Anthony M. Valeri

Incidence of Nephrogenic Systemic Fibrosis at Two Large Medical Centers

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.

Adult Minimal-Change Disease: Clinical Characteristics, Treatment, and Outcomes

Minimal-change disease (MCD) counts for 10 to 15% of cases of primary nephrotic syndrome in adults. Few series have examined this disease in adults. A retrospective review was performed of 95 adults who had MCD and were seen at a single referral center. Examined were presenting features, response to daily versus alternate-day steroids, response to second-line agents, relapse patterns, complications of the disease and therapy, presence of acute renal failure (ARF), and outcome data. Sixty-five patients received daily and 23 received alternate-day steroids initially. There were no differences in remissions, time to remission, relapse rate, or time to relapse between daily- and alternate-day-treated patients. More than one quarter of patients were steroid resistant. At least one relapse occurred in 73% of patients; 28% were frequently relapsing. A significant proportion of frequently relapsing patients became steroid dependent. Second-line agents were used for steroid dependence, steroid resistance, or frequent relapses. No single agent proved superior. There were more remissions with second-line agents in steroid-dependent patients compared with steroid-resistant patients, and remissions were more likely to be complete in steroid-dependent patients. ARF occurred in 24 patients; they tended to be older and hypertensive with lower serum albumin and more proteinuria than those without ARF. At follow up, patients with an episode of ARF had higher serum creatinine than those without ARF. Four patients progressed to ESRD. These patients were less likely to have responded to steroids and more likely to have FSGS on repeat renal biopsy. In this referral MCD population, response to daily and alternate-day steroids is similar. Second-line agents give greater response in patients who are steroid dependent. ARF occurs in a significant number of adult MCD patients and may leave residual renal dysfunction. Few patients progress to ESRD.

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.

Renal Monoclonal Immunoglobulin Deposition Disease: A Report of 64 Patients from a Single Institution

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.

Acute Postinfectious Glomerulonephritis in the Modern Era : Experience With 86 Adults and Review of the Literature

Acute postinfectious glomerulonephritis (APIGN) is uncommon in adults, and its incidence is progressively declining in developed countries. To our knowledge there are no modern North American series addressing epidemiology and outcome. Here we report the clinical and pathologic findings in 86 cases of adult APIGN diagnosed by renal biopsy in a large New York referral center between 1995 and 2005. The male:female ratio was 2:1, and mean age was 56 years, with 33.7% aged older than 64 years. Of the patients, 38.4% had an immunocompromised background, including diabetes (29.1%), malignancy (4.7%), alcoholism (2.3%), acquired immunodeficiency syndrome (AIDS) (2.3%), and intravenous drug use (1.2%). The most common sites of infection were upper respiratory tract (23.3%), skin (17.4%), lung (17.4%), and heart/endocarditis (11.6%). The 2 most frequently identified infectious agents were streptococcus (27.9%) and staphylococcus (24.4%). Hypocomplementemia was present in 73.9% of patients. The most common histologic patterns were diffuse (72.1%), focal (12.8%), and mesangial (8.1%) proliferative glomerulonephritis. Outcome analysis was performed on the 52 patients with a follow-up of ≥3 months (mean, 25 mo). Among the 41 patients without underlying diabetic glomerulosclerosis, 23 (56.1%) achieved complete remission, 11 (26.8%) had persistent renal dysfunction, and 7 (17.1%) progressed to end-stage renal disease (ESRD). Of the 11 patients with underlying diabetic glomerulosclerosis, 2 (18.2%) had persistent renal dysfunction, and the remaining 9 (81.8%) progressed to ESRD (p < 0.001). In patients without underlying diabetic glomerulosclerosis, correlates of complete remission were younger age, female sex, lower serum creatinine at biopsy, and absence of immunocompromised state. By multivariate analysis, age and serum creatinine at biopsy inversely correlated with complete remission, and serum creatinine at biopsy was the only correlate with ESRD. Outcome did not correlate with any pathologic feature (including crescents) or steroid treatment. Diabetes and aging have emerged as major risk factors for adult APIGN. Full recovery of renal function can be expected in just over half of patients, and prognosis is dismal in those with underlying diabetic glomerulosclerosis. Abbreviations: APIGN = acute postinfectious glomerulonephritis, C = serum complement, DGS = diabetic glomerulosclerosis, EM = electron microscopy, ESRD = end-stage renal disease, GN = glomerulonephritis, H & E = hematoxylin and eosin stain, IF = immunofluorescence, IVDU = intravenous drug use, LM = light microscopy, MPGN = membranoproliferative glomerulonephritis, URT = upper respiratory tract.

Dense Deposit Disease: Clinicopathologic Study of 32 Pediatric and Adult Patients

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.

Clinicopathologic Correlations in Multiple Myeloma: A Case Series of 190 Patients With Kidney Biopsies

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.

Angiotensin converting enzyme inhibition in chronic allograft nephropathy.

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 ≥6 months dialysis-free follow-up at our institution. A total of 32 patients treated for ≥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 ≥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.

Postinfectious Glomerulonephritis in the Elderly

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.

Biopsy-proven acute interstitial nephritis, 1993-2011: a case series.

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.