Varun Agrawal

Accelerated Atherosclerotic Calcification and Mönckeberg's Sclerosis: A Continuum of Advanced Vascular Pathology in Chronic Kidney Disease

Autopsy studies have demonstrated the near universal presence of fatty streaks and fibroatheromas in the general population from which patients with chronic kidney disease (CKD) arise. The vast majority of patients with CKD have multiple conventional cardiovascular risk factors. Vascular atherosclerotic calcification develops in most patients as they transition from the general population to significant CKD as part of cholesterol crystallization within atherosclerotic lesions. Once present, however, atherosclerotic medial calcification can become prominent and has been previously identified as Mönckebergs sclerosis. A unifying concept supported by the preponderance of pathologic evidence contends that Mönckebergs sclerosis is a manifestation of accelerated atherosclerosis in patients with CKD. The term has also been used in rare cases to describe vascular calcinosis not related to CKD. This clarification is critical to advance the field in terms of pathologic diagnosis and treatment of CKD bone and mineral disorder. Factors that seem to promote the osteoblastic transformation of vascular smooth muscle cells and enhance deposition of calcium hydroxyapatite crystals include phosphorus activation of the Pit-1 receptor, bone morphogenic proteins 2 and 4, leptin, endogenous 1,25 dihydroxyvitamin D, vascular calcification activating factor, and measures of oxidative stress. These entities work to accelerate the atherosclerotic process in patients with CKD and may be future targets for diagnosis and treatment because randomized trials with hydroxymethylglutaryl-CoA reductase inhibitors have failed to attenuate the rate of progressive vascular calcification.

Cardiovascular implications of proteinuria: an indicator of chronic kidney disease

Proteinuria, defined as urine protein excretion greater than 300 mg over 24 h, is a strong and independent predictor of increased risk for all-cause and cardiovascular mortality in patients with and without diabetes. Proteinuria is a sign of persistent dysfunction of the glomerular barrier and often precedes any detectable decline in renal filtration function. Measurement of proteinuria is important in stratifying the risk for cardiovascular disease and chronic kidney disease progression. A variety of basic pathophysiologic mechanisms that can partially explain simultaneous renal and cardiac disease will be discussed in this Review. In addition to being a prognostic marker, proteinuria is being considered as a therapeutic target in cardiovascular medicine. Therapeutic strategies for amelioration of proteinuria by achieving blood pressure targets, glycemic control in diabetes, treatment of hyperlipidemia, and reducing dietary salt and protein intake are also reviewed in this paper. Future clinical studies are needed to assess if proteinuria reduction should be a target of treatment to reduce the burden of end-stage renal disease, cardiovascular disease, and improve survival in this high-risk population.

Relation between degree of weight loss after bariatric surgery and reduction in albuminuria and C-reactive protein.

BACKGROUND Bariatric surgery achieves long-term weight loss in obese adults with amelioration of diabetes and hypertension. Improvement in albuminuria and high-sensitivity C-reactive protein (hs-CRP) has also been reported. We investigated, at a weight control center in a community hospital setting, the relation between degree of surgical weight loss and reduction in the cardiovascular risk markers, albuminuria and hs-CRP. METHODS We performed a retrospective study of 62 obese adults who had undergone Roux-en-Y gastric bypass surgery and had a median follow-up of 15 months. RESULTS The baseline (preoperative) mean age was 46 years, 82% were women, 26 had a blood pressure of > or =140/90 mm Hg, and 25 had type 2 diabetes. During follow-up (postoperative), a decrease occurred in the body mass index (mean +/- standard deviation 49.2 +/- 8.7 kg/m(2) to 34.1 +/- 8.1 kg/m(2); P <.0001), excess body weight (mean +/- SD 76.1 +/- 23.6 kg to 34.9 +/- 21.7 kg; P <.0001), hemoglobin A1c (mean +/- SD 6.5% +/- 1.3% to 5.6% +/- 0.8%; P <.0001), systolic blood pressure (mean +/- SD 133.7 +/- 14.3 mm Hg to 112.9 +/- 14.6 mm Hg; P < .0001), urine albumin creatinine ratio (from a median of 8.0 mg/g [interquartile range 5.0-29.3] to a median of 6.0 mg/g [interquartile range 3.3-11.5]; P <.0001), and hs-CRP (mean +/- SD 11.2 +/- 9.8 mg/L to 4.7 +/- 5.9 mg/L; P <.0001). The study sample was divided into tertiles of the percentage of excess body weight loss; the mean percentage of excess body weight loss was -37.1% +/- 5.5% in the first tertile, -54.3% +/- 6.8% in the second tertile, and -75.8% +/- 10.9% in the third tertile. The median percentage of change in albuminuria was greatest (median -52.8%, interquartile range -79.1% to -17.5%) in the third tertile, intermediate (median -45.5%, interquartile range -72.4% to 0%) in the second tertile, and lowest (-42.6%, interquartile range -80.5% to 16.7%) in the first tertile (P = .953). The mean percentage of change in hs-CRP was greatest (-72.4% +/- 30.4%) in the third tertile, intermediate (-55.4% +/- 31.9%) in the second tertile, and lowest (-44.8% +/- 30.6%) in the first tertile (P = .037). CONCLUSION The results of our study have shown that obese adults experience a reduction in albuminuria and hs-CRP after bariatric surgery, with a greater reduction in hs-CRP observed with more surgical weight loss.

Awareness and Knowledge of Clinical Practice Guidelines for CKD Among Internal Medicine Residents: A National Online Survey

BACKGROUND The National Kidney Foundation published Kidney Disease Outcomes Quality Initiative guidelines that recommend early detection and management of chronic kidney disease (CKD) and timely referral to a nephrologist. Many patients with CKD are seen by primary care physicians who are less experienced than nephrologists to offer optimal pre-end-stage renal disease care. It is not known whether current postgraduate training adequately prepares a future internist in CKD management. STUDY DESIGN Cross-sectional study using an online questionnaire survey. SETTING & PARTICIPANTS Internal medicine residents in the United States (n = 479) with postgraduate year (PGY) distribution of 166 PGY1, 187 PGY2, and 126 PGY3. PREDICTOR Awareness and knowledge of CKD clinical practice guidelines measured by using the questionnaire instrument. OUTCOMES & MEASUREMENTS Total performance score (maximum = 30). RESULTS Half the residents did not know that the presence of kidney damage (proteinuria) for 3 or more months defines CKD. One-third of the residents did not know the staging of CKD. All residents (99%) knew the traditional risk factors for CKD of diabetes and hypertension, but were less aware of other risk factors of obesity (38%), elderly age (71%), and African American race (68%). Most residents (87%) were aware of estimated glomerular filtration rate in the evaluation of patients with CKD. Most residents (90%) knew goal blood pressure (<130/80 mm Hg) for patients with CKD. Most residents identified anemia (91%) and bone disorder (82%) as complications of CKD, but only half recognized CKD as a risk factor for cardiovascular disease. Most residents (90%) chose to refer a patient with a glomerular filtration rate less than 30 mL/min/1.73 m(2) to a nephrologist. A small improvement in mean performance score was observed with increasing PGY (PGY1, 68.8% +/- 15.4%; PGY2, 72.9% +/- 14.7%; and PGY3, 74.0% +/- 12.0%; P = 0.004). LIMITATIONS Self-selection, lack of nonrespondent data. CONCLUSIONS Our survey identified specific gaps in knowledge of CKD guidelines in internal medicine residents. Educational efforts in increasing awareness of these guidelines may improve CKD management and clinical outcomes.

Impact of treating the metabolic syndrome on chronic kidney disease.

The metabolic syndrome is defined by the concurrent presence of at least three metabolic disorders that are associated with an increased risk of cardiovascular disease and diabetes. Results from prospective and cross-sectional studies also point to an association between the metabolic syndrome and chronic kidney disease. Visceral obesity and insulin resistance are two important features of the metabolic syndrome that might explain renal injury. We reviewed the literature to examine whether treatment of the metabolic syndrome can favorably influence renal outcomes. Weight loss, regular exercise, and a low-calorie, low-fat diet are first-line treatments of the metabolic syndrome, yet few data are available to indicate that such lifestyle interventions can prevent or reverse renal damage. Similarly, results from few studies show little or no beneficial effect of blood pressure control, use of statins, fibrates, thiazolidinediones or metformin on renal parameters in patients with metabolic syndrome. The reasons for the lack of trials in this research field are also discussed. This Review identifies the need to improve understanding of the role of metabolic syndrome in chronic kidney disease, define consistent criteria for metabolic syndrome and perform clinical trials that analyze renal outcomes as primary end points.

Cardiorespiratory fitness and obstructive sleep apnea syndrome in morbidly obese patients.

BACKGROUND Conflicting data exist regarding the effects of obstructive sleep apnea syndrome (OSAS) on cardiorespiratory fitness in morbidly obese individuals with normal resting left ventricular function. METHODS Ninety-two morbidly obese subjects without any prior diagnosis of OSAS underwent cardiorespiratory fitness testing, two-dimensional echocardiography, and overnight polysomnography. Using the results of the polysomnogram, comparisons were made between subjects with (n = 42) and without (n = 50) OSAS. RESULTS Mean body mass index (BMI) for the study population (n = 92) was 48.6 +/- 9.3 kg/m(2) (+/- SD); mean age was 45.5 +/- 9.8 years, and approximately 69% were female. Despite having a higher resting, exercise, and resting mean arterial pressures, the OSAS cohort had a maximum oxygen consumption that was lower than the cohort without OSAS (21.1 mL/kg/min vs 17.6 mL/kg/min; p < 0.001). There was no difference in BMI, age, gender, waist circumference, and neck circumference between those with and without OSAS. Differences were observed between the cohorts in systolic BP, diastolic BP, and heart rate during rest, exercise, and recovery periods. There was no difference in ejection fraction, diastolic dysfunction, and treadmill test duration between cohorts. CONCLUSIONS Morbidly obese individuals with OSAS demonstrate reduced cardiorespiratory fitness and differing hemodynamic responses to exercise testing as compared with their counterparts without this disorder. These data suggest chronic sympathetic nervous system activation negatively influences aerobic capacity in OSAS.

Perception of Indications for Nephrology Referral among Internal Medicine Residents: A National Online Survey

BACKGROUND AND OBJECTIVES Many patients with chronic kidney disease (CKD) are seen by primary care physicians who may not be aware of indications or benefits of timely nephrologist referral. Late referral to a nephrologist may lead to suboptimal pre-end stage renal disease care and greater mortality. It is not known whether current postgraduate training adequately prepares a future internist in this aspect of CKD management. DESIGN, SETTING, PARTICIPANTS, AND MEASUREMENTS The authors performed an online questionnaire survey of internal medicine residents in the United States to determine their perceptions of indications for nephrology referral in CKD management. RESULTS Four hundred seventy-nine residents completed the survey with postgraduate year (PGY) distribution of 166 PGY 1,187 PGY 2 and 126 PGY 3. Few residents chose nephrology referral for proteinuria (45%), uncontrolled hypertension (64%), or hyperkalemia (26%). Twenty-eight percent of the residents considered consulting a nephrologist for anemia of CKD, whereas 45% would do so for bone disorder of CKD. Most of the residents would involve a nephrologist at glomerular filtration rate (GFR) <30 ml/min/1.73 m(2) (90%) and for rapid decline in GFR (79%). Many residents would refer a patient for dialysis setup at GFR 15 to 30 ml/min/1.73 m(2) (59%); however, 18% would do so at GFR <15 ml/min/1.73 m(2). Presence of CKD clinic experience or an in-house nephrology fellowship program did not considerably change these perceptions. CONCLUSIONS Results show that internal medicine residents have widely differing perceptions of indications for nephrology referral. Educational efforts during residency training to raise awareness and benefits of early referral may improve CKD management by facilitating better collaboration between internist and nephrologist.

Albuminuria and renal function in obese adults evaluated for obstructive sleep apnea.

Background: Obstructive sleep apnea (OSA) is associated with hypertension, obesity and metabolic syndrome that are risk factors for cardiovascular and chronic kidney disease. Few data are available regarding renal parameters in patients with OSA. Methods: We conducted a cross-sectional study of 91 obese adults who had routine polysomnography before bariatric surgery. Presence and severity of OSA were determined by the apnea-hypopnea index (AHI <5 = no OSA and AHI ≥5 = OSA). Clinical and laboratory data were available within a month of polysomnography. Results: Mean ± SD age was 44.9 ± 9.9 years. There were 66 women. Mean ± SD body mass index was 48.3 ± 8.9 kg/m2 with hypertension and type 2 diabetes present in 55 and 31 subjects, respectively. There were 36 subjects with no OSA and 55 with OSA. The two groups had similar demographic characteristics, blood pressure (BP), lipid profile and medication use except for difference in mean ± SD hemoglobin A1c (5.6 ± 0.6% in no OSA, 6.0 ± 0.8% in OSA; p = 0.029) and use of renin-angiotensin system blocking agents (22.2% in no OSA, 46.4% in OSA; p = 0.024). Median (interquartile range) urine albumin:creatinine ratio (ACR) was not different between the two groups [6 (4–14.5) mg/g in no OSA, 8 (5–16) mg/g in OSA; p = 0.723], while significant difference existed in serum creatinine (0.8 ± 0.2 mg/dl in no OSA, 0.9 ± 0.2 mg/dl in OSA, p = 0.013). Age- and gender-adjusted correlations were observed between log-log ACR and systolic BP (r = 0.265; p = 0.016), log-log ACR and diastolic BP (r = 0.245; p = 0.026) and between serum creatinine and log AHI (r = 0.188, p = 0.089). Multiple linear regression analysis demonstrated log-log ACR to be associated with diastolic BP (p = 0.046), while serum creatinine was associated with log AHI (p = 0.044). Conclusion: In obese adults, increasing severity of OSA is associated with higher serum creatinine but not greater degree of albuminuria.

Renal Sarcoidosis Presenting as Acute Kidney Injury With Granulomatous Interstitial Nephritis and Vasculitis

Among the various renal manifestations of sarcoidosis, granulomatous inflammation confined to the tubulointerstitial compartment is the most commonly reported finding. We present the case of a 66-year-old man with acute kidney injury, hypercalcemia, mild restrictive pulmonary disease, and neurologic signs of parietal lobe dysfunction. Kidney biopsy showed diffuse interstitial inflammation with noncaseating granulomas that exhibited the unusual feature of infiltrating the walls of small arteries with destruction of the elastic lamina, consistent with granulomatous vasculitis. The findings of granulomatous interstitial nephritis on kidney biopsy, hypercalcemia, and possible cerebral and pulmonary involvement in the absence of other infectious, drug-induced, or autoimmune causes of granulomatous disease established the diagnosis of sarcoidosis. Pulse methylprednisolone followed by maintenance prednisone therapy led to improvement in kidney function, hypercalcemia, and neurologic symptoms. Vasculocentric granulomatous interstitial nephritis with granulomatous vasculitis is a rare and under-recognized manifestation of renal sarcoidosis.

Calcium oxalate supersaturation increases early after Roux-en-Y gastric bypass

BACKGROUND Calcium oxalate (CaOx) nephrolithiasis is an adverse effect of Roux-en-Y gastric bypass surgery (RYGB). It is unknown when the increased risk for CaOx stone formation occurs after surgery. METHODS We studied 13 morbidly obese adults undergoing RYGB with 24-hour urine collections at 4 weeks before and 1, 2, 4, and 6 months after surgery and computed CaOx relative saturation ratio (RSR) by EQUIL2. RESULTS Eleven patients were female, mean ± standard deviation age was 41.1 ± 7.2 years, and none had diabetes or chronic kidney disease. Median (interquartile range) urinary oxalate excretion increased linearly from 12.6 (10.9-37.9) mg/24 hr at baseline to 28.4 (14.4-44.0) mg/24 hr at 6 months (slope = .188; P = .005). CaOx RSR increased significantly at 2 months after RYGB (1.4 [1.2-2.4] to 4.9 [1.7-10.0]; P = .017) and rose throughout the study to 5.7 (3.7-12.2) at 6 months (P = .001) with a positive linear slope (.255; P = .001). One patient had critical CaOx supersaturation (RSR = 34.7) and severe hyperoxaluria (101.7 mg/24 hr) at 6 months after RYGB. Significant decreases over time were seen in urine volume and sodium and potassium excretion, but no changes were noted in urinary pH, calcium, magnesium, or citrate. CONCLUSIONS Our data suggest that CaOx RSR, and thus risk for nephrolithiasis, rises as early as 2 months after RYGB and increases gradually in the first 6 months, largely because of reduced urine volume and increased urinary oxalate excretion. Interventions to reduce CaOx RSR, such as adequate fluid intake and agents to bind enteric oxalate, need to be evaluated in patients at risk for nephrolithiasis after RYGB.