Adenine phosphoribosyltransferase (APRT) deficiency is a rare autosomal recessive disorder causing 2,8-dihydroxyadenine stones and renal failure secondary to intratubular crystalline precipitation. Little is known regarding the clinical presentation of APRT deficiency, especially in the white population. We retrospectively reviewed all 53 cases of APRT deficiency (from 43 families) identified at a single institution between 1978 and 2009. The median age at diagnosis was 36.3 years (range 0.5 to 78.0 years). In many patients, a several-year delay separated the onset of symptoms and diagnosis. Of the 40 patients from 33 families with full clinical data available, 14 (35%) had decreased renal function at diagnosis. Diagnosis occurred in six (15%) patients after reaching ESRD, with five diagnoses made at the time of disease recurrence in a renal allograft. Eight (20%) patients reached ESRD during a median follow-up of 74 months. Thirty-one families underwent APRT sequencing, which identified 54 (87%) mutant alleles on the 62 chromosomes analyzed. We identified 18 distinct mutations. A single T insertion in a splice donor site in intron 4 (IVS4 ϩ 2insT), which produces a truncated protein, accounted for 40.3% of the mutations. We detected the IVS4 ϩ 2insT mutation in two (0.98%) of 204 chromosomes of healthy newborns. This report, which is the largest published series of APRT deficiency to date, highlights the underdiagnosis and potential severity of this disease. Early diagnosis is crucial for initiation of effective treatment with allopurinol and for prevention of renal complications.
Catalytic antibodies are immunoglobulins endowed with enzymatic activity. Catalytic IgG has been reported in several human autoimmune and inflammatory diseases. In particular, low levels of catalytic IgG have been proposed as a prognostic marker for chronic allograft rejection in patients undergoing kidney transplant. Kidney allograft is a treatment of choice for patients with end-stage renal failure. Intravenous immunoglobulins, a therapeutic pool of human IgG, is used in patients with donor-specific antibodies, alone or in conjunction with other immunosuppressive treatments, to desensitize the patients and prevent the development of acute graft rejection. Here, we followed for a period of 24 months the levels of catalytic IgG towards the synthetic peptide Pro-Phe-Arg-methylcoumarinimide in a large cohort of patients undergoing kidney transplantation. Twenty-four percent of the patients received IVIg at the time of transplantation. Our results demonstrate a marked reduction in levels of catalytic antibodies in all patients three months following kidney transplant. The decrease was significantly pronounced in patients receiving adjunct IVIg therapy. The results suggests that prevention of acute graft rejection using intravenous immunoglobulins induces a transient reduction in the levels of catalytic IgG, thus potentially jeopardizing the use of levels of catalytic antibodies as a prognosis marker for chronic allograft nephropathy.
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Renal transplant is the treatment of choice for patients with terminal end-stage renal disease. We have previously identified low levels of catalytic IgG as a potential prognosis marker for chronic allograft rejection. The origin and physiopathological relevance of catalytic antibodies is not well understood owing to the fact that catalytic antibodies have been studied in relatively small cohorts of patients with rare diseases and/or without systematic follow-up. In the present study, we have followed the evolution of the levels of catalytic IgG in a large cohort of renal transplant patients over a 2-year period. Our results demonstrate that, prior to transplant, patients with renal failure present with heterogeneous levels of IgG hydrolyzing the generic PFR-MCA substrate. PFR-MCA hydrolysis was greater for patients’ IgG than for a therapeutic preparation of pooled IgG from healthy donors. Renal transplant was marked by a drastic decrease in levels of catalytic IgG over three months followed by a steady increase during the next 21 months. Patients who displayed high levels of catalytic IgG pre-transplant recovered high levels of catalytic antibodies 2 years post-transplant. Interestingly, IgG-mediated hydrolysis of a model protein substrate, pro-coagulant factor VIII, did not correlate with that of PFR-MCA prior transplantation, while it did 12 months post-transplant. Taken together, our results suggest that the level of circulating catalytic IgG under pathological conditions is an intrinsic property of each individual’s immune system, and that recovery of pre-transplant levels of catalytic IgG is accompanied by changes in the repertoire of target antigens.
The origin and physiopathological relevance of catalytic antibodies is not well understood owing to the fact that catalytic antibodies have been studied in relatively small cohorts of patients with rare diseases and/or without systematic follow-up. In the present study, we have followed the evolution of the levels of catalytic IgG in a large cohort of 100 renal transplant patients over a 2-year period. Prior to transplant, hydrolysis of the generic substrate PFR-MCA was greater for patients’ IgG than for a therapeutic preparation of pooled IgG from healthy donors (6.6±0.9 vs 0.65±0.03 fmol/min per pmol). Renal transplant was marked by a drastic decrease in levels of catalytic IgG over 3 months (6.6±0.9 vs 2.4±0.2 fmol/min/pmol; P<0.0001) followed by a steady increase at 12 months (3.2±0.3 fmol/min/pmol; P=0.015) and further at 24 months (5.1±0.6 fmol/min/pmol; P=0.004). When divided into quartiles based on the rates of IgG-mediated PFR-MCA hydrolysis measured in pre-transplant samples, the IgG catalytic activity in the upper quartile of patients was significantly high both pre-transplant (12.03±1.6 vs 2.7±0.2 fmol/min/pmol, P<0.0001) and 24 months post-transplant (6.8±1.2 vs 4.6±0.7, fmol/min/pmol, P=0.0004). Interestingly, IgG-mediated hydrolysis of a model protein substrate, pro-coagulant factor VIII, did not correlate with that of PFR-MCA prior transplantation, while it did 12 months post-transplant (P<0.0001, R2=0.4). Taken together, our results suggest that the level of circulating catalytic IgG under pathological conditions is an intrinsic property of each individual’s immune system, and that recovery of pre-transplant levels of catalytic IgG is accompanied by changes in the repertoire of target antigens.
Catalytic antibodies are immunoglobulins endowed with enzymatic activity. Catalytic IgG has been reported in several human autoimmune and inflammatory diseases. In particular, low levels of catalytic IgG have been proposed as a prognostic marker for chronic allograft rejection in patients undergoing kidney transplant. Kidney allograft is treatment of choice for patients with end-stage renal failure. Intravenous immunoglobulins, a therapeutic pool of normal human IgG, is used in patients with donor-specific antibodies, alone or in conjunction with other immunosuppressive treatments, in order to desensitize the patients and prevent the development of acute graft rejection. In the present study, we followed for a period of 24 months the levels of catalytic IgG in a large cohort of patients undergoing kidney transplantation. Twenty-four percent of the patients received IVIg at the time of transplantation. Our results demonstrate a marked reduction in the levels of catalytic antibodies in all patients three months following kidney transplant. The decrease was significantly more pronounced in patients receiving adjunct IVIg therapy. The results suggests that prevention of acute graft rejection using intravenous immunoglobulins induces a transient reduction in the levels of catalytic IgG, thus potentially jeopardizing the use of levels of catalytic antibodies as a prognosis marker for chronic allograft nephropathy.
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