Enteric Oxalate Secretion Mediated by Slc26a6 Defends against Hyperoxalemia in Murine Models of Chronic Kidney Disease

BackgroundA state of oxalate homeostasis is maintained in patients with healthy kidney function. However, as GFR declines, plasma oxalate (Pox) concentrations start to rise. Several groups of researchers have described augmentation of oxalate secretion in the colon in models of CKD, but the oxalate transporters remain unidentified. The oxalate transporter Slc26a6 is a candidate for contributing to the extrarenal clearance of oxalate via the gut in CKD.MethodsFeeding a diet high in soluble oxalate or weekly injections of aristolochic acid induced CKD in age- and sex-matched wild-type and Slc26a6−/− mice. qPCR, immunohistochemistry, and western blot analysis assessed intestinal Slc26a6 expression. An oxalate oxidase assay measured fecal and Pox concentrations.ResultsFecal oxalate excretion was enhanced in wild-type mice with CKD. This increase was abrogated in Slc26a6−/− mice associated with a significant elevation in plasma oxalate concentration. Slc26a6 mRNA and protein expression were greatly increased in the intestine of mice with CKD. Raising Pox without inducing kidney injury did not alter intestinal Slc26a6 expression, suggesting that changes associated with CKD regulate transporter expression rather than elevations in Pox.ConclusionsSlc26a6-mediated enteric oxalate secretion is critical in decreasing the body burden of oxalate in murine CKD models. Future studies are needed to address whether similar mechanisms contribute to intestinal oxalate elimination in humans to enhance extrarenal oxalate clearance.

A Brief Presentation of the Characteristics of Hemodialysis Membranes

The survival of CKD patients has known significant improvement with the appearance of extrarenal clearance methods. Being a domain in a rapid progression, the hemodialysis membranes have been, in time, one of the key modifying points. In this paper will make a short presentation of the features of hemodialysis membranes and will point out aspects which need future research.

Generation of a New Cystatin C–Based Estimating Equation for Glomerular Filtration Rate by Use of 7 Assays Standardized to the International Calibrator

BACKGROUND Many different cystatin C–based equations exist for estimating glomerular filtration rate. Major reasons for this are the previous lack of an international cystatin C calibrator and the nonequivalence of results from different cystatin C assays. METHODS Use of the recently introduced certified reference material, ERM-DA471/IFCC, and further work to achieve high agreement and equivalence of 7 commercially available cystatin C assays allowed a substantial decrease of the CV of the assays, as defined by their performance in an external quality assessment for clinical laboratory investigations. By use of 2 of these assays and a population of 4690 subjects, with large subpopulations of children and Asian and Caucasian adults, with their GFR determined by either renal or plasma inulin clearance or plasma iohexol clearance, we attempted to produce a virtually assay-independent simple cystatin C–based equation for estimation of GFR. RESULTS We developed a simple cystatin C–based equation for estimation of GFR comprising only 2 variables, cystatin C concentration and age. No terms for race and sex are required for optimal diagnostic performance. The equation, eGFR=130×cystatin C−1.069×age−0.117−7, is also biologically oriented, with 1 term for the theoretical renal clearance of small molecules and 1 constant for extrarenal clearance of cystatin C. CONCLUSIONS A virtually assay-independent simple cystatin C–based and biologically oriented equation for estimation of GFR, without terms for sex and race, was produced.

The Kidney and Homocysteine Metabolism

Homocysteine (Hcy) is an intermediate of methionine metabolism that, at elevated levels, is an independent risk factor for vascular disease and atherothrombosis. Patients with renal disease, who exhibit unusually high rates of cardiovascular morbidity and death, tend to be hyperhomocysteinemic, particularly as renal function declines. This observation and the inverse relationship between Hcy levels and GFR implicate the kidney as an important participant in Hcy handling. The normal kidney plays a major role in plasma amino acid clearance and metabolism. The existence in the kidney of specific Hcy uptake mechanisms and Hcy-metabolizing enzymes suggests that this role extends to Hcy. Dietary protein intake may affect renal Hcy handling and should be considered when measuring Hcy plasma flux and renal clearance. The underlying cause of hyperhomocysteinemia in renal disease is not entirely understood but seems to involve reduced clearance of plasma Hcy. This reduction may be attributable to defective renal clearance and/or extrarenal clearance and metabolism, the latter possibly resulting from retained uremic inhibitory substances. Although the currently available evidence is not conclusive, it seems more likely that a reduction in renal Hcy clearance and metabolism is the cause of the hyperhomocysteinemic state. Efforts to resolve this important issue will advance the search for effective Hcy-lowering therapies in patients with renal disease.

Drawbacks of the constant-infusion technique for measurement of renal function

We investigated the validity of the steady-state constant infusion method (CIM), in which quantitative urinary recovery and constant plasma concentrations of the solute infused are required. Successive 3-h clearances of inulin and p-aminohippuric acid (PAH) were determined for 27 h in 25 patients with renal disease. Results were compared with the standard method of bladder clearance (StM) and with a modified CIM (ModCIM). The 24-h urinary recovery was incomplete for both inulin and PAH. Mean 24-h ModCIM inulin clearance overestimated StM by 4.5 ml.min-1 x 1.73 m-2 (range 0–9, P < 0.001) independent of the extent of renal impairment and pointed to slow distribution and/or extrarenal clearance of inulin. For PAH, the difference between ModCIM and StM clearance was related to the average PAH clearance by ModCIM and StM (r = 0.78). Furthermore, neither plasma inulin nor PAH became completely constant, because of the circadian rhythm in renal function. In conclusion, the conditions of the steady-state CIM technique are not fulfilled, and the method is not suitable for accurate measurement of inulin and PAH clearance, especially when the clearance is low.

Extrarenal clearance of oxalate increases with progression of renal failure in the rat.

Oxalic acid is an end product of metabolism, and no significant degradation of oxalate occurs in mammals. The sole route of oxalate excretion is believed to be via the kidney. The extrarenal clearance of oxalate in control rats (N = 16) and in 5/6 nephrectomized rats (N = 25) with renal insufficiency was investigated. [14C]oxalic acid, approximately 2 microCi/day, was infused sc by a mini osmotic pump over 4 days. Excretion of 14C was measured in urine, in feces, and in expired CO2. The 14C content of kidney, heart, liver, muscle and bone was also determined at the time the animals were killed. Plasma oxalate was determined by an enzymatic method and by an isotopic dilution procedure. Creatinine clearance in the controls was 1.82 +/- 0.1 mL/min (mean +/- SE) compared with 0.31 +/- 0.04 mL/min (P < 0.0005) in the nephrectomized rats. Plasma oxalate was 5.6 +/- 0.6 mumol/L in controls and 27.0 +/- 3.9 (mean +/- SE; N = 24) in nephrectomized animals (P < 0.0005). The total 14C recovered in urine, feces, and CO2 combined was similar in both groups. The 14C excreted in the feces over the 4-day period was 27.8 +/- 1.5% (of the 14C recovered) in rats with renal failure and 6.5 +/- 0.5% in controls (P < 0.0005). Percent fecal 14C excretion in nephrectomized rats was inversely correlated with creatinine clearance (r = 0.80; P < 0.0001) and directly correlated with plasma oxalate (r = 0.66; P < 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)