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Rationale & Objective: Amyloidosis derived from apolipoprotein C-II (AApoCII) is a recently discovered, rare form of amyloidosis. Data on clinical presentations and natural history are very limited. This study defines the clinicopathologic, proteomic and outcome characteristics of renal AApoCII., Study Design: Case series., Setting & Participants: Twenty-five renal AApoCII cases were identified from the Mayo Clinic Tissue Proteomics Laboratory archives from January 2008 through January 2024., Findings: All patients were White, 19 were ≥65 years old at diagnosis, and 18 were female. Seven had a family history of CKD. Patients presented with proteinuria (median 3.3 g/day) and reduced kidney function (n=16, median creatinine 1.6 mg/dl). No patient had clinical evidence of other organ involvement by amyloidosis or features of monogenic hypertriglyceridemia. Histologically, amyloid deposits were often weakly positive for Congo red and involved glomeruli in all cases (with a nodular pattern in 22), whereas extraglomerular involvement was less common and generally mild. Proteomic analysis revealed abundant spectra for Apo C-II and for all 3 amyloid signature proteins (Apo E, Apo A-IV and SAP) in all cases, and detected an Apo C-II variant in 14 (K19T [p.Lys41Thr] in 12 and E47V [p.Glu69Val] in 2). Among 22 patients with follow-up available, there were 12 ESKD events and 2 deaths without ESKD during an average (SE) follow up of 75.5 (12.5) months., Limitations: Retrospective design, small sample size, APOC2 gene sequencing performed in a smaller subset., Conclusions: AApoCII mostly affects the kidney, and manifests in the elderly with proteinuria and CKD. A minority of these patients had a family history of kidney disease. Kidney failure occurred in about half, whereas overall survival was more favorable., (Copyright © 2024. Published by Elsevier Inc.)

Rationale & Objective: Crystalglobulinemia is a rare syndrome characterized by intravascular crystallization of monoclonal immunoglobulins (MIg). Data on kidney involvement are limited to case reports. This series characterizes the clinicopathologic spectrum of crystalglobulin-induced nephropathy (CIN)., Study Design: Case series., Setting & Participants: Nineteen CIN cases identified from the nephropathology archives of Mayo Clinic and Columbia University. CIN was defined by intravascular (extracellular) MIg crystals visible by light microscopy (LM) and electron microscopy (EM)., Results: Among the cases, 68% were male, and 65% were Caucasian (median age, 56 years). Most patients presented with severe acute kidney injury (AKI) (median creatinine, 3.5mg/dL), hematuria, and mild proteinuria (median, 1.1g/day). Common extrarenal manifestations were constitutional (67%), cutaneous (56%), and rheumatologic (50%). Fifty percent of cases had hypocomplementemia. The hematologic disorders were monoclonal gammopathy of renal significance (MGRS) (72%), lymphoma (17%), or myeloma (11%), with 65% of these disorders discovered concomitantly with CIN. All patients had MIg identified on serum protein electrophoresis/immunofixation (IgGκ in 65%). The serum free light chain ratio was outside the renal range in 40%, and bone marrow biopsy detected the responsible clone in 67%. On LM, crystals involved glomeruli (100%) and vessels (47%), often with an inflammatory reaction (89%) and fibrin (58%). All cases exhibited crystal substructures (mostly paracrystalline) by EM. Immunofluorescence on paraffin-embedded tissue was more sensitive than frozen tissue (92% vs 47%) for demonstrating the crystal composition (IgGκ in 63%). Follow-up observation (median, 20 months) was available in 16 patients. Eighty-one percent received steroids, 44% plasmapheresis, 38% hemodialysis, and 69% chemotherapy. Ninety-percent of patients who received clone-directed therapy achieved kidney recovery versus 20% of those who did not (P=0.02)., Limitations: Retrospective design, small sample size., Conclusions: CIN is a rare cause of nephropathy associated with lymphoplasmacytic disorders (mostly MGRS) and typically presents with severe AKI and extrarenal manifestations. Diagnosis often requires immunofluorescence performed on paraffin-embedded kidney tissue. Prompt initiation of clone-directed therapy, coupled with corticosteroids and plasmapheresis, may lead to recovery of kidney function., (Copyright © 2024 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)

Objective: To report the clinicopathologic characteristics, prognostic indicators, prognosis, and transplant outcome of secondary oxalate nephropathy (ON)., Patients and Methods: We performed a retrospective analysis of 113 consecutive patients with secondary ON diagnosed at Mayo Clinic in Rochester, Minnesota, between January 1, 2001, and March 1, 2023., Results: The incidence of secondary ON among all native biopsies from Mayo Clinic patients over the study period (n=11,617) was 0.97%. ON was attributed to enteric hyperoxaluria in 60% of the 113 patients (68; most commonly Roux-en-Y gastric bypass), excessive ingestion of foods high in oxalate or oxalate precursors in 23% (26) (most commonly vitamin C), and idiopathic in 17% (19). Most patients presented with acute kidney injury (AKI) (particularly in the ingestion group) or AKI on chronic kidney disease, and 53% (60 of 113) were diabetic. Calcium oxalate crystals were accompanied by acute tubular injury, inflammation, and interstitial fibrosis and tubular atrophy. Concurrent pathologic conditions were present in 53% of the patients (60 of 113), most commonly diabetic nephropathy. After a median follow-up of 36 months, 27% of the patients (30 of 112) had kidney recovery, 19% (21 of 112) had persistent kidney dysfunction, 54% (61 of 112) had development of kidney failure, and 29% (32 of 112) died. The mean kidney survival was worse for patients with a concurrent pathologic lesion (30 months vs 96 months for those without a concurrent pathologic lesion; P<.001). Independent predictors of kidney failure were the degree of interstitial fibrosis and tubular atrophy and nadir estimated glomerular filtration rate but not the degree of crystal deposition. After a median follow-up of 58 months in 23 patients who received kidney transplant, 4 had graft loss (due to ON in 3). The 2-, 5-, and 10-year graft survivals were 90% (18 of 20), 79% (11 of 14), and 50% (6 of 12)., Conclusion: ON is a rare cause of AKI or AKI on chronic kidney disease. Most patients have comorbid pathologic conditions, particularly diabetic nephropathy, which worsen the prognosis. Recurrence in the renal allograft and graft loss may occur if hyperoxaluria is not controlled., (Copyright © 2023 Mayo Foundation for Medical Education and Research. Published by Elsevier Inc. All rights reserved.)

Monoclonal immunoglobulin light chain (LC) crystalline inclusions within podocytes are rare, poorly characterized entities. To provide more insight, we now present the first clinicopathologic series of LC crystalline podocytopathy (LCCP) encompassing 25 patients (68% male, median age 56 years). Most (80%) patients presented with proteinuria and chronic kidney disease, with nephrotic syndrome in 28%. Crystalline keratopathy and Fanconi syndrome were present in 22% and 10%, respectively. The hematologic condition was monoclonal gammopathy of renal significance (MGRS) in 55% and multiple myeloma in 45%. The serum monoclonal immunoglobulin was IgG κappa in 86%. Histologically, 60% exhibited focal segmental glomerulosclerosis (FSGS), often collapsing. Ultrastructurally, podocyte LC crystals were numerous with variable effacement of foot processes. Crystals were also present in proximal tubular cells as light chain proximal tubulopathy (LCPT) in 80% and in interstitial histiocytes in 36%. Significantly, frozen-section immunofluorescence failed to reveal the LC composition of crystals in 88%, requiring paraffin-immunofluorescence or immunohistochemistry, with identification of kappa LC in 87%. The LC variable region gene segment, determined by mass spectrometry of glomeruli or bone marrow plasma cell sequencing, was IGKV1-33 in four and IGKV3-20 in one. Among 21 patients who received anti-plasma cell-directed chemotherapy, 50% achieved a kidney response, which depended on a deep hematologic response. After a median follow-up of 36 months, 26% progressed to kidney failure and 17% died. The mean kidney failure-free survival was 57.6 months and was worse in those with FSGS. In sum, LCCP is rare, mostly associates with IgG κappa MGRS, and frequently has concurrent LCPT, although Fanconi syndrome is uncommon. Paraffin-immunofluorescence and electron microscopy are essential to prevent misdiagnosis as primary FSGS since kidney survival depends on early diagnosis and subsequent clone-directed therapy., (Copyright © 2022 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)

The clinicopathologic characteristics and long-term outcome of non-hepatitis-associated cryoglobulinemic glomerulonephritis (CryoGN) are not well-defined and cases with undetectable serum cryoglobulin (seronegative CryoGN) have not been investigated. To resolve this, we retrospectively identified 81 patients with biopsy-proven non-hepatitis CryoGN, including 22 with seronegative CryoGN. The median age was 61 years and 76% presented with nephritic syndrome. A hematologic condition was found in 89% of patients, including monoclonal gammopathy of renal significance (65%) and symptomatic lymphoproliferative disorder (35%). In the seropositive group, 56% had type II, 29% type I, and 8% type III cryoglobulin. Extrarenal manifestations, mostly of skin, were present in 64% and were significantly less common in seronegative CryoGN. Glomerular deposits by immunofluorescence were IgM dominant (84%) and polytypic (70%) in the seropositive group, whereas 52% of seronegative cases had monotypic deposits (i.e., type I cryoglobulin). Ultrastructurally, the deposits were organized in 77% of cases. Substructure appearance significantly differed according to the type of CryoGN, forming most commonly short cylindrical structures in type II and other organized substructures in type I CryoGN. Most patients were treated with clone-directed therapy. On follow up (median 33 months), 77% had partial or complete remission, 10% reached kidney failure and 14% died. Predictors of kidney failure on univariate analysis were AKIN stage 3, positive rheumatoid factor and biclonal gammopathy at diagnosis. We conclude that most CryoGN cases (types I and II) are due to a hematologic condition and are associated with favorable outcome after clone-directed therapy. Seronegative CryoGN accounts for about a quarter of cases and is mostly a kidney-limited disease. Thus, further investigations are needed to unravel the pathophysiology of seronegative CryoGN., (Copyright © 2022 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)

The type of monoclonal light chain nephropathy is thought to be largely a function of the structural and physiochemical properties of light chains; hence most affected patients have only one light chain kidney disease type. Here, we report the first series of kidney light chain deposition disease (LCDD) concomitant with light chain amyloidosis (LCDD+AL), with or without light chain cast nephropathy (LCCN). Our LCDD+AL cohort consisted of 37 patients (54% females, median age 70 years (range 40-86)). All cases showed Congo red-positive amyloid deposits staining for one light chain isotype on immunofluorescence (62% lambda), and LCDD with diffuse linear staining of glomerular and tubular basement membranes for one light chain isotype (97% same isotype as the amyloidogenic light chain) and ultrastructural non-fibrillar punctate deposits. Twelve of 37 cases (about 1/3 of patients) had concomitant LCCN of same light chain isotype. Proteomic analysis of amyloid and/or LCDD deposits in eight revealed a single light chain variable domain mutable subgroup in all cases (including three with separate microdissections of LCDD and amyloid light chain deposits). Clinical data on 21 patients showed proteinuria (100%), hematuria (75%), kidney insufficiency and nephrotic syndrome (55%). Extra-kidney involvement was present in 43% of the patients. Multiple myeloma occurred in 68% (about 2/3) of these patients; none had lymphoma. On follow up (median 16 months), 63% developed kidney failure and 56% died. The median kidney and patient survivals were 12 and 32 months, respectively. LCDD+AL mainly affected patients 60 years of age or older. Thus, LCDD+AL could be caused by two pathological light chains produced by subclones stemming from one immunoglobulin light chain lambda or kappa rearrangement, with a distinct mutated complementary determining region., (Copyright © 2021 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)

Introduction: A large proportion of patients with COVID-19 develop acute kidney injury (AKI). While the most severe of these cases require renal replacement therapy (RRT), little is known about their clinical course., Methods: We describe the clinical characteristics of COVID-19 patients in the ICU with AKI requiring RRT at an academic medical center in New York City and followed patients for outcomes of death and renal recovery using time-to-event analyses., Results: Our cohort of 115 patients represented 23% of all ICU admissions at our center, with a peak prevalence of 29%. Patients were followed for a median of 29 days (2542 total patient-RRT-days; median 54 days for survivors). Mechanical ventilation and vasopressor use were common (99% and 84%, respectively), and the median Sequential Organ Function Assessment (SOFA) score was 14. By the end of follow-up 51% died, 41% recovered kidney function (84% of survivors), and 8% still needed RRT (survival probability at 60 days: 0.46 [95% CI: 0.36-0.56])). In an adjusted Cox model, coronary artery disease and chronic obstructive pulmonary disease were associated with increased mortality (HRs: 3.99 [95% CI 1.46-10.90] and 3.10 [95% CI 1.25-7.66]) as were angiotensin-converting-enzyme inhibitors (HR 2.33 [95% CI 1.21-4.47]) and a SOFA score >15 (HR 3.46 [95% CI 1.65-7.25)., Conclusions and Relevance: Our analysis demonstrates the high prevalence of AKI requiring RRT among critically ill patients with COVID-19 and is associated with a high mortality, however, the rate of renal recovery is high among survivors and should inform shared-decision making., Competing Interests: The authors declare that they have no financial conflicts of interest to disclose. MRO and MJC are both investigators for Remdesivir (sponsored by Gilead) and convalescent plasma (sponsored by Amazon). This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Background: Coexistence of fibrillary glomerulonephritis (FGN) and immunoglobulin A (IgA) nephropathy (IgAN) in the same kidney biopsy (FGN-IgAN) is rare, and the clinicopathologic characteristics and outcome of this dual glomerulopathy are unknown., Methods: In this study, 20 patients with FGN-IgAN were studied and their characteristics were compared with 40 FGN and 40 IgAN control patients., Results: Concurrent IgAN was present in 1.8% of 847 consecutive FGN cases and was the second most common concurrent glomerulopathy after diabetic nephropathy. FGN-IgAN patients were overwhelmingly White (94%) and contrary to FGN patients were predominantly (60%) males. Compared with IgAN patients, FGN-IgAN patients were older, had higher proteinuria, a higher incidence of renal insufficiency, and a lower incidence of microhematuria and gross hematuria at diagnosis. Six (30%) patients had malignancy, autoimmune disease or hepatitis C infection, but none had a secondary cause of IgAN or clinical features of Henoch-Schonlein purpura. Histologically, all cases exhibited smudgy glomerular staining for immunoglobulin G and DnaJ homolog subfamily B member 9 (DNAJB9) with corresponding fibrillary deposits and granular mesangial staining for IgA with corresponding mesangial granular electron-dense deposits. On follow-up (median 27 months), 10 of 18 (56%) FGN-IgAN patients progressed to end-stage kidney disease (ESKD), including 5 who subsequently died. Serum creatinine at diagnosis was a poor predictor of renal survival. The proportion of patients reaching ESKD or died was higher in FGN-IgAN than in IgAN. The median Kaplan-Meier ESKD-free survival time was 44 months for FGN-IgAN, which was shorter than IgAN (unable to compute, P =   0.013) and FGN (107 months, P = 0.048)., Conclusions: FGN-IgAN is very rare, with clinical presentation and demographics closer to FGN than IgAN. Prognosis is guarded with a median renal survival of 3.6 years. The diagnosis of this dual glomerulopathy requires careful evaluation of immunofluorescence findings, and electron microscopy or DNAJB9 immunohistochemistry., (© The Author(s) 2020. Published by Oxford University Press on behalf of ERA-EDTA.)

Background: The relative immunosuppression and high prevalence of comorbidities in patients with ESKD on dialysis raise concerns that they may have an elevated risk of severe coronavirus disease 2019 (COVID-19), but outcomes for COVID-19 in such patients are unclear., Methods: To examine presentation and outcomes of COVID-19 in patients with ESKD on dialysis, we retrospectively collected clinical data on 59 patients on dialysis who were hospitalized with COVID-19. We used Wilcoxon rank sum and Fischer exact tests to compare patients who died versus those still living., Results: Two of the study's 59 patients were on peritoneal dialysis, and 57 were on hemodialysis. Median age was 63 years, with high prevalence of hypertension (98%) and diabetes (69%). Patients who died were significantly older than those still living (median age, 75 versus 62 years) and had a higher median Charlson comorbidity index (8 versus 7). The most common presenting symptoms were fever (49%) and cough (39%); initial radiographs most commonly showed multifocal or bilateral opacities (59%). By end of follow-up, 18 patients (31%) died a median 6 days after hospitalization, including 75% of patients who required mechanical ventilation. Eleven of those who died had advanced directives against intubation. The remaining 41 patients (69%) were discharged home a median 8 days after admission. The median initial white blood cell count was significantly higher in patients who died compared with those still living (7.5 versus 5.7×10 3 / μ l), as was C-reactive protein (163 versus 80 mg/L)., Conclusions: The association of COVID-19 with high mortality in patients with ESKD on dialysis reinforces the need to take appropriate infection control measures to prevent COVID-19 spread in this vulnerable population., (Copyright © 2020 by the American Society of Nephrology.)

Rationale & Objective: Congo Red positivity with birefringence under polarized light has traditionally permitted classification of organized glomerular deposits as from amyloid or nonamyloid diseases. The absence of congophilia has been used to differentiate fibrillary glomerulonephritis (GN) from amyloidosis. We describe a series of fibrillary GN cases in which the deposits are Congo Red-positive (congophilic fibrillary GN) and discuss the role of DNAJB9 in distinguishing congophilic fibrillary GN from amyloidosis., Study Design: Case series., Setting & Participants: Analysis of the clinicopathologic characteristics of 18 cases of congophilic fibrillary GN. Mass spectrometry was performed and compared with 24 cases of Congo Red-negative fibrillary GN, 145 cases of amyloidosis, and 12 apparently healthy individuals. DNAJB9 immunohistochemistry was obtained for a subset of cases., Results: The proteomic signature of amyloid was not detected using mass spectrometry among cases of congophilic fibrillary GN. DNAJB9, a recently discovered proteomic marker for fibrillary GN, was detected using mass spectrometry in all cases of fibrillary GN regardless of congophilia and was absent in cases of amyloidosis and in healthy individuals. DNAJB9 immunohistochemistry confirmed the mass spectrometry findings. The congophilic fibrillary GN cases included 11 men and 7 women with a mean age at diagnosis of 65 years. Concomitant monoclonal gammopathy, hepatitis C virus infection, malignancy, or autoimmune disease was present in 35%, 22%, 17%, and 11% of patients, respectively. No patient had evidence of extrarenal amyloidosis. Patients presented with proteinuria (100%), nephrotic syndrome (47%), hematuria (78%), and chronic kidney disease (83%). After a mean follow-up of 23 months, 31% of patients progressed to end-stage kidney disease and the remaining 69% had persistently reduced kidney function., Limitations: Retrospective nature. Blinded pathology evaluations were not performed., Conclusions: The congophilic properties of organized fibrillary deposits should not be solely relied on in differentiating fibrillary GN from renal amyloidosis. Mass spectrometry and DNAJB9 immunohistochemistry can be useful in making this distinction., (Copyright © 2018 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)

The characteristics of allograft proliferative glomerulonephritis with monoclonal immunoglobulin G deposits (PGNMID) are not well defined. To better characterize this disease we retrospectively identified 26 patients with allograft PGNMID, including 16 followed with early protocol biopsies. PGNMID was found to be a recurrent disease in most (89%) patients. A diagnostic biopsy was done for proteinuria and/or increased creatinine in most patients. Median time from transplant to diagnostic biopsy was 5.5 months, with detection within three to four months post-transplant in 86% of patients. Mesangial proliferative glomerulonephritis was the most common pattern on the diagnostic biopsy with 89% of cases showing immunoglobulin G3 subtype restriction. A detectable serum paraprotein was present in 20% of patients. During a mean follow up of 87 months from implantation, 11 of 25 patients lost their allograft largely due to PGNMID within a mean of 36 months from diagnosis. Median graft survival was 92 months. Independent predictors of graft loss were a higher degree of peak proteinuria and longer time from implantation to diagnosis. Sixteen patients were treated with immunosuppressive therapy which resulted in over 50% reduction in proteinuria in 60%, and improvement of glomerular pathology in nine of 13 patients. However, 44% of responders subsequently relapsed. Thus, PGNMID has a high recurrence rate in renal allografts occurring early with detection enhanced by protocol biopsies. Graft outcome is guarded as nearly half of patients lose their graft within three years from diagnosis. Hence, there is a need for better treatment strategies for this disease., (Copyright © 2018 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)

Introduction: Alport syndrome (AS) is a genetic disorder characterized by progressive hematuric nephropathy with or without sensorineural hearing loss and ocular lesions. Previous studies on AS included mostly children., Methods: To determine the prognostic value of loss of staining for collagen type IV alpha 5 (COL4A5) and its relationship with the ultrastructural glomerular basement membrane alterations, we performed direct immunofluorescence using a mixture of fluorescein isothiocyanate-conjugated and Texas-red conjugated antibodies against COL4A5 and COL4A2, respectively, on renal biopsies of 25 males with AS (including 16 who were diagnosed in adulthood)., Results: All patients showed normal positive staining of glomerular basement membranes and tubular basement membranes for COL4A2. Of the 25 patients, 10 (40%) patients showed loss of staining for COL4A5 (including 89% of children and 13% of adults) and the remaining 15 (60%) had intact staining for COL4A5. Compared with patients with intact staining for COL4A5, those with loss of staining had more prominent ultrastructural glomerular basement membrane alterations and were younger at the time of biopsy. By Kaplan-Meier survival analysis and Cox regression analysis, loss of staining for COL4A5 predicted earlier progression to overt proteinuria and stage 2 chronic kidney disease or worse. By multivariate Cox regression analysis, loss of staining for COL4A5 was an independent predictor of the development of overt proteinuria and stage 2 chronic kidney disease or worse., Discussion: Thus, the COL4A5 expression pattern has an important prognostic value and it correlates with the severity of ultrastructural glomerular basement membrane alterations in males with AS. Loss of COL4A5 staining is uncommon in patients with AS diagnosed in their adulthood.

Light chain proximal tubulopathy (LCPT) is characterized by cytoplasmic inclusions of monoclonal LC within proximal tubular cells. The significance of crystalline versus noncrystalline LCPT and the effect of modern therapies are unknown. We reported the clinical-pathologic features of 40 crystalline and six noncrystalline LCPT patients diagnosed between 2000 and 2014. All crystalline LCPTs were κ-restricted and displayed acute tubular injury. One-third of noncrystalline LCPT patients displayed λ-restriction or acute tubular injury. Only crystalline LCPT frequently required antigen retrieval to demonstrate monoclonal LC by immunofluorescence. In five of 38 patients, crystals were not detectable by light microscopy, but they were visible by electron microscopy. Hematolymphoid neoplasms, known before biopsy in only 15% of patients, included 21 monoclonal gammopathies of renal significance; 15 multiple myelomas; seven smoldering multiple myelomas; and three other neoplasms. Biopsy indications included Fanconi syndrome (38%; all with crystalline LCPT), renal insufficiency (83%), and proteinuria (98%). Follow-up was available for 30 (75%) patients with crystalline LCPT and all six patients with noncrystalline LCPT, of whom 11 underwent stem cell transplant, 16 received chemotherapy only, and nine were untreated. Complete or very good partial hematologic remissions occurred in six of 22 treated crystalline LCPT patients. By multivariable analysis, the only independent predictor of final eGFR was initial eGFR, highlighting the importance of early detection. All patients with crystalline LCPT treated with stem cell transplant had stable or improved kidney function, indicating the effectiveness of aggressive therapy in selected patients., (Copyright © 2016 by the American Society of Nephrology.)

Acute interstitial nephritis (AIN) is an important cause of acute kidney injury (AKI), and its prevalence in the elderly may be increasing. It is largely unknown whether AIN in the elderly is similar to that in younger adults; therefore, we investigated the causes and characteristics of AIN in 45 elderly patients (65 years and older) and in 88 younger adults (18-64 years old). Compared with younger patients, the elderly had significantly more drug-induced AIN (87 vs. 64%), proton pump inhibitor-induced AIN (18 vs. 6%), but significantly less AIN due to autoimmune or systemic causes (7 vs. 27%). The two most common culprit drugs in the elderly were penicillin and omeprazole. Compared with younger patients, the elderly had higher prevalence of baseline CKD, higher peak creatinine, and more need for dialysis, all of which were significant. Among the elderly, 86% showed partial or complete recovery within 6 months. Significantly shorter delays in initiation of steroids correlated with recovery at 6 months. Lack of early recovery tended to correlate with progressive CKD. Compared with antibiotic-induced AIN, proton pump inhibitor-induced AIN had less severe AKI, but a longer duration of drug exposure, and was less likely to recover by 6 months, all significant. Thus, the vast majority of AIN cases in the elderly are due to drugs, primarily owing to proton pump inhibitors and antibiotics, while AIN of autoimmune or systemic origin is uncommon.

Background: Acute interstitial nephritis (AIN) is an important cause of acute kidney injury, especially in hospitalized patients. The cause and outcome of AIN, particularly that due to drugs, is changing with prevalent medication use. The effectiveness of steroids for treatment of AIN is debated., Study Design: Case series., Setting & Participants: 133 patients with biopsy-proven AIN from 1993 through 2011 at a single center., Outcomes: Recovery of kidney function by 6 months, either complete, partial, or none. Complete recovery was defined as improvement in serum creatinine level to within 25% of baseline (or < 1.4 mg/dL), and partial recovery, as a ≥ 50% decrease in serum creatinine level from its peak value but not reaching within 25% of its baseline value., Results: Causes of AIN included drugs (70%), autoimmune diseases (20%), and infections (4%). Drug-induced AIN was due to antibiotics in 49%, proton pump inhibitors (PPIs) in 14%, and nonsteroidal anti-inflammatory drugs (NSAIDs) in 11%. Overall, the top 3 drug causes were omeprazole (12%), amoxicillin (8%), and ciprofloxacin (8%). Patients with drug-induced compared to non-drug-induced AIN were older and had higher baseline kidney function, but more severe acute kidney injury. Patients with PPI-induced AIN were older, were less symptomatic, and had longer durations of drug exposure and longer delays in getting kidney biopsy and steroids than for antibiotic-induced or NSAID-induced AIN. At 6 months postbiopsy, 49% of patients with drug-induced AIN treated with steroids achieved complete recovery; 39%, partial recovery; and 12%, no recovery. Correlates of poor recovery included a longer duration of drug exposure (15 vs 30 vs 130 days for complete, partial, and no recovery, respectively; P = 0.04) and longer delay in starting steroid therapy (8 vs 11 vs 35 days, respectively; P = 0.05)., Limitations: Retrospective study, selection bias in patients who had kidney biopsy, single-center experience., Conclusions: The cause of AIN may be shifting; PPIs are emerging as an important contributor to this disease. Delays in discontinuation of the culprit drug and in initiating steroid treatment adversely affect recovery of kidney function., (Copyright © 2014 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)

Amyloidosis derived from leukocyte chemotactic factor 2 (ALECT2) is a recently described disease. Here, we report the characteristics and outcome of 72 patients with renal ALECT2, which included 19 who had another kidney disease on biopsy. Ninety-two percent of patients were Hispanics and over half were elderly. Three had other organ, but not cardiac, amyloidosis involvement. All patients without concurrent disease, except three, presented with chronic renal insufficiency. Proteinuria was variable and absent in a third, whereas nephrotic syndrome and hematuria were rare. After a median follow-up of 26 months, one-third developed end-stage renal disease (ESRD). The median renal survival was 62 months. Independent predictors of renal survival were serum creatinine at diagnosis, with a value of 2.0 mg/dl being the best cutoff for predicting ESRD, percentage global glomerulosclerosis, and presence of diabetes. Only four patients died and four had received chemotherapy for an erroneous diagnosis of immunoglobulin light chain-derived amyloidosis. Five patients underwent kidney transplantation; none had graft loss but one had disease recurrence. Patient survival is superior to renal immunoglobulin light chain-derived amyloidosis and reactive amyloidosis largely due to the absence of cardiac involvement. Thus, renal ALECT2 mainly affects elderly Hispanics who typically present with chronic renal insufficiency and bland urine sediment, with or without proteinuria.

Background and Objectives: The kidney is the organ most commonly involved in systemic amyloidosis. This study reports the largest clinicopathologic series of renal amyloidosis., Design, Setting, Participants, & Measurements: This study provides characteristics of 474 renal amyloidosis cases evaluated at the Mayo Clinic Renal Pathology Laboratory from 2007 to 2011, including age, sex, serum creatinine, proteinuria, type of amyloid, and tissue distribution according to type., Results: The type of amyloid was Ig amyloidosis in 407 patients (85.9%), AA amyloidosis in 33 (7.0%), leukocyte chemotactic factor 2 amyloidosis in 13 (2.7%), fibrinogen A α chain amyloidosis in 6 (1.3%), Apo AI, Apo AII, or Apo AIV amyloidosis in 3 (0.6%), combined AA amyloidosis/Ig heavy and light chain amyloidosis in 1 (0.2%), and unclassified in 11 (2.3%). Laser microdissection/mass spectrometry, performed in 147 cases, was needed to determine the origin of amyloid in 74 of the 474 cases (16%), whereas immunofluorescence failed to diagnose 28 of 384 light chain amyloidosis cases (7.3%). Leukocyte chemotactic factor 2 amyloidosis and Apo AI, Apo AII, or Apo AIV amyloidosis were characterized by diffuse interstitial deposition, whereas fibrinogen A α chain amyloidosis showed obliterative glomerular involvement. Compared with other types, Ig amyloidosis was associated with lower serum creatinine, higher degree of proteinuria, and amyloid spicules., Conclusions: In the authors' experience, the vast majority of renal amyloidosis cases are Ig derived. The newly identified leukocyte chemotactic factor 2 amyloidosis form was the most common of the rarer causes of renal amyloidosis. With the advent of laser microdissection/mass spectrometry for amyloid typing, the origin of renal amyloidosis can be determined in >97% of cases.

Little is known about the rare entities of heavy- and light-chain amyloidosis (AHL) and heavy-chain amyloidosis (AH). Here, we report the renal and hematological characteristics, pathology, and outcome of 16 patients with renal AH/AHL (5 with AH and 11 with AHL) and compare them with 202 patients with renal light-chain amyloidosis (AL) diagnosed during the same time period. All cases were diagnosed by kidney biopsy that showed Congo red-positive deposits. Amyloid typing was done by laser microdissection and mass spectrometry (LMD/MS) on 12 patients or by immunofluorescence on four patients. All patients with renal AH/AHL were Caucasians, with a male/female ratio of 2.2 and a median age at biopsy of 63 years. Compared with patients with renal AL, those with renal AH/AHL had less frequent concurrent cardiac involvement, higher likelihood of having circulating complete monoclonal immunoglobulin, lower sensitivity of fat pad biopsy and bone marrow biopsy for detecting amyloid, higher incidence of hematuria, and better patient survival. The hematological response to chemotherapy was comparable with renal AL. In 42% of patients, AH/AHL could not have been diagnosed without LMD/MS. Thus, renal AH/AHL is an uncommon and underrecognized form of amyloidosis, and its diagnosis is greatly enhanced by the use of LMD/MS for amyloid typing. The accurate histological diagnosis of renal AH/AHL and distinction from AL may have important clinical and prognostic implications.

Background: Renal involvement is common in multiple myeloma. In this study, we examined kidney biopsy findings in patients with multiple myeloma and correlated them with their clinical renal and hematologic characteristics., Study Design: Case series., Setting & Participants: 190 Mayo Clinic patients with multiple myeloma who underwent kidney biopsy between 1997-2011 were identified from our kidney biopsy database. Patients had an established diagnosis of multiple myeloma or multiple myeloma was diagnosed shortly after the results of kidney biopsy, which prompted bone marrow biopsy., Predictors: Myeloma cast nephropathy (MCN), AL amyloidosis, and monoclonal immunoglobulin deposition disease (MIDD)., Outcomes & Measurements: Renal morphologic changes, clinical renal and hematologic characteristics at kidney biopsy, renal and patient outcomes., Results: Paraprotein-associated lesions were seen in 73% of patients; non-paraprotein-associated lesions, in 25%; and no pathology, in 2%. The most common paraprotein-associated lesions were MCN (33%), MIDD (22%), and amyloidosis (21%). The most common non-paraprotein-associated lesions were acute tubular necrosis (9%), hypertensive arteriosclerosis (6%), and diabetic nephropathy (5%). Patients with MIDD were younger than those with MCN or amyloidosis. Urine paraprotein size and bone marrow plasma cell percentage were higher in MCN than amyloidosis or MIDD. Nephrotic syndrome was more common in amyloidosis than MIDD. Percentage of albuminuria was highest in amyloidosis and lowest in MCN. Median kidney survival from kidney biopsy was 20, 30, and 51 months for MCN, amyloidosis, and MIDD, respectively (P = 0.2). Median patient survival from multiple myeloma diagnosis was 44, 58, and 62 months for MCN, amyloidosis, and MIDD, respectively (P = 0.4)., Limitations: Retrospective nature., Conclusions: The spectrum of renal lesions in multiple myeloma is more heterogeneous than previously reported. Clinical features favoring amyloidosis over MIDD include older age, absence of kidney failure, presence of nephrotic syndrome, absence of hematuria, and >50% albuminuria., (Copyright © 2012 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)

Background: In patients without overt cardiac disease, the degree of left ventricular hypertrophy (LVH) gets worse following hemodialysis (HD) initiation; however, in patients with both advanced chronic kidney disease (CKD) and symptomatic heart failure (HF) with reduced ejection fraction (EF), the short-term effect of HD on LVH and LV geometry has not been examined. We hypothesized that left ventricular mass index (LVMI) would decrease following HD initiation in CKD patients with symptomatic HF., Methods: We retrospectively evaluated changes in LVMI, LV geometry, and LV fractional shortening (LVFS), assessed by 2D transthoracic echocardiography (TTE), in 41 patients with HF initiating HD while hospitalized from 1995 to 2006. HF was defined by LVEF ≤ 45% or dyspnea plus two of the following: raised jugular venous pressure, bibasilar crackles, pulmonary venous hypertension, interstitial edema on chest X-ray, or both. TTE was performed within 3 months prior to first HD and repeated 8.6 ± 5.2 months after start of HD. TTE recordings were obtained from storage and analyzed by a cardiologist blinded to patient clinical characteristics., Results: Before initiation of HD, LVMI in 39 patients was 167.9 ± 53.1 g/m2 and it decreased by -24.3 ± 35.4 g/m2 by follow-up, p < 0.001. 26% of patients with concentric LVH at baseline had concentric remodeling or eccentric LVH at follow-up. LVFS did not significantly change over time in all 41 patients with HF (25.7 ± 8.7% vs. 26.4 ± 8.7%, p = 0.66). However, in an expanded analysis of all 69 patients with serial TTEs, a 1% increase in LVFS after starting HD was associated with a 16% reduction in risk of cardiovascular hospitalization at follow-up (HR 0.84, 95% CI 0.73 - 0.96, p = 0.01)., Conclusions: LVMI decreases following HD initiation in CKD patients with symptomatic HF and reduced LVEF, possibly due to relief of venous congestion. Increase in LVFS following HD initiation predicts improved cardiac outcome.

Background and Objectives: To better define the clinical-pathologic spectrum and prognosis of monoclonal immunoglobulin deposition disease (MIDD), this study reports the largest series., Design, Setting, Participants, & Measurements: Characteristics of 64 MIDD patients who were seen at Mayo Clinic are provided., Results: Of 64 patients with MIDD, 51 had light chain deposition disease, 7 had heavy chain deposition disease, and 6 had light and heavy chain deposition disease. The mean age at diagnosis was 56 years, and 23 patients (36%) were ≤50 years of age. Clinical evidence of dysproteinemia was present in 62 patients (97%), including multiple myeloma in 38 (59%). M-spike was detected on serum protein electrophoresis in 47 (73%). Serum free light chain ratio was abnormal in all 51 patients tested. Presentation included renal insufficiency, proteinuria, hematuria, and hypertension. Nodular mesangial sclerosis was seen in 39 patients (61%). During a median of 25 months of follow-up (range, 1-140) in 56 patients, 32 (57%) had stable/improved renal function, 2 (4%) had worsening renal function, and 22 (39%) progressed to ESRD. The mean renal and patient survivals were 64 and 90 months, respectively. The disease recurred in three of four patients who received a kidney transplant., Conclusions: Patients with MIDD generally present at a younger age than those with light chain amyloidosis or light chain cast nephropathy. Serum free light chain ratio is abnormal in all MIDD patients, whereas only three-quarters have abnormal serum protein electrophoresis. The prognosis for MIDD is improving compared with historical controls, likely reflecting earlier detection and improved therapies.

Background and Objectives: Fibrillary glomerulonephritis (FGN) is a rare primary glomerular disease. Most previously reported cases were idiopathic. To better define the clinical-pathologic spectrum and prognosis, we report the largest single-center series with the longest follow-up., Design, Setting, Participants, & Measurements: The characteristics of 66 FGN patients who were seen at Mayo Clinic, Rochester, between 1993 and 2010 are provided., Results: The mean age at diagnosis was 53 years. Ninety-five percent of patients were white, and the female:male ratio was 1.2:1. Underlying malignancy (most commonly carcinoma), dysproteinemia, or autoimmune disease (most commonly Crohn's disease, SLE, Graves' disease, and idiopathic thrombocytopenic purpura), were present in 23, 17, and 15% of patients, respectively. Presentation included proteinuria (100%), nephrotic syndrome (38%), renal insufficiency (66%), hematuria (52%), and hypertension (71%). The most common histologic pattern was mesangial proliferative/sclerosing GN followed by membranoproliferative GN. During an average of 52.3 months of follow-up for 61 patients with available data, 13% had complete or partial remission, 43% had persistent renal dysfunction, and 44% progressed to ESRD. The disease recurred in 36% of 14 patients who received a kidney transplant. Independent predictors of ESRD by multivariate analysis were older age, higher creatinine and proteinuria at biopsy, and higher percentage of global glomerulosclerosis., Conclusions: Underlying malignancy, dysproteinemia, or autoimmune diseases are not uncommon in patients with FGN. Prognosis is poor, although remission may occur in a minority of patients without immunosuppressive therapy. Age, degree of renal impairment at diagnosis, and degree of glomerular scarring are predictors of renal survival., (© 2011 by the American Society of Nephrology)

Postinfectious glomerulonephritis (PIGN) is primarily a childhood disease that occurs after an upper respiratory tract infection or impetigo; its occurrence in older patients is not well characterized. Here, we report 109 cases of PIGN in patients ≥65 years old diagnosed by renal biopsy. The male to female ratio was 2.8:1. An immunocompromised background was present in 61%, most commonly diabetes or malignancy. The most common site of infection was skin, followed by pneumonia and urinary tract infection. The most common causative agent was staphylococcus (46%) followed by streptococcus (16%) and unusual gram-negative organisms. Hypocomplementemia was present in 72%. The mean peak serum creatinine was 5.1 mg/dl, and 46% of patients required acute dialysis. The most common light microscopic patterns were diffuse (53%), focal (28%), and mesangial (13%) proliferative glomerulonephritis. IgA-dominant PIGN occurred in 17%. Of the 72 patients with ≥3 months of follow-up (mean, 29 months), 22% achieved complete recovery, 44% had persistent renal dysfunction, and 33% progressed to ESRD. The presence of diabetes, higher creatinine at biopsy, dialysis at presentation, the presence of diabetic glomerulosclerosis, and greater tubular atrophy and interstitial fibrosis predicted ESRD. In summary, the epidemiology of PIGN is shifting as the population ages. Older men and patients with diabetes or malignancy are particularly at risk, and the sites of infection and causative organisms differ from the typical childhood disease. Prognosis for these older patients is poor, with fewer than 25% recovering full renal function.

FSGS is an important cause of ESRD and tends to recur in allografts (rFSGS). Older series suggest recurrence rates of 30-60%. In the modern era of transplant immunosuppression, recurrence rates are unknown. There are also few data regarding prevalence of known genetic mutations in adult FSGS patients who undergo transplantation. Recently, FSGS has been subdivided into histological variants, which may predict renal outcomes; there is little information on patterns of recurrence and outcomes in these variants. Finally, treatment for rFSGS relies upon up-titrating calcineurin inhibitors and plasmapheresis. Insufficient information exists on the use of these regimens for rFSGS in the era of modern immunosuppression. We conducted a retrospective chart review involving all renal transplant recipients at Columbia University Medical Center from December 1999 to March 2007. Those with biopsy confirmed primary FSGS were included and information regarding baseline characteristics, histologic variants, genetics, treatment, and clinical outcomes were collected. FSGS recurred in 23% of patients. Those with collapsing histology on native kidney biopsy, tended to recur with the same histology. No known genetic mutations were identified among those with recurrence. Plasmapheresis resulted in complete or partial remission in 75% of those with recurrence. Recurrent FSGS resulted in a trend toward the combined outcome of ESRD or death compared to those without recurrence (27% vs. 12%). Modern immunosuppression does not reduce the rate of rFSGS, known genetic mutations are uncommon in such adult patients, collapsing FSGS tends to recur with the same histology, and plasmapheresis may be helpful in the treatment of recurrence.

C1q nephropathy is an uncommon glomerular disease characterized by dominant or codominant mesangial staining for C1q in the absence of systemic lupus erythematosus. There are no series in the literature addressing the significance of C1q deposition in the renal allograft. We retrospectively analyzed 24 patients, most of whom were white (83%) and male (63%), with a mean age at transplant of 31 years. None of the patients were diagnosed with C1q nephropathy in the native kidney or had any features of systemic lupus erythematosus. The mean time from transplant to detection of mesangial C1q deposits was 37 months (>12 months in 71% of cases). Half of the patients had a preceding infection. The indication for biopsy was surveillance (63%) or graft dysfunction (37%). At biopsy, 52% had proteinuria (>1g/day in only 17%). The mean creatinine was 1.8 mg per 100 ml. Only 9% developed hematuria and none had hypoalbuminemia. The glomerular pattern on light microscopy was mesangial hypercellularity (46%), focal segmental glomerulosclerosis (21%), or no lesions (33%). All cases showed intense (>or=2+) dominant (67%) or codominant (33%) mesangial staining for C1q on immunofluorescence. Mesangial electron-dense deposits were seen in 82% of cases. On follow-up (mean 1 year) of the 10 patients without rejection, most had stable creatinine with no or stable proteinuria, and none lost their graft. We conclude that C1q-dominant mesangial deposition in the renal allograft is a morphological pattern with no apparent clinical significance in the majority of patients. It is usually detected after the first year. The rate of preceding infection and the prevalence of proteinuria seem to be similar to the renal transplant recipients in general. Most cases show mesangial hypercellularity or no glomerular changes on light microscopy.

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.

Background and Objectives: Only rare cases of concurrent membranous glomerulonephritis (MGN) and antineutrophil cytoplasmic antibody (ANCA)-associated necrotizing and crescentic glomerulonephritis (NCGN) have been reported., Design, Setting, Participants, & Measurements: The authors report the clinical and pathologic findings in 14 patients with MGN and ANCA-associated NCGN., Results: The cohort consisted of eight men and six women with a mean age of 58.7 yr. ANCA positivity was documented by indirect immunofluorescence or ELISA in all patients. Indirect immunofluorescence was positive in 13 patients (seven P-ANCA, five C-ANCA, one atypical ANCA). ELISA was positive in nine of 10 patients (five MPO-ANCA, three PR3-ANCA, one MPO- and PR3-ANCA). Clinical presentation included heavy proteinuria (mean 24-hr urine protein 6.5 g/d), hematuria, and acute renal failure (mean creatinine 4.4 mg/dl). Pathologic evaluation revealed MGN and NCGN, with crescents involving a mean of 32% of glomeruli. On ultrastructural evaluation, the majority of cases showed stage I or II membranous changes. Follow-up was available for 13 patients, 12 of whom were treated with steroids and cyclophosphamide. At a mean follow-up of 24.3 mo, five patients progressed to ESRD, seven had stabilization or improvement in renal function, and one had worsening renal function. Five patients, including three with ESRD, died during the follow-up period. The only independent predictor of progression to ESRD was serum creatinine at biopsy., Conclusions: MGN with ANCA-associated NCGN is a rare dual glomerulopathy seen in patients with heavy proteinuria, acute renal failure, and active urine sediment. Prognosis is variable, with 50% of patients reaching endpoints of ESRD or death.

Background and Objectives: Dense deposit disease (DDD) is a rare disorder that most commonly affects children. This study reports the largest North American series addressing clinicopathologic and outcome differences in children and adults., Design, Setting, Participants, & Measurements: Thirty-two patients with DDD were analyzed from the archives of Columbia University between 1977 and 2007. Characteristic intramembranous electron-dense deposits defined all diagnoses., Results: The cohort included 14 children (<16 yr) and 18 adults, with 39% of adults >60 yr. The female/male ratio was 1.9. At presentation, the mean 24-h urine protein was 4.6 g, nephrotic syndrome was present in 33%, renal insufficiency in 59%, and hematuria in 87% of patients. Compared with adults, children had lower incidence of renal insufficiency and were more likely to have reduced C3. Histologic pattern included membranoproliferative, mesangial, endocapillary, and crescentic glomerulonephritis. Treatment included immunosuppression (IS) alone in seven, renin angiotensin system (RAS) blockade alone in six, and combined IS/RAS blockade in 11. On follow-up (mean 63 mo) available in 27 patients, 26% had complete response, 48% had persistent renal dysfunction, and 26% had ESRD. Correlates of ESRD were older age and higher creatinine at biopsy, the absence of combined IS/RAS blockade therapy and the presence of subepithelial humps, but not histologic pattern. On multivariate analysis, age and creatinine emerged as the only independent predictors of ESRD., Conclusions: DDD is clinically and pathologically heterogeneous. Adults have worse outcome than children, despite similar treatment. Combined IS/RAS blockade appears superior to either agent alone.

Purpose: To determine the incidence and associated risk factors of nephrogenic systemic fibrosis (NSF) in patients who undergo gadolinium-based contrast agent (GBCA)-enhanced magnetic resonance (MR) imaging., Materials and Methods: Institutional review board approval was obtained for retrospective review of the medical records from two hospitals to identify all cases of biopsy-confirmed NSF and all patients administered a GBCA from January 1, 1997, to June 30, 2007. Informed patient consent was not required. The incidence of NSF was calculated for patients who received a standard dose of GBCA, patients who received a high dose, and subgroups of patients with renal impairment., Results: Fifteen patients developed NSF after gadolinium-enhanced MR imaging. All of them had an estimated glomerular filtration rate (eGFR) lower than 30 mL/min, and 11 had acute renal failure or acute deterioration of chronic renal failure. The incidence of NSF after gadolinium-enhanced MR imaging without screening for renal function was zero of 74,124 patients with the standard dose of GBCA and 15 (0.17%) of 8997 patients with the high dose (P < .001). The NSF incidence associated with a high dose of GBCA increased to 0.4% in patients in a chronic hemodialysis program and to 8.8% in those who had an eGFR lower than 15 mL/min but were not undergoing hemodialysis (P < .001). The NSF incidence in the patients with acute renal failure who received a high dose when their creatinine level was increasing was 19% (11 of 58 patients) when hemodialysis was delayed for longer than 2 days. More patients with NSF had proinflammatory events, and compared with patients without NSF, these patients had lower pH, younger age, lower eGFR, elevated serum phosphorus levels, and a longer delay between GBCA injection and hemodialysis., Conclusion: For patients with an eGFR lower than 15 mL/min, hemodialysis helped to prevent NSF. For patients with an eGFR lower than 30 mL/min who received a high dose of GBCA, acute renal failure, delayed hemodialysis after contrast agent injection, proinflammatory events, and hyperphosphatemia were associated with increased risk of NSF., (RSNA, 2008)

Background and Objectives: Pauci-immune necrotizing and crescentic glomerulonephritis (PNCGN) superimposed on diabetic glomerulosclerosis (DGS) is a rare occurrence. Only limited data on this dual glomerulopathy are available., Design, Setting, Participants, & Measurements: Twenty-three cases of PNCGN superimposed on DGS were identified from the archives of the Renal Pathology Laboratory of Columbia University. The clinical features, pathologic findings, and outcomes are described., Results: The majority of patients were white, elderly, and had longstanding diabetes. Patients presented with acute renal failure and an active urine sediment. Antinuclear cytoplasmic autoantibody (ANCA) testing was positive by indirect immunofluorescence in 18 of 22 patients. Sixteen patients had a P-ANCA pattern, 9 of whom underwent further testing and were found to be MPO-ANCA positive by enzyme-linked immunosorbent assay. Among the two patients with C-ANCA by indirect immunofluorescence, enzyme-linked immunosorbent assay was performed in one and revealed PR3-ANCA. Eight patients had extrarenal manifestations of vasculitis, including 6 with pulmonary hemorrhage. At the time of presentation and renal biopsy, 11 patients required hemodialysis. The mean percentages of glomeruli with cellular crescents, fibrous crescents, and necrosis were 24.9, 8.4, and 12.9, respectively. Most patients were treated with cyclophosphamide and prednisone. At a mean follow-up of 14.6 mo (available in 21 patients), 8 patients had died and 8 of the remaining 13 patients had reached end-stage renal disease. Correlates of end-stage renal disease were hemodialysis at presentation and the degree of DGS., Conclusions: PNCGN may occur superimposed on DGS. The prognosis for this dual glomerulopathy is dismal despite aggressive therapy.

In diagnostic renal pathology, electron microscopy is ideally performed on glutaraldehyde-fixed, plastic resin-embedded tissue (EM-G). When no glomeruli are present in the portion of the biopsy fixed in glutaraldehyde, formalin-fixed, paraffin-embedded tissue can be reprocessed for electron microscopy (EM-F). The usefulness of this salvage technique for the diagnosis of thin basement membrane nephropathy (TBMN) has not been studied systematically. Here we compare the glomerular basement membrane (GBM) thickness by EM-G vs EM-F in 21 renal biopsies, including TBMN (eight patients), normals (two patients), minimal change disease (MCD) (six patients) and diabetic nephropathy (DN) (five patients). There was significant reduction of the GBM thickness by EM-F compared with EM-G across all diagnostic categories in all 21 cases. The mean percentage reduction in GBM thickness was 23% for the TBMN cases, 40% for the normal/MCD cases and 34% for the DN cases. Four patients with MCD had a mean GBM thickness by EM-F that fell below the defining threshold for diagnosis of TBMN. For the TBMN cases, the 99th percentile for GBM thickness by EM-F was 194 nm, suggesting that the diagnosis of TBMN by EM-F can be excluded with confidence if the GBM thickness is above 200 nm. No clear criteria could be established to diagnose TBMN by EM-F. Renal pathologists should be aware that reprocessing of paraffin tissue for EM causes artifactual GBM thinning that precludes accurate diagnosis of TBMN.

Five pathologic variants of idiopathic focal segmental glomerulosclerosis (FSGS) are recognized: collapsing (COLL), cellular (CELL), glomerular tip lesion (GTL), perihilar, and not otherwise specified (NOS). The prognostic significance of CELL FSGS has not been determined. We compared the presenting clinical and pathologic characteristics in 225 patients with CELL (N=22), COLL (N=56), GTL (N=60), and NOS (N=87) variants of idiopathic FSGS. CELL, COLL, and tip lesion all showed greater frequency and severity of nephrotic syndrome, and shorter time to biopsy compared to NOS. Predictors of end-stage renal disease (ESRD) for all FSGS patients included initial serum creatinine, % global sclerosis, % COLL lesions, chronic tubulo-interstitial injury score, and lack of remission response. COLL FSGS had the highest rate of renal insufficiency at presentation, most extensive glomerular involvement and chronic tubulo-interstitial disease, fewest remissions (13.2%), and highest rate of ESRD (65.3%). GTL patients were older and showed the highest remission rate (75.8%) and lowest rate of ESRD (5.7%). CELL variant showed intermediate rates of remission (44.5%) and ESRD (27.8%) compared to COLL and tip lesion. CELL variant may include cases of unsampled tip or COLL lesion, underscoring the importance of adequate sampling. Our data support the view that CELL and COLL FSGS are not equivalent and validates an approach to pathologic classification that distinguishes between COLL, CELL, and tip lesion variants of FSGS.

Background: The glomerular tip lesion (GTL) is a distinctive but controversial histopathologic lesion occurring in patients with idiopathic nephrotic syndrome. The relationship of GTL to minimal change disease (MCD) and idiopathic focal segmental glomerulosclerosis (FSGS) has been disputed., Methods: In order to define the clinical features and natural history of GTL, we retrospectively reviewed the presenting clinical features, biopsy findings and outcome of 47 cases. Presenting clinical features of GTL were compared to those of controls with MCD (N= 61) or idiopathic FSGS (N= 50)., Results: The cohort of GTL consisted of 45 adults and two children (mean age 47.5 years; range 12 to 79 years), including 76.6% Caucasians and 53% males. At presentation, 93.6% of patients had edema, 89.1% had nephrotic syndrome (mean urine protein 8.31 g, mean serum albumin 2.27 g/dL, and mean cholesterol 340.6 mg/dL), and 34.8% had renal insufficiency. Mean time from onset of renal disease to biopsy was 2.4 months. At biopsy, glomerular segmental lesions included GTL alone in 26%, GTL and peripheral lesions in 6%, GTL and indeterminate lesions in 36%, and GTL with peripheral and indeterminate lesions in 32%. No initial biopsy contained perihilar sclerosis and most (81%) segmental lesions were cellular. Follow-up data were available in 29 patients, of whom 21 received steroids alone and eight received sequential therapy with steroids and a cytotoxic agent. At a mean follow-up of 21.5 months, 58.6% of patients achieved complete remission of nephrotic syndrome, 13.8% had partial remission, and 27.6% had persistent nephrotic proteinuria. Only one patient progressed to end-stage renal disease (ESRD). Predictors of nonremission included severity of proteinuria at presentation and % peripheral lesions. When compared to controls with MCD and idiopathic FSGS, GTL more closely resembled MCD with respect to high incidence of nephrotic syndrome (P < 0.001), severity of proteinuria (P < 0.05), short duration from onset to biopsy (P < 0.001), and absence of chronic tubulointerstitial disease (P < 0.0054)., Conclusion: Within the MCD/FSGS spectrum, GTL is a distinctive and prognostically favorable clinical-pathologic entity whose presenting features and outcome more closely approximate those of MCD.

Background: Secondary focal segmental glomerulosclerosis (FSGS) is a pattern of glomerular injury mediated by hyperfiltration and other adaptive structural-functional responses. We describe 3 non-obese patients with elevated body mass index (BMI) owing to increased muscle mass who had renal biopsy findings favoring a form of secondary FSGS., Methods: Clinical and pathologic data were obtained on 3 patients with 1) renal biopsy findings of focal segmental and/or global glomerulosclerosis with glomerulomegaly; 2) BMI > or = 30; 3) body fat percentage < 20%; 4) "highly muscular" appearance, and 5) proteinuria > or = 1 g/d without nephrotic syndrome. 24-hour urine creatinine excretion was used to estimate lean body mass and percentage body fat., Results: The 3 patients were males (age 38 - 48 years) employed in jobs requiring strenuous physical activity. BMIs ranged from 30.4 - 32.1 kg/m2 with body fat percentages of 12.9 - 16.8%. Creatinine clearances at time of biopsy ranged from 113 - 208 ml/min. Renal biopsies showed focal segmental and/or global glomerulosclerosis affecting a minority of glomeruli with glomerular hypertrophy and minimal (mean 15%) foot process effacement. Treatments included angiotensin-converting enzyme inhibitor, angiotensin II receptor blocker, or weight loss. Over a mean follow-up time of 24.3 months, serum creatinine remained stable and proteinuria decreased in all patients., Conclusions: Non-obese patients with increased BMI due to elevated muscle mass are at risk of developing a secondary form of FSGS that resembles obesity-related glomerulopathy.

Background: C1q nephropathy is a poorly understood and controversial entity with distinctive immunopathologic features. In order to better define the clinical-pathologic spectrum, we report the largest single-center series., Methods: Nineteen biopsies with C1q nephropathy were identified from among 8909 native kidney biopsies received from 1994 to 2002 (0.21%). Defining criteria included (1). dominant or co-dominant immunofluorescence staining for C1q, (2). mesangial electron dense deposits, and (3). no clinical or serologic evidence of systemic lupus erythematosus (SLE)., Results: The 19 patients were predominantly African American (73.7%), female (73.7%), young adults and children (range, 3 to 42 years; mean, 24.2 years). Presentation included nephrotic range proteinuria (78.9%), nephrotic syndrome (50%), renal insufficiency (27.8%), and hematuria (22.2%). No patient had hypocomplementemia or evidence of underlying autoimmune or infectious disease. Renal biopsy revealed focal segmental glomerulosclerosis (FSGS) in 17 (including six collapsing and two cellular) and minimal-change disease (MCD) in two. All biopsies displayed co-deposits of immunoglobulin G (IgG), with more variable IgM (84.2%), IgA (31.6%), and C3 (52.6%). Foot process effacement varied from 20% to 100% (mean, 51%). Twelve of 16 patients with available follow-up received immunosuppressive therapy. One patient had complete remission of proteinuria and six had partial remission. Four patients with FSGS pattern had progressive renal insufficiency, including two who reached end-stage renal disease (ESRD). Median time from biopsy to ESRD was 81 months. On multivariate analysis, the best correlate of renal insufficiency at biopsy and at follow-up was the degree of tubular atrophy and interstitial fibrosis (P = 0.0495 and 0.0341, respectively)., Conclusion: C1q nephropathy falls within the clinical-pathologic spectrum of MCD/FSGS. Although further studies are needed to determine the pathomechanism of C1q deposition, we hypothesize that it may be a non-specific marker of increased mesangial trafficking in the setting of glomerular proteinuria.

Background: Controversy surrounds the relatedness of fibrillary glomerulonephritis (FGN) and immunotactoid glomerulonephritis (IT)., Methods: To better define their clinicopathologic features and outcome, we report the largest single center series of 67 cases biopsied from 1980 to 2001, including 61 FGN and 6 IT. FGN was defined by glomerular immune deposition of Congo red-negative randomly oriented fibrils of < 30 nm (mean, 20.1 +/- 0.4 nm). IT was defined by glomerular deposition of hollow, stacked microtubules of > or = 30 nm (mean, 38.2 +/- 5.7 nm)., Results: FGN comprised 0.6% of total native kidney biopsies and IT was tenfold more rare (0.06%). Deposits in FGN were immunoglobulin G (IgG) dominant and polyclonal in 96%. IgG subtype analysis in 19 FGN cases showed monotypic deposits in four (two IgG1 and two IgG4) and oligotypic deposits in 15 (all combined IgG1 and IgG4). In IT, deposits were IgG dominant in 83% and monoclonal in 67% (three IgG1 kappa and one IgG1 lambda). FGN patients were a mean age of 57 years, 92% were Caucasian, and 39% were male. At biopsy, FGN patients had the following clinical characteristics (mean, range): creatinine 3.1 mg/dL (0.5 to 14), proteinuria 6.5 g/day (0.8 to 25), 60% microhematuria, and 59% hypertension. Histologic patterns of FGN were diverse, including diffuse proliferative glomerulonephritis (DPGN) (nine cases), membranoproliferative glomerulonephritis (MPGN) (27 cases), mesangial proliferative/sclerosing (MES) (13), membranous glomerulonephritis (MGN) (four), and diffuse sclerosing (DS) (eight). The more proliferative (MPGN and DPGN) and sclerosing (DS) forms presented with a higher creatinine and greater proteinuria compared to MES and MGN. Median time to end-stage renal disease (ESRD) was 24.4 months for FGN and mean time to ESRD varied by histologic subtype: DS 7 months, DPGN 20 months, MPGN 44 months, compared to MES 80 months and MGN 87 months. There was no statistically significant effect of immunosuppressive therapy (given to 36% of FGN patients). By Cox regression (hazard ratio, confidence interval, P value), independent predictors of progression to ESRD were creatinine at biopsy [2.05 (1.55 to 2.72) P < 0.001] and severity of interstitial fibrosis [2.01 (1.05 to 3.85) P = 0.034]. Although IT had similar presentation, histologic patterns, and outcome compared to FGN, it had a greater association with monoclonal gammopathy (P = 0.014), underlying lymphoproliferative disease (P = 0.020), and hypocomplementemia (P = 0.032)., Conclusion: FGN is an idiopathic condition characterized by polyclonal immune deposits with restricted gamma isotypes. Most patients present with significant renal insufficiency and have a poor outcome despite immunosuppressive therapy, and outcome correlates with histologic subtype. By contrast, IT often contains monoclonal IgG deposits and has a significant association with underlying dysproteinemia and hypocomplementemia. Differentiation of FGN from the much more rare entity IT appears justified on immunopathologic, ultrastructural, and clinical grounds.

Idiopathic nodular glomerulosclerosis (ING) is an enigmatic condition that resembles nodular diabetic glomerulosclerosis but occurs in nondiabetic patients. We reviewed clinicopathologic features, immunohistochemical profiles, and outcomes in 23 patients with ING diagnosed from among 5,073 native renal biopsy samples (0.45%) at Columbia University from January 1996 to March 2001. This cohort, in which diabetes mellitus was excluded, consisted predominantly of older (mean age, 68.2 years) white (73.9%) men (78.3%). Clinical findings at presentation included renal insufficiency in 82.6% (mean serum creatinine = 2.4 mg/dL), proteinuria (> 3 g/d in 69.6%; mean 24-hour urine protein = 4.7 g/d), and-less frequently-full nephrotic syndrome (21.7%). There was a high prevalence of hypertension (95.7%; mean = 15.1 +/- 3.4 years), smoking (91.3%; mean = 52.9 +/- 6.9 pack-years), hypercholesterolemia (90%), and extrarenal vascular disease (43.5%). All 23 patients had prominent diffuse and nodular mesangial sclerosis, glomerular basement membrane thickening, arteriosclerosis, and arteriolosclerosis. Immunohistochemical staining for CD34, a marker of endothelial cells, showed an increased number of vascular channels within ING glomeruli compared with normal controls. Follow-up data were available for 17 patients, 6 of whom reached end-stage renal disease (ESRD) (35.3%). By Kaplan-Meier estimates, the median time after biopsy to ESRD was 26 months. Predictors of progression to ESRD included continuation of smoking (P =.0165), lack of angiotensin II blockade (P =.0007), degree of tubular atrophy and interstitial fibrosis (P =.0517), and degree of arteriosclerosis (P =.0096). In conclusion, ING is a progressive vasculopathic lesion linked to hypertension and cigarette smoking., (Copyright 2002, Elsevier Science (USA). All rights reserved.)

Background: Although angiotensin-converting enzyme inhibition has been shown to slow progression of chronic allograft nephropathy in animal models, no studies have examined its efficacy in humans., Methods: We retrospectively analyzed 63 patients with biopsy-proven chronic allograft nephropathy who had > or =6 months dialysis-free follow-up at our institution. A total of 32 patients treated for > or =6 consecutive months with angiotensin-converting enzyme inhibition and/or angiotensin-receptor blocker (ARB) therapy (group 1) were compared with 31 patients not on these agents (group 2)., Results: Except for a higher incidence of hypertension (100 vs. 78%, P=0.005) in group 1, there were no significant differences in baseline clinical characteristics at time of biopsy. With a mean follow-up time of 27 months in both groups, 6 of 32 (19%) group 1 patients vs. 12 of 31 (39%) group 2 reached the primary endpoint of > or =50% increase in serum creatinine (P=0.10). Mean time to primary endpoint was 46.6 months in group 1 vs. 32.7 months in group 2 (P=0.07). Three of 32 (9%) of group 1 patients vs. 8 of 31 (26%) of group 2 returned to dialysis during this time (P=0.11). Significantly fewer patients in group 1 reached the combined secondary endpoint of allograft failure or death (9.4 vs. 35.5%, P=0.01); in addition, group 1 had a longer mean time to this endpoint (51.2 vs. 37.6 months, P=0.03). On multivariate analysis, the only predictor of progression to primary endpoint was a high baseline serum creatinine (P=0.02). No significant differences in hyperkalemia or anemia were found between the two groups., Conclusions: Angiotensin-converting enzyme inhibition/angiotensin-receptor blocker therapy is well tolerated in renal allograft recipients with chronic allograft nephropathy. It is associated with a trend of slowing renal insufficiency as well as a significant survival benefit in the combined endpoint of allograft failure or death.

This study reports the clinicopathologic findings and outcome in 34 patients with renal monoclonal immunoglobulin deposition disease (MIDD), which included 23 light-chain DD (LCDD), 5 light- and heavy-chain DD (LHCDD), and 6 heavy-chain DD (HCDD). A total of 23 patients had pure MIDD, whereas 11 patients had LCDD with coexistent myeloma cast nephropathy (LCDD & MCN). Renal biopsy diagnosis preceded clinical evidence of dysproteinemia in 68% of all cases. By immunofluorescence, the composition of deposits included 11kappa/1lambda (LCDD), 3IgGkappa/2IgGlambda (LHCDD), 5gamma/1alpha (HCDD), and 10kappa/1lambda (LCDD & MCN). Patients with pure MIDD presented with mean serum creatinine of 4.2 mg/dl, nephrotic proteinuria, and hypertension. Cases of HCDD were associated with a CH1 deletion and frequently had hypocomplementemia and a positive hepatitis C virus antibody but negative hepatitis C virus PCR. LCDD & MCN is a morphologically and clinically distinct entity from pure MIDD, presenting with higher creatinine (mean, 7.8 mg/dl; P = 0.01), greater dialysis dependence (64 versus 26%; P = 0.053), subnephrotic proteinuria, and less nodular glomerulopathy (18 versus 100%; P < 0.0001). Multiple myeloma was more frequently diagnosed in LCDD & MCN than in pure MIDD (91 versus 31%; P = 0.025). Renal and patient survivals were significantly worse in patients with LCDD & MCN (mean, 4 and 22 mo, respectively), compared with patients with pure MIDD (mean, 22 and 54 mo). Chemotherapy stabilized or improved renal function in 10 of 15 patients (67%) with pure MIDD who presented with creatinine of <5.0 mg/dl, emphasizing the importance of early detection. On multivariate analysis, initial creatinine was the only predictor of renal and patient survival in pure MIDD, underscoring the prognostic significance of the renal involvement.

Background: We report the first large renal biopsy-based clinicopathologic study on obesity-related glomerulopathy., Methods: Obesity was defined as body mass index (BMI)> 30 kg/m2. Obesity-related glomerulopathy (ORG) was defined morphologically as focal segmental glomerulosclerosis and glomerulomegaly (O-FSGS; N = 57) or glomerulomegaly alone (O-GM; N = 14)., Results: Review of 6818 native renal biopsies received from 1986 to 2000 revealed a progressive increase in biopsy incidence of ORG from 0.2% in 1986-1990 to 2.0% in 1996-2000 (P = 0.0001). Mean BMI in ORG was 41.7 (range 30.9 to 62.7). Indications for renal biopsy included proteinuria (N = 40) or proteinuria and renal insufficiency (N = 31). Seventy-one patients with ORG were compared to 50 patients with idiopathic FSGS (I-FSGS). Patients with ORG were older (mean 42.9 vs. 32.6 years, P < 0.001) and more often Caucasian (75% vs. 52%; P = 0.003). ORG patients had a lower incidence of nephrotic range proteinuria (48% vs. 66%; P = 0.007) and nephrotic syndrome (5.6% vs. 54%; P < 0.001), with higher serum albumin (3.9 vs. 2.9 g/dL; P < 0.001), lower serum cholesterol (229 vs. 335 mg/dL; P < 0.001), and less edema (35% vs. 68%; P = 0.003). On renal biopsy, patients with ORG had fewer lesions of segmental sclerosis (10 vs. 39%; P < 0.001), more glomerulomegaly (100% vs. 10%; P < 0.001), and less extensive foot process effacement (40 vs. 75%; P < 0.001). Glomerular diameter in ORG (mean 226 mu) was significantly larger than age- and sex-matched normal controls (mean 168 mu; P < 0.001). Follow-up was available in 56 ORG patients (mean 27 months) and 50 idiopathic FSGS controls (mean 38 months). A total of 75% of ORG patients received angiotensin-converting enzyme (ACE) inhibition or A2 blockade while 78% of the I-FSGS patients received immunosuppressive therapy. ORG patients had less frequent doubling of serum creatinine (14.3% vs. 50%; P < 0.001) and progression to ESRD (3.6% vs. 42%; P < 0.001). On multivariate analysis, presenting serum creatinine and severity of proteinuria were the only predictors of poor outcome in ORG., Conclusion: ORG is distinct from idiopathic FSGS, with a lower incidence of nephrotic syndrome, more indolent course, consistent presence of glomerulomegaly, and milder foot process fusion. The ten-fold increase in incidence over 15 years suggests a newly emerging epidemic. Heightened physician awareness of this entity is needed to ensure accurate diagnosis and appropriate therapy.

This study examines the clinical features, pathologic findings, and outcome of 24 patients with biopsy-proven lithium toxicity. The patient population was 50% male, 87.5% Caucasian, and had a mean age of 42.5 yr (range, 26 to 57). Mean duration of lithium therapy for bipolar disorder was 13.6 yr (range, 2 to 25). All patients were biopsied for renal insufficiency (mean serum creatinine 2.8 mg/dl; range, 1.3 to 8.0), with associated proteinuria >1.0 g/d in 41.7%. Nephrotic proteinuria (>3.0 g/d) was present in 25%. Other features included nephrogenic diabetes insipidus in 87% and hypertension in 33.3%. Renal biopsy revealed a chronic tubulointerstitial nephropathy in 100%, with associated cortical and medullary tubular cysts (62.5%) or dilatation (33.3%). All of the renal cysts stained for epithelial membrane antigen, while 51.4% stained with lectin Arachis hypogaea, and only 3.8% stained with Tetragonolobus purpureas, indicating they originated from distal and collecting tubules. The degree of tubular atrophy and interstitial fibrosis was graded as severe in 58.3%, moderate in 37.5%, and mild in 4.2% of cases. There was a surprisingly high prevalence of focal segmental glomerulosclerosis (50%) and global glomerulosclerosis (100%), sometimes of equivalent severity to the chronic tubulointerstitial disease. The significant degree of foot process effacement (mean 34%, five of 14 cases with >50%) suggests a potential direct glomerular toxicity. Focal segmental glomerulosclerosis correlated with proteinuria >1.0 g/d (P = 0.0014, Fisher exact test). Despite discontinuation of lithium, seven of nine patients with initial serum creatinine values >2.5 mg/dl progressed to end-stage renal disease (ESRD). Only three patients, all with initial serum creatinine <2.1 mg/dl, had subsequent improvement in renal function. By Kaplan-Meier survival analysis, the only significant predictor of progression to ESRD was serum creatinine >2.5 mg/dl at biopsy (P = 0. 008). In conclusion, lithium nephrotoxicity primarily targets distal and collecting tubules, with a higher incidence of proteinuria and associated glomerular pathology than recognized previously. Renal dysfunction is often irreversible despite lithium withdrawal, and early detection is essential to prevent progression to ESRD.

Experiments were performed to determine if the sulfhydryl protease, papain (EC 3.4.22.2), reacts with the plasma protease inhibitor antithrombin (antithrombin III, heparin cofactor) on a specific manner analogous to the reaction of thrombin (EC 3.4.21.5) and other serine proteases with this inhibitor. The esterolytic activity of papain is blocked by the addition of antithrombin, but not by antithrombin-thrombin complex or by protein substrates such as bovine serum albumin. Likewise, in the presence of papain, antithrombin was unable to displace the active site dye proflavine from thrombin, or to inhibit thrombin-catalysed hydrolysis of an anilide substrate. The reaction of antithrombin and papain was not accelerated by low concentrations of heparin. Approximately stoichiometric amounts of heparin completely inhibited the reaction of papain with antithrombin. The mutual inhibition indicates that plasma antithrombin does react with papain but the reaction differs from the interaction with coagulation factors, particularly in the heparin effect.