anti-TBM Nephritis Research Articles

Renal Transplantation for End-Stage Renal Disease Following Bone Marrow Transplantation: A 10-Year Outcomes Review.

Abstract 4294 BackgroundThe incidence of hematopoietic stem cell transplantations (HSCTs) in the US is increasing dramatically each year. Nephrotoxic agents used in these patients often lead to kidney injury that can be severe and progress to end-stage renal disease (ESRD) requiring long term dialysis or kidney transplant. Kidney transplantation is the best method of renal replacement therapy and maintenance immunosuppression is the mainstay to prevent graft rejection. Immune tolerance is of substantial interest because it obviates the need for long-term immunosuppression. MethodsWe performed a retrospective analysis of nine patients that developed ESRD after HSCT at the Medical College of Wisconsin. Chart review was performed to obtain demographic information and details of the transplants, patient and transplant outcomes, and various renal and HSCT related parameters. ResultsA total of nine patients were reviewed. Patient age at the time of HSCT ranged from 25-40 years. ESRD was caused by bone marrow transplant nephropathy (BMT-Np) in seven patients, HUS/TTP in one patient, and anti-TBM nephritis in one patient. Six patients received their kidney from a living related donor (LRD), whereas two patients received living unrelated renal transplants (LURRTx), and one recipient received a deceased donor transplant. Three of the six LRD recipients had same-donor renal and hematopoietic stem cell (HSC) transplants and did not require post-transplant maintenance immunosuppression. Of the two LURRTx recipients, no maintenance immunosuppression was required for the patient receiving same-donor organs. The deceased donor transplant recipient continues to be on immunosuppression. Follow-up ranges from 12-23 years post HSCT and 3-12 years post-renal transplant. Seven of the nine patients have functioning bone marrow and kidney transplants. Their serum creatinine ranges from 0.77 to 1.7 mg/dL. One patient died 24 months post-renal transplant from metastatic vaginal squamous cell cancer and had a functioning bone marrow and kidney at the time of death. Another patient was lost to follow-up and died of unknown cause, although her renal function 34 months post transplant was excellent off maintenance immunosupression. ConclusionsBased on our case series, we conclude that the long-term outcome of renal allografts in patients who have received a renal transplant after HSCT is excellent. The overall requirement for immunosuppressive medications in this population is reduced. Disclosures:No relevant conflicts of interest to declare.

Isolation and characterization of the tubular basement membrane antigen associated with human tubulo-interstitial nephritis

The target antigen, a 54-kD glycoprotein (gp54), reactive with sera from patients with anti-tubular basement membrane (anti-TBM) nephritis, was isolated from collagenase-digested (CD) bovine TBM. The purified gp54 was shown to be non-collagenous by amino acid analysis, and to be a unique basement membrane component by amino-terminal sequencing. The nephritogenicity of gp54 was demonstrated by immunizing strain XIII guineapigs with purified gp54, and producing anti-gp54 antibody and tubulo-interstitial nephritis. Anti-gp54 antibody, affinity-purified from sera of patients with anti-TBM nephritis, bound by immunoblotting to 54-kD and, to a lesser extent, 48-kD components of partially purified human CD-TBM. Indirect immunofluorescence showed that gp54 was present in the basement membrane of proximal tubules of the kidneys of normal human, cow, rabbit, guineapig and Brown-Norway rat but not in Lewis rat. Immunoelectron microscopy revealed localization of gp54 along the interstitial side of the TBM and its association with interstitial collagen fibres. These results indicate that gp54 is the nephritogenic antigen involved in tubulo-interstitial nephritis, and is unique in chemical characteristics and localization in the kidney.

Experimental glomerulonephritis induced by hydrocarbon exposure: a systematic review.

BackgroundMuch epidemiological evidence suggests that hydrocarbon exposure may induce glomerulonephritis and worsen its course in many patients. The mechanisms are unknown, however, no specific microscopic pattern has been identified, and it has also been argued that hydrocarbon exposure causes tubular damage mainly. Studying experimental animals may best answer these questions, and as no systematic review of glomerulonephritis produced experimentally by hydrocarbon exposure has been performed previously, I found it relevant to search for and analyse such studies.MethodsAnimal experiments having mimicked human glomerulonephritis by hydrocarbon exposure were sought on Medline and ToxnetResultsTwenty-six experiments using thirteen different hydrocarbons were identified. Several human subtypes were observed including IgA nephritis, mesangial, proliferative and extracapillary glomerulonephritis, focal and focal-segmental sclerosis, minimal change nephropathy, anti-GBM and anti-TBM nephritis, and glomerulonephritis associated with peiarteritis nodosa. Glomerular proteinuria was seen in 10/12 experiments that included urine analyses, and renal failure in 5/8 experiments that included measurements of glomerular function. All experiments resulted in various degrees of tubular damage as well. In most studies, where the animals were examined at different times during or after the exposure, the renal microscopic and functional changes were seen immediately, whereas deposits of complement and immunoglobulins appeared late in the course, if at all.ConclusionThese experiments are in accord with epidemiological evidence that hydrocarbon exposure may cause glomerulonephritis and worsen renal function. Probable mechanisms include an induction of autologous antibodies and a disturbance of normal immunological functions. Also, tubular damage may increase postglomerular resistance, resulting in a glomerular deposition of macromolecules. In most models a causal role of glomerular immune complex formation was unlikely, but may rather have been a secondary phenomenon. As most glomerulonephritis subgroups were seen and as some of the hydrocarbons produced more than one subgroup, the microscopic findings in a patient cannot be used as a clue to the causation of his disease. By the same reason, the lack of a specific histological pattern in patients with glomerulonephritis assumed to have been caused by hydrocarbon exposure is not contradictive.

Membranous glomerulopathy: emphasis on secondary forms and disease variants.

Membranous glomerulopathy (MGN) is characterized by subepithelial immune complex deposits and glomerular basement membrane (GBM) thickening. The majority of patients present with nephrotic syndrome and outcomes are variable. Pathologically, deposits at sites other than the subepithelial aspect of the GBM favor the presence of secondary forms of MGN which are seen most commonly in the setting of autoimmune disease, infection, neoplasia, and with certain therapeutic agents. MGN is the most common form of de novo glomerular disease seen in the renal allograft and may be seen concurrently with other forms of glomerular disease including focal segmental glomerulosclerosis, IgA nephropathy, diabetic nephropathy, and anti-TBM nephritis. This review emphasizes the detection of secondary forms and variants of MGN.

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.

A Method for Preparation of Renal Tubular Basement Membrane

A method is presented for the preparation of tubular basement membrane from renal cortex. The procedure utilizes a Polytron tissue disrupter, differential sieving, and for some species, sucrose density centrifugation. The procedure is especially useful for obtaining highly purified rabbit and bovine tubular basement membranes. Human tubular and glomerular basement membranes can be prepared with some cross contamination. The method offers the capability of rapidly generating large quantities of the basement membranes that retain the Goodpasture antigen and a TBM antigen associated with anti-TBM nephritis.

Role of sensitized cells in antitubular basement membrane interstitial nephritis.

The pathogenic effect of antitubular basement membrane (TBM) antibodies in anti-TBM interstitial nephritis has been demonstrated. To determine the relative role of sensitized cells in inducing this lesion, lymph node cells (LNC) alone or a combination of LNC and peritoneal exudate cells were transferred from Brown Norway (BN) rats, previously immunized with TBM into unimmunized BN-recipient rats. Cells were transferred directly under the recipients' renal capsules. Although significant tubular lesions were induced by the cells, the lesions were usually mild and always focal. Hence, sensitized cells do not appear to be central to the pathogenesis of anti-TBM nephritis.