Vimal K. Derebail

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.

Venous Thromboembolism in Patients with Membranous Nephropathy

BACKGROUND AND OBJECTIVES The aims of this study were to determine the frequency of venous thromboembolic events in a large cohort of patients with idiopathic membranous nephropathy and to identify predisposing risk factors. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS We studied patients with biopsy-proven membranous nephropathy from the Glomerular Disease Collaborative Network (n=412) and the Toronto Glomerulonephritis Registry (n=486) inception cohorts. The cohorts were pooled after establishing similar baseline characteristics (total n=898). Clinically apparent and radiologically confirmed venous thromboembolic events were identified. Potential risk factors were evaluated using multivariable logistic regression models. RESULTS Sixty-five (7.2%) subjects had at least one venous thromboembolic event, and this rate did not differ significantly between registries. Most venous thromboembolic events occurred within 2 years of first clinical assessment (median time to VTE = 3.8 months). After adjusting for age, sex, proteinuria, and immunosuppressive therapy, hypoalbuminemia at diagnosis was the only independent predictor of a venous thromboembolic event. Each 1.0 g/dl reduction in serum albumin was associated with a 2.13-fold increased risk of VTE. An albumin level <2.8 g/dl was the threshold below which risk for a venous thromboembolic event was greatest. CONCLUSIONS We conclude that clinically apparent venous thromboembolic events occur in about 7% of patients with membranous nephropathy. Hypoalbuminemia, particularly <2.8 g/dl, is the most significant independent predictor of venous thrombotic risk.

Rituximab Therapy for Membranous Nephropathy: A Systematic Review

BACKGROUND AND OBJECTIVES The treatment of membranous nephropathy (MN) remains controversial. Rituximab, which selectively targets B cells, has emerged as a possible alternative treatment option with limited toxicity. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS The available data on rituximab therapy for MN were reviewed using the MEDLINE database (inception to August 1, 2008), Google Scholar, and selected reference lists. English-language studies investigating the use of rituximab in idiopathic and secondary MN, in native and transplanted kidneys, were included. Study design, subject number, clinical characteristics (diagnosis, previous and concomitant treatment courses, baseline proteinuria, baseline renal function), rituximab protocol, follow-up period, achievement of complete or partial remission, changes in proteinuria and renal function, and adverse effects of therapy were extracted. RESULTS Twenty-one articles were included for review; all were either case reports or case series without controls. More than half of the published cases (50 of 85) came from one center where rituximab was used as primary immunosuppression for idiopathic MN. The available data suggest that rituximab, dosed either as 375 mg/m(2) once weekly for 4 wk or as 1 g on days 1 and 15, achieves a 15 to 20% rate of complete remission and a 35 to 40% rate of partial remission. The drug was well tolerated with minimal adverse events. CONCLUSIONS Although rituximab may prove to be a better treatment option for MN than alkylating agents or calcineurin inhibitors, the current literature only supports using the drug in research protocols. Whether, when, how, and why to use rituximab in MN remains to be determined.

Association of Sickle Cell Trait With Chronic Kidney Disease and Albuminuria in African Americans

IMPORTANCE The association between sickle cell trait (SCT) and chronic kidney disease (CKD) is uncertain. OBJECTIVE To describe the relationship between SCT and CKD and albuminuria in self-identified African Americans. DESIGN, SETTING, AND PARTICIPANTS Using 5 large, prospective, US population-based studies (the Atherosclerosis Risk in Communities Study [ARIC, 1987-2013; n = 3402], Jackson Heart Study [JHS, 2000-2012; n = 2105], Coronary Artery Risk Development in Young Adults [CARDIA, 1985-2006; n = 848], Multi-Ethnic Study of Atherosclerosis [MESA, 2000-2012; n = 1620], and Womens Health Initiative [WHI, 1993-2012; n = 8000]), we evaluated 15,975 self-identified African Americans (1248 participants with SCT [SCT carriers] and 14,727 participants without SCT [noncarriers]). MAIN OUTCOMES AND MEASURES Primary outcomes were CKD (defined as an estimated glomerular filtration rate [eGFR] of <60 mL/min/1.73 m2 at baseline or follow-up), incident CKD, albuminuria (defined as a spot urine albumin:creatinine ratio of >30 mg/g or albumin excretion rate >30 mg/24 hours), and decline in eGFR (defined as a decrease of >3 mL/min/1.73 m2 per year). Effect sizes were calculated separately for each cohort and were subsequently meta-analyzed using a random-effects model. RESULTS A total of 2233 individuals (239 of 1247 SCT carriers [19.2%] vs 1994 of 14,722 noncarriers [13.5%]) had CKD, 1298 (140 of 675 SCT carriers [20.7%] vs 1158 of 8481 noncarriers [13.7%]) experienced incident CKD, 1719 (150 of 665 SCT carriers [22.6%] vs 1569 of 8249 noncarriers [19.0%]) experienced decline in eGFR, and 1322 (154 of 485 SCT carriers [31.8%] vs 1168 of 5947 noncarriers [19.6%]) had albuminuria during the study period. Individuals with SCT had an increased risk of CKD (odds ratio [OR], 1.57 [95% CI, 1.34-1.84]; absolute risk difference [ARD], 7.6% [95% CI, 4.7%-10.8%]), incident CKD (OR, 1.79 [95% CI, 1.45-2.20]; ARD, 8.5% [95% CI, 5.1%-12.3%]), and decline in eGFR (OR, 1.32 [95% CI, 1.07-1.61]; ARD, 6.1% [95% CI, 1.4%-13.0%]) compared with noncarriers. Sickle cell trait was also associated with albuminuria (OR, 1.86 [95% CI, 1.49-2.31]; ARD, 12.6% [95% CI, 7.7%-17.7%]). CONCLUSIONS AND RELEVANCE Among African Americans in these cohorts, the presence of SCT was associated with an increased risk of CKD, decline in eGFR, and albuminuria, compared with noncarriers. These findings suggest that SCT may be associated with the higher risk of kidney disease in African Americans.

Sickle-Cell Trait: Novel Clinical Significance

There is a long-standing controversy in the literature as to whether sickle-cell trait (SCT) should be viewed as a benign carrier state or as an intermediate disease phenotype. Because SCT is routinely detected by neonatal screening for sickle-cell disease, it becomes imperative that consensus on this issue be achieved in order to provide the best medical advice to affected individuals. The issue of selective screening in the post-neonatal period was thrust into the limelight recently by the National Collegiate Athletic Associations recommendation that its member colleges and universities test student-athletes to confirm their carrier status if not already known. The stated goal of this recommendation was to prevent exercise-related sudden death in athletes with SCT. We review some of the reported complications of SCT for which new information has emerged, focusing particularly on venous thromboembolism and renal manifestations.

High Prevalence of Sickle Cell Trait in African Americans with ESRD

Sickle cell trait (HbAS) associates with impaired urinary concentration, hematuria, and renal papillary necrosis, but its prevalence among African Americans with ESRD is unknown. We performed a cross-sectional study reviewing available hemoglobin phenotypes for 188 of 206 adult African-American patients receiving renal replacement therapy in four dialysis units. Results from the state newborn screening program in corresponding counties provided the local population prevalence of sickle trait among African Americans. Compared with the general African-American population, HbAS was twice as common among African Americans with ESRD (15% versus 7%, P < 0.001). Prevalence of hemoglobin C trait (HbAC) was similarly more common (5% versus 2%, P < 0.01). The higher prevalence of HbAS and HbAC in the ESRD population raises the possibility that these hemoglobinopathies contribute to a decline in kidney function, either alone or in conjunction with other known risk factors for renal disease. The potential effect of HbAS on the development and progression of CKD and its effect on the course and management of patients with ESRD deserve further study.

The glomerulopathy of sickle cell disease

Sickle cell disease (SCD) produces many structural and functional abnormalities in the kidney, including glomerular abnormalities. Albuminuria is the most common manifestation of glomerular damage, with a prevalence between 26 and 68% in adult patients. The pathophysiology of albuminuria in SCD is likely multifactorial, with contributions from hyperfiltration, glomerular hypertension, ischemia‐reperfusion injury, oxidative stress, decreased nitric oxide (NO) bioavailability, and endothelial dysfunction. Although its natural history in SCD remains inadequately defined, albuminuria is associated with increased echocardiography‐derived tricuspid regurgitant jet velocity, systemic blood pressure, and hypertension, as well as history of stroke, suggesting a shared vasculopathic pathophysiology. While most patients with albuminuria are treated with angiotensin converting enzyme inhibitors/angiotensin receptor blockers, there are no published long‐term data on the efficacy of these agents. With the improved patient survival following kidney transplantation, SCD patients with end‐stage renal disease should be considered for this treatment modality. Given the high prevalence of albuminuria and its association with multiple SCD‐related clinical complications, additional studies are needed to answer several clinically important questions in a bid to adequately elucidate its pathophysiology, natural history, and treatment. Am. J. Hematol. 89:907–914, 2014.

Prospective study of sickle cell trait and venous thromboembolism incidence.

Sickle cell trait may increase risk of venous thromboembolism, but this is not fully established.

Diagnostic significance of peritubular capillary basement membrane multilaminations in kidney allografts: Old concepts revisited

Background Injury to peritubular capillaries and capillary basement membrane multilamination (PTCL) is a hallmark of antibody-mediated chronic renal allograft rejection. However, the predictive diagnostic value of PTCL is incompletely studied. Methods We analyzed the diagnostic significance of PTCL and propose diagnostic strategies. We evaluated 360 diagnostic native and 187 transplant kidney specimens by electron microscopy (terminology: PTCL-C, severe; PTCL subgroup C3, very severe multilamination; see Materials and Methods for definitions). Results PTCL was not pathognomonic for any specific disease. PTCL-C/C3 was rare in native kidneys (C, 6%; C3, 1%), associated mainly with late thrombotic microangiopathy (C: 78%; C3: 11% of cases). In allografts, PTCL-C/C3 was significantly more common, especially in specimens more than 24 months after transplantation (C, 47%; C3, 31%). PTCL-C/C3 was found in acute (C, 20%; C3, 7%) and chronic T-cell rejection (C, 67%; C3, 29%), calcineurin inhibitor toxicity (C, 36%; C3, 18%), or C4d+ specimens (C, 61%; C3, 50%) with odds ratios between 4 and 36. PTCL-C3 was more predominant in cases with antibody-mediated injury. Highest odds ratios (81–117) for PTCL-C/C3 were noted in combined injuries, that is, mixed chronic T-cell and concurrent chronic antibody–mediated rejection. Positive predictive values of PTCL-C and C3 are the following: all rejection types, 89% and 93%; all Banff chronic rejection types, 69% and 71%; and chronic presumptive antibody rejection, 37% and 49%, respectively. Corresponding negative predictive values of C and C3 for different Banff rejection categories are between 50% and 94%. Conclusions The presence of PTCL-C3 is a helpful adjunct finding to diagnose rejection-induced tissue injury but cannot precisely predict the Banff rejection category. Conversely, the absence of PTCL-C3 is helpful in excluding chronic, Banff category II antibody–mediated rejection.

Hydroxyurea is associated with lower prevalence of albuminuria in adults with sickle cell disease

BACKGROUND Albuminuria is an early manifestation of sickle cell nephropathy. Prior small case series suggests benefit of hydroxyurea in reducing albuminuria, with a similar trend noted in pediatric studies. We aimed to comprehensively evaluate hydroxyurea use and prevalence of albuminuria in adult sickle cell patients. METHODS We performed a cross-sectional study of 149 adult patients followed between 2000 and 2011 in a comprehensive sickle cell clinic. All patients were assessed for albuminuria either by direct measurement or by urinary chemical strip (dipstick) testing. Urinary albumin-to-creatinine ratios (UACRs) were available for 112 patients. Hydroxyurea exposure was defined as ≥3 months of therapy before the assessment of albuminuria. Albuminuria was defined as either UACR ≥30 mg/g or ≥1+ proteinuria on two separate dipsticks. We constructed a multivariate logistic regression model to assess the association between hydroxyurea and albuminuria. RESULTS The prevalence of albuminuria was lower among patients on hydroxyurea (34.7 versus 55.4%; P = 0.01) as was median albumin excretion (17.9 versus 40.5 mg/g; P = 0.04). In multivariate analysis, hydroxyurea was associated with a lower likelihood of albuminuria (odds ratio 0.28, 95% CI: 0.11-0.75, P = 0.01), adjusting for age, angiotensin-converting enzyme inhibitor/angiotensin receptor blocker use, tricuspid regurgitant jet velocity, hypertension and acute chest syndrome. CONCLUSIONS In our population of sickle cell patients, those using hydroxyurea were less than one-third as likely to exhibit albuminuria. Hydroxyurea use may prevent development of overt nephropathy or the progression of sickle cell disease nephropathy to end-stage renal disease, and its use for this indication merits further investigation.