Frequently relapsing anti-glomerular basement membrane antibody disease with changing clinical phenotype and antibody characteristics over time.

Anti-glomerular basement membrane (GBM) antibody disease is a typically monophasic autoimmune disease with severe pulmonary and renal involvement. We report an atypical case of frequently relapsing anti-GBM antibody disease with both anti-GBM antibody-positive flares with pulmonary and renal involvement, and anti-GBM antibody-negative flares that were pulmonary limited with no histologic renal disease. This is the first report of alternating disease phenotype and anti-GBM antibody status over time. Disease severity paralleled the detection of anti-GBM antibodies but was independent of IgG subtype staining along the GBM. This case suggests a role for changing subpopulations of pathogenic antibodies as an explanation for variation in disease phenotype and anti-GBM antibody results.

Isolated endarteritis and kidney transplant survival: a multicenter collaborative study.

Isolated endarteritis of kidney transplants is increasingly recognized. Notably, microarray studies revealed absence of immunologic signatures of rejection in most isolated endarteritis biopsy samples. We investigated if isolated endarteritis responds to rejection treatment and affects kidney transplant survival. We retrospectively enrolled recipients of kidney transplant who underwent biopsies between 1999 and 2011 at seven American and Canadian centers. Exclusion criteria were recipients were blood group-incompatible or crossmatch-positive or had C4d-positive biopsy samples. After biopsy confirmation, patients were divided into three groups: isolated endarteritis (n=103), positive controls (type I acute T cell-mediated rejection with endarteritis; n=101), and negative controls (no diagnostic rejection; n=103). Primary end points were improved kidney function after rejection treatment and transplant failure. Mean decrease in serum creatinine from biopsy to 1 month after rejection treatment was 132.6 µmol/L (95% confidence interval [95% CI], 78.7 to 186.5) in patients with isolated endarteritis, 96.4 µmol/L (95% CI, 48.6 to 143.2) in positive controls (P=0.32), and 18.6 µmol/L (95% CI, 1.8 to 35.4) in untreated negative controls (P<0.001). Functional improvement after rejection treatment occurred in 80% of patients with isolated endarteritis and 81% of positive controls (P=0.72). Over the median 3.2-year follow-up period, kidney transplant survival rates were 79% in patients with isolated endarteritis, 79% in positive controls, and 91% in negative controls (P=0.01). In multivariate analysis, isolated endarteritis was associated with an adjusted 3.51-fold (95% CI, 1.16 to 10.67; P=0.03) risk for transplant failure. These data indicate that isolated endarteritis is an independent risk factor for kidney transplant failure.

Renal leukocyte chemotactic factor 2 (LECT2) amyloidosis in First Nations people in Northern British Columbia, Canada: a report of 4 cases.

Leukocyte chemotactic factor 2 (LECT2) amyloidosis is a recently identified type of amyloidosis that may represent an underdiagnosed cause of chronic kidney disease. LECT2 amyloidosis typically is reported as being renal limited and, in the United States, more prevalent in Hispanic patients. We add to the epidemiologic data of this condition by describing 4 First Nations people from Northern British Columbia, Canada, who presented with slowly progressive chronic kidney disease that was found to be due to LECT2 amyloidosis.

Proliferative glomerulonephritis with monoclonal IgG deposits secondary to chronic lymphocytic leukemia. Report of two cases.

Proliferative glomerulonephritis with monoclonal IgG deposits (PGNMID) is a recently described entity that is only rarely associated with a hematological or lymphoproliferative malignancy. We describe the cases of two men with preexisting chronic lymphocytic leukemia (CLL) who developed endocapillary proliferative glomerulonephritis with nonorganized monoclonal IgG(1) deposits. One biopsy also showed CLL infiltration of the cortex. Both patients were treated with rituximab in addition to cyclophosphamide in one case and fludarabine in the other with significant improvement of their renal disease and CLL. This report provides additional evidence to support the use of rituximab in the therapy of CLL-associated PGNMID.

Biodistribution and tissue toxicity of amphotericin B in mice following multiple dose administration of a novel oral lipid-based formulation (iCo-009).

OBJECTIVES: The purpose of this study was to assess the biodistribution and toxicity of amphotericin B (AMB) following multiple dose administration of an oral lipid-based formulation (iCo-009). METHODS: BALB/c female mice were used. ICo-009 was administered twice daily for 5 days at doses of 2.5-20 mg/kg. Untreated animals, oral vehicle or intravenous Fungizone® (1 or 2 mg/kg) served as control groups. The animals were sacrificed 12 h following the last administration of AMB, and blood and multiple tissues were harvested for drug analysis and histopathological evaluation. Plasma or tissue samples were analysed for concentrations of AMB or creatinine by means of HPLC-UV. RESULTS: A dose-dependent accumulation of AMB in liver, spleen, kidney and lung tissues was found. The concentration of the drug in all these organs exceeded the corresponding concentrations in plasma at the same dose. The concentrations of AMB in heart and brain were similar to the corresponding concentrations in plasma. Creatinine concentrations were elevated above normal concentrations in the 2 mg/kg Fungizone® group only. Histopathological analysis of kidney and liver tissues revealed a normal pattern in all treated groups, except the 2 mg/kg Fungizone® group. No gastrointestinal toxicity was found in this study. CONCLUSIONS: A multiple dose treatment regimen with iCo-009 in mice results in a gradual accumulation of AMB in tissues. Despite significant concentrations of AMB, no kidney or liver toxicity of orally administered AMB was detected in this study. Furthermore, multiple oral administration of iCo-009 or of vehicle control did not induce gastrointestinal toxicity.

Screening for de novo anti-human leukocyte antigen antibodies in nonsensitized kidney transplant recipients does not predict acute rejection.

BACKGROUND: The purpose of this study was to determine whether screening for anti-human leukocyte antigen (HLA) antibodies (Abs) could predict development of acute rejection (AR) before clinical evidence of kidney allograft dysfunction in nonsensitized recipients. METHODS: Eighty-four non-HLA identical kidney transplant recipients were prospectively tested for anti-HLA Abs (FlowPRA analysis and anti-HLA Ab specificity determination) at 0, 10, 20, 30, 60, 90, 180 and 365 posttransplantation, and at the time of clinical suspicion of AR. Allograft biopsies were performed at the time of engraftment, 3 and 12 months posttransplantation, when patients developed new anti-HLA Abs, or when clinically indicated. RESULTS: Among the 70 patients without preformed anti-HLA Abs, 11 developed de novo anti-HLA Abs (8 donor-specific Abs) at a median of 30 days (q1-q3=10-180 days) after transplantation. Patients with de novo anti-HLA Abs had a shorter time to AR than patients without de novo anti-HLA Abs, P=0.06. However, in all cases, de novo anti-HLA Abs developed concomitantly or after a clinically evident AR. CONCLUSIONS: Although de novo anti-HLA Abs were associated with AR, routine screening for anti-HLA Abs was not useful in identifying patients at risk for AR before clinical evidence of allograft dysfunction.

Monocytes/macrophages in renal allograft rejection.

Monocytes/macrophages (MO) have long been recognized to be involved in renal allograft rejection. Monocytes/macrophages have been detected in the glomerular, vascular, and tubulointerstitial compartments during rejection. The recent demonstration that peritubular capillary deposition of complement split factor C4d, a marker for antibody-mediated rejection, is associated with relatively marked MO infiltration of the allograft during acute rejection is a significant development in our understanding of the role of the MO in rejection. High levels of MO in rejecting allografts have been associated with severe rejection, and glomerular MO infiltration in particular has been shown to be an indicator of poor graft outcome.

Salt-resistant blood pressure and salt-sensitive renal autoregulation in chronic streptozotocin diabetes.

Hyperfiltration occurs in early type 1 diabetes mellitus in both rats and humans. It results from afferent vasodilation and thus may impair stabilization of glomerular capillary pressure by autoregulation. It is inversely related to dietary salt intake, the "salt paradox." Restoration of normal glomerular filtration rate (GFR) involves increased preglomerular resistance, probably mediated by tubuloglomerular feedback (TGF). To begin to test whether the salt paradox has pathogenic significance, we compared intact vs. diabetic (streptozotocin) Long-Evans rats with normal and increased salt intake, 1 and approximately 3% by weight of food eaten, respectively. Weekly 24-h blood pressure records were acquired by telemetry before and during diabetes. Blood glucose was maintained at approximately 20 mmol/l by insulin implants. GFR was significantly elevated only in diabetic rats on normal salt intake, confirming diabetic hyperfiltration and the salt paradox. Renal blood flow dynamics show strong contributions to autoregulation by both TGF and the myogenic mechanism and were not impaired by diabetes or by increased salt intake. Separately, systolic pressure was not elevated in diabetic rats at any time during 12 wk with normal or high salt intake. Autoregulation was effective in all groups, and the diabetic-normal salt group showed significantly improved autoregulation at low perfusion pressures. Histological examination revealed very minor glomerulosclerosis and modest mesangial expansion, although neither was diagnostic of diabetes. Periodic acid-Schiff-positive droplets found in distal tubules and collecting duct segments were diagnostic of diabetic kidneys. Biologically significant effects attributable to increased salt intake were abrogation of hyperfiltration and of the left shift in autoregulation in diabetic rats.

Focal segmental glomerulosclerosis in mild IgA nephropathy: a clinical-pathologic study.

BACKGROUND: The significance of focal segmental glomerulosclerosis (FSGS) in mild IgA nephropathy is uncertain. METHODS: All consecutive renal biopsies performed between 1996 and 2005 in adults with a diagnosis of mild IgA nephropathy (Lee Grade 1 or 2) at St Paul's Hospital, Vancouver, Canada, were reviewed. RESULTS: Seventy-five patients were included, 26 (35%) with IgA nephropathy and FSGS (FSGS+ group) and 49 (65%) with IgA nephropathy without FSGS (FSGS- group). The mean follow-up was 3 years. At the time of renal biopsy the FSGS+ group had a lower eGFR (60 versus 73 mL/min, P = 0.02), lower serum albumin (38 versus 41 g/L, P = 0.02), higher mean arterial pressure (103 versus 97 mmHg, P = 0.03) and greater protein excretion (3.0 versus 1.3 g/day, P < 0.01) than the FSGS- group. On histology, the FSGS+ group had a higher percentage of obsolete glomeruli (23.4% versus 12.7%, P < 0.01), and 31% of FSGS+ biopsies had >or=25% tubular atrophy/interstitial fibrosis while this was not observed in the FSGS- group (P < 0.01). The primary outcome measure, DeltaGFR, was -2.56 mL/ min/year in the FSGS+ group and +1.14 mL/min/year in the FSGS- group, difference: 3.70 mL/min/year (P = 0.03) (univariate). In the multivariate model, the FSGS+ group declined at 0.19 mL/min/year (-14.16, 13.78) and the FSGS- group improved at 2.85 mL/min/year (-11.64, 17.34), difference 3.04 mL/min/year, P = 0.18. CONCLUSIONS: Our study suggests that the focal segmental glomerulosclerosis lesion and associated clinical and pathologic findings in patients with mild IgA nephropathy are associated with a worse renal outcome.

Exploring mitochondrial nephrotoxicity as a potential mechanism of kidney dysfunction among HIV-infected patients on highly active antiretroviral therapy.

BACKGROUND: Tenofovir (TDF) exposure has been associated with renal dysfunction. Mitochondrial nephrotoxicity was investigated as an underlying mechanism. Given the interaction between TDF and didanosine (ddl), their concurrent use was also investigated. DESIGN: Relative kidney biopsy mitochondrial DNA (mtDNA) to nuclear DNA ratios were measured retrospectively. HIV+ individuals on TDF within 6 months preceeding the biopsy (HIV+/TDF+, n=21) were compared to HIV+ individuals who never received TDF (HIV+/TDF-, n=10) and to HIV uninfected controls (HIV-,n=22). Twelve of the HIV+/TDF+ individuals received concurrent ddl, 10 of those once at unadjusted ddl dosage. Tubular mitochondria morphology was also examined by electron microscopy. Statistical analyses were done on log-transformed mtDNA/nDNA, using non-parametric tests. RESULTS: Kidney mtDNA levels were different among the three groups (P=0.046). mtDNA ratios were lower in HIV+/TDF+ subjects (7.5 [2.0-12.1]) than in HIV- ones (14.3 [6.0-16.5], P=0.014), but not lower than HIV+/TDF- controls (6.4 [2.8-11.9], P=0.82). Among HIV+ subjects, there was a difference between TDF-, TDF+/ddl- and TDF+/ddl+ (P=0.005), with concurrent TDF/ddl use associated with lower mtDNA (2.1 [1.9-5.5], n=12) than TDF+/ddl- (13.8 [7.5-16.4], n=9, P=0.003). No TDF-/ddl+ biopsies were available. In regression analyses, only HIV infection (P=0.03), and TDF/ddl use (P=0.003) were associated with lower mtDNA. At the ultrastructural level, abnormal tubular mitochondria was more prevalent in HIV+/TDF+ biopsies than HIV+/TDF- and HIV- ones together (P<0.001) but not more so in TDF+/ddl+ biopsies than TDF+/ddl- ones (P=0.67). CONCLUSIONS: Renal dysfunction in this population may be mediated through mitochondrial nephrotoxicity that involves more than one drug and/or pathogenesis. Kidney mtDNA depletion was associated with HIV infection and concurrent TDF/ddl therapy but not TDF use alone, while kidney ultrastructural mitochondrial abnormalities were seen with TDF use. The interaction between TDF and ddl may be relevant in the kidney where both drugs are cleared. The clinical relevance of our findings needs to be evaluated given the current recommendation for reduced doses of ddl when used in conjunction with TDF.

Glomerular monocytes predict worse outcomes after acute renal allograft rejection independent of C4d status.

BACKGROUND: Both peritubular capillary (PTC) C4d deposition and macrophage/monocyte (MO) infiltration in acute rejection (AR) have separately been shown to be associated with reduced graft survival and recently were demonstrated to be closely correlated in AR. Whether MO infiltration is an independent predictor of graft outcome is uncertain. METHODS: All patients with biopsy-proven AR (over a 3-year period) were included (N= 96). All biopsies (N= 121) were graded according to the Banff 97 criteria and immunohistochemically stained for C4d and MO (CD68). The primary outcome was glomerular filtration rate (GFR) <30 mL/min 1-year posttransplant as estimated by the Modified Diet in Renal Disease (MDRD) Formula. Secondary outcomes at 2 and 4 years' posttransplant were also explored. A variety of clinical and biopsy variables were statistically analyzed to establish univariate predictors of graft outcome. Stepwise multivariate logistic regression modeling was applied to determine independent predictors of outcomes. RESULTS: There was a close correlation between PTC C4d and glomerular MO infiltration (P < 0.001). Univariate predictors of primary outcome (GFR <30 mL/min 1-year posttransplant) included mean glomerular MO count > or =1.0 MO/glomerulus (P= 0.014), female sex (P= 0.02), higher peak (P= 0.005), and pretransplant (P= 0.003) panel-reactive antibody levels, cadaveric donor (P= 0.006), transplant glomerulitis (P= 0.004), and longer cold ischemic time (CIT) (P= 0.002). Mean MO/glomerulus > or =1.0 [OR 10.3 (1.23, 87.1)], female sex [OR 5.27(1.31, 21.1)], and CIT [OR 1.14 (1.06, 1.25)] were identified as independent predictors of adverse graft outcome. Furthermore, mean MO/glomerulus > or =1.0 independently predicted poor renal function at 2 years [OR 3.89 (1.19, 12.70)] and 4 years [OR 4.03 (1.22, 13.28)] posttransplant. CONCLUSION: The results demonstrate that glomerular MO infiltration is an independent predictor of worse outcomes posttransplant following acute renal allograft rejection.

Infiltrating cell types in transplant glomerulitis: relationship to peritubular capillary C4d deposition.

BACKGROUND: Transplant glomerulitis may be part of the acute rejection process in some transplant recipients. Glomerular monocytes have been shown to be the predominant cell type in transplant glomerulitis associated with peritubular capillary C4d deposition. Whether this applies to peritubular capillary C4d-negative (C4d-) biopsy specimens with transplant glomerulitis is unknown. METHODS: Forty-two biopsy specimens with acute rejection and transplant glomerulitis were immunostained for monocytes, T cells, and C4d. In each biopsy specimen, glomerular monocytes and T cells were counted, and mean numbers of monocytes per glomerulus and T cells per glomerulus were determined. RESULTS: Peritubular capillary C4d staining was present in 20 biopsy specimens (C4d-positive [C4d+] group) and negative in 22 specimens (C4d- group). There was no significant difference between mean Banff 97 glomerular scores for the 2 groups (C4d+ , 1.60 +/- 0.80; C4d- , 1.77 +/- 0.90). Although the C4d+ group showed a significantly higher mean number of monocytes per glomerulus (3.01 +/- 2.35) than the C4d- group (0.95 +/- 1.00; P < 0.0001), the C4d- group showed a significantly higher mean number of T cells per glomerulus (4.05 +/- 3.05) than the C4d+ group (1.36 +/- 1.24; P = 0.0007). There were proportionately more C4d+ biopsy specimens with a monocyte-T-cell ratio greater than 1.0 (75%) than C4d- specimens (14%; P < 0.0001). Mean glomerular monocyte-T-cell ratio was 3.66 +/- 4.24 for the C4d+ group and 0.39 +/- 0.54 for the C4d- group; the difference was significant (P = 0.0009). CONCLUSION: In acute rejection with no peritubular capillary C4d deposition, the predominant infiltrating endocapillary cell in transplant glomerulitis is the T cell, unlike acute rejection with peritubular capillary C4d deposition, in which the predominant infiltrating glomerular cell is the monocyte.

Monocytes and peritubular capillary C4d deposition in acute renal allograft rejection.

BACKGROUND: Peritubular capillary (PTC) deposition of complement split factor C4d in renal allografts has been shown to be closely associated with circulating antidonor antibodies and a marker for relatively poor graft survival. Monocyte/macrophage (MO) infiltration of renal allografts has been shown to adversely affect graft survival. The purpose of this study was to assess whether the two phenomena are related. METHODS: Twenty-three biopsies (from 15 patients) demonstrated diffuse strong staining of PTC for C4d (C4d+ group) and acute tubular injury with or without significant cellular rejection, while 28 biopsies (with acute rejection) but negative for PTC C4d served as controls (C4d- group). RESULTS: The C4d+ group demonstrated significantly greater glomerular and interstitial MO infiltration than did the C4d- group [3.4 +/- 2.0 vs. 0.2 +/- 0.3 MO/glomerulus, P < 0.0001; 12.9 +/- 9.2 vs. 6.5 +/- 5.0 MO/high power field (hpf), P = 0.0030]. Neutrophilic (PMN) infiltration of glomeruli and PTC was also significantly greater in the C4d+ group than in the C4d- one (0.8 +/- 0.6 vs. 0.3 +/- 0.3 PMN/glomerulus, P = 0.0003; 0.9 +/- 0.8 vs. 0.4 +/- 0.3 PTC PMN/hpf, P = 0.0035). CONCLUSION: The results indicate a close association between PTC C4d deposition and MO infiltration, particularly glomerular, and confirm previous observations regarding the correlation of PTC C4d staining and PMN infiltration.

Isolated renal giant cell arteritis.

Giant cell arteritis, which most commonly affects the temporal arteries, may involve intrarenal vessels and may be associated with a variety of renal lesions, including necrotizing arteritis, necrotizing glomerulonephritis, granulomatous glomerulonephritis, and membranous glomerulopathy. Isolated giant cell arteritis of the kidney is a rare cause of renal failure. We report a case of a previously healthy 54-year-old white woman who presented with nonoliguric renal failure and a 4-week history of persistent low-grade fever associated with diffuse mild myalgias. She had no history of previous renal or neurologic disease and denied any headaches or visual disturbances. Antinuclear antibody and antineutrophilic cytoplasmic antibody were negative. Renal biopsy revealed noncaseating granulomatous infiltration of arterial and arteriolar walls, a patchy mononuclear cell interstitial infiltrate, and no significant glomerular changes. Treatment with prednisone resulted in dramatic improvement of renal function.

C4d deposition in acute rejection: an independent long-term prognostic factor.

Peritubular capillary deposition of C4d has been demonstrated to be associated with both acute humoral and vascular rejection and increased graft loss. Whether it is an independent predictor of long-term graft survival rates is uncertain. The biopsies (n = 126) from all patients (n = 93) with a tissue diagnosis of acute rejection that were performed between July 1, 1995, and December 31, 1997, were classified according to Cooperative Clinical Trials in Transplantation (CCTT) criteria. Fresh frozen tissue was immunostained for C4d. There were 58 patients with CCTT type I (interstitial) rejection and 35 with CCTT type II (vascular) rejection. For 34 patients, at least one biopsy exhibited peritubular C4d deposition (C4d+ group). The C4d+ group had proportionately more female patients (P = 0.003), more patients with high (>30%) panel-reactive antibody levels (P = 0.024), more patients with resistance to conventional antirejection therapy (P = 0.010), and fewer patients with postrejection hypertension (P = 0.021) and exhibited a greater rate of graft loss (38 versus 7%, P = 0.001). Peritubular C4d deposition was associated with significantly lower graft survival rates in the CCTT type I rejection group (P = 0.003) and the CCTT type II rejection group (P = 0.003). Multivariate analyses demonstrated that peritubular C4d deposition (P = 0.0002), donor age (P = 0.0002), cold ischemic time (P = 0.0211), and HLA matches (P = 0.0460) were significant independent determinants of graft survival rates. Peritubular C4d deposition is a significant predictor of graft survival rates and is independent of histologic rejection type and a variety of clinical prognostic factors.