Anjali A. Satoskar

Proliferative Glomerulonephritis with Monoclonal IgG Deposits

Dysproteinemias that result in monoclonal glomerular deposits of IgG are relatively uncommon. Here, we report the largest series of proliferative glomerulonephritis with monoclonal IgG deposits, a form of renal involvement by monoclonal gammopathy that mimics immune-complex glomerulonephritis. We retrospectively identified 37 patients, most of whom were white (81%), female (62%), or older than 50 yr (65%). At presentation, 49% had nephrotic syndrome, 68% had renal insufficiency, and 77% had hematuria. In 30% of the patients, we identified a monoclonal serum protein with the same heavy- and light-chain isotypes as the glomerular deposits (mostly IgG1 or IgG2), but only one patient had myeloma. Histologic patterns were predominantly membranoproliferative (57%) or endocapillary proliferative (35%) with membranous features. Electron microscopy revealed granular, nonorganized deposits, and immunofluorescence demonstrated glomerular deposits that stained for a single light-chain isotype and a single heavy-chain subtype, most commonly IgG3kappa (53%). During an average of 30.3 mo of follow-up for 32 patients with available data, 38% had complete or partial recovery, 38% had persistent renal dysfunction, and 22% progressed to ESRD. Correlates of ESRD on univariate analysis were higher creatinine at biopsy, percentage of glomerulosclerosis, and degree of interstitial fibrosis but not immunomodulatory treatment or presence of a monoclonal spike. On multivariate analysis, higher percentage of glomerulosclerosis was the only independent predictor of ESRD. Only one patient lacking a monoclonal spike at presentation subsequently developed a monoclonal spike and no patient with a monoclonal spike at presentation subsequently developed a hematologic malignancy. We conclude that proliferative glomerulonephritis with monoclonal IgG deposits does not seem to be a precursor of myeloma in the vast majority of patients.

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.

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.

Staphylococcus Infection-Associated Glomerulonephritis Mimicking IgA Nephropathy

The association of methicillin-resistant Staphylococcus aureus (MRSA) infection with glomerulonephritis (GN) has been well documented in Japan but not in North America. Recently, eight renal biopsies with IgA-predominant or -codominant GN from eight patients with underlying staphylococcal infection, but without endocarditis, were observed at a single institution in a 12-mo period. Renal biopsies were worked up by routinely used methodologies. Eight cases of primary IgA nephropathy were used as controls. Five patients had MRSA infection, one had methicillin-resistant S. epidermidis (MRSE) infection, and two had methicillin-sensitive S. aureus infection. Four patients became infected after surgery; two patients were diabetic and had infected leg ulcers. All patients developed acute renal failure, with active urine sediment and severe proteinuria. Most renal biopsies showed only mild glomerular hypercellularity. Two biopsies had prominent mesangial and intracapillary hypercellularity; one of them (the MRSE-associated case) had large glomerular hyalin thrombi. This patient also had a positive cryoglobulin test. Rare glomerular hyalin thrombi were noted in two other cases. Immunofluorescence showed IgA pre- or codominance in all biopsies. Electron microscopy revealed mesangial deposits in all cases. Five biopsies had rare glomerular capillary deposits as well. In the MRSE-associated GN, large subendothelial electron-dense deposits were present. These cases demonstrate that staphylococcal (especially MRSA) infection-associated GN occurs in the US as well, and a rising incidence is possible. It is important to differentiate a Staphylococcus infection-associated GN from primary IgA nephropathy to avoid erroneous treatment with immunosuppressive medications.

Proteinuria in a patient receiving anti-VEGF therapy for metastatic renal cell carcinoma

Background A 59-year-old man who had undergone a left nephrectomy for renal cell carcinoma was found to have metastatic disease during a restaging examination. The patient was started on treatment with interferon α2b plus bevacizumab, a humanized monoclonal anti-vascular endothelial growth factor antibody. After 9 months of this therapy, the patient developed proteinuria, which gradually increased to over 6 g/day.Investigations Physical examination, urine and blood analysis, biopsy of the right kidney, and histologic evaluation of the non-neoplastic portion of the left nephrectomy specimen.Diagnosis Thrombotic microangiopathy and IgA immune-complex deposition in the glomerular capillary walls and mesangium.Management Discontinuation of interferon α2b and bevacizumab, control of blood pressure with an angiotensin-converting-enzyme inhibitor and an angiotensin-receptor blocker.

De novo Thrombotic Microangiopathy in Renal Allograft Biopsies—Role of Antibody‐Mediated Rejection

The most common cause of thrombotic microangiopathy (TMA) in renal allografts is thought to be calcineurin inhibitor toxicity. Antibody‐mediated rejection (AMR) can also cause TMA, but its true impact on de novo TMA is unknown. In a retrospective review of renal allograft biopsies from January 2003 to December 2008 at our institution, we determined the prevalence of TMA in patients with C4d positive (n = 243) and C4d negative (n = 715) biopsies. Over 90% of patients received cyclosporine in both groups. De novo TMA was seen in 59 (6.1%) patients; most of them (55%) with C4d positive biopsy. Among patients with C4d positive biopsies, 13.6% had TMA, as compared to only 3.6% patients with C4d negative biopsies (p < 0.0001). Incidence of graft loss between C4d positive and C4d negative TMA groups was not significantly different, but 70% of patients with C4d positive TMA who received plasmapheresis had slightly lower graft loss rate. In biopsies with AMR‐associated TMA, glomerulitis and peritubular capillaritis were significantly more prominent. AMR is the most common cause of TMA in renal allografts in our patient population. It is important to recognize AMR‐related TMA because plasmapheresis treatment may be beneficial.

Typing of amyloidosis in renal biopsies: diagnostic pitfalls.

CONTEXT Amyloidosis represents a group of diseases with extracellular deposition of congophilic fibrils of similar morphology but differing chemical composition. The types commonly involving the kidney are AL (light chain amyloid) and AA (serum amyloid A). Familial amyloidosis can also affect the kidney, but we have not encountered such a case during the study period. Distinguishing between the AL and AA forms of amyloid is clinically important because of the different treatments and outcomes. The classification of amyloidosis is made by immunostaining with antibodies to kappa and lambda immunoglobulin light chains and for serum amyloid A protein. OBJECTIVE To draw attention to the nonspecific immunofluorescence staining patterns in renal biopsies with amyloidosis, causing potential diagnostic pitfalls. DESIGN Renal biopsies from 15 patients, including 13 cases of AL and 2 cases of AA amyloidosis, were studied. Immunofluorescence staining with routine antibody panel and immunoperoxidase staining for amyloid A were performed. RESULTS Of the 13 cases of AL amyloidosis, 2 cases showed little difference in staining intensity between kappa and lambda light chains (2+ and 3+, respectively) and 4 cases showed only moderate intensity (2+) of the predominant light chain. The 2 cases diagnosed as AA amyloidosis also exhibited staining for light chains. One case had strong (3+) signal for kappa and moderate (2+) for lambda light chain, while the other showed weaker staining. CONCLUSIONS Immunofluorescence staining for immunoglobin light chains on renal biopsy, as the first step to differentiate between AL and AA amyloidosis, may sometimes be inconclusive or even misleading. Applying amyloid A immunostain on a routine basis and detailed clinical history are essential to avoid misclassification.

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.

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 ≧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.

Macrophage migration inhibitory factor (MIF) is critical for the host resistance against Toxoplasma gondii

Macrophage migration inhibitory factor (MIF) exerts either a protective or a deleterious role in the immune response to different pathogens. We analyzed herein the role of MIF in the host control of toxoplasmosis using MIF−/− mice backcrossed to either the BALB/c or the C57BL/6 genetic backgrounds. Both, wild‐type (WT) BALB/c and MIF−/− BALB/c mice were susceptible to infection with highly virulent RH as well as moderately virulent ME49 strains of T. gondii.MIF−/− mice, however, showed greater liver damage and more brain cysts, produced less proinflammatory cytokines, and succumbed significantly faster than WT mice. Bone marrow‐derived dendritic cells (BMDCs) from MIF−/− mice produced less interleukin‐1β, interleukin‐12, and tumor necrosis factor‐α than WT BMDCs after stimulation with soluble Toxoplasma antigen (STAg). Similar observations were made in CD11c+ low‐density cells isolated from the spleens of MIF−/− mice challenged with STAg. MIF−/−C57BL/6 mice succumbed to ME49 infection faster than their WT counterparts. C57BL/6 mice that succumbed to infection with the ME49 strain produced less MIF than resistant BALB/c mice similarly infected. Interestingly, an analysis of brains from patients with cerebral toxoplasmosis showed low levels of MIF expression. Together, these findings demonstrate that MIF plays a critical role in mediating host resistance against T. Gondii.—Flores, M., Saavedra, R., Bautista, R., Viedma, R., Tenorio, E. P., Leng, L., Sánchez, Y., Juárez, I., Satoskar, A. A., Shenoy, A. S., Terrazas, L. I., Bucala, R., Barbi J., Satoskar, A. R., Rodriguez‐Sosa, M. Macrophage migration inhibitory factor (MIF) is critical for the host resistance against Toxoplasma gondii. FASEB J. 22, 3661–3671 (2008)