Subclinical celiac disease and crystal-induced kidney disease following kidney transplant.

Decreased kidney function from kidney deposition of calcium oxalate has been described previously in inflammatory bowel disease and after jejuno-ileal and Roux-en-Y gastric bypass surgeries. Although celiac disease is the most prevalent bowel abnormality associated with intestinal malabsorption, its relationship to high kidney oxalate burden and decreased kidney function has not been established. We report a case of subclinical celiac disease and hyperoxaluria that presented with loss of kidney function as a result of high oxalate load in the absence of overt diarrhea, documented intestinal fat malabsorption, and nephrolithiasis. Subclinical celiac disease is commonly overlooked and hyperoxaluria is not usually investigated in kidney patients. We propose that this entity should be suspected in patients with chronic kidney disease in which the cause of kidney damage has not been clearly established.

Rapid improvement of nephrogenic systemic fibrosis with rapamycin therapy: possible role of phospho-70-ribosomal-S6 kinase.

Nephrogenic systemic fibrosis (NSF) is a fibrosing disorder that occurs in some patients with renal insufficiency. Exposure to gadolinium-based contrast agents (GdCA) has been associated with the development of NSF. No uniformly effective treatment options exist. We present immunohistochemical evidence to show that the proliferating fibrocytes of NSF express phospho-70-s6 kinase (PI-3-K), a protein downstream of PI-3-K, and the target of the drug rapamycin. In our patient, use of rapamycin resulted in rapid clinical improvement marked by reduced edema, reduced skin induration, and decreased pain. This suggests a possible role for PI-3-K and rapamycin (mTOR) pathways in the pathogenesis of NSF. Drugs that inhibit these pathways may be a target for future therapy. While our patient did attribute disease onset to GdCA exposure, used on a single occasion for abdominal imaging, he was also exposed to iron, calcium, and darbepoetin alpha at the time of imaging.

Morphologic manifestations of combined light-chain deposition disease and light-chain cast nephropathy.

There are few data on morphology of light-chain deposition disease (LCDD) of kidney with coexistent light-chain cast nephropathy (LCCN). Here, the authors report the morphology in 23 cases of LCDD and LCCN. They retrospectively evaluated 23 renal biopsies with light (LM), immunofluorescence (IF), and electron microscopy (EM). Twenty-one patients had myeloma, 1 had a monoclonal gammopathy, and in 1 no illness was found. Nodular glomerulosclerosis, the LM lesion suggestive of LCDD, was noted in only 3 of 23 cases. Glomeruli were unremarkable in 16 (69%) cases. The diagnostic casts of LCCN were seen in all biopsies. Linear light chain (LC) immunoreactivity was observed in 23 (100%) cases (18 kappa, 5 lambda); GBM + TBM in 13, TBM only in 7, GBM only in 1, TBM and interstitium in 1, GBM, TBM and mesangium in 1. Casts were positive with same LC in all cases (100%). Fifteen cases (65%) showed granular electron-dense deposits; GBM only in 5, TBM only in 5, GBM and TBM in 4, mesangium in 1. In 8 patients without EM deposits, the diagnosis of LCDD was rendered by IF. Fifteen (65%) had deposits detectable by IF and EM, 8 (37%) had deposits with IF only. LCCN dominated the LM findings in all patients. There were minimal or no glomerular changes by LM. This study shows the lack of characteristic LM findings of LCDD in combined cases of LCDD and LCCN and emphasizes the difficulty for-definitive diagnosis-without IF and EM.

Distinct epitopes for anti-glomerular basement membrane alport alloantibodies and goodpasture autoantibodies within the noncollagenous domain of alpha3(IV) collagen: a janus-faced antigen.

Alport posttransplantation anti-glomerular basement membrane (GBM) nephritis is mediated by alloantibodies against the noncollagenous (NC1) domains of the alpha3alpha4alpha5(IV) collagen network, which is present in the GBM of the allograft but absent from Alport kidneys. The specificity of kidney-bound anti-GBM alloantibodies from a patient who had autosomal recessive Alport syndrome (ARAS) and developed posttransplantation nephritis was compared with that of Goodpasture autoantibodies from patients with autoimmune anti-GBM disease. Allograft-eluted alloantibodies reacted specifically with alpha3alpha4alpha5 NC1 hexamers, targeting their alpha3NC1 and alpha4NC1 subunits, and recognized a noncontiguous alloepitope formed jointly by the E(A) and E(B) regions of alpha3NC1 domain. In contrast, human Goodpasture autoantibodies recognized the separate E(A) and E(B) autoepitopes of alpha3NC1 but not the composite alloepitope. Molecular modeling of alpha3NC1 revealed that the alloepitope is more accessible within the NC1 hexamers than the partially sequestered Goodpasture autoepitopes. Overall, the specificity of alloantibodies indicated a selective lack of immune tolerance toward the alpha3 and alpha4(IV) collagen chains not expressed in patients with ARAS. Using COL4A3 knockout mice, a model of ARAS, it was shown further that acid-dissociated rather than native alpha3alpha4alpha5 NC1 hexamers elicited murine anti-GBM antibodies most closely resembling human ARAS alloantibodies. In contrast, alpha3NC1 monomers elicited Goodpasture-like murine antibodies, targeting the E(A) and E(B) autoepitopes. Thus, the identity of alpha3NC1 epitopes targeted by anti-GBM antibodies is strongly influenced by the molecular organization of the immunogen. These findings suggest that different isoforms of alpha3(IV) collagen may be implicated in the pathogenesis of ARAS posttransplantation anti-GBM nephritis and Goodpasture disease.

Sirolimus-induced thrombotic microangiopathy in a renal transplant recipient.

A rare but well-documented serious adverse reaction to the administration of the calcineurin inhibitors tacrolimus and cyclosporine in renal transplant recipients is the development of medication-induced thrombotic microangiopathy. The recently introduced immunosuppressive medication sirolimus has a very similar molecular structure to tacrolimus and also binds to the same intracellular proteins. Despite these similarities with tacrolimus, sirolimus has a different side-effect profile and reportedly lacks documented specific renal toxicity. This is a case report of the isolated administration of sirolimus without a concomitant calcineurin inhibitor being associated with the development of renal transplant biopsy-proven thrombotic microangiopathy. The patient is a 47-year-old African-American woman whose primary cause of renal failure was not thrombotic micrangiopathy, and she received a 5-antigen mismatched cadaveric renal transplant. Because of preexisting nephrosclerosis in the renal transplant, this patient was never administered a calcineurin inhibitor but was always maintained on sirolimus. With recent animal data showing that sirolmus can be nephrotoxic in a renal ischemic-reperfusion model (similar to what happens with a renal transplant), the authors speculate on a mechanism for this adverse reaction.

Increased early rejection rate after conversion from tacrolimus in kidney and pancreas transplantation.

CONTEXT: A successful immunosuppression regimen for combined kidney and pancreas transplants is tacrolimus, mycophenolate mofetil, and prednisone. However, not all patients tolerate these immunosuppressants especially tacrolimus. OBJECTIVE: To evaluate the efficacy of cyclosporine as a rescue agent for tacrolimus toxicity in combined kidney and pancreas transplants. DESIGN: Retrospective. SETTING: Single center. PATIENTS: Thirty-five combined kidney and pancreas transplants were performed between July 1994 and January 1999. All patients were insulin dependent diabetics with end-stage renal disease. Twenty-eight (mean age: 36 years and 57% female) were available with at least 12 month follow-up. INTERVENTIONS: Conversion to cyclosporine following renal (biopsy proven) or pancreatic dysfunction. MAIN OUTCOME MEASURES: Toxicity, rejection rate, and patient/transplant organ survival. RESULTS: Nineteen transplant recipients (68%) were continuously maintained on tacrolimus while nine (32%) required conversion to cyclosporine 75 +/- 20 days post-transplant. Reasons for conversion included: hyperglycemia (n=2), hemolytic-uremic syndrome (n=1), and severe tacrolimus nephrotoxicity (n=6). By 12 months post-transplant, the 19 patients maintained on tacrolimus had 5 rejections (26%). Three of the 9 patients (33%) converted to cyclosporine had an acute rejection prior to conversion. Seven of these 9 patients (78%; P=0.017 vs. patients maintained on tacrolimus) had rejections an average of 25 +/- 4 days post-conversion. Four of the 7 patients had no previous rejections prior to conversion. In spite of increased rejections, the 1- and 2-year patient/graft survivals were unchanged by converting. CONCLUSIONS: Converting to cyclosporine from tacrolimus was associated with an increased risk of acute rejection especially within the first 30 days post conversion.