Donor-Derived ALECT2 Amyloidosis and Recurrent Fibrillary Glomerulonephritis in a Transplant Allograft.

The occurrence of renal amyloidosis and fibrillary glomerulonephritis in the same biopsy specimen is exceptional and poses a diagnostic challenge. We describe the case of a non-Hispanic White patient with end-stage kidney disease due to fibrillary glomerulonephritis who received a second living donor kidney from a Hispanic individual. A 40-month-posttransplantation biopsy performed for an elevated serum creatinine level revealed interstitial congophilic deposits and glomerular noncongophilic fibrillary deposits, in addition to rejection. Separate laser microdissections of the glomerular and interstitial deposits followed by liquid chromatography-tandem mass spectrometry (LC MS/MS) revealed DNAJB9 peptide spectra in glomeruli and a peptide profile consistent with leukocyte chemotactic factor 2 (ALECT2) amyloidosis in the interstitium. Based on these findings, a 2-week-posttransplantation biopsy was re-reviewed and analyzed using LC MS/MS, which revealed a peptide profile consistent with ALECT2 amyloidosis in the interstitium, without peptide spectra for ALECT2 or DNAJB9 in glomeruli. The findings were consistent with donor-derived ALECT2 amyloidosis and recurrent fibrillary glomerulonephritis. At 49 months posttransplantation, allograft function was stable with minimal proteinuria. Thus, LC MS/MS was crucial to establish the accurate diagnosis of these 2 nephropathies characterized by fibrillary deposits. The indolent posttransplantation course suggests that donated kidneys with focal interstitial ALECT2 deposits may be suitable for transplantation but the deposits persist for many years.

The acceptable reactive crossmatch (ARC), post-transplant monitoring, and their impact on kidney transplantation: a single center experience.

Although the adverse allograft outcomes associated with HLA antibodies are well documented, some controversy exists regarding the importance of low-level donor specific anti-HLA antibodies (DSA). To provide further detail on this controversy, we prospectively looked at low-level DSA in negative T- and B-cell flow cytometric crossmatch (FCXM) or acceptable reactive crossmatch (ARC) patients who each underwent protocol based post-transplant antibody monitoring. HLA Class I and II antibody screening and specificity determination was conducted via a solid phase assay (SPA) and FCXM versus donor and autologous T and B cells. Post-transplant patients were immunosuppressed with quadruple maintained immunosuppressive therapy, rabbit anti-thymocyte globulin induction, and HLA antibody monitoring. Out of 31 ARC patients transplanted, 65% had a PRA > 50% and 26% showed increased DSA at 7-14 days post-transplant. Antibody mediated rejection (AMR) was treated with pharmacological and/or plasmapheresis (PP) therapy. DSA were lowered and remained at low-levels (MFI 1000- 3000) or below FCXM cutoffs. None of the 31 patients transplanted developed de-novo antibodies. Two patients lost their allografts, one to polyoma (BK) virus, and one to antibody mediated rejection (AMR). In conclusion, our experience demonstrates that patients deemed higher risk for an immunological event due to low-level DSA should be transplanted with an ARC and followed post-transplant according to an established alloantibody monitoring protocol. With close monitoring, 5-year outcomes can be expected to approach that of low-immunologic risk transplant patients.

Henoch-Schönlein purpura and recurrent renal failure.

We present an 18-year-old patient with Henoch-Schönlein purpura (HSP) who had multiple episodes of severe acute renal failure, including one episode for which he required hemodialysis for 2 months and a second episode for which dialysis was considered before his spontaneous recovery of renal function. Multiple treatment options, including steroids, mycophenolate mofetil, cyclophosphamide, and plasmapheresis, were tried but we could not confidently point to the utility of any of these measures. We highlight the unusual severity and lability of our patient's clinical course and how such a course makes the evaluation of treatment effectiveness extraordinarily difficult.

Pauci-immune and immune glomerular lesions in kidney transplants for systemic lupus erythematosus.

BACKGROUND AND OBJECTIVES: Glomerular lesions in allografts in recipients with end-stage nephritis resulting from systemic lupus erythematosus (SLE) were examined to determine the spectrum of glomerular pathology in recurrent glomerulonephritis (GN). DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: A total of 156 biopsy samples, from 49 serial allografts in 43 recipients with end-stage lupus nephritis, were examined by light microscopy, and by immunofluorescence and electron microscopy in selected cases. These were compared with control allografts (n = 35). RESULTS: Glomerular lesions best explained by recurrent lupus nephritis were observed in 19 of 49 allografts (38.8%) in lupus recipients. Three categories of glomerulopathies were identified: 1) immune complex glomerulopathies, including mesangial GN (28%) and membranous GN (4%); 2) atypical glomerulopathies, including acute proliferative GN (32%) and focal segmental glomerulosclerosis (12%), with scant immune deposits in glomerular capillaries, frequent endothelial tubuloreticular inclusions, and thrombotic microangiopathy; and 3) transplant-associated glomerulopathies (24%). CONCLUSIONS: Allografts from recipients with SLE had typical immune complex-mediated GN and atypical pauci-immune, proliferative GN and segmental glomerular sclerosis. Atypical glomerulopathies like these suggest a role for nonimmune complex-mediated glomerular injury in recurrent lupus GN.

Platelet CD61 expression in vascular calcineurin inhibitor toxicity of renal allografts.

Calcineurin inhibitor (CI) toxicity in renal allografts is frequently associated with arteriolar injury. Platelet activation occurs in response to vascular injury associated with CI therapy. Platelets are detectable in tissue sections by immunohistochemistry for CD61. This immunohistochemical study examines patterns of platelet deposition in CI-associated vascular toxicity of renal allografts. Renal allograft biopsies were grouped into (i) CI-associated thrombotic microangiopathy (CITMA, n = 28); (ii) vascular CI toxicity without thrombotic microangiopathy (VTox, n = 43); and (iii) allograft controls with minimal arteriolopathy abnormalities, both with CI exposure (MA, n = 10) and without CI exposure (NCI, n = 15). Two-micrometer paraffin sections were stained using a monoclonal antibody to CD61 by standard immunoperoxidase methods. Mural and luminal CD61 deposits in arterioles were graded from 0 to 3+, and proportions of arteriolar and glomerular profiles with CD61 deposits were determined for each biopsy. Granular CD61 deposits were detected in arterioles in biopsies with CITMA (92.9%) and VTox (81%) and less frequently in MA (30%) and NCI (33%). The proportion of arterioles with CD61 deposits was greater in CITMA than in VTox (46.3% +/- 28.5% vs 21.3% +/- 22.2%, P = .001) and more extensive than in controls (MA, 3.6% +/- 8.9%; NCI, 3.2% +/- 5.5%). Median arteriolar CD61 grades for CITMA exceeded grades for VTox (2 vs 0.5, P = .001), and CD61 grades in VTox were significantly greater than in controls with MA (0) and NCI (0) (P = .0001). In conclusion, arteriolar mural platelet CD61 deposition was observed in vascular CI toxicity and was most extensive and severe in CI-associated thrombotic microangiopathy. Identification of "insudative platelet arteriolopathy" in renal allograft biopsies, by immunohistochemical detection of CD61, may facilitate recognition of vascular CI toxicity.

The broad spectrum of quality in deceased donor kidneys.

The quality of the deceased donor organ clearly is one of the most crucial factors in determining graft survival and function in recipients of a kidney transplant. There has been considerable effort made towards evaluating these organs culminating in an amendment to allocation policy with the introduction of the expanded criteria donor (ECD) policy. Our study, from first solitary adult deceased donor transplant recipients from 1996 to 2002 in the National Scientific Transplant Registry database, presents a donor kidney risk grade based on significant donor characteristics, donor-recipient matches and cold ischemia time, generated directly from their risk for graft loss. We investigated the impact of our donor risk grade in a naive cohort on short- and long-term graft survival, as well as in subgroups of the population. The projected half-lives for overall graft survival in recipients by donor risk grade were I (10.7 years), II (10.0 years), III (7.9 years), IV (5.7 years) and V (4.5 years). This study indicates that there is great variability in the quality of deceased donor kidneys and that the assessment of risk might be enhanced by this scoring system as compared to the simple two-tiered system of the current ECD classification.

Quinine induced HUS-TTP: an unusual presentation.

A 67-year-old white woman developed severe nausea, vomiting, diffuse abdominal cramping pain, and blurred vision followed by a syncopal episode after taking 1 tablet of quinine for leg cramps. Examination was significant for fever, elevated blood pressure, and confusion without any focal neurological deficits. Laboratory studies showed markedly elevated liver enzymes, elevated lactate dehydrogenase, anemia, thrombocytopenia, and acute renal failure. Peripheral smear showed many schistocytes and burr cells. She later recalled taking quinine more than 40 years before while on a trip to the Philippines. The patient was treated with 7 sessions of plasmapheresis with a rapid normalization of her hematological parameters. Three weeks of dialysis support were required before return of renal function to baseline. Re-exposure to quinine can cause a rapid onset of hemolytic uremic syndrome-like syndrome. We are not aware of any cases of hemolytic uremic syndrome-thrombotic thrombocytopenic purpura in response to re-exposure to a single tablet of the drug 40 years after first use.

Decreased renal function is a strong risk factor for cardiovascular death after renal transplantation.

BACKGROUND: Chronic kidney disease is thought to be a potential risk factor for cardiovascular death. In renal-allograft recipients, cardiovascular disease is the most significant cause of death. The purpose of this study was to investigate if renal function has a significant role in determining the risk for cardiovascular death in renal-allograft recipients. METHODS: We analyzed 58,900 adult patients registered in the United States Renal Data System who received a primary renal transplant between 1988 and 1998 and who had at least 1 year of graft survival. The primary study endpoint was death from a cardiovascular event beyond 1 year of transplantation. Secondary endpoints were death caused by infections and malignancy-related deaths. Cox proportional-hazard models were used to estimate the effect of renal function on cardiovascular death, infectious death, and malignancy-related death while correcting for potential confounding variables, such as donor and recipient age, gender, race, cause of end-stage renal disease, length of dialysis before transplantation, year of transplantation, donor source and age, delayed graft function, and immunosuppressive regimen. RESULTS: Serum creatinine values at 1 year after transplantation were strongly associated with the risk for cardiovascular death. Above a serum creatinine value of 1.5 mg/dL, there was a significant and progressive increase in the risk for cardiovascular death. The risk of cardiovascular death was significantly higher when patients who lost allograft function were included in the analysis. There was an association between worsening renal function and infectious death, but there was no association between renal function and malignancy-related death. CONCLUSION: Serum creatinine at 1 year is strongly associated with the incidence of cardiovascular death independent of known risk factors.