Anti-tubular Basement Membrane Nephritis Research Articles

Dent disease presenting as partial Fanconi syndrome and hypercalciuria

CASE PRESENTATION A 6-year-old Korean-American boy was found to have asymptomatic proteinuria and glycosuria during routine urinary screening. His birth was complicated by polyhydramnios. His 4-year-old brother was also found to have glycosuria and proteinuria on routine urinalysis (Table 1). There was no history of hematuria, renal failure, hearing loss, or nephrolithiasis. He was taking no medications. There was no other family history of renal disease or renal calculi. Physical examination revealed a healthy-appearing young boy with a normal blood pressure of 90/60 mm Hg and no edema. Physical examination was normal, and there was no evidence of cataracts, rickets, or mental retardation. Height and weight were in the 25th percentiles. Renal ultrasound showed 7.5 cm kidneys with echogenic medullary regions and one echogenic focus suggestive of a calculus. Laboratory examination showed a hematocrit of 34.4% (normal 37–45%), white blood cell count 10.7 10/L (normal 4.5–13.5 10/L) with normal differential, platelet count 527 10/L (normal 150–450 10/L), blood urea nitrogen 15 mg/dL (5.4 mmol/L) (normal 7–18 mg/dL (2.5–6.4 mmol/L)), serum creatinine 0.3 mg/dL, total serum protein 7.6 g/dL (76 g/L) (normal 6–8.2 g/dL (60–82 g/L)), serum albumin 4.3 g/dL (43 g/L) (normal 3.4–5.0 g/dL (34–50 g/L)). The serum electrolytes, including calcium, magnesium, and phosphorus were normal. TCO2 was 25.7 mM (normal 22–32 mM). Serologic testing for antinuclear antibody was negative and the serum complement levels, including C3 and C4, were within normal range. Urinalysis revealed a specific gravity of 1030, pH 5, protein 4300 mg/dL, glucose 100 mg/dL, heme moderate, and leukocyte esterase negative. The urine protein/creatinine ratio was 4.3 and the urine calcium/creatinine ratio was 0.339 (normal o0.200). Urine protein electrophoresis revealed 354 mg/dL of protein of which 26% was albumin with a large fraction of low molecular weight proteins and a markedly elevated b2-microglobulin of 159 000mg/dL (normal 0–300mg/dL). The urinary amino-acid profile showed no abnormality. Urinary uric acid was 633.6 mg/dL (normal 250–750 mg/dL), magnesium 54 mg/24 h (normal 12–293 mg/24 h), phosphorus 880 mg/24 h (normal 400–1300 mg/24 h), and copper 32mg/24 h (normal 3–25mg/24 h). The clinical differential diagnosis included conditions, both inherited and acquired, that impair proximal tubular function producing a partial Fanconi syndrome (glycosuria and low molecular weight proteinuria (LMWP), without proximal renal tubular acidosis, aminoaciduria, or hyperphosphaturia). Acquired conditions to be considered in this age group include heavy metal toxicity, anti-tubular basement membrane nephritis, and other forms of interstitial nephritis. The family history of two affected brothers strongly suggested an inherited disorder, possibly X-linked or autosomal recessive. Inherited forms of Fanconi syndrome to be considered include Dent disease, Lowe syndrome, cystinosis, and a mitochondriopathy. In addition, causes of hypercalciuria such as hyperparathyroidism or excessive calcium intake were considered, although the absence of hypercalcemia and the presence of proteinuria argued against that possibility. Among causes of inherited Fanconi syndrome, Dent disease is the only form that typically manifests marked hypercalciuria. A renal biopsy was performed to determine the cause of the subnephrotic proteinuria and glycosuria. t h e r e n a l c o n s u l t http://www.kidney-international.org

RENAL TRANSPLANTATION FOR ESRD FOLLOWING BONE MARROW TRANSPLANTATION: A REPORT OF 5 CASES, WITH AND WITHOUT IMMUNOSUPPRESSION

657 Over 12,000 bone marrow transplantations (BMT) are performed in the USA each year. This procedure is associated with significant morbidity including acute and chronic renal failure (CRF). CRF is usually secondary to radiation and/or CsA toxicity. Survival on dialysis therapy for patients with radiation nephropathy is poor (Cohen, et al, JASN, 1997 (8); 135A) and renal transplantation may be a preferable form of renal replacement therapy. This report summarizes our experience with renal transplantation in 5 patients with ESRD (three due to radiation nephropathy; one secondary to TTP/HUS; and one due to anti-tubular basement membrane nephritis) following BMT. All five patients were Caucasian, with 4 females and 1 male included in this study. Their ages at the time of renal transplant ranged from 27-40 years. BMT was performed for chronic myelogenous leukemia in 2 patients, acute myelogenous leukemia in 2, and acute lymphocytic leukemia in 1. ESRD developed after a mean of 100 months (range 84-132 months) post-BMT and 4 of the 5 patients were maintained on dialysis for a mean of 11 months (range 1-13 months) prior to renal transplantation. The kidney source was from an LRD in 4 patients, and CAD in one patient. In two recipients, the bone marrow and kidneys were from the same donor. One of these recipients is managed without any immunosuppressive therapy and the other is maintained on azathioprine (25 mg/day) alone. The other three are maintained on triple therapy (prednisone, MMF/azathioprine, and CsA/FK506). Immediately post-transplant, one patient had a ureteral leak, and one patient had acute rejection, treated with OKT3. In all five patients renal function stabilized after transplantation. One patient experienced urosepsis two months after renal transplantation, which responded to treatment. These patients have been followed for up to 22 months (range 2-22 months) post-transplant and all are alive with functioning bone marrow and renal allografts. Their creatinines range from 0.8 to 2.1 mg/dl (mean 1.2 mg/dl). In summary: 1) Renal transplant is a feasible alternative for patients with ESRD following BMT; 2) If bone marrow and kidney are from the same donor, the recipient requires little or no maintenance immunosuppression; 3) Short-term results show good survival, but long-term follow-up is needed.

RENAL TRANSPLANTATION FOR ESRD FOLLOWING BONE MARROW TRANSPLANTATION: A REPORT OF 5 CASES, WITH AND WITHOUT IMMUNOSUPPRESSION.

657 Over 12,000 bone marrow transplantations (BMT) are performed in the USA each year. This procedure is associated with significant morbidity including acute and chronic renal failure (CRF). CRF is usually secondary to radiation and/or CsA toxicity. Survival on dialysis therapy for patients with radiation nephropathy is poor (Cohen, et al, JASN, 1997 (8); 135A) and renal transplantation may be a preferable form of renal replacement therapy. This report summarizes our experience with renal transplantation in 5 patients with ESRD (three due to radiation nephropathy; one secondary to TTP/HUS; and one due to anti-tubular basement membrane nephritis) following BMT. All five patients were Caucasian, with 4 females and 1 male included in this study. Their ages at the time of renal transplant ranged from 27-40 years. BMT was performed for chronic myelogenous leukemia in 2 patients, acute myelogenous leukemia in 2, and acute lymphocytic leukemia in 1. ESRD developed after a mean of 100 months (range 84-132 months) post-BMT and 4 of the 5 patients were maintained on dialysis for a mean of 11 months (range 1-13 months) prior to renal transplantation. The kidney source was from an LRD in 4 patients, and CAD in one patient. In two recipients, the bone marrow and kidneys were from the same donor. One of these recipients is managed without any immunosuppressive therapy and the other is maintained on azathioprine (25 mg/day) alone. The other three are maintained on triple therapy (prednisone, MMF/azathioprine, and CsA/FK506). Immediately post-transplant, one patient had a ureteral leak, and one patient had acute rejection, treated with OKT3. In all five patients, renal function stabilized after transplantation. One patient experienced urosepsis two months after renal transplantation, which responded to treatment. These patients have been followed for up to 22 months(range 2-22 months) post-transplant and all are alive with functioning bone marrow and renal allografts. Their creatinines range from 0.8 to 2.1 mg/dl(mean 1.2 mg/dl). In summary: 1) Renal transplant is a feasible alternative for patients with ESRD following BMT; 2) If bone marrow and kidney are from the same donor, the recipient requires little or no maintenance immunosuppression; 3) Short-term results show good survival, but long-term follow-up is needed.

Role of a basement membrane glycoprotein in anti-tubular basement membrane nephritis

Tubulointerstitial nephritis antigen (TIN antigen) is a basement membrane component which is recognized by human autoantibodies in TIN and has been shown to induce TIN in Brown Norway (BN) rats. Detectable by immunofluorescent microscopy, TIN antigen reacts with monoclonal, polyclonal, and human autoantibodies in basement membranes of kidney cortex, small intestine, skin and cornea. Specific sites of TIN antigen within kidney cortex include basement membranes of proximal tubules, distal tubules, Bowman's capsule and peritubular capillaries, with highest concentration in proximal tubular basement membrane (TBM). TIN antigen is also present in interstitium between tubules and in the periarterial sheath, but not in glomerular basement membrane or mesangial matrix. Immunoblotting of TIN antigen isolated from rabbit TBM reveals a major 58 kDa component with minor components of 300 kDa, 175 kDa, 160 kDa, 100 kDa and 50 kDa. Partial protein sequence analysis indicates that 58 kDa TIN antigen represents a newly defined glycoprotein. The structural relationships between various molecular weight forms are currently being investigated. High molecular weight (HMW) forms of TIN antigen, consisting of a mixture of 300 kDa, 175 kDa and 160 kDa forms, are more efficient than low molecular weight (LMW) forms (58 kDa and 50 kDa forms) in inducing TIN in BN rats. The resultant antibody specificity of rats injected with either HMW TIN antigen or LMW TIN antigen is identical as determined by immunofluorescent microscopy and Western analysis. Higher antibody titers and greater amounts of kidney-bound IgG are found in the HMW TIN antigen-immunized animals. TIN antigen is the primary target of anti-TBM antibodies in human and experimental immunologically-mediated anti-TBM nephritis.

Role of antibodies to tubulointerstitial nephritis antigen in human anti-tubular basement membrane nephritis associated with membranous nephropathy

We report three patients, from two unrelated families, with anti-tubular basement membrane (TBM) antibody nephritis associated with membranous nephropathy. This rare disorder is characterized by nephrotic syndrome, tubular dysfunction, and progression to renal failure. Direct immunofluorescent studies in these patients revealed linear IgG deposition along the proximal TBM, while circulating antibodies reacting with proximal TBM but not with glomerular basement membrane were identified by indirect immunofluorescence. Sera from all three patients reacted by enzyme-linked immunosorbent assay and Western immunoblotting with purified 58-kd tubulointerstitial nephritis (TIN) antigen isolated from TBM. Additional reactivity with a 175-kd component, which may be a higher-molecular-weight form of TIN antigen, was observed by immunoblotting. Since recurrent Fanconi syndrome was seen after transplantation in one patient, anti-TBM antibodies were removed by plasmapheresis prior to kidney transplantation in the other two patients. Neither patient has clinical evidence of recurrent anti-TBM nephritis in the allograft despite the post-transplantation reappearance of anti-TBM antibodies in the serum of one patient. Serologic and molecular HLA class I and class II polymorphism analysis has identified the presence of both HLA-B7 and -DRw8 antigens in two unrelated affected individuals (0.3% expected frequency in the white population). We conclude that sera from patients with anti-TBM nephritis associated with membranous nephropathy react with 58-kd TIN antigen previously implicated in the pathogenesis of primary anti-TBM nephritis. This rare autoimmune disorder may be HLA associated with B7 and/or DRw8, providing susceptibility to the disease. Further investigation is needed to understand the pathogenesis of recurrent anti-TBM nephritis in the renal allograft.

Immunologic studies in two patients with antitubular basement membrane nephritis

Immunologic studies in two patients with antitubular basement membrane nephritis

Identification of a target antigen in human anti-tubular basement membrane nephritis

Sera from two patients with primary anti-tubular-basement-membrane-mediated tubulointerstitial nephritis, one a renal allograft recipient and the other with spontaneous anti-tubular-basement-membrane disease, were analyzed for the specificity of their autoantibodies. Both sera had circulating antibodies that reacted by ELISA with extracts of tubular basement membrane from several species, but failed to react significantly with extracts of glomerular basement membrane. Reactive antigen was solubilized with 6 M guanidine-HCl, 6 M urea, with reduction and alkylation, and with sodium dodecylsulfate. Digestion of the basement membrane with collagenase released relatively small quantities of antigen from the membrane, and trypsin and pepsin destroyed its antigenicity. The antigenic activity was characterized with respect to its size distribution by gel filtration and by immuno-overlay analysis of protein blots. Collectively, the results indicate that the major reactivity of both sera is directed towards a Mr 58,000 component that is unique to the tubular basement membrane. Minor reactivities toward high molecular weight components common to both glomerular and tubular basement membranes were detected by immuno-overlay analysis. This study identifies an antigen that is involved in human anti-tubular-basement-membrane-mediated tubulointerstitial nephritis, and demonstrates an advantage of the use of denaturing extraction over proteolytic methods to prepare the antigen.

1512 MONONUCLEAR CELL CHEMOTAXIS IN EXPERIMENTAL INTERSTITIAL NEPHRITIS

Because the inflammatory infiltrate in antitubular basement membrane nephritis in guinea pigs (Steblay nephritis) is predominantly mononuclear, the stimulus for monocyte and macrophage recruitment was studied. The tubulointerstitial inflammation begins 10-14 days following injection with heterologous tubular basement membrane antigen. Sera were obtained from the renal vein in order to avoid the difficulties of systemic inactivation or dilution encountered when trying to identify chemotactic activity (CA) from peripheral blood. These samples, as well as renal homogenates, were compared to renal arterial sera for CA using peritoneal mononuclear cells. Sera and homogenates were obtained from nephritic and control animals at several times in the course of the disease. CA is detected in samples obtained from day 7-15 and is maximal at day 10. The CA is heat stable and is most prominent in the renal venous serum suggesting an origin from the kidney. Use of the sera as a chemoattractant for guinea pig polymorphonuclear leukocytes produces no cell recruitment and suggests the CA is specific for mononuclear cells The alternative pathway of complement has been implicated in the pathogenesis of Steblay nephritis and complement derived chemotactic factors may prove to be responsible for CA. However, measurable complement activation reflected in decreased hemolytic activity (CH50) or in depletion of complement proteins (C3, C4) does not occur.