Menaka Sarav

Renal FcRn Reclaims Albumin but Facilitates Elimination of IgG

The widely distributed neonatal Fc receptor (FcRn) contributes to maintaining serum levels of albumin and IgG in adults. In the kidney, FcRn is expressed on the podocytes and the brush border of the proximal tubular epithelium. Here, we evaluated the role of renal FcRn in albumin and IgG metabolism. Compared with wild-type controls, FcRn(-/-) mice had a lower t((1/2)) for albumin (28.7 versus 39.9 h) and IgG (29.5 versus 66.1 h). Renal loss of albumin could account for the former, suggested by the progressive development of hypoalbuminemia in wild-type mice transplanted with FcRn-deficient kidneys. Furthermore, serum albumin levels returned to normal in FcRn(-/-) recipients of wild-type kidneys after removing the native FcRn-deficient kidneys. In contrast, renal loss could not account for the enhanced elimination of IgG in FcRn(-/-) mice. These mice had minimal urinary excretion of native and labeled IgG, which increased to wild-type levels in FcRn(-/-) recipients of a single FcRn-sufficient kidney (t((1/2)) of IgG was 21.7 h). Taken together, these data suggest that renal FcRn reclaims albumin, thereby maintaining the serum concentration of albumin, but facilitates the loss of IgG from plasma protein pools.

Chronic kidney disease induced in mice by reversible unilateral ureteral obstruction is dependent on genetic background.

Chronic kidney disease (CKD) begins with renal injury; the progression thereafter depends upon a number of factors, including genetic background. Unilateral ureteral obstruction (UUO) is a well-described model of renal fibrosis and as such is considered a model of CKD. We used an improved reversible unilateral ureteral obstruction (rUUO) model in mice to study the strain dependence of development of CKD after obstruction-mediated injury. C57BL/6 mice developed CKD after reversal of three or more days of ureteral obstruction as assessed by blood urea nitrogen (BUN) measurements (>40 mg/dl). In contrast, BALB/c mice were resistant to CKD with up to 10 days ureteral obstruction. During rUUO, C57BL/6 mice exhibited pronounced inflammatory and intrinsic proliferative cellular responses, disruption of renal architecture, and ultimately fibrosis. By comparison, BALB/c mice had more controlled and measured extrinsic and intrinsic responses to injury with a return to normal within several weeks after release of ureteral obstruction. Our findings provide a model that allows investigation of the genetic basis of events during recovery from injury that contribute to the development of CKD.

A Technology-Based Quality Innovation to Identify Undiagnosed Hypertension Among Active Primary Care Patients

PURPOSE The goal of this study was to develop a technology-based strategy to identify patients with undiagnosed hypertension in 23 primary care practices and integrate this innovation into a continuous quality improvement initiative in a large, integrated health system. METHODS In phase 1, we reviewed electronic health records (EHRs) using algorithms designed to identify patients at risk for undiagnosed hypertension. We then invited each at-risk patient to complete an automated office blood pressure (AOBP) protocol. In phase 2, we instituted a quality improvement process that included regular physician feedback and office-based computer alerts to evaluate at-risk patients not screened in phase 1. Study patients were observed for 24 additional months to determine rates of diagnostic resolution. RESULTS Of the 1,432 patients targeted for inclusion in the study, 475 completed the AOBP protocol during the 6 months of phase 1. Of the 1,033 at-risk patients who remained active during phase 2, 740 (72%) were classified by the end of the follow-up period: 361 had hypertension diagnosed, 290 had either white-coat hypertension, prehypertension, or elevated blood pressure diagnosed, and 89 had normal blood pressure. By the end of the follow-up period, 293 patients (28%) had not been classified and remained at risk for undiagnosed hypertension. CONCLUSIONS Our technology-based innovation identified a large number of patients at risk for undiagnosed hypertension and successfully classified the majority, including many with hypertension. This innovation has been implemented as an ongoing quality improvement initiative in our medical group and continues to improve the accuracy of diagnosis of hypertension among primary care patients.

Summary Points and Consensus Recommendations from the International Protein Summit

The International Protein Summit in 2016 brought experts in clinical nutrition and protein metabolism together from around the globe to determine the impact of high-dose protein administration on clinical outcomes and address barriers to its delivery in the critically ill patient. It has been suggested that high doses of protein in the range of 1.2-2.5 g/kg/d may be required in the setting of the intensive care unit (ICU) to optimize nutrition therapy and reduce mortality. While incapable of blunting the catabolic response, protein doses in this range may be needed to best stimulate new protein synthesis and preserve muscle mass. Quality of protein (determined by source, content and ratio of amino acids, and digestibility) affects nutrient sensing pathways such as the mammalian target of rapamycin. Achieving protein goals the first week following admission to the ICU should take precedence over meeting energy goals. High-protein hypocaloric (providing 80%-90% of caloric requirements) feeding may evolve as the best strategy during the initial phase of critical illness to avoid overfeeding, improve insulin sensitivity, and maintain body protein homeostasis, especially in the patient at high nutrition risk. This article provides a set of recommendations based on assessment of the current literature to guide healthcare professionals in clinical practice at this time, as well as a list of potential topics to guide investigators for purposes of research in the future.

Acquired Amino Acid Deficiencies: A Focus on Arginine and Glutamine

Nonessential amino acids are synthesized de novo and therefore not diet dependent. In contrast, essential amino acids must be obtained through nutrition since they cannot be synthesized internally. Several nonessential amino acids may become essential under conditions of stress and catabolic states when the capacity of endogenous amino acid synthesis is exceeded. Arginine and glutamine are 2 such conditionally essential amino acids and are the focus of this review. Low arginine bioavailability plays a pivotal role in the pathogenesis of a growing number of varied diseases, including sickle cell disease, thalassemia, malaria, acute asthma, cystic fibrosis, pulmonary hypertension, cardiovascular disease, certain cancers, and trauma, among others. Catabolism of arginine by arginase enzymes is the most common cause of an acquired arginine deficiency syndrome, frequently contributing to endothelial dysfunction and/or T-cell dysfunction, depending on the clinical scenario and disease state. Glutamine, an arginine precursor, is one of the most abundant amino acids in the body and, like arginine, becomes deficient in several conditions of stress, including critical illness, trauma, infection, cancer, and gastrointestinal disorders. At-risk populations are discussed together with therapeutic options that target these specific acquired amino acid deficiencies.

Going Gluten Free: the History and Nutritional Implications of Today’s Most Popular Diet

Purpose of ReviewThe gluten-free diet (GFD) has become one of the most popular diets in modern history. Claims of improved health and increased energy fuel this popularity, though there is little evidence to substantiate these claims. The present review focuses on outlining known gluten-related disorders (GRD), discussing the GFD in the general population, exploring nutritional considerations, and providing advice for physicians in managing these patients.Recent FindingsCurrently, about a quarter of the population reports keeping a GFD despite GRDs affecting less than half of these individuals. Reduced intake of calcium, B vitamins, and fiber as well as enhanced consumption of fat and simple carbohydrates has consistently been reported and needs to be continually addressed.SummaryAlthough a necessity in proper management of GRDs, unforeseen nutritional complications may develop in patients who are gluten free for which enhanced physician awareness is vital to achieving optimal patient care.

Protein Requirements for Critically Ill Patients With Renal and Liver Failure

Diseases leading to critical illness induce proteolysis resulting in muscle wasting and negative nitrogen balance. Muscle wasting has been associated with poor intensive care unit (ICU)–related outcomes, including an increased risk for mortality. Acute kidney injury (AKI) represents a common organ dysfunction associated with ICU-related disorders, such as sepsis, trauma, and respiratory failure. AKI and renal replacement therapy lead to amino acid loss. Decompensated liver cirrhosis (DLC) and acute liver failure (ALF) represent more severe forms of liver dysfunction leading to ICU admission. DLC and ALF are associated with proteolysis and amino acid loss. AKI, DLC, and ALF uniquely contribute to negative nitrogen balance. The purpose of this review is to outline proteolysis associated with critical illness; define specific protein abnormalities in AKI, DLC, and ALF; define protein requirements in AKI, DLC, and ALF; and discuss barriers associated with optimal protein supplementation in these disorders.

Mesangial cell complement receptor 1‐related protein y limits complement‐dependent neutrophil accumulation in immune complex glomerulonephritis

The absence of complement receptor 1 (CR1) related gene/protein y (Crry) leads to embryonic lethality as a result of unrestricted complement activation and concomitant neutrophil infiltration. Here we used Crry−/−C3+/− mice to investigate the role of Crry in the pathogenesis of immune complex glomerulonephritis (GN). After 3 weeks of immunization with horse spleen apoferritin, six of nine Crry−/− C3+/− mice and none of the six control C3+/− mice developed proliferative GN (P = 0·010). After 5 weeks of immunization, GN scores in Crry−/− C3+/− mice were 0·67 ± 0·22 mean ± standard error of the mean (SEM), compared with 0·32 ± 0·16 in C3+/− mice. Glomerular hypercellularity was attributable to neutrophil infiltration in mice with GN (1·7 ± 0·3/glomerulus) compared with those without GN (0·4 ± 0·1/glomerulus) (P = 0·001). Absent staining for α‐smooth muscle actin and proliferating cell nuclear antigen suggested that mesangial cell proliferation did not play a significant role in this model. Serum C3 levels in Crry−/− C3+/− mice were approximately 20% and 30% those of wild‐type mice and C3+/− mice, respectively. To determine whether this acquired hypocomplementaemia was relevant to this GN model system, Crry−/− C3+/− mouse kidneys were transplanted into wild‐type mice followed by immunization with apoferritin for 1 or 2 weeks. Surprisingly, none of the Crry−/− C3+/− mouse kidneys developed GN at these early time‐points, indicating that increasing circulating C3 levels several‐fold did not increase susceptibility to GN. Renal expression of decay‐accelerating factor was not different among any of the groups studied. Thus, our data indicate that mesangial cell Crry limits complement activation and subsequent neutrophil recruitment in the setting of local immune complex deposition.

Use of Intradialytic Parenteral Nutrition in Patients Undergoing Hemodialysis

Intradialytic parenteral nutrition (IDPN) is a form of supplemental nutrition used to treat patients with malnutrition who receive hemodialysis. Once the diagnosis of malnutrition is made in such patients, encouragement of oral intake is the first-line treatment. If this fails, then enteral or parenteral nutrition may be needed. This review examines the literature on the use of IDPN and summarizes the current recommendations. There is considerable controversy over indications and benefits of IDPN, and well-controlled, long-term studies are needed to help tease out these issues. In the interim, clinical judgment should be used when considering IDPN for individual patients.

Protein Energy Wasting in Hemodialysis Patients

Protein energy wasting (PEW) is a state of decreased body stores of protein and energy fuels, and is associated with diminished functional capacity, impaired quality of life, and increased morbidity and mortality in patients with CKD ([1][1]). The prevalence of PEW ranges from 30% to 70% among