Immunostaining for galactose-deficient immunoglobulin A is not specific for primary immunoglobulin A nephropathy.

BACKGROUND: Primary immunoglobulin A nephropathy (IgAN) is characterized by IgA1-dominant or codominant glomerular deposits, postulated to be galactose deficient (Gd). However, glomerular IgA deposition can also occur in nonrenal diseases such as liver cirrhosis, psoriasis and inflammatory bowel disease ('secondary IgAN') or be an incidental finding in biopsies with other pathologies. A glomerulonephritis resembling IgAN can develop in patients with bacterial, mainly staphylococcal infections [staphylococcal infection-associated glomerulonephritis (SAGN)]. There are no specific histological features to distinguish between these, but differentiation is critical for appropriate management. The aim of this study was to investigate whether a recently described antibody to Gd-IgA1 (KM-55) could aid in differentiating primary IgAN from other conditions with glomerular IgA deposition, especially SAGN. METHODS: We performed a retrospective cohort study of patients who underwent kidney biopsy for clinical indications and were found to have glomerular IgA deposits. RESULTS: We evaluated 100 biopsies, including primary IgAN (n = 44), secondary IgAN (n = 27), SAGN (n = 13), incidental IgA deposition (n = 8) and lupus nephritis (n = 8). There was no difference in Gd-IgA staining intensity or the proportion of positive cases between primary and secondary IgAN. SAGN and cases with incidental IgA deposits had significantly lower Gd-IgA staining intensity than primary IgAN, but up to 69% of SAGN cases were positive (albeit weaker). CONCLUSIONS: Gd-IgA staining is present not only in primary IgAN, but also in biopsies with secondary IgAN, SAGN and incidental IgA. Weak or negative staining may favor SAGN, especially in the setting of infection, or incidental IgA in the absence of nephritic symptoms or in the presence of other unrelated glomerular pathologies. However, positive staining for Gd-IgA alone is not specific enough for a diagnosis of primary IgAN.

Differential gene expression pattern in biopsies with renal allograft pyelonephritis and allograft rejection.

Differentiating acute pyelonephritis (APN) from acute rejection (AR) in renal allograft biopsies can sometimes be difficult because of overlapping clinical and histologic features, lack of positive urine cultures,and variable response to antibiotics. We wanted to study differential gene expression between AR and APN using biopsy tissue. Thirty-three biopsies were analyzed using NanoString multiplex platform and PCR (6 transplant baseline biopsies, 8 AR, 15 APN [8 culture positive, 7 culture negative], and 4 native pyelonephritis [NP]). Additional 22 biopsies were tested by PCR to validate the results. CXCL9, CXCL10, CXCL11, and IDO1 were the top differentially expressed genes, upregulated in AR. Lactoferrin (LTF) and CXCL1 were higher in APN and NP. No statistically significant difference in transcript levels was seen between culture-positive and culture-negative APN biopsies. Comparing the overall mRNA signature using Ingenuity pathway analysis, interferon-gamma emerged as the dominant upstream regulator in AR and allograft APN, but not in NP (which clustered separately). Our study suggests that chemokine pathways in graft APN may differ from NP and in fact resemble AR, due to a component of alloreactivity, resulting in variable response to antibiotic treatment. Therefore, cautious addition of steroids might help in resistant cases of graft APN.

Acute kidney injury and hyperbilirubinemia in a young male after ingestion of Tribulus terrestris.

Acute tubular necrosis (ATN), especially from toxic injury is frequently accompanied by tubular casts and crystals. Myeloma casts, myoglobin, red blood cell and granular casts are well described. However, bile casts in tubules are rarely seen. We describe a case of Tribulus terrestris toxicity in a young healthy male, presenting with severe hyperbilirubinemia followed by acute renal failure and bile containing casts in the tubules. Tribulus terrestris is an herb often used by athletes as a nutritional supplement for performance enhancement. Although it is thought to be relatively safe, serious side effects have been reported before. Our aim is to increase awareness of the potential toxicities of performance enhancing herbal medications. These are often sold over-the-counter and therefore casually used, especially by young healthy individuals. Beneficial effects are controversial. Under-reporting by patients and infrequent documentation by health-care providers can delay diagnosis. We elaborately describe the kidney biopsy findings in Tribulus terrestris toxicity, and also provide a concise overview of the spectrum of tubular casts and their staining patterns, found in various kidney diseases.

Warfarin-related nephropathy is the tip of the iceberg: direct thrombin inhibitor dabigatran induces glomerular hemorrhage with acute kidney injury in rats.

BACKGROUND: Excessive anticoagulation with warfarin can result in acute kidney injury (AKI) by causing glomerular hemorrhage and renal tubular obstruction by red blood cell (RBC) casts in some patients, especially in those with chronic kidney disease (CKD). This condition was described as warfarin-related nephropathy (WRN). Recent evidence suggests that WRN-like syndromes are not confined to anticoagulation with warfarin, but may be seen with other anticoagulants, such as dabigatran. The aim of this study was to investigate dabigatran effects on kidney function in an animal model of CKD and possible pathogenic mechanisms of AKI. METHODS: Control and 5/6 nephrectomy rats were treated with different doses of dabigatran and protease-activated receptor 1 (PAR-1) inhibitor SCH79797. RESULTS: Dabigatran resulted in changes in coagulation in rats similar to those in humans at 50 mg/kg/day. Dabigatran resulted in a dose-dependent increase in serum creatinine (Scr) and hematuria in both control and 5/6 nephrectomy rats. SCH79797 also increased Scr and hematuria, more prominent in animals with CKD. Morphologically, numerous RBC tubular casts were seen in 5/6 nephrectomy rats treated with either dabigatran or SCH79797 and only occasional RBC casts in control rats. CONCLUSIONS: Our data indicate that WRN represents part of a broader syndrome, anticoagulant-related nephropathy (ARN). ARN, at least partially, is mediated via PAR-1. Our findings suggest that not only CKD patients, but other patients as well, are at high risk of developing AKI if the therapeutic range of anticoagulation with dabigatran is exceeded. Close monitoring of kidney function in patients on dabigatran therapy is warranted.

N-acetylcysteine ameliorates acute kidney injury but not glomerular hemorrhage in an animal model of warfarin-related nephropathy.

Warfarin-related nephropathy (WRN) occurs under conditions of overanticoagulation with warfarin. WRN is characterized by glomerular hemorrhage with occlusive tubular red blood cell (RBC) casts and acute kidney injury (AKI). Herein we test the hypothesis that oxidative stress plays a role in the AKI of WRN. 5/6 Nephrectomy rats were treated with either warfarin (0.04 mg·kg⁻¹·day⁻¹) alone or with four different doses of the antioxidant N-acetylcysteine (NAC). Also tested was the ability of our NAC regimen to mitigate AKI in a standard ischemia-reperfusion model in the rat. Warfarin resulted in a threefold or greater increase in prothrombin time in each experimental group. Serum creatinine (Scr) increased progressively in animals receiving only warfarin + vehicle. However, in animals receiving warfarin + NAC, the increase in Scr was lessened, starting at 40 mg·kg⁻¹·day⁻¹ NAC, and completely prevented at 80 mg·kg⁻¹·day⁻¹ NAC. NAC did not decrease hematuria or obstructive RBC casts, but mitigated acute tubular injury. Oxidative stress in the kidney was increased in animals with WRN and it was decreased by NAC. The NAC regimen used in the WRN model preserved kidney function in the ischemia-reperfusion model. Treatment with deferoxamine (iron chelator) did not affect WRN. No iron was detected in tubular epithelial cells. In conclusion, this work taken together with our previous works in WRN shows that glomerular hematuria is a necessary but not sufficient explanation for the AKI in WRN. The dominant mechanism of the AKI of WRN is tubular obstruction by RBC casts with increased oxidative stress in the kidney.

IgG subclass staining in renal biopsies with membranous glomerulonephritis indicates subclass switch during disease progression.

Recent breakthrough findings revealed that most patients with idiopathic (primary) membranous glomerulonephritis have IgG4 antibodies to the phospholipase A2 receptor (PLA2R). These IgG4 antibodies can be detected in the glomerular immune complexes and they colocalize with PLA2R. In secondary forms of membranous glomerulonephritis, such IgG4 antibodies are absent or less prevalent. There are no studies addressing the IgG subclass distribution across different stages of membranous glomerulonephritis. During a 25-month period, we identified 157 consecutive biopsies with membranous glomerulonephritis with adequate tissue for light, immunofluorescence and electron microscopy. Of the 157 membranous glomerulonephritis cases, 114 were primary membranous glomerulonephritis and 43 were secondary membranous glomerulonephritis. We compared the intensity of IgG subclass staining (on a semiquantitative scale of 0 to 3+) and the IgG subclass dominance between primary and secondary membranous glomerulonephritis and between the different stages of membranous glomerulonephritis. In primary membranous glomerulonephritis most (76% of cases) were IgG4 dominant. In contrast, in secondary membranous glomerulonephritis IgG1 was dominant in 60% of biopsies (P=0.0018). Interestingly, in early stage (stage 1) primary membranous glomerulonephritis, IgG1 was the dominant IgG subclass (64% of cases); in all later stages IgG4 dominated (P=0.0493). It appears that there is an inverse relationship between the intensity of glomerular capillary IgG4 and C1q staining. In secondary forms of membranous glomerulonephritis (heterogeneous group with low case numbers), we did not find such associations. Our data indicate that in early stage membranous glomerulonephritis, antibody response is different from later stages, with IgG1 dominant deposits. It is possible that early on, antigens other than PLA2R have an important role, Alternately, there may be an IgG subclass switch in the antibody response with IgG4 taking over later as the dominant immunoglobulin.

When size matters: diagnostic value of kidney biopsy according to the gauge of the biopsy needle.

BACKGROUND: Kidney biopsy is a vital tool in the diagnosis of kidney disease. Although it has become a routine procedure, it is not complication-free. Some serious complications of percutaneous kidney biopsy include retroperitoneal hemorrhage and death. There is an increased belief that smaller biopsy needle size results in a lower complication rate. As renal pathologists, we witness an increased number of kidney biopsies performed with a small needle size (as low as gauge 22), which results in inadequate tissue sampling and often non-diagnostic biopsy results. Herein we report the diagnostic value of kidney biopsies according to the size of the biopsy needles. METHODS: We performed kidney biopsies from nephrectomy specimens using biopsy needles of different sizes. Morphologic parameters were analyzed. RESULTS: We found that biopsies performed by small needles (gauges 20 and 22) contain significantly lower numbers of glomeruli and blood vessels, which limits pathologic evaluation. Data from our institution do not show differences in kidney biopsy complication rates between 16- and 18-gauge needles. CONCLUSIONS: Our data indicate that small biopsy needles do not provide sufficient material for diagnosis, and they increase the likelihood for a repeat biopsy.

Henoch-Schönlein purpura-like presentation in IgA-dominant Staphylococcus infection - associated glomerulonephritis - a diagnostic pitfall.

BACKGROUND: In children and adults, Henoch-Schönlein purpura (HSP) has a characteristic clinical presentation that includes a purpuric lower extremity skin rash, IgA-dominant glomerulonephritis, and abdominal and joint pain. A similar clinical presentation can be seen in adults who have a systemic infection with methicillin-resistant Staphylococcus aureus. It is critically important to distinguish the IgAdominant glomerulonephritis of HSP from the IgA-dominant glomerulonephritis of staphylococcal infection, because HSP may need to be treated with corticosteroids and immunosuppressives, while Staphylococcus infection-associated glomerulonephritis requires antibiotics. DESIGN: We searched our renal biopsy database for cases of Staphylococcus infection-associated IgA-dominant glomerulonephritis, to identify those with an HSP-like presentation. Their clinical, laboratory, and biopsy findings are reviewed. RESULTS: Between 2004 and 2011, we identified 37 patients with culture-proven Staphylococcus infection-associated glomerulonephritis. Of these, 8 (22%) had an HSP-like presentation manifested by lower extremity purpuric skin rash. Mesangial IgA and C3 deposits were consistent findings on kidney biopsy. Crescents were uncommon. Four of the 8 patients received glucocorticoid (steroid) therapy for a presumed diagnosis of HSP. Renal function worsened in 3 patients, and 1 patient ultimately improved but developed sepsis during the course. Overall, renal outcome was poor in 71% of the cases despite mild chronic renal injury in the biopsy. CONCLUSION: In adult patients with an HSPlike presentation, a high index of suspicion for underlying Staphylococcal infection is warranted. Blood cultures are frequently negative. Cultures from the site of infection should be performed. Steroid treatment did not improve outcomes. Renal outcomes were frequently poor.

Characterization of glomerular diseases using proteomic analysis of laser capture microdissected glomeruli.

The application of molecular techniques to characterize clinical kidney biopsies has the potential to provide insights into glomerular diseases that cannot be revealed by traditional renal pathology. The present work is a proof-of-concept approach to test whether proteomic analysis of glomeruli isolated from clinical biopsies by laser capture microdissection can provide unique information regarding differentially expressed proteins relevant to disease pathogenesis. The proteomes of glomeruli isolated by laser capture microdissection from biopsies of normal kidneys (living-related donor kidneys) were compared with those from patients with diabetic nephropathy, lupus nephritis, and fibronectin glomerulopathy. Glomerular proteins were extracted, trypsin digested, and subjected to liquid chromatography-tandem mass spectrometry for identification and quantitation. Relative to normal glomeruli, all disease-associated glomeruli showed an increased presence of complement components, a marked decline in podocyte-associated proteins, and a decrease in proteins associated with cellular metabolism. Additionally, fibronectin glomerulopathy glomeruli differed from all the other glomeruli because of a significant accumulation of fibronectin and fibulin. This study demonstrates that our method acquires reproducible and quantitative proteomic information from laser capture microdissection isolates that can be used to characterize the molecular features of glomerular diseases.

Warfarin-related nephropathy modeled by nephron reduction and excessive anticoagulation.

An acute increase in international normalized ratio (INR) to >3.0 in patients with chronic kidney disease (CKD) can associate with an unexplained acute increase in serum creatinine and accelerated progression of CKD. A subset of these patients have renal tubular obstruction by casts of red blood cells, presumably the dominant mechanism of the acute kidney injury described as warfarin-related nephropathy. Here, we developed an animal model of this acute kidney injury that is based on the 5/6-nephrectomy model to aid future investigation of the pathogenesis of this condition. We found that acute excessive anticoagulation with brodifacoum ("superwarfarin") increased serum creatinine levels and hematuria in 5/6-nephrectomized rats but not in controls. In addition, morphologic findings in 5/6-nephrectomized rats included glomerular hemorrhage, occlusive red blood cell casts, and acute tubular injury, similar to the biopsy findings among affected patients. Furthermore, in the rat model, we observed an increase in apoptosis of glomerular endothelial cells. In summary, the 5/6-nephrectomy model combined with excessive anticoagulation may be a useful tool to study the pathogenesis of warfarin-related nephropathy.

Warfarin-related nephropathy occurs in patients with and without chronic kidney disease and is associated with an increased mortality rate.

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.

Proliferative glomerulonephritis with monoclonal IgG deposits recurs or may develop de novo in kidney allografts.

Proliferative glomerulonephritis with monoclonal immunoglobulin G (IgG) deposits (PGNMIGD) is a recently recognized glomerular disease. Light microscopy usually resembles membranoproliferative glomerulonephritis. Glomerular deposits are mostly IgG3 κ; however, unlike in the usual forms of monoclonal immunoglobulin deposition disease, extraglomerular deposits are absent. If PGNMIGD is secondary to the glomerular deposition of circulating monoclonal IgG, it is expected to recur in kidney allografts with the same pattern of monoclonal IgG deposition. We reviewed our kidney biopsy files between January 1, 2003, and January 4, 2010, and identified 21 biopsy specimens with PGNMIGD, mostly with glomerular IgG3 κ deposits. Of the 21 biopsy specimens, 4 were from kidney allografts; 2 were recurrent and the other 2 were de novo diseases. Recurrent PGNMIGD develops rapidly, causing proteinuria. This rapid recurrence of PGNMIGD in kidney allografts provides further proof that PGNMIGD is secondary to the glomerular deposition of circulating monoclonal IgG.

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 Ab-mediated injury to allograft parenchyma is not well understood. We used a well-characterized murine hepatocellular allograft model to determine the mechanism of Ab-mediated destruction of transplanted liver parenchymal cells. In this model, allogeneic hepatocytes are transplanted into CD8-deficient hosts to focus on CD4-dependent, alloantibody-mediated rejection. Host serum alloantibody levels correlated with in vivo allospecific cytotoxic activity in CD8 knockout 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 Ab-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.

Warfarin therapy that results in an International Normalization Ratio above the therapeutic range is associated with accelerated progression of chronic kidney disease.

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 > or =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 justify extra caution in warfarin-treated CKD patients to avoid overanticoagulation.

An experimental model of acute humoral rejection of renal allografts associated with concomitant cellular rejection.

Acute humoral rejection (AHR), which occurs in up to 8% of kidney transplant recipients, is a significant cause of renal allograft dysfunction and loss. More efficacious treatment modalities are needed to eliminate or curtail alloantibody production and its deleterious effects on the kidney. The availability of animal models mimicking human AHR is essential to understand its pathophysiology and develop new treatment strategies. Using a mouse kidney transplant model, we demonstrate that presensitization of recipients with donor skin grafts results in rejection of subsequent renal allografts. All presensitized mice developed renal failure 8.6 +/- 4.3 days after engraftment, with serum creatinine values near 100 micromol/dl. Graft histology revealed mild, diffuse, interstitial, mononuclear cell infiltrates; prominent peritubular capillary inflammatory cell margination; patchy interstitial hemorrhage; interstitial edema; and focal glomerular fibrin deposition. Complement (C3d) deposition was diffuse and prominent in peritubular capillaries. Serum analysis demonstrated high levels of circulating alloantibodies with broad cross-reactivity to many MHC haplotypes. The clinical setting and histological findings of our model strongly resemble AHR, which is frequently associated with cellular rejection, a situation commonly encountered in human renal allograft recipients. This animal model provides a valuable tool to study the pathogenesis of AHR, its relationship to cellular alloimmunity, its contribution to graft injury, and the effects of various potential therapeutic interventions.

Acute kidney injury during warfarin therapy associated with obstructive tubular red blood cell casts: a report of 9 cases.

Acute kidney injury (AKI) during warfarin therapy usually is hemodynamic secondary to massive blood loss. Here, we report pathological findings in kidney biopsy specimens from 9 patients with warfarin overdose, hematuria, and AKI. Kidney biopsy specimens from patients on warfarin therapy with AKI were identified in our database within a 5-year period. Each kidney biopsy specimen was evaluated by using semiquantitative morphometric techniques, and medical history was reviewed for conditions explaining AKI. Biopsy specimens with morphological findings of active glomerulonephritis and active inflammatory lesions were excluded from the study. Biopsy specimens from 9 patients were selected. At presentation with AKI, each patient had an abnormal international normalized ratio (mean 4.4 +/- 0.7 IU) and increased serum creatinine level (mean, 4.3 +/- 0.8 mg/dL). Morphologically, each biopsy specimen showed evidence of acute tubular injury and glomerular hemorrhage: red blood cells (RBCs) in Bowman space and numerous occlusive RBC casts in tubules. Each biopsy specimen showed chronic kidney injury. Six of 9 patients did not recover from AKI. These data suggest that warfarin therapy can result in AKI by causing glomerular hemorrhage and renal tubular obstruction by RBC casts. Our experience suggests that this may be a potentially serious complication of warfarin therapy, especially in older patients with underlying chronic kidney injury.

Biomarkers of lupus nephritis determined by serial urine proteomics.

Lupus nephritis is a frequent and serious complication of systemic lupus erythematosus (SLE), the treatment of which often requires the use of immunosuppressives that can have severe side effects. Here we determined the low-molecular weight proteome of serial lupus urine samples to uncover novel and predictive biomarkers of SLE renal flare. Urine from 25 flare cycles of 19 patients with WHO Class III, IV, and V SLE nephritis were obtained at baseline, pre-flare, flare and post-flare. Each sample was first fractionated to remove proteins larger than 30 kDa, then applied onto weak cation exchanger protein chips for analysis by SELDI-TOF mass spectrometry. We found 176 protein ions of which 27 were differentially expressed between specific flare intervals. On-chip peptide sequencing by integrated tandem mass spectrometry positively identified the 20 and 25 amino-acid isoforms of hepcidin, as well as fragments of alpha1-antitrypsin and albumin among the selected differentially expressed protein ions. Hepcidin 20 increased 4 months before renal flare and returned to baseline at renal flare, whereas hepcidin 25 decreased at renal flare and returned to baseline 4 months after the flare. These studies provide a beginning proteomic analysis aimed at predicting impending renal relapse, relapse severity, and the potential for recovery after SLE nephritis flare.

Peritubular capillary C4d staining in late acute renal allograft rejection--is it relevant?

BACKGROUND: In the early post-transplant period, renal allograft rejection with diffuse peritubular capillary (PTC) C4d deposition predicts poor graft survival. In the late post-transplant setting, that is, one or more yr after transplantation, the implication of diffuse PTC C4d deposition is still a topic of debate. The purpose of our study was to see if diffuse PTC C4d deposition, in late acute rejection (LAR), occurring more than one yr post-transplant, has any impact on graft survival and function. METHODS: We selected cases, both cadaveric as well as living donor renal transplant recipients, in whom acute rejection with PTC C4d deposition was first detected after the first year post-transplant. Recipients with multiple acute rejection episodes during the first year post-transplant were excluded from the study. The first biopsy diagnosed with LAR was considered the index biopsy (n = 40). We formed two groups: group 1, C4d-positive LAR (n = 20), and group 2, C4d-negative LAR (n = 20). Groups were matched for maintenance and post-rejection immunosuppressive therapy, baseline serum creatinine levels before the time of the index biopsy, time from transplant to index biopsy, as well as chronic allograft damage index (CADI) score in the index biopsies. We compared the rate of graft loss, and the graft function of the surviving grafts at the end of the study period, as well as histologic parameters in the index biopsy specimens between the two groups. The mean follow-up period was 20 months. RESULTS: No significant differences in the rate of graft loss or graft function were found between groups 1 and 2 at the end of the follow-up period. Histologically, PTC margination and transplant glomerulopathy were more common in the C4d-positive group, and this difference was statistically significant. There was no statistically significant difference in the degree of plasma cell infiltrates. CONCLUSIONS: Unlike in the acute setting, the presence or absence of PTC C4d staining in renal allografts with LAR may not have a predictive value regarding graft outcome.

Fibrillary glomerulonephritis with splenic involvement: a detailed autopsy study.

Fibrillary glomerulonephritis (FGN) is characterized by the deposition of IgG-positive, randomly arranged, nonbranching, non-Congophilic fibrils in the glomeruli. The possibility of multiorgan involvement, as in amyloidosis, has been raised. The authors report the first detailed autopsy study on a patient with FGN, with thorough examination of the organs by electron microscopy, colloidal gold immunoelectron microscopy, and immunofluorescence staining. Thin, wavy fibrils (extracellular matrix filaments) ranging from 6 to 17 nm were seen in all other organs, but only kidney and spleen showed the typical rigid, nonbranching fibrils of FGN with specific gold label. This study suggests that FGN is mainly a renal-limited disease with possible involvement of the spleen.