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1.  Novel gelsolin variant as the cause of nephrotic syndrome and renal amyloidosis in a large kindred 
Familial Amyloidosis of Finnish type (FAF) is a rare type of autosomal dominant hereditary amyloidosis associated with genetic variants of gelsolin. Three amyloidogenic mutations have previously been reported characteristically presenting with ophthalmologic abnormalities, progressive cranial neuropathy and cutis laxa. We report a novel gelsolin variant in a 62 year old man with nephrotic range proteinuria of 13.2 grams/day as the only presenting symptom. Renal biopsy followed by laser microdissection and mass spectrometry showed amyloidosis derived from gelsolin. DNA sequencing revealed the novel gelsolin mutation (c.633C>A) encoding p.N211K protein variant. Four of 13 asymptomatic family members were found to be heterozygous for the p.N211K mutation, three of whom had proteinuria of varying degree including one who proceeded to renal biopsy and was confirmed to have renal amyloidosis. Follow up of these cases might give us more insight into pathogenicity and potential treatment strategy of this atypical presentation of gelsolin amyloidosis.
doi:10.3109/13506129.2014.891502
PMCID: PMC4061150  PMID: 24601799
Amyloidosis; Gelsolin; Proteinuria
2.  Strong tranthyretin immunostaining, potential pitfall in cardiac amyloid typing 
Although systemic amyloidosis commonly presents with renal disease, cardiac involvement usually determines the patient's prognosis. Cardiac involvement is seen in AL and transthyretin amyloidosis. Distinguishing between these is critical because prognosis and treatment differ. Our study demonstrates the unreliability of transthyretin immunostaining in subtyping cardiac amyloid. Between January 2003 and August 2010, we retrieved 229 native endomyocardial biopsies, 24 had amyloid. Immunohistochemistry for kappa, lambda, transthyretin and serum amyloid A protein were performed on formalin fixed paraffin-embedded sections. Staining was graded as weak (trace to 1+); or strong (2 to 3+). Mass spectrometry (MS) based proteomic typing of microdissected amyloid material was performed on selected cases. Fifteen of the patients had monoclonal gammopathy/plasma cell dyscrasia with cardiac amyloid. Eight of them (53%) showed strong transthyretin staining in the cardiac amyloid deposits. MS was performed in five out of these eight biopsies, and all five revealed AL type amyloid. Two of these five AL amyloid biopsies did not even have concomitant strong staining for the appropriate light chain. Among the 15 cases with plasma cell dyscrasia, only seven biopsies showed strong staining for the corresponding monoclonal light chain.
Strong false positive immunostaining for transthyretin in cardiac amyloid is a potential pitfall, augmented by the frequent lack of staining for immunoglobulin light chains. Therefore, the presence of amyloid in the cardiac biopsy should prompt a search for plasma cell dyscrasia irrespective of transthyretin staining. Confirmation with MS should be sought particularly if there is any discrepancy between kappa/lambda staining and serum immunofixation results.
doi:10.1097/PAS.0b013e3182263d74
PMCID: PMC4061151  PMID: 21945954
cardiac amyloid; transthyretin; immunohistochemistry
3.  Warfarin-related nephropathy occurs in patients with and without chronic kidney disease and is associated with an increased mortality rate 
Kidney international  2011;80(2):181-189.
An acute increase in the international normalized ratio (INR; a comparison of prothrombin time to monitor the effects of warfarin) over 3 in patients with chronic kidney disease (CKD) is often associated with an unexplained acute increase in serum creatinine (SC) and an accelerated progression of CKD. Kidney biopsy in a subset of these patients showed obstruction of the renal tubule by red blood cell casts, and this appears to be the dominant mechanism of the acute kidney injury. We termed this warfarin-related nephropathy (WRN), and previously reported cases of WRN only in patients with CKD. We now assess whether this occurs in patients without CKD, its risk factors, and consequences. In 15,258 patients who initiated warfarin therapy during a 5-year period, 4006 had an INR over 3 and SC measured at the same time; however, the large data set precluded individual patient clinical assessment. A presumptive diagnosis of WRN was made if the SC increased by over 0.3 mg/dl within 1 week after the INR exceeded 3 with no record of hemorrhage. WRN occurred in 20.5% of the entire cohort, 33.0% of the CKD cohort, and 16.5% of the no-CKD cohort. Other risk factors included age, diabetes mellitus, hypertension, and cardiovascular disease. The 1-year mortality was 31.1% with compared with 18.9% without WRN, an increased risk of 65%. Thus, WRN may be a common complication of warfarin therapy in high-risk patients and CKD doubles this risk. The mechanisms of these risks are unclear.
doi:10.1038/ki.2011.44
PMCID: PMC3675881  PMID: 21389969
acute kidney injury; mortality; warfarin
4.  Warfarin Therapy That Results in an International Normalization Ratio above the Therapeutic Range Is Associated with Accelerated Progression of Chronic Kidney Disease 
Nephron. Clinical Practice  2010;115(2):c142-c146.
Background/Aims
We had previously reported that acute kidney injury (AKI) in warfarin-treated chronic kidney disease (CKD) patients may occur shortly after an acute increase in the International Normalization Ratio (INR) >3.0 with formation of occlusive red blood casts. Recovery from this warfarin-associated AKI is poor. Here we investigated whether excessive warfarin therapy could accelerate the progression of CKD.
Methods
We analyzed serum creatinine (SC) and INR in 103 consecutive CKD patients on warfarin therapy in our Nephrology program from 2005 to the present.
Results
Forty-nine patients experienced at least 1 episode of INR >3.0. Of these, 18 patients (37%, Group 1) developed an unexplained increase in SC ≥0.3 mg/dl coincident with INR >3.0 (mean SC increase 0.61 ± 0.44 mg/dl); 31 patients (63%, Group 2) showed stable SC (mean SC change 0.04 ± 0.19 mg/dl). Subsequent CKD progression was accelerated in Group 1, but not in Group 2. The 2 groups were not different with respect to demographics, comorbidities, blood pressure, or therapies. However, African Americans were overrepresented in Group 1 (p = 0.035).
Conclusions
Overanticoagulation is associated with faster progression of CKD in a high percentage of patients. Our results indicate the need for prospective trials. Nevertheless, we suggest that our findings are sufficiently compelling at this point to justi- fy extra caution in warfarin-treated CKD patients to avoid overanticoagulation.
doi:10.1159/000312877
PMCID: PMC3696377  PMID: 20413993
Warfarin; Serum creatinine; Acute kidney injury; Chronic kidney disease
5.  Critical Role of Effector Macrophages in Mediating CD4-dependent Alloimmune Injury of Transplanted Liver Parenchymal Cells 
Despite the recognition that humoral rejection is an important cause of allograft injury, the mechanism of antibody-mediated injury to allograft parenchyma is not well understood. We used a well-characterized murine hepatocellular allograft model to determine the mechanism of antibody-mediated destruction of transplanted liver parenchymal cells. In this model allogeneic hepatocytes are transplanted into CD8-deficient hosts in order to focus on CD4-dependent, alloantibody-mediated rejection. Host serum alloantibody levels correlated with in vivo allospecific cytotoxic activity in CD8 KO hepatocyte rejector mice. Host macrophage depletion, but not CD4+ T cell, NK cell, neutrophil, or complement depletion, inhibited in vivo allocytotoxicity. Recipient macrophage deficiency delayed CD4-dependent hepatocyte rejection and inhibited in vivo allocytotoxicity without influencing alloantibody production. Furthermore, hepatocyte coincubation with alloantibody and macrophages resulted in antibody-dependent hepatocellular cytotoxicity in vitro. These studies are consistent with a paradigm of acute humoral rejection in which CD4+ T cell-dependent alloantibody production results in the targeting of transplanted allogeneic parenchymal cells for macrophage-mediated cytotoxic immune damage. Consequently, strategies to eliminate recipient macrophages during CD4-dependent rejection pathway may prolong allograft survival.
PMCID: PMC3022512  PMID: 18606676
macrophages; alloantibody; hepatocytes; antibody-mediated cellular cytotoxicity; transplantation
6.  Biomarker Discovery for Lupus Nephritis Through Longitudinal Urine Proteomics 
Kidney international  2008;74(6):799-807.
Lupus nephritis is a frequent and serious complication of systemic lupus erythematosus (SLE). Treatment often requires the use of immunosuppression, and may be associated with severe side effects. The ability to predict relapse, relapse severity, and recovery could be used to more effectively implement therapy and reduce toxicity. We postulated that a proteomic analysis of the low-molecular weight urine proteome using serial urine samples obtained before, during, and after SLE nephritis flares would demonstrate potential biomarkers of SLE renal flare. This study was undertaken to test our hypothesis.
Urine from 25 flare cycles of 19 WHO Class III, IV, and V SLE nephritis patients was used. Urine samples included a baseline, and pre-flare, flare, and post-flare specimens. The urines were fractionated to remove proteins larger than 30 kDa, and spotted onto weak cation exchanger (CM10) protein chips for analysis by surface-enhanced laser desorption/ionization time-of-flight mass spectrometry (SELDI-TOF MS).
SELDI-TOF MS screening showed 176 protein ions between 2-20 kDa of which 27 were found to be differentially-expressed between specific flare intervals. On-chip peptide sequencing by integrated tandem mass spectrometry was used to positively identify selected differentially-expressed protein ions. The identified proteins included the 20 and 25 amino acid isoforms of hepcidin, a fragment of α1-antitrypsin, and an albumin fragment. Hepcidin 20 increased 4 months pre-flare and returned to baseline at renal flare, whereas hepcidin 25 decreased at renal flare and returned to baseline 4 months post-flare.
Using SELDI-TOF urine protein profiling in lupus nephritis, several candidate biomarkers of renal flare were found. To verify these candidates as true biomarkers, further identification and validation are needed in an independent SLE cohort.
doi:10.1038/ki.2008.316
PMCID: PMC2614389  PMID: 18596723
lupus nephritis; biomarker; SELDI

Results 1-6 (6)