Donor-specific antibodies have become an established biomarker predicting antibody-mediated rejection. Antibody-mediated rejection is the leading cause of graft loss after kidney transplant. There are several phenotypes of antibody-mediated rejection along post-transplant course that are determined by the timing and extent of humoral response and the various characteristics of donor-specific antibodies, such as antigen classes, specificity, antibody strength, IgG subclasses, and complement binding capacity. Preformed donor-specific antibodies in sensitized patients can trigger hyperacute rejection, accelerated acute rejection, and early acute antibody-mediated rejection. donor-specific antibodies are associated with late acute antibody-mediated rejection, chronic antibody-mediated rejection, and transplant glomerulopathy. The pathogeneses of antibody-mediated rejection include not only complement-dependent cytotoxicity, but also complement-independent pathways of antibody-mediated cellular cytotoxicity and direct endothelial activation and proliferation. The novel assay for complement binding capacity has improved our ability to predict antibody-mediated rejection phenotypes. C1q binding donor-specific antibodies are closely associated with acute antibody-mediated rejection, more severe graft injuries, and early graft failure, whereas C1q nonbinding donor-specific antibodies correlate with subclinical or chronic antibody-mediated rejection and late graft loss. IgG subclasses have various abilities to activate complement and recruit effector cells through the Fc receptor. Complement binding IgG3 donor-specific antibodies are frequently associated with acute antibody-mediated rejection and severe graft injury, whereas noncomplement binding IgG4 donor-specific antibodies are more correlated with subclinical or chronic antibody-mediated rejection and transplant glomerulopathy. Our in-depth knowledge of complex characteristics of donor-specific antibodies can stratify the patient's immunologic risk, can predict distinct phenotypes of antibody-mediated rejection, and hopefully, will guide our clinical practice to improve the transplant outcomes.

Longitudinal and cross-sectional studies suggest that a large number of obese patients have a high prevalence of hypertension. This association causes the following changes: insulin and leptin resistance with a suppressed biologic activity of natriuretic peptide, which contributes to sodium retention with concomitant expanded cardiopulmonary volume and increased cardiac output. The cellular metabolism of cations may be altered in obesity and may lead to changes in vascular responsiveness and increased vascular resistance. These changes lead to structural adaptations in the heart characterized by concentric-eccentric left ventricular hypertrophy. The hypertrophic condition provides the basis for the development of congestive heart failure and cardiac arrhythmias that may explain the higher rates of cardiac sudden death in those patients. In the kidneys, obesity hypertension may initiate a derangement of renal function. The increased deposit of interstitial cells and of extracellular matrix between the tubules induces higher interstitial hydrostatic pressure and tubular sodium reabsorption. The consequent increase in renal flow and glomerular filtration enhances albuminuria excretion and the susceptibility to the development of renal damage. In summary, the hemodynamic and structural adaptations related to obesity hypertension is the cause of greater risk for adverse cardiovascular and renal events.

Abstract. The localization and transporting properties of a kidney protein homologous to human erythrocyte protein CHIP28 was evaluated. The cDNA encoding rat kidney protein CHIP28k was isolated from a rat renal cortex cDNA library. A 2.8-kb cDNA was identified which contained an 807 bp open reading frame encoding a 28.8 kD protein with 94% amino acid identity to CHIP28. in vitro translation of CHIP28k cDNA in rabbit reticulocyte lysate generated a 28-kD protein; addition of ER-derived microsomes gave a 32-kD transmembrane glycoprotein. Translation of truncated RNA demonstrated glycosylation of residue Asn42 which is predicted to lie between the first and second transmembrane domains. Expression of in vitro transcribed mRNA encoding CHIP28k in Xenopus oocytes increased oocyte osmotic water permeability (Pf) from (4 + 1) x 10 -4 to (33 + 4) x 10 -4 cm/s at 10~ the increase in oocyte Pf was weakly temperature dependent and inhibited by HgC12. Two-electrode voltage clamp measurements indicated that CHIP28k was not permeable to ions. Oocyte Pf also increased with expression of total mRNA from kidney cortex and papilla; the increase in Pf with mRNA from cortex, but not kidney papilla, was blocked by coinjection with excess antisense CHIP28k cRNA. In situ hybridization of a 150 base cRNA antisense probe to tissue sections from rat kidney showed selective CHIP28k localization to epithelial cells in proximal tubule and thin descending limb of Henle. Pf in purified apical membrane vesicles from rat and human proximal tubule, and in proteoliposomes reconstituted with purified protein, was very high and inhibited by HgC12; stripping of apical vesicles with N-lauroylsarcosine enriched a 28-kD protein by 25-fold and yielded a vesicle population with high water, but low urea and proton permeabilities. CHIP28k identity was confirmed by NH2-terminus sequence analysis. These results indicate that CHIP28k is a major and highly selective water transporting protein in the kidney proximal tubule and thin descending limb of Henle, but not collecting duct.

Tertiary hyperparathyroidism (tHPT) usually regresses after renal transplantation. Persistent tHPT after successful renal transplantation may require parathyroidectomy (PTX). PTX has been reported to be associated with deterioration of renal function and graft survival. We retrospectively analyzed 794 kidney transplants performed at our center with at least 3 years of follow-up to examine the effect of PTX on the renal function and graft survival. Forty-nine of the 794 renal transplant recipients were diagnosed with hyperparathyroidism (HPT) before transplant. Nineteen of 49 patients had persistent tHPT and underwent PTX after kidney transplants. Patients with HPT and non-HPT had similar 3-year graft survival (88% versus 84%, P = 0.51). PTX was associated with a decreased glomerular filtration rate at 3 years (44.7 ± 20.0 versus 57.7 ± 23.7 mL/min, P = 0.04); however, there was no statistical difference in the 3-year graft survival (71% versus 88%, P = 0.06). PTX in renal transplant recipients seems to be a safe and effective therapy for persistent tHPT. PTX may be associated with worsening glomerular filtration rate, but it may not be associated with significantly decreased longterm graft survival. Key Indexing TermsHyperparathyroidism; Parathyroidectomy; Kidney transplant; Graft function; Graft survival Nowadays, the term tertiary hyperparathyroidism (tHPT) is used almost exclusively in the context of persistent hyperparathyroidism (HPT) after successful renal transplantation. Development of tHPT is multifactorial, although phosphate retention and loss of renal 1-hydroxylase activity with low 1,25-(OH) 2 vitamin D 3 level are the principal factors. 1 For hyperparathyroidism in patients with end-stage renal disease, the currently accepted practice for management is initially medical therapy with parathyroidectomy (PTX) reserved for refractory disease. 2 The incidence of tHPT is reported in up to 50% of patients who undergo kidney transplantation,3 and its occurrence is thought to be related to the duration of dialysis before transplantation.3 , 4 Although tHPT has been recognized for a long time, the management of the disease is still controversial. Currently, guidelines for referral of these patients for surgery do not exist. Hypercalcemia usually gradually resolves within the first year after successful kidney transplantation. 4 Therefore, patients with persistent hypercalcemia should be considered for PTX, which includes subtotal or total PTX with auto-transplantation. Indications NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript for surgical intervention include persistent hypercalcemia, symptomatic tHPT, or deterioration of kidney function associated with tHPT. 4 Although it was previously reported that patients with functioning kidney grafts had unaffected renal function after PTX, there are recent reports that PTX might seriously endanger the long-term graft survival. [5][6][7] The purpose of this study was to examine our 10-year experience with patients with end-stage re...

Functional magnetic resonance imaging (fMRI) studies regularly use univariate general-linear-model-based analyses (GLM). Their findings are often inconsistent across different studies, perhaps because of several fundamental brain properties including functional heterogeneity, balanced excitation and inhibition (E/I), and sparseness of neuronal activities. These properties stipulate heterogeneous neuronal activities in the same voxels and likely limit the sensitivity and specificity of GLM. This paper selectively reviews findings of histological and electrophysiological studies and fMRI spatial independent component analysis (sICA) and reports new findings by applying sICA to two existing datasets. The extant and new findings consistently demonstrate several novel features of brain functional organization not revealed by GLM. They include overlap of large-scale functional networks (FNs) and their concurrent opposite modulations, and no significant modulations in activity of most FNs across the whole brain during any task conditions. These novel features of brain functional organization are highly consistent with the brain’s properties of functional heterogeneity, balanced E/I, and sparseness of neuronal activity, and may help reconcile inconsistent GLM findings.