Stephen B. Erickson

Rituximab-Induced Depletion of Anti-PLA2R Autoantibodies Predicts Response in Membranous Nephropathy

Autoantibodies to the M-type phospholipase A(2) receptor (PLA(2)R) are sensitive and specific for idiopathic membranous nephropathy. The anti-B cell agent rituximab is a promising therapy for this disease, but biomarkers of early response to treatment currently do not exist. Here, we investigated whether levels of anti-PLA(2)R correlate with the immunological activity of membranous nephropathy, potentially exhibiting a more rapid response to treatment than clinical parameters such as proteinuria. We measured the amount of anti-PLA(2)R using Western blot immunoassay in serial serum samples from a total of 35 patients treated with rituximab for membranous nephropathy in two distinct cohorts. Pretreatment samples from 25 of 35 (71%) patients contained anti-PLA(2)R, and these autoantibodies declined or disappeared in 17 (68%) of these patients within 12 months after rituximab. Those who demonstrated this immunologic response fared better clinically: 59% and 88% attained complete or partial remission by 12 and 24 months, respectively, compared with 0% and 33% among those with persistent anti-PLA(2)R levels. Changes in antibody levels preceded changes in proteinuria. One subject who relapsed during follow-up had a concomitant return of anti-PLA(2)R. In summary, measuring anti-PLA(2)R levels by immunoassay may be a method to follow and predict response to treatment with rituximab in membranous nephropathy.

Rituximab therapy in idiopathic membranous nephropathy: a 2-year study.

BACKGROUND AND OBJECTIVES It was postulated that in patients with membranous nephropathy (MN), four weekly doses of Rituximab (RTX) would result in more effective B cell depletion, a higher remission rate, and maintaining the same safety profile compared with patients treated with RTX dosed at 1 g every 2 weeks. This hypothesis was supported by previous pharmacokinetic (PK) analysis showing that RTX levels in the two-dose regimen were 50% lower compared with nonproteinuric patients, which could potentially result in undertreatment. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS Twenty patients with MN and proteinuria >5 g/24 h received RTX (375 mg/m(2) × 4), with re-treatment at 6 months regardless of proteinuria response. PK analysis was conducted simultaneously with immunological analyses of T and B cells to ascertain the effect of RTX on lymphocyte subpopulations. RESULTS Baseline proteinuria of 11.9 g/24 h decreased to 4.2 and 2.0 g/24 h at 12 and 24 months, respectively, whereas creatinine clearance increased from 72.4 ml/min per 1.73 m(2) at baseline to 88.4 ml/min per 1.73 m(2) at 24 months. Of 18 patients who completed 24-month follow-up, 4 are in complete remission, 12 are in partial remission, 1 has a limited response, and 1 patient relapsed. Serum RTX levels were similar to those obtained with two doses of RTX. CONCLUSIONS Four doses of RTX resulted in more effective B cell depletion, but proteinuria reduction was similar to RTX at 1 g every 2 weeks. Baseline quantification of lymphocyte subpopulations did not predict response to RTX therapy.

The Association of Nephrolithiasis and Autosomal Dominant Polycystic Kidney Disease

Despite the frequency and morbidity of nephrolithiasis in autosomal dominant polycystic kidney disease (ADPKD), this association has not been subject to a detailed study. One hundred fifty-one of 751 ADPKD patients seen at the Mayo Clinic between 1976 and 1986 had nephrolithiasis. Seventy-four had passed calculi or had stones surgically removed. Stone analysis was available in 30 patients: uric acid, calcium oxalate, calcium phosphate, and struvite were present in 56.6%, 46.6%, 20%, and 10%, respectively. Calculi were observed in 71 of 79 patients with excretory urograms available for review. Faintly opaque and bulls eye stones, probably containing uric acid, were present in 12.7% and 14.1% of these patients, respectively. Precaliceal tubular ectasia was observed in 15.5%. Ninety-seven patients had preserved renal function (serum creatinine less than 1.5 mg/dL) at the initial evaluation. Six were excluded because they had other known causes of stone disease. The most common metabolic abnormality in the remaining 91 patients was hypocitric aciduria (ten of 15 patients with measurements). The urine pH in the first voided morning specimens (5.66 +/- 0.05) was significantly lower than that of an unselected control population (5.92 +/- 0.03, P less than 0.001). Hyperuricosuria, hyperoxaluria, and hypercalciuria were observed in six of 32 (18.8%), six of 31 (19.4%), and three of 39 (9.7%) patients with preserved renal function. The composition of the stones, the frequency of hypocitric aciduria, and the low urine pH (possibly related to the defect in excretion of ammonia described in ADPKD), suggest that metabolic, along with mechanical, factors are responsible for the frequent occurrence of nephrolithiasis in this disease.

Associations of sugar‐sweetened and artificially sweetened soda with chronic kidney disease: A systematic review and meta‐analysis

The risk of chronic kidney disease (CKD) in patients who regularly drink soda is controversial. The objective of this meta‐analysis was to evaluate the associations between consumption of sugar‐sweetened and artificially sweetened soda and CKD.

Proton pump inhibitors linked to hypomagnesemia: a systematic review and meta-analysis of observational studies.

Abstract Background: The reported risk of hypomagnesemia in patients with proton pump inhibitor (PPI) use is conflicting. The objective of this meta-analysis was to assess the association between the use of PPIs and the risk of hypomagnesemia. Methods: A literature search of observational studies was performed using MEDLINE, EMBASE and Cochrane Database of Systematic Reviews from inception through September 2014. Studies that reported odd ratios or hazard ratios comparing the risk of hypomagnesemia in patients with PPI use were included. Pooled risk ratios (RRs) and 95% confidence interval (CI) were calculated using a random-effect, generic inverse variance method. Results: Nine observational studies (three cohort studies, five cross-sectional studies and a case-control study) with a total of 109,798 patients were identified and included in the data analysis. The pooled RR of hypomagnesemia in patients with PPI use was 1.43 (95% CI, 1.08–1.88). The association between the use of PPIs and hypomagnesemia remained significant after the sensitivity analysis including only studies with high quality score (Newcastle–Ottawa scale score ≥ 8) with a pooled RR of 1.63 (95% CI, 1.14–2.23). Conclusions: Our study demonstrates a statistically significant increased risk of hypomagnesemia in patients with PPI use. The finding of this meta-analysis of observational studies suggests that PPI use is associated with hypomagnesemia and may impact clinical management of patients who are taking PPIs and at risk for hypomagnesemia related cardiovascular events.

A Randomized, Controlled Trial of Rituximab in IgA Nephropathy with Proteinuria and Renal Dysfunction

IgA nephropathy frequently leads to progressive CKD. Although interest surrounds use of immunosuppressive agents added to standard therapy, several recent studies have questioned efficacy of these agents. Depleting antibody-producing B cells potentially offers a new therapy. In this open label, multicenter study conducted over 1-year follow-up, we randomized 34 adult patients with biopsy-proven IgA nephropathy and proteinuria >1 g/d, maintained on angiotensin-converting enzyme inhibitors or angiotensin receptor blockers with well controlled BP and eGFR<90 ml/min per 1.73 m2, to receive standard therapy or rituximab with standard therapy. Primary outcome measures included change in proteinuria and change in eGFR. Median baseline serum creatinine level (range) was 1.4 (0.8-2.4) mg/dl, and proteinuria was 2.1 (0.6-5.3) g/d. Treatment with rituximab depleted B cells and was well tolerated. eGFR did not change in either group. Rituximab did not alter the level of proteinuria compared with that at baseline or in the control group; three patients in each group had ≥50% reduction in level of proteinuria. Serum levels of galactose-deficient IgA1 or antibodies against galactose-deficient IgA1 did not change. In this trial, rituximab therapy did not significantly improve renal function or proteinuria assessed over 1 year. Although rituximab effectively depleted B cells, it failed to reduce serum levels of galactose-deficient IgA1 and antigalactose-deficient IgA1 antibodies. Lack of efficacy of rituximab, at least at this stage and severity of IgA nephropathy, may reflect a failure of rituximab to reduce levels of specific antibodies assigned salient pathogenetic roles in IgA nephropathy.

Preoperative renin–angiotensin system inhibitors use linked to reduced acute kidney injury: a systematic review and meta-analysis

BACKGROUND Previous trials of interventions to prevent acute kidney injury (AKI) have been unsuccessful and additional interventions are needed. Existing reviews of preoperative renin-angiotensin system (RAS) inhibitors have suggested harm. We included more recent studies and conducted this meta-analysis to evaluate the risk of postoperative AKI in patients who received preoperative RAS inhibitors. METHODS A literature search was performed using MEDLINE, EMBASE and Cochrane Database of Systematic Reviews from inception through October, 2014. Studies that reported relative risks, odds ratios or hazard ratios comparing the AKI risk in patients who received preoperative RAS inhibitors versus those who did not were included. We performed the prespecified sensitivity analysis including only propensity score-based studies. Mortality risk was evaluated among the studies that reported AKI outcome. Pooled risk ratios (RR) and 95% confidence interval (CI) were calculated using a random-effect, generic inverse variance method. RESULTS Twenty-four studies (1 randomized controlled trial and 23 cohort studies) with 102 675 patients were included in the analysis to assess the risk of postoperative AKI and preoperative RAS inhibitors use. The pooled RR of AKI in patients receiving RAS inhibitors was 1.05 (95% CI: 0.92-1.20). The meta-analysis of the RCT and 11 studies with propensity score analysis demonstrated the pooled RR of AKI in patients receiving RAS inhibitors of 0.92 (95% CI: 0.85-0.99). Within the selected studies, preoperative RAS inhibitor therapy was not associated with a significant increase or decrease in mortality (RR: 0.93; 95% CI: 0.80-1.09). CONCLUSIONS Our meta-analysis demonstrates an association between preoperative RAS inhibitor treatment and lower incidence of AKI.

The risk of kidney cancer in patients with kidney stones: a systematic review and meta-analysis

BACKGROUND The objective of this meta-analysis was to evaluate the association between a history of kidney stones and kidney cancer. METHODS A literature search was performed from inception until June 2014. Studies that reported odds ratios or hazard ratios comparing the risk of renal cell carcinoma (RCC) and transitional cell carcinoma (TCC) of the upper urinary tract in patients with the history of kidney stones versus those without the history of kidney stones were included. Pooled risk ratios (RRs) and 95% confidence interval (CI) were calculated using a random-effect, generic inverse variance method. RESULT Seven studies were included in our analysis to assess the association between a history of kidney stones and RCC. The pooled RR of RCC in patients with kidney stones was 1.76 (95% CI, 1.24-2.49). The subgroup analysis found that the history of kidney stones was associated with increased RCC risk only in males (RR, 1.41 [95% CI, 1.11-1.80]), but not in females (RR, 1.13 [95% CI, 0.86-1.49]). Five studies were selected to assess the association between a history of kidney stones and TCC. The pooled RR of TCC in patients with kidney stones was 2.14 (95% CI, 1.35-3.40). CONCLUSION Our study demonstrates a significant increased risk of RCC and TCC in patients with prior kidney stones. However, the increased risk of RCC was noted only in male patients. This finding suggests that a history of kidney stones is associated with kidney cancer and may impact clinical management and cancer surveillance.

Sugar and artificially sweetened soda consumption linked to hypertension: a systematic review and meta-analysis.

Abstract Background/objectives: The risk of hypertension (HTN) in patients who regularly drink soda is controversial. The objective of this meta-analysis was to assess the associations between consumption of sugar and artificially sweetened soda and HTN. Methods: A literature search was performed using MEDLINE, EMBASE and Cochrane Database of Systematic Reviews from inception through January 2015. Studies that reported relative risks, odd ratios or hazard ratios comparing the risk of HTN in patients consuming a significant amount of either sugar or artificially sweetened soda versus those who did not consume soda were included. Pooled risk ratios (RR) and 95% confidence interval (CI) were calculated using a random-effect, generic inverse variance method. Results: Eight studies were included in our analysis to assess the association between consumption of sugar-sweetened soda and HTN. The pooled RR of HTN in patients consuming sugar-sweetened soda was 1.12 (95% CI, 1.03–1.23). Four studies were selected to assess the association between consumption of artificially sweetened soda and HTN. The pooled RR of HTN in patients consuming artificially sweetened soda was 1.15 (95% CI, 1.11–1.19). Conclusions: Our study demonstrates statistically significant associations between both sugar and artificially sweetened soda consumption and HTN. This finding may impact clinical management and primary prevention of HTN.

Oral hydration for prevention of contrast-induced acute kidney injury in elective radiological procedures: a systematic review and meta-analysis of randomized controlled trials.

Background: The reports on efficacy of oral hydration treatment for the prevention of contrast-induced acute kidney injury (CIAKI) in elective radiological procedures and cardiac catheterization remain controversial. Aims: The objective of this meta-analysis was to assess the use of oral hydration regimen for prevention of CIAKI. Materials and Methods: Comprehensive literature searches for randomized controlled trials (RCTs) of outpatient oral hydration treatment was performed using MEDLINE, EMBASE, Cochrane Database of Systematic Reviews, Cochrane Central Register of Controlled Trials Systematic Reviews, and clinicaltrials.gov from inception until July 4th, 2014. Primary outcome was the incidence of CIAKI. Results: Six prospective RCTs were included in our analysis. Of 513patients undergoing elective procedures with contrast exposures,45 patients (8.8%) had CIAKI. Of 241 patients with oral hydration regimen, 23 (9.5%) developed CIAKI. Of 272 patients with intravenous (IV) fluid regimen, 22 (8.1%) had CIAKI. Study populations in all included studies had relatively normal kidney function to chronic kidney disease (CKD) stage 3. There was no significant increased risk of CIAKI in oral fluid regimen group compared toIV fluid regimen group (RR = 0.94, 95% confidence interval, CI = 0.38-2.31). Conclusions: According to our analysis,there is no evidence that oral fluid regimen is associated with more risk of CIAKI in patients undergoing elective procedures with contrast exposures compared to IV fluid regimen. This finding suggests that the oral fluid regimen might be considered as a possible outpatient treatment option for CIAKI prevention in patients with normal to moderately reduced kidney function.