Dana V. Rizk

Quality of life in autosomal dominant polycystic kidney disease patients not yet on dialysis

BACKGROUND AND OBJECTIVES Autosomal dominant polycystic kidney disease (ADPKD) is an inherited progressive disorder associated with significant pain and discomfort affecting quality of life. This study determined the impact of pain medication use and other clinical, biochemical and genetic characteristics on the physical and mental well being of predialysis ADPKD patients using the Short Form 36 (SF-36) questionnaire. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS The authors prospectively evaluated ADPKD patients in the Cohort Study, funded by the Polycystic Kidney Disease Foundation. Data on clinical, biochemical, and radiologic variables were collected in patients who were given the Short Form-36 questionnaire. Variables independently associated with the Physical Component Summary (PCS) and the Mental Component Summary (MCS) scores were identified. RESULTS One hundred fifty-two patients had a mean PCS and MCS of 46.9 +/- 11.3 and 51.0 +/- 9.0, similar to the general population and better than the ESRD population. Eleven (7%) reported pain medication intake within 1 mo of evaluation and demonstrated lower PCS than those not taking pain medications. Patients with GFR >or= 80 ml/min/1.73 m(2) had greater PCS than those with GFR < 80 ml/min/1.73 m(2). Age, BMI, pulse pressure, pain medication use, and education level independently associate with PCS and account for 32% of the variability of the measurement. Pulse pressure correlated with MCS. CONCLUSIONS Predialysis ADPKD patients assess their quality of life similar to the general population. Age, BMI, pulse pressure, pain medication intake, and education level link to their physical well-being.

Age-Specific Association of Reduced Estimated Glomerular Filtration Rate and Albuminuria with All-Cause Mortality

BACKGROUND AND OBJECTIVES It has been suggested that reduced estimated GFR (eGFR) among older adults does not necessarily reflect a pathologic phenomenon. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS We examined the association between eGFR and albumin-to-creatinine ratio (ACR) and all-cause mortality stratified by age (45 to 59.9, 60 to 69.9, 70 to 79.9, and ≥80 years) among 24,350 U.S. adults in the population-based REasons for Geographic and Racial Differences in Stroke (REGARDS) study. A spot urine sample was used to calculate ACR, and the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation was used to calculate eGFR. All-cause mortality was assessed over a median follow-up of 4.5 years. RESULTS Among participants ≥80 years of age (n = 1669), the age, race, gender, and geographic region of residence adjusted hazard ratios (95% confidence intervals) for mortality associated with eGFR levels of 45 to 59.9 and <45 ml/min per 1.73 m(2), versus ≥60 ml/min per 1.73 m(2), were 1.6 (1.3 - 2.1) and 2.2 (1.7 - 2.9), respectively. Also, among participants ≥80 years of age, the hazard ratios for mortality associated with ACR levels of 10 to 29.9, 30 to 299.9, and ≥300 mg/g, versus <10 mg/g, were 1.7 (1.3 - 2.1), 2.5 (1.9 - 3.3), and 5.1 (3.6 - 7.4), respectively. These associations were present after further multivariable adjustment and within the younger age groupings studied. CONCLUSIONS These data suggest that reduced eGFR and albuminuria confer an increased risk for mortality in all age groups, including adults ≥80 years of age.

Cardiovascular Risk Factors in CKD Associate with Both ESRD and Mortality

The American Heart Associations Lifes Simple 7 initiative allows individuals to assess health factors (BP, cholesterol, and glucose) and health behaviors (cigarette smoking, physical activity, diet, and body mass index) to promote improved cardiovascular health. Because several cardiovascular risk factors also associate with progressive kidney disease, Lifes Simple 7 may also inform an individuals risk for ESRD. Here, we investigated the association of Lifes Simple 7 components with both ESRD incidence and all-cause mortality among 3093 participants with an estimated GFR (eGFR) <60 ml/min per 1.73 m(2) from the population-based Reasons for Geographic and Racial Differences in Stroke (REGARDS) Study. During a median 4 years of follow-up, 160 participants developed ESRD, and 610 participants died. Compared with individuals who had zero or one of the Lifes Simple 7 components in the ideal range, those individuals with two, three, and four ideal factors had progressively lower risks for ESRD; furthermore, no participant with five to seven ideal factors developed ESRD. The risk for all-cause mortality exhibited a similar trend. Adjusting for eGFR and albuminuria, however, completely attenuated the associations between the number of ideal factors and the risks for both ESRD and all-cause mortality. In conclusion, a favorable cardiovascular risk profile among individuals with CKD associates with a reduced risk for ESRD and mortality, but whether the severity of kidney disease confounds or mediates this association requires additional investigation.

Racial differences in albuminuria, kidney function, and risk of stroke

Background: The objective of this study was to examine the joint associations of estimated glomerular filtration rate (eGFR) and urinary albumin excretion with incident stroke in a large national cohort study. Methods: Associations of urinary albumin to creatinine ratio (ACR) and eGFR with incident stroke were examined in 25,310 participants of the Reasons for Geographic and Racial Differences in Stroke (REGARDS) study, a prospective study of black and white US adults ≥45 years of age. Results: A total of 548 incident strokes were observed over a median of 4.7 years of follow-up. Higher ACR values were associated with lower stroke-free survival in both black and white participants. Among black participants, as compared to an ACR <10 mg/g, the hazard ratios of stroke associated with an ACR of 10–29.99, 30–300, and >300 mg/g were 1.41 (95% confidence interval [CI] 1.01–1.98), 2.10 (95% CI 1.48–2.99), and 2.70 (95% CI 1.58–4.61), respectively, in analyses adjusted for traditional stroke risk factors and eGFR. In contrast, the hazard ratios among white subjects were only modestly elevated and not statistically significant after adjustment for established stroke risk factors. eGFR <60 mL/min/1.73 m2 was not associated with incident stroke in black or white participants after adjustment for established stroke risk factors. Conclusions: Higher ACR was independently associated with higher risk of stroke in black but not white participants from a national cohort. Elucidating the reasons for these findings may uncover novel mechanisms for persistent racial disparities in stroke.

Association between urinary albumin excretion and coronary heart disease in black vs white adults.

IMPORTANCE Excess urinary albumin excretion is more common in black than white individuals and is more strongly associated with incident stroke risk in black vs white individuals. Whether similar associations extend to coronary heart disease (CHD) is unclear. OBJECTIVE To determine whether the association of urinary albumin excretion with CHD events differs by race. DESIGN, SETTING, AND PARTICIPANTS Prospective cohort study of black and white US adults aged 45 years and older who were enrolled within the Reasons for Geographic and Racial Differences in Stroke (REGARDS) study between 2003 and 2007 with follow-up through December 31, 2009. We examined race-stratified associations of urinary albumin-to-creatinine ratio (ACR) in 2 groups: (1) incident CHD among 23,273 participants free of CHD at baseline; and (2) first recurrent CHD event among 4934 participants with CHD at baseline. MAIN OUTCOMES AND MEASURES Expert-adjudicated incident and recurrent myocardial infarction and acute CHD death. RESULTS A total of 616 incident CHD events (421 nonfatal MIs and 195 CHD deaths) and 468 recurrent CHD events (279 nonfatal MIs and 189 CHD deaths) were observed over a mean time of 4.4 years of follow-up. Among those free of CHD at baseline, age- and sex-adjusted incidence rates of CHD per 1000 person-years of follow-up increased with increasing categories of ACR in black and white participants, with rates being nearly 1.5-fold greater in the highest category of ACR (>300 mg/g) in black participants (20.59; 95% CI, 14.36-29.51) vs white participants (13.60; 95% CI, 7.60-24.25). In proportional hazards models adjusted for traditional cardiovascular risk factors and medications, higher baseline urinary ACR was associated with greater risk of incident CHD among black participants (hazard ratio [HR] comparing ACR >300 vs <10 mg/g, 3.21 [95% CI, 2.02-5.09]) but not white participants (HR comparing ACR >300 vs <10 mg/g, 1.49 [95% CI, 0.80-2.76]) (P value for interaction = .03). Among those with CHD at baseline, fully adjusted associations of baseline urinary ACR with first recurrent CHD event were similar between black participants (HR comparing ACR >300 vs <10 mg/g, 2.21 [95% CI, 1.22-4.00]) vs white participants (HR comparing ACR >300 vs <10 mg/g, 2.48 [95% CI, 1.61-3.78]) (P value for interaction = .53). CONCLUSIONS AND RELEVANCE Higher urinary ACR was associated with greater risk of incident but not recurrent CHD in black individuals when compared with white individuals. These data confirm that black individuals appear more susceptible to vascular injury.

Treatment of autosomal dominant polycystic kidney disease (ADPKD): the new horizon for children with ADPKD

Polycystic kidney disease (PKD) is the most common inherited renal disorder. Patients with PKD remain clinically asymptomatic for decades, while significant anatomic and physiologic systemic changes take place. Sequencing of the responsible genes and identification of their protein products have significantly expanded our understanding of the pathophysiology of PKD. The molecular basis for cystogenesis is being unraveled, leading to new targets for therapy and giving hope to millions of people suffering from PKD. This has direct implications for children with PKD with regard to screening for the disease and identification of high-risk individuals. In this article we provide a review of the clinical manifestations in children with autosomal dominant polycystic kidney disease (ADPKD), the genetic and molecular basis for the disease, and a concise review of potential therapies being evaluated.

Warfarin-related nephropathy: another newly recognized complication of an old drug

Since its approval in the 1950s, warfarin has been the most often prescribed anticoagulant, with attendant risks of bleeding. Brodsky et al. describe another potential complication of warfarin therapy. Warfarin-related nephropathy (WRN) has been described in patients with chronic kidney disease and appears to accelerate the rate of progression and increase the risk of death. The interactions between warfarin and chronic kidney disease are complex, and the recognition of the potential complications is expanding.

The Origin and Activities of IgA1-Containing Immune Complexes in IgA Nephropathy.

IgA nephropathy (IgAN) is the most common primary glomerulonephritis, frequently leading to end-stage renal disease, as there is no disease-specific therapy. IgAN is diagnosed from pathological assessment of a renal biopsy specimen based on predominant or codominant IgA-containing immunodeposits, usually with complement C3 co-deposits and with variable presence of IgG and/or IgM. The IgA in these renal deposits is galactose-deficient IgA1, with less than a full complement of galactose residues on the O-glycans in the hinge region of the heavy chains. Research from the past decade led to the definition of IgAN as an autoimmune disease with a multi-hit pathogenetic process with contributing genetic and environmental components. In this process, circulating galactose-deficient IgA1 (autoantigen) is bound by antiglycan IgG or IgA (autoantibodies) to form immune complexes. Some of these circulating complexes deposit in glomeruli, and thereby activate mesangial cells and induce renal injury through cellular proliferation and overproduction of extracellular matrix components and cytokines/chemokines. Glycosylation pathways associated with production of the autoantigen and the unique characteristics of the corresponding autoantibodies in patients with IgAN have been uncovered. Complement likely plays a significant role in the formation and the nephritogenic activities of these complexes. Complement activation is mediated through the alternative and lectin pathways and probably occurs systemically on IgA1-containing circulating immune complexes as well as locally in glomeruli. Incidence of IgAN varies greatly by geographical location; the disease is rare in central Africa but accounts for up to 40% of native-kidney biopsies in eastern Asia. Some of this variation may be explained by genetically determined influences on the pathogenesis of the disease. Genome-wide association studies to date have identified several loci associated with IgAN. Some of these loci are associated with the increased prevalence of IgAN, whereas others, such as deletion of complement factor H-related genes 1 and 3, are protective against the disease. Understanding the molecular mechanisms and genetic and biochemical factors involved in formation and activities of pathogenic IgA1-containing immune complexes will enable the development of future disease-specific therapies as well as identification of non-invasive disease-specific biomarkers.

Prevalence and prognosis of unrecognized myocardial infarctions in chronic kidney disease

BACKGROUND Unrecognized myocardial infarctions (UMIs) are common in the general population but have not been well studied in patients with chronic kidney disease (CKD). The purpose of this study was to determine the prevalence and prognosis for mortality of UMI among adults with CKD. METHODS The current study included 18 864 participants in the population-based REasons for Geographic And Racial Differences in Stroke (REGARDS) study who completed a baseline examination including a 12-lead electrocardiogram (ECG). UMI was defined as the presence of myocardial infarction (MI) by Minnesota ECG classification in the absence of self-reported or recognized MI (RMI). Estimated glomerular filtration rate (eGFR) was calculated using the Chronic Kidney Disease Epidemiology Collaboration equation and albuminuria using albumin-to-creatinine ratio from a spot urine sample. All-cause mortality was assessed over a median 4 years of follow-up. RESULTS The prevalence of UMI was 4, 6, 6 and 13% among participants with eGFR levels of ≥ 60, 45-59.9, 30-44.9 and <30 mL/min/1.73 m(2), respectively, and 4, 5, 7 and 10% among participants with albuminuria levels of <10, 10-29.9, 30-299.9 and ≥ 300 mg/g, respectively. Compared to those with no MI, the multivariable adjusted hazard ratio for all-cause mortality associated with UMI and RMI was 1.65 [95% confidence interval (CI): 1.09-2.49] and 1.65 (95% CI: 1.20-2.26), respectively, among individuals with an eGFR <60 mL/min/1.73 m(2) and 1.49 (95% CI: 1.03-2.16) and 1.88 (95% CI: 1.40-2.52) among individuals with albuminuria ≥ 30 mg/g. Conclusion UMIs are common among individuals with an eGFR <60 mL/min/1.73 m(2) and albuminuria and associated with an increased mortality risk.

New Insights into the Pathogenesis of IgA Nephropathy

Background: IgA nephropathy, a frequent cause of end-stage renal disease, is an autoimmune disease wherein immune complexes consisting of IgA1 with galactose-deficient O-glycans (autoantigen) and anti-glycan autoantibodies deposit in glomeruli and induce renal injury. Multiple genetic loci associated with disease risk have been identified. The prevalence of risk alleles varies geographically: it is the highest in eastern Asia and northern Europe, lower in other parts of Europe and North America, and the lowest in Africa. IgA nephropathy is diagnosed by the pathological assessment of a renal biopsy specimen. Currently, therapy is not disease targeted but rather focused on maintaining control of blood pressure and proteinuria, ideally with suppression of angiotensin II. Possible additional approaches differ between countries. Disease-specific therapy as well as new tools for the diagnosis, prognosis, and assessment of responses to therapy are needed. Summary: Glycosylation pathways associated with aberrant O-glycosylation of IgA1 and, thus, production of autoantigen, have been identified. Furthermore, unique characteristics of the autoantibodies in IgA nephropathy have been uncovered. Many of these biochemical features are shared by patients with IgA nephropathy and Henoch-Schönlein purpura nephritis, suggesting that the two diseases may represent opposite ends of a spectrum of a disease process. Understanding the molecular mechanisms involved in the formation of pathogenic IgA1-containing immune complexes will enable the development of disease-specific therapies as well as diagnostic and prognostic biomarkers. Key Messages: IgA nephropathy is an autoimmune disease caused by the glomerular deposition of nephritogenic circulating immune complexes consisting of galactose-deficient IgA1 (autoantigen) bound by anti-glycan autoantibodies. A better understanding of the multi-step process of the pathogenesis of IgA nephropathy and the genetic and environmental contributing factors will lead to the development of biomarkers to identify patients with progressive disease who would benefit from a future disease-specific therapy.