Felix Knauf

Identification of a chloride-formate exchanger expressed on the brush border membrane of renal proximal tubule cells

A key function of the proximal tubule is retrieval of most of the vast quantities of NaCl and water filtered by the kidney. Physiological studies using brush border vesicles and perfused tubules have indicated that a major fraction of Cl− reabsorption across the apical membrane of proximal tubule cells occurs via Cl−-formate exchange. The molecular identity of the transporter responsible for renal brush border Cl−-formate exchange has yet to be elucidated. As a strategy to identify one or more anion exchangers responsible for mediating Cl− reabsorption in the proximal tubule, we screened the expressed sequence tag database for homologs of pendrin, a transporter previously shown to mediate Cl−-formate exchange. We now report the cDNA cloning of CFEX, a mouse pendrin homolog with expression in the kidney by Northern analysis. Sequence analysis indicated that CFEX very likely represents the mouse ortholog of human SLC26A6. Immunolocalization studies detected expression of CFEX, but not pendrin, on the brush border membrane of proximal tubule cells. Functional expression studies in Xenopus oocytes demonstrated that CFEX mediates Cl−-formate exchange. Taken together, these observations identify CFEX as a prime candidate to mediate Cl−-formate exchange in the proximal tubule and thereby to contribute importantly to renal NaCl reabsorption. Given its wide tissue distribution, CFEX also may contribute to transcellular Cl− transport in additional epithelia such as the pancreas and contribute to transmembrane Cl− transport in nonepithelial tissues such as the heart.

ESRD as a Window into America's Cost Crisis in Health Care

The United States is facing a severe crisis over health care costs. Although nearly 15% of the population—some 45 million people—lack health insurance,1 per capita health care expenditures in the United States are approximately twice as high as in other industrialized countries,2 most of which provide near-universal health insurance coverage. Despite these high per capita health care expenditures, health outcomes in the United States are no better, and arguably significantly worse, than in these other countries.3 Moreover, because health care expenditures in the United States have been rising at a rate almost 3% faster than the economy as a whole over the past 30 yr, health care expenses have been absorbing an ever-increasing fraction of the gross domestic product (GDP).4 Even before the current severe recession, it had been estimated that if current trends continue, health care expenses would represent 30% of the GDP within 30 yr, and that the Medicare hospital insurance trust fund would be exhausted within a decade.5 Some have argued that the projected increase in health care expenditures to consume a higher and higher fraction of GDP is not necessarily a problem.6,7 After all, the health care industry itself is an important driving force of the economy and its growth creates new jobs. Moreover, as long as the economy as a whole enjoys sufficient growth, devoting an increasing share of GDP to health care need not reduce absolute spending in areas other than health care, and therefore need not reduce the standard of living. But now that it represents over one-sixth of the national economy, the inefficiency of the American health care system represents a grave threat to Americas economic competitiveness. Again, it should be emphasized that per capita health care expenditures in the United States are twice …

An update on the role of the inflammasomes in the pathogenesis of kidney diseases

Innate immune response pathways play a critical role as the first line of defense. Initiation of an immune response requires sensors that can detect noxious stimuli within the cellular microenvironment. Inflammasomes are signaling platforms that are assembled in response to both microbe-specific and nonmicrobial antigens. Upon activation, proinflammatory cytokines are released to engage immune defenses and to trigger an inflammatory cell death referred to as pyroptosis. The aim of this review is to provide an overview of the current knowledge of the role of the inflammasomes in the pathogenesis of kidney diseases. As crystal deposition in the kidney is a frequent cause of acute kidney injury and chronic kidney disease in children, recent insights into mechanisms of inflammasome activation by renal crystals are highlighted. This may be of particular interest to pediatric patients and nephrologists in need of new therapeutic approaches. Lastly, current data findings that inflammasomes are not only of major importance in host defense but are also a key regulator of the intestinal microbiota and the progression of systemic diseases are reviewed.

Oxalate-induced chronic kidney disease with its uremic and cardiovascular complications in C57BL/6 mice

Chronic kidney disease (CKD) research is limited by the lack of convenient inducible models mimicking human CKD and its complications in experimental animals. We demonstrate that a soluble oxalate-rich diet induces stable stages of CKD in male and female C57BL/6 mice. Renal histology is characterized by tubular damage, remnant atubular glomeruli, interstitial inflammation, and fibrosis, with the extent of tissue involvement depending on the duration of oxalate feeding. Expression profiling of markers and magnetic resonance imaging findings established to reflect inflammation and fibrosis parallel the histological changes. Within 3 wk, the mice reproducibly develop normochromic anemia, metabolic acidosis, hyperkalemia, FGF23 activation, hyperphosphatemia, and hyperparathyroidism. In addition, the model is characterized by profound arterial hypertension as well as cardiac fibrosis that persist following the switch to a control diet. Together, this new model of inducible CKD overcomes a number of previous experimental limitations and should serve useful in research related to CKD and its complications.

Dabigatran and kidney disease: a bad combination.

Dabigatran is an oral direct thrombin inhibitor widely used to prevent and treat various thromboembolic complications. An advantage of this agent over other anticoagulants is that routine laboratory monitoring and related dose adjustments are considered unnecessary. A major disadvantage is the absence of a reliable means of reversing its anticoagulant effect. After U.S. Food and Drug Administration approval, recently emerged data suggest a higher bleeding risk with dabigatran, especially in the elderly. Clinicians are thus faced with caring for patients with serious bleeding events without readily available tests to measure drug levels or the anticoagulant effects of dabigatran and without effective antidotes to rapidly reverse the anticoagulant effect. On the basis of dabigatrans pharmacokinetic profile, hemodialysis and continuous renal replacement therapy have been used to remove dabigatran with the hope, still unproven, that this would rapidly reverse the anticoagulant effect and reduce bleeding in patients with normal and those with reduced kidney function. However, the best clinical approach to the patient with serious bleeding is not known, and the risks of placing a hemodialysis catheter in an anticoagulated patient can be substantial. This article reviews this issue, addressing clinical indications, drug pharmacokinetics, clinical and laboratory monitoring tests, and dialytic and nondialytic approaches to reduce bleeding in dabigatran-treated patients.

Oxalate, inflammasome, and progression of kidney disease.

Purpose of reviewOxalate is an end product of metabolism excreted via the kidney. Excess urinary oxalate, whether from primary or enteric hyperoxaluria, can lead to oxalate deposition in the kidney. Oxalate crystals are associated with renal inflammation, fibrosis, and progressive renal failure. It has long been known that as the glomerular filtration rate becomes reduced in chronic kidney disease (CKD), there is striking elevation of plasma oxalate. Taken together, these findings raise the possibility that elevation of plasma oxalate in CKD may promote renal inflammation and more rapid progression of CKD independent of primary cause. Recent findingsThe inflammasome has recently been identified to play a critical role in oxalate-induced renal inflammation. Oxalate crystals have been shown to activate the NOD-like receptor family, pyrin domain containing 3 inflammasome (also known as NALP3, NLRP3, or cryopyrin), resulting in release of IL-1&bgr; and macrophage infiltration. Deletion of inflammasome proteins in mice protects from oxalate-induced renal inflammation and progressive renal failure. SummaryThe findings reviewed in this article expand our understanding of the relevance of elevated plasma oxalate levels leading to inflammasome activation. We propose that inhibiting oxalate-induced inflammasome activation, or lowering plasma oxalate, may prevent or mitigate progressive renal damage in CKD, and warrants clinical trials.

Drosophila: a fruitful model for calcium oxalate nephrolithiasis?

Even though the prevalence of nephrolithiasis is increasing, our understanding of the pathophysiology has not kept pace and new therapeutic approaches have not emerged. The potential of a new physiological model (the fruitfly) is exciting. The model has strengths, namely the low cost of maintaining colonies and rapid deployment of new transgenic lines, but also weaknesses that may ultimately limit its usefulness, such as the mechanism of tubular fluid formation and difficulties in following plasma and urine biochemistries.

Sat1 is Dispensable for Active Oxalate Secretion in Mouse Duodenum

Mice deficient for the apical membrane oxalate transporter SLC26A6 develop hyperoxalemia, hyperoxaluria, and calcium oxalate stones due to a defect in intestinal oxalate secretion. However, the nature of the basolateral membrane oxalate transport process that operates in series with SLC26A6 to mediate active oxalate secretion in the intestine remains unknown. Sulfate anion transporter-1 (Sat1 or SLC26A1) is a basolateral membrane anion exchanger that mediates intestinal oxalate transport. Moreover, Sat1-deficient mice also have a phenotype of hyperoxalemia, hyperoxaluria, and calcium oxalate stones. We, therefore, tested the role of Sat1 in mouse duodenum, a tissue with Sat1 expression and SLC26A6-dependent oxalate secretion. Although the active secretory flux of oxalate across mouse duodenum was strongly inhibited (>90%) by addition of the disulfonic stilbene DIDS to the basolateral solution, secretion was unaffected by changes in medium concentrations of sulfate and bicarbonate, key substrates for Sat1-mediated anion exchange. Inhibition of intracellular bicarbonate production by acetazolamide and complete removal of bicarbonate from the buffer also produced no change in oxalate secretion. Finally, active oxalate secretion was not reduced in Sat1-null mice. We conclude that a DIDS-sensitive basolateral transporter is involved in mediating oxalate secretion across mouse duodenum, but Sat1 itself is dispensable for this process.

Loss of Cystic Fibrosis Transmembrane Regulator Impairs Intestinal Oxalate Secretion

Patients with cystic fibrosis have an increased incidence of hyperoxaluria and calcium oxalate nephrolithiasis. Net intestinal absorption of dietary oxalate results from passive paracellular oxalate absorption as modified by oxalate back secretion mediated by the SLC26A6 oxalate transporter. We used mice deficient in the cystic fibrosis transmembrane conductance regulator gene (Cftr) to test the hypothesis that SLC26A6-mediated oxalate secretion is defective in cystic fibrosis. We mounted isolated intestinal tissue from C57BL/6 (wild-type) and Cftr-/- mice in Ussing chambers and measured transcellular secretion of [14C]oxalate. Intestinal tissue isolated from Cftr-/- mice exhibited significantly less transcellular oxalate secretion than intestinal tissue of wild-type mice. However, glucose absorption, another representative intestinal transport process, did not differ in Cftr-/- tissue. Compared with wild-type mice, Cftr-/- mice showed reduced expression of SLC26A6 in duodenum by immunofluorescence and Western blot analysis. Furthermore, coexpression of CFTR stimulated SLC26A6-mediated Cl--oxalate exchange in Xenopus oocytes. In association with the profound defect in intestinal oxalate secretion, Cftr-/- mice had serum and urine oxalate levels 2.5-fold greater than those of wild-type mice. We conclude that defective intestinal oxalate secretion mediated by SLC26A6 may contribute to the hyperoxaluria observed in this mouse model of cystic fibrosis. Future studies are needed to address whether similar mechanisms contribute to the increased risk for calcium oxalate stone formation observed in patients with cystic fibrosis.

Implementation of Patient-Centered Education for Chronic-Disease Management in Uganda: An Effectiveness Study.

Background The majority of non-communicable disease related deaths occur in low- and middle-income countries. Patient-centered care is an essential component of chronic disease management in high income settings. Objective To examine feasibility of implementation of a validated patient-centered education tool among patients with heart failure in Uganda. Design Mixed-methods, prospective cohort. Settings A private and public cardiology clinic in Mulago National Referral and Teaching Hospital, Kampala, Uganda. Participants Adults with a primary diagnosis of heart failure. Interventions PocketDoktor Educational Booklets with patient-centered health education. Main Measures The primary outcomes were the change in Patient Activation Measure (PAM-13), as well as the acceptability of the PocketDoktor intervention, and feasibility of implementing patient-centered education in outpatient clinical settings. Secondary outcomes included the change in satisfaction with overall clinical care and doctor-patient communication. Key Results A total of 105 participants were enrolled at two different clinics: the Mulago Outpatient Department (public) and the Uganda Heart Institute (private). 93 participants completed follow up at 3 months and were included in analysis. The primary analysis showed improved patient activation measure scores regarding disease-specific knowledge, treatment options and prevention of exacerbations among both groups (mean change 0.94 [SD = 1.01], 1.02 [SD = 1.15], and 0.92 [SD = 0.89] among private paying patients and 1.98 [SD = 0.98], 1.93 [SD = 1.02], and 1.45 [SD = 1.02] among public paying patients, p<0.001 for all values) after exposure to the intervention; this effect was significantly larger among indigent patients. Participants reported that materials were easy to read, that they had improved knowledge of disease, and stated improved communication with physicians. Conclusions Patient-centered medical education can improve confidence in self-management as well as satisfaction with doctor-patient communication and overall care in Uganda. Our results show that printed booklets are locally appropriate, highly acceptable and feasible to implement in an LMIC outpatient setting across socioeconomic groups.