Andrew S. Bomback

Eculizumab for Dense Deposit Disease and C3 Glomerulonephritis

BACKGROUND AND OBJECTIVES The principle defect in dense deposit disease and C3 glomerulonephritis is hyperactivity of the alternative complement pathway. Eculizumab, a monoclonal antibody that binds to C5 to prevent formation of the membrane attack complex, may prove beneficial. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS In this open-label, proof of concept efficacy and safety study, six subjects with dense deposit disease or C3 glomerulonephritis were treated with eculizumab every other week for 1 year. All had proteinuria >1 g/d and/or AKI at enrollment. Subjects underwent biopsy before enrollment and repeat biopsy at the 1-year mark. RESULTS The subjects included three patients with dense deposit disease (including one patient with recurrent dense deposit disease in allograft) and three patients with C3 glomerulonephritis (including two patients with recurrent C3 glomerulonephritis in allograft). Genetic and complement function testing revealed a mutation in CFH and MCP in one subject each, C3 nephritic factor in three subjects, and elevated levels of serum membrane attack complex in three subjects. After 12 months, two subjects showed significantly reduced serum creatinine, one subject achieved marked reduction in proteinuria, and one subject had stable laboratory parameters but histopathologic improvements. Elevated serum membrane attack complex levels normalized on therapy and paralleled improvements in creatinine and proteinuria. CONCLUSIONS Clinical and histopathologic data suggest a response to eculizumab in some but not all subjects with dense deposit disease and C3 glomerulonephritis. Elevation of serum membrane attack complex before treatment may predict response. Additional research is needed to define the subgroup of dense deposit disease/C3 glomerulonephritis patients in whom eculizumab therapy can be considered.

Change in Proteinuria After Adding Aldosterone Blockers to ACE Inhibitors or Angiotensin Receptor Blockers in CKD: A Systematic Review

BACKGROUND The use of mineralocorticoid receptor blockers (MRBs) in patients with chronic kidney disease is growing, but data for efficacy in decreasing proteinuria are limited by a relative paucity of studies, many of which are small and uncontrolled. STUDY DESIGN We performed a systematic review using the MEDLINE database (inception to November 1, 2006), abstracts from national meetings, and selected reference lists. SETTING & POPULATION Adult patients with chronic kidney disease and proteinuria. SELECTION CRITERIA FOR STUDIES English-language studies investigating the use of MRBs added to long-term angiotensin-converting enzyme (ACE)-inhibitor and/or angiotensin receptor blocker (ARB) therapy in adult patients with proteinuric kidney disease. INTERVENTION MRBs as additive therapy to conventional renin-angiotensin-aldosterone system blockade in patients with chronic kidney disease. OUTCOMES Changes in proteinuria as the primary outcome; rates of hyperkalemia, changes in blood pressure, and changes in glomerular filtration rate as secondary outcomes. RESULTS 15 studies met inclusion criteria for our review; 4 were parallel-group randomized controlled trials, 4 were crossover randomized controlled trials, 2 were pilot studies, and 5 were case series. When MRBs were added to ACE-inhibitor and/or ARB therapy, the reported proteinuria decreases from baseline ranged from 15% to 54%, with most estimates in the 30% to 40% range. Hyperkalemic events were significant in only 1 of 8 randomized controlled trials. MRB therapy was associated with statistically significant decreases in blood pressure and glomerular filtration rate in approximately 40% and 25% of included studies, respectively. LIMITATIONS Reported results were insufficient for meta-analysis, with only 2 studies reporting sufficient data to calculate SEs of their published estimates. We were unable to locate studies that showed no effect of MRB treatment over placebo, raising concern for publication bias. CONCLUSIONS Although data suggest that adding MRBs to ACE-inhibitor and/or ARB therapy yields significant decreases in proteinuria without adverse effects of hyperkalemia and impaired renal function, routine use of MRBs as additive therapy in patients with chronic kidney disease cannot be recommended yet. However, the findings of this review promote interesting hypotheses for future study.

Prevalence of CKD and Comorbid Illness in Elderly Patients in the United States: Results From the Kidney Early Evaluation Program (KEEP)

BACKGROUND Elderly individuals with chronic kidney disease (CKD) have high rates of comorbid conditions, including cardiovascular disease and its risk factors, and CKD-related complications. In individuals aged > or = 65 years, we sought to describe the prevalence of CKD determined from laboratory test results in the Kidney Early Evaluation Program (KEEP; n = 27,017) and National Health and Nutrition Examination Survey (NHANES) 1999-2006 (n = 5,538) and the prevalence of diagnosed CKD determined from billing codes in the Medicare 5% sample (n = 1,236,946). In all 3 data sources, we also explored comorbid conditions and CKD-related complications. METHODS CKD was identified as decreased estimated glomerular filtration rate (<60 mL/min/1.73 m(2)) or increased albumin-creatinine ratio in KEEP and NHANES; CKD was identified using International Classification of Diseases, Ninth Revision, Clinical Modification codes in Medicare. Investigated comorbid conditions included diabetes, hypertension, high cholesterol level, coronary artery disease, congestive heart failure, cerebrovascular disease, peripheral vascular disease, and cancer, and CKD-related complications included anemia, hypocalcemia, hyperphosphatemia, and hyperparathyroidism. RESULTS The prevalence of CKD was approximately 44% in both KEEP and NHANES participants, and the prevalence of diagnosed CKD was 7% in Medicare beneficiaries. In all 3 data sets, the prevalence of CKD or diagnosed CKD was higher in participants aged > or = 80 years and those with comorbid conditions. For KEEP and NHANES participants, the prevalence of most comorbid conditions and CKD complications increased with decreasing estimated glomerular filtration rate. For participants with CKD stages 3-5, a total of 29.2% (95% CI, 27.8-30.6) in KEEP and 19.9% (95% CI, 17.0-23.1) in NHANES had anemia, 0.7% (95% CI, 0.4-0.9) and 0.6% (95% CI, 0.3-1.3) had hypocalcemia, 5.4% (95% CI, 4.7-6.1) and 6.4% (95% CI, 5.1-8.0) had hyperphosphatemia, and 52.0% (95% CI, 50.4-53.6) and 30.0% (95% CI, 25.9-34.3) had hyperparathyroidism, respectively. CONCLUSIONS CKD is common in the elderly population and is associated with high frequencies of concomitant comorbid conditions and biochemical abnormalities. Because CKD is not commonly diagnosed, greater emphasis on physician education may be beneficial.

Updates on the Treatment of Lupus Nephritis

The treatment of lupus nephritis has changed significantly over the past decade in large part because of data from well-conducted randomized clinical trials. The concept of two phases of therapy-induction and maintenance-is widely accepted. The histopathologic classification of lupus nephritis continues to guide therapy, and treatment for all major classes of lupus nephritis has seen some shift in management during this time. New regimens using lower doses and shorter treatment durations of intravenous cyclophosphamide have been advanced to reduce toxicity without sacrificing efficacy of therapy. Mycophenolate mofetil has emerged as a viable alternative to cyclophosphamide for induction therapy of both proliferative and membranous lupus nephritis. Combination induction treatment with multiple agents has also been successful. Large controlled trials using mycophenolate mofetil and azathioprine for maintenance therapy have been performed. Here, we review recent additions to the growing body of literature on how to most effectively treat lupus nephritis with the least amount of toxicity. We discuss new treatment strategies currently being explored in clinical trials.

Pathology after Eculizumab in Dense Deposit Disease and C3 GN

Eculizumab might benefit C3 glomerulopathies mediated by dysregulation of the alternative complement pathway. Here, we report renal biopsy findings before and after eculizumab therapy in three patients with dense deposit disease and two with C3 GN. All pretreatment biopsies had glomerular and tubular basement membrane deposits that stained exclusively for C3 without significant Ig. After 1 year of therapy, there was reduction in active glomerular proliferation and neutrophil infiltration in three of five patients, consistent with effective C5 blockade, which prevents production of chemotactin C5a. One individual with mild mesangial disease had no significant change in activity or chronicity. One patient exhibited persistent activity and worsening chronicity despite therapy. Immunofluorescence showed no significant reduction in C3 or C5b-9, and electron microscopy revealed persistent deposits in all cases, suggesting a long t(1/2) of C5b-9 in extracellular matrix. Normal renal biopsies stained positive for C5b-9 in glomeruli, tubular basement membranes, and vessel walls, albeit at lower intensity than in C3 glomerulopathy. This indication of physiologic levels of C5b-9 activation in normal kidney potentially explains the localization of deposits in patients with dysregulation of the alternative complement pathway. All post-treatment biopsies showed de novo monoclonal staining for IgG-κ in the same distribution as C3 and C5b-9, mimicking monoclonal Ig deposition disease (MIDD). Staining of the γ heavy chain was restricted to the IgG2 and IgG4 subclasses, suggesting the binding of monoclonal eculizumab to C5 in renal tissues. The long-term effects of this apparent drug-tissue interaction are unknown.

Pathogenesis of the C3 glomerulopathies and reclassification of MPGN

Until recently, membranoproliferative glomerulonephritis (MPGN) was clinically classified as either primary, idiopathic MPGN or as secondary MPGN when an underlying aetiology was identifiable. Primary MPGN was further classified into three types—type I, type II, and type III—based principally on the ultrastructural appearance and location of electron-dense deposits. Both the clinical and histopathologic schemes presented problems, however, as neither was based on disease pathogenesis. An improved understanding of the role of complement in the pathogenesis of MPGN has led to a proposed reclassification into immunoglobulin-mediated disease (driven by the classical complement pathway) and non-immunoglobulin-mediated disease (driven by the alternative complement pathway). This reclassification has led to improved diagnostic clinical algorithms and the emergence of a new grouping of diseases known as the C3 glomerulopathies, best represented by dense deposit disease and C3 glomerulonephritis. In this Review, we re-examine the previous and current classification schemes of MPGN, focusing on the role of complement. We survey current data about the pathogenesis of the C3 glomerulopathies, including familial studies and patient cohorts from the USA and Europe. In addition, we discuss the diagnosis, treatment, and prognosis of the C3 glomerulopathies.

Sugar-sweetened soda consumption, hyperuricemia, and kidney disease

The metabolism of high-fructose corn syrup used to sweeten soda drinks may lead to elevations in uric acid levels. Here we determined whether soda drinking is associated with hyperuricemia and, as a potential consequence, reduced kidney function. At baseline, 15,745 patients in the Atherosclerosis Risk in Communities Study completed a dietary questionnaire and had measurements of their serum creatinine and uric acid. After 3 and 9 years of follow-up, multivariate odds ratios from logistic regressions for binary outcome of hyperuricemia and chronic kidney disease (eGFR less than 60 ml/min per 1.73 m(2)) were evaluated. Compared to participants who drank less, consumption of over one soda per day was associated with increased odds of prevalent hyperuricemia and chronic kidney disease. The odds ratio for chronic kidney disease significantly increased to 2.59 among participants who drank more than one soda per day and had a serum uric acid level over 9.0 mg/dl. In longitudinal analyses, however, drinking more than one soda per day was not associated with hyperuricemia or chronic kidney disease. Neither preexistent hyperuricemia nor development of hyperuricemia modified the lack of association between soda drinking and incident chronic kidney disease. Thus our study shows that high consumption of sugar-sweetened soda was associated with prevalent but not incident hyperuricemia and chronic kidney disease.

The Modern Spectrum of Renal Biopsy Findings in Patients with Diabetes

BACKGROUND AND OBJECTIVES Renal biopsies performed in diabetic patients are increasing in number and complexity. This study sought to determine the usefulness of renal biopsy in patients with diabetes and the predictability of diagnosing diabetic nephropathy (DN) versus nondiabetic renal disease (NDRD) from clinical and laboratory data. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS To assess modern trends, a retrospective study was performed of clinical-pathologic findings in all patients with diabetes who had a biopsy in 2011. Among 2642 native kidney biopsies, 620 (23.5%) were from patients with diabetes. RESULTS The cohort included 371 men (60.7%) aged a median (interquartile range) 62 years (52-69) with 10-year (5-15) duration of diabetes mellitus (DM). Median serum creatinine was 2.5 mg/dl (1.6-4.4), and 52% of patients had stage 4-5 CKD. On biopsy, 37% of patients had DN alone, 36% had NDRD alone, and 27% had DN plus NDRD. In NDRD alone, FSGS (22%), hypertensive nephrosclerosis (18%), acute tubular necrosis (ATN) (17%), IgA nephropathy (11%), membranous GN (8%), and pauci-immune GN (7%) comprised 80% of diagnoses, compared with ATN (43%), hypertensive nephrosclerosis (19%), FSGS (13%), and IgA nephropathy (7%) for DN plus NDRD. In multivariate analyses, longer duration of DM was associated with a greater likelihood of DN and a lower likelihood of NDRD: each added year of DM reduced the odds of NDRD by 5% (odds ratio, 0.95; 95% confidence interval, 0.91 to 0.98; P=0.004). DM duration ≥ 12 years was the best predictor (58% sensitivity, 73% specificity) of DN alone. CONCLUSIONS Approximately one-quarter of all renal biopsies are performed in patients with DM. Judicious use of renal biopsy has uncovered NDRD alone or superimposed on DN in the majority of such biopsies. ATN is emerging as an important category of NDRD, which has not been reported previously.

A Simple Algorithm to Predict Incident Kidney Disease

BACKGROUND Despite the growing burden of chronic kidney disease (CKD), there are no algorithms (to our knowledge) to quantify the effect of concurrent risk factors on the development of incident disease. METHODS A combined cohort (N = 14 155) of 2 community-based studies, the Atherosclerosis Risk in Communities Study and the Cardiovascular Health Study, was formed among men and women 45 years or older with an estimated glomerular filtration rate (GFR) exceeding 60 mL/min/1.73 m(2) at baseline. The primary outcome was the development of a GFR less than 60 mL/min/1.73 m(2) during a follow-up period of up to 9 years. Three prediction algorithms derived from the development data set were evaluated in the validation data set. RESULTS The 3 prediction algorithms were continuous and categorical best-fitting models with 10 predictors and a simplified categorical model with 8 predictors. All showed discrimination with area under the receiver operating characteristic curve in a range of 0.69 to 0.70. In the simplified model, age, anemia, female sex, hypertension, diabetes mellitus, peripheral vascular disease, and history of congestive heart failure or cardiovascular disease were associated with the development of a GFR less than 60 mL/min/1.73 m(2). A numeric score of at least 3 using the simplified algorithm captured approximately 70% of incident cases (sensitivity) and accurately predicted a 17% risk of developing CKD (positive predictive value). CONCLUSIONS An algorithm containing commonly understood variables helps to stratify middle-aged and older individuals at high risk for future CKD. The model can be used to guide population-level prevention efforts and to initiate discussions between practitioners and patients about risk for kidney disease.

Association of C-Reactive Protein and Microalbuminuria (from the National Health and Nutrition Examination Surveys, 1999 to 2004)

Chronic kidney disease and cardiovascular disease share many risk factors. Injury to the vascular endothelium, measured by elevated levels of serum C-reactive protein (CRP), may play a role in kidney and cardiovascular disease. We therefore examined the association of CRP with microalbuminuria, a marker of early kidney injury. We conducted a cross-sectional analysis of a nationally representative, population-based survey. Weighted multiple logistic regression was used to study the association between CRP and microalbuminuria, adjusting for well-known risk factors. CRP was analyzed by a continuous variable and two categorized variables using quartiles and clinically recommended cutpoints. CRP concentration was positively associated with microalbuminuria. In the multivariate model, a one unit (in milligrams per liter) increase in CRP concentration was associated with a 2% increased odds of microalbuminuria (odds ratio 1.02, 95% confidence interval [CI] 1.01 to 1.02, p=0.0003). When CRP concentrations were stratified by clinically recommended cutpoints, compared with persons with CRP concentrations<1 mg/dl, persons with CRP concentrations between 1 and 3 mg/L and >3 mg/L were 1.15 times (95% CI 0.94 to 1.42) and 1.33 times (95% CI 1.08 to 1.65) more likely to have microalbuminuria, respectively. In subgroup analyses, the strength of association was comparable or stronger. In conclusion, elevated CRP levels were associated with microalbuminuria in a large, nationally representative data set. Vascular inflammation, as measured by CRP, may be a common contributor to early heart and kidney disease.