements, uremic symptoms, intercurrent nonrenal illnesses, fatigue, and difficulties in daily activities. Significant quality-of-life differences were observed across treatment modalities for satisfaction/happiness and pessimism/illness-related concerns but not for depression/distress. Perceived illness intrusiveness correlated significantly with each of these quality-of-life measures. Results were stable over time. These findings substantiate the construct of illness intrusiveness as a mediator of the psychosocial impact of chronic, life-threatening illness.

Evolution of membranous nephropathy into anti-glomerular-basement-membrane glomerulonephritis.

Abstract In a patient with biopsy-proved membranous nephropathy (nephrotic syndrome) acute fatal renal failure suddenly developed. Autopsy revealed rapidly progressive glomerulonephritis superimposed on the previous membranous changes. IgG eluted from the kidney was shown by immunofluorescence technic to bind to the glomerular basement membrane of normal human and monkey kidneys, and was capable of producing an acute anti-glomerular-basement-membrane nephritis in two monkeys. The IgG antibody, by radioisotopic methods, was specifically directed against primate kidney. It is postulated that immune complexes responsible for the original membranous nephropathy induced release of antigenic glomerular-basement-membrane fragments into the circulation, stimulating formation of antibodies to the membrane and producing fatal acute glomerulonephritis. (N Engl J Med 290:1340–1344, 1974)

Immune complex-mediated interstitial cystitis as a major manifestation of systemic lupus erythematosus

Abstract The etiology of chronic interstitial cystitis (IC) is unknown; various factors have been suggested but none have been proven. It has several features of autoimmune disease and some authors have regarded it as belonging to that group characterized by organ-specific damage produced by non-organ-specific autoantibodies. We report the demonstration of denatured DNA [one of the antigens known to be present in the immune complexes in systemic lupus erythematosus (SLE)], IgG, IgM, IgA, and C3 in the bladder deposits in a young female patient with documented SLE who developed chronic interstitial cystitis as her main manifestation of the disease. We suggest that in some cases IC represents a local manifestation of SLE in the bladder.

Autoimmune cell-mediated tubulointerstitial nephritis induced in lewis rats by renal antigens

Abstract Lewis rats were injected with homogenates of renal or liver tissue or saline in complete Freunds adjuvant, plus pertussis vaccine, and were sacrificed at intervals ranging from 4 to 56 days. No renal lesions were observed in liver-or saline-injected animals. However, in rats injected with kidney preparations, severe tubulointerstitial nephritis was observed at 10–14 days; the lesions were characterized by irregular mononuclear cell infiltrates and tubular cell damage. At later intervals, milder more focal lesions were found. By immunofluorescence no tubulointerstitial deposits of immunoglobulin or C3 were detected. Transfer of lymph node, spleen, or peritoneal exudate cells from kidney-injected donors to normal Lewis rats resulted in focal interstitial infiltrates and tubular cell damage at 24 to 48 hr. Transfer of serum from kidney-injected donors or cells or serum from liver- or saline-injected donors produced no renal lesions. The migration of peritoneal macrophages from kidney-injected animals was inhibited by kidney, but not liver or spleen antigens. MIF activity was found in culture supernatants when lymph node or spleen cells from kidney-injected animals were cultured with kidney, but not with liver antigen preparations. The findings are interpreted as indicating that the tubulointerstitial lesions resulted from cell-mediated reactivity against kidney-specific antigens.

Reversible sclerosing cholangitis secondary to cryptosporidiosis in a renal transplant patient

Cryptosporidium parvum is a well-known cause of chronic diarrhea. In human immunodeficiency virus (HIV)-infected patients as well as in other immunocompromised patients it has also been shown to cause sclerosing cholangitis. We report a case of reversible C. parvum-induced sclerosing cholangitis in a renal transplant patient. This 40-year-old female received a renal transplant 9 years prior to presentation. She had no history of liver disease and was doing well on tacrolimus, prednisone, and azathioprine. She developed diarrhea and was found to have C. parvum present in the stool. Shortly after, she developed clinical, biochemical, radiologic, and histologic features of SC. After accidental reduction in her immunesuppression secondary to starting her on rifampin to treat her itching, she cleared C. parvum from her stool and had a marked improvement in her diarrhea, jaundice, and general health. Her liver enzymes normalized and magnetic resonance cholangiography showed complete resolution of biliary abnormalities. To our knowledge, this is the first case of C. parvum-induced sclerosing cholangitis in a renal transplant patient and one of a few in non-HIV patients. It is also the first to document resolution of sclerosing cholangitis after eradication of C. parvum in a non-HIV patient.

Lentivector Iterations and Pre-Clinical Scale-Up/Toxicity Testing: Targeting Mobilized CD34+ Cells for Correction of Fabry Disease

Fabry disease is a rare lysosomal storage disorder (LSD). We designed multiple recombinant lentivirus vectors (LVs) and tested their ability to engineer expression of human α-galactosidase A (α-gal A) in transduced Fabry patient CD34+ hematopoietic cells. We further investigated the safety and efficacy of a clinically directed vector, LV/AGA, in both ex vivo cell culture studies and animal models. Fabry mice transplanted with LV/AGA-transduced hematopoietic cells demonstrated α-gal A activity increases and lipid reductions in multiple tissues at 6 months after transplantation. Next we found that LV/AGA-transduced Fabry patient CD34+ hematopoietic cells produced even higher levels of α-gal A activity than normal CD34+ hematopoietic cells. We successfully transduced Fabry patient CD34+ hematopoietic cells with “near-clinical grade” LV/AGA in small-scale cultures and then validated a clinically directed scale-up transduction process in a GMP-compliant cell processing facility. LV-transduced Fabry patient CD34+ hematopoietic cells were subsequently infused into NOD/SCID/Fabry (NSF) mice; α-gal A activity corrections and lipid reductions were observed in several tissues 12 weeks after the xenotransplantation. Additional toxicology studies employing NSF mice xenotransplanted with the therapeutic cell product demonstrated minimal untoward effects. These data supported our successful clinical trial application (CTA) to Health Canada and opening of a “first-in-the-world” gene therapy trial for Fabry disease.