Chronic dehydration induces injury pathways in rats, but does not mimic histopathology of chronic interstitial nephritis in agricultural communities.

CINAC-patients present renal proximal tubular cell lysosomal lesions which are also observed in patients experiencing calcineurin inhibitor (CNI) nephrotoxicity, suggesting that CINAC is a toxin-induced nephropathy. An alternative hypothesis advocates chronic dehydration as a major etiological factor for CINAC. Here, we evaluated histological and molecular changes in dehydrated versus toxin exposed rats. Wistar rats were divided in 3 groups. Group 1 (n = 6) had free access to drinking water (control group). Group 2 (n = 8) was water deprived for 10 h per 24 h, 5 days/week and placed in an incubator (37 °C) for 30 min/h during water deprivation. Group 3 (n = 8) underwent daily oral gavage with cyclosporine (40 mg/kg body weight). After 28 days, renal function, histopathology and proteomic signatures were analysed. Cyclosporine-treated rats developed focal regions of atrophic proximal tubules with associated tubulo-interstitial fibrosis. PASM staining revealed enlarged argyrophilic granules in affected proximal tubules, identified as lysosomes by immunofluorescent staining. Electron microscopy confirmed the enlarged and dysmorphic phenotype of the lysosomes. Overall, these kidney lesions resemble those that have been previously documented in farmers with CINAC. Dehydration resulted in none of the above histopathological features. Proteomic analysis revealed that dehydration and cyclosporine both induce injury pathways, yet of a clear distinct nature with a signature of toxicity only for the cyclosporine group. In conclusion, both cyclosporine and dehydration are injurious to the kidney. However, dehydration alone does not result in kidney histopathology as observed in CINAC patients, whereas cyclosporine administration does. The histopathological analogy between CINAC and calcineurin inhibitor nephrotoxicity in rats and humans supports the involvement of an as-yet-unidentified environmental toxin in CINAC etiology.

Metformin and Canagliflozin Are Equally Renoprotective in Diabetic Kidney Disease but Have No Synergistic Effect.

Diabetic Kidney Disease (DKD) is a major microvascular complication for diabetic patients and is the most common cause of chronic kidney disease (CKD) and end-stage renal disease. Antidiabetic drugs, such as metformin and canagliflozin, have been shown to exert renoprotective effects. Additionally, quercetin recently showed promising results for the treatment of DKD. However, the molecular pathways through which these drugs exert their renoprotective effects remain partly unknown. The current study compares the renoprotective potential of metformin, canagliflozin, metformin + canagliflozin, and quercetin in a preclinical rat model of DKD. By combining streptozotocin (STZ) and nicotinamide (NAD) with daily oral N(ω)-Nitro-L-Arginine Methyl Ester (L-NAME) administration, DKD was induced in male Wistar Rats. After two weeks, rats were assigned to five treatment groups, receiving vehicle, metformin, canagliflozin, metformin + canagliflozin, or quercetin for a period of 12 weeks by daily oral gavage. Non-diabetic vehicle-treated control rats were also included in this study. All rats in which diabetes was induced developed hyperglycemia, hyperfiltration, proteinuria, hypertension, renal tubular injury and interstitial fibrosis, confirming DKD. Metformin and canagliflozin, alone or together, exerted similar renoprotective actions and similar reductions in tubular injury and collagen accumulation. Renoprotective actions of canagliflozin correlated with reduced hyperglycemia, while metformin was able to exert these effects even in the absence of proper glycemic control. Gene expression revealed that the renoprotective pathways may be traced back to the NF-κB pathway. No protective effect was seen with quercetin. In this experimental model of DKD, metformin and canagliflozin were able to protect the kidney against DKD progression, albeit in a non-synergistic way. These renoprotective effects may be attributable to the inhibition of the NF-κB pathway.

Progression of established non-diabetic chronic kidney disease is halted by metformin treatment in rats.

Current treatment strategies for chronic kidney disease (CKD) mainly focus on controlling risk factors. Metformin, a first-line drug for type 2 diabetes, exerts beneficial pleiotropic actions beyond its prescribed use and incipient data have revealed protective effects against the development of kidney impairment. This study evaluated the therapeutic efficacy of metformin and canagliflozin, a sodium-glucose cotransporter-2 (SGLT2) inhibitor recently approved by the United States Food and Drug Administration to treat diabetic nephropathy, in slowing the progression of established non-diabetic CKD. Rats with adenine-induced CKD were assigned to different treatment groups to receive either 200 mg/kg metformin, four or five weeks after the start of the adenine diet (established mild-moderate CKD), or 25 mg/kg canagliflozin four weeks after the start of the diet, by daily oral gavage administered during four weeks. Each treatment group was compared to a vehicle group. Chronic adenine dosing resulted in severe CKD in vehicle-treated rats as indicated by a marked rise in serum creatinine levels, a marked decrease in creatinine clearance, and a disturbed mineral metabolism. Metformin, but not canagliflozin, halted functional kidney decline. Additionally, kidneys of metformin-treated animals showed less interstitial area and inflammation as compared to the vehicle group. Proteomic analyses revealed that metformin's kidney-protective effect was associated with the activation of the Hippo signaling pathway, a highly conserved multiprotein kinase cascade that controls tissue development, organ size, cell proliferation, and apoptosis. Thus, metformin demonstrated therapeutic efficacy by halting the progression of established CKD in a rat model.

L-NAME Administration Enhances Diabetic Kidney Disease Development in an STZ/NAD Rat Model.

One of the most important risk factors for developing chronic kidney disease (CKD) is diabetes. To assess the safety and efficacy of potential drug candidates, reliable animal models that mimic human diseases are crucial. However, a suitable model of diabetic kidney disease (DKD) is currently not available. The aim of this study is to develop a rat model of DKD by combining streptozotocin and nicotinamide (STZ/NAD) with oral N(ω)-Nitro-L-Arginine Methyl Ester (L-NAME) administration. Diabetes was induced in male Wistar rats by intravenous injection of 65 mg/kg STZ, 15 min after intraperitoneal injection of 230 mg/kg NAD. Rats were assigned to different groups receiving L-NAME (100 mg/kg/day) (STZ/NAD/L-NAME) or vehicle (STZ/NAD) for a period of 9 or 12 weeks by daily oral gavage. All rats developed hyperglycemia. Hyperfiltration was observed at the start of the study, whereas increased serum creatinine, albumin-to-creatinine ratio, and evolving hypofiltration were detected at the end of the study. Daily L-NAME administration caused a rapid rise in blood pressure. Histopathological evaluation revealed heterogeneous renal injury patterns, which were most severe in the STZ/NAD/L-NAME rats. L-NAME-induced NO-deficiency in STZ/NAD-induced diabetic rats leads to multiple characteristic features of human DKD and may represent a novel rat model of DKD.

Haemodynamic frailty - A risk factor for acute kidney injury in the elderly.

Clinical frailty in the elderly is defined by a composite measure of functional psychomotor decline. Herein, we develop the concept of haemodynamic frailty (HDF), a state of increased predisposition to disease prevalent in the elderly and characterised by impairment of the network of compensatory responses governing the defence of circulatory volume and adaptive haemodynamic function. We review the factors predisposing the elderly to HDF, with a focus on the impaired capacity to sustain total body water balance. As a component of HDF, dehydration generates vulnerability to diseases caused by tissue hypoperfusion, including acute kidney injury. We provide a detailed mechanistic explanation of how dehydration and depletion of the intravascular volume impacts on renal blood flow to become an important element of the heightened risk of acute kidney injury (AKI) in the elderly. We bring these mechanistic considerations into the clinical context with reference to examples of how pre-renal (haemodynamic) and intrinsic (involving renal parenchymal damage) AKI risk is elevated in the setting of dehydration. Finally, we present HDF as a state of opportunity to prevent disease, for which diagnostic and interventional standards need to be refined. Further prospective studies are warranted to help clarify the clinical utility of assessing and managing HDF with regard to the mitigation of AKI risk in the elderly.

Chronic interstitial nephritis in agricultural communities: a new perspective on etiology, diagnosis and mechanism.

Chronic interstitial nephritis in agricultural communities is a devastating kidney disease with a globally increasing prevalence. Its cause is unknown. Two predominant etiologies are hypothesised: recurrent episodes of dehydration and exposure to environmental toxins, such as agrochemicals and metals. In this review, we summarise arguments on: 1) why heat stress/dehydration is an unlikely cause of this disease and 2) why chronic interstitial nephritis in agricultural communities is to be considered a toxin-induced nephropathy. Mechanistically, we provide arguments for a putative role of pesticides on the one hand, and the calcineurin pathway on the other hand, both of which require further investigation. Finally, we summarise several important perspectives for research on chronic interstitial nephritis in agricultural communities.

Renoprotective effects of sucroferric oxyhydroxide in a rat model of chronic renal failure.

INTRODUCTION: Sucroferric oxyhydroxide (PA21) is an efficacious, well-tolerated iron-based phosphate binder and a promising alternative to existing compounds. We compared the effects of PA21 with those of a conventional phosphate binder on renal function, mineral homeostasis and vascular calcification in a chronic kidney disease-mineral and bone disorder (CKD-MBD) rat model. METHODS: To induce stable renal failure, rats were administered a 0.25% adenine diet for 8 weeks. Concomitantly, rats were treated with vehicle, 2.5 g/kg/day PA21, 5.0 g/kg/day PA21 or 3.0 g/kg/day calcium carbonate (CaCO3). Renal function and calcium/phosphorus/iron metabolism were evaluated during the study course. Renal fibrosis, inflammation, vascular calcifications and bone histomorphometry were quantified. RESULTS: Rats treated with 2.5 or 5.0 g/kg/day PA21 showed significantly lower serum creatinine and phosphorus and higher ionized calcium levels after 8 weeks of treatment compared with vehicle-treated rats. The better preserved renal function with PA21 went along with less severe anaemia, which was not observed with CaCO3. Both PA21 doses, in contrast to CaCO3, prevented a dramatic increase in fibroblast growth factor (FGF)-23 and significantly reduced the vascular calcium content while both compounds ameliorated CKD-related hyperparathyroid bone. CONCLUSIONS: PA21 treatment prevented an increase in serum FGF-23 and had, aside from its phosphate-lowering capacity, a beneficial impact on renal function decline (as assessed by the renal creatinine clearance) and related disorders. The protective effect of this iron-based phosphate binder on the kidney in rats, together with its low pill burden in humans, led us to investigate its use in patients with impaired renal function not yet on dialysis.

Chronic interstitial nephritis in agricultural communities is a toxin-induced proximal tubular nephropathy.

Almost 30 years after the detection of chronic interstitial nephritis in agricultural communities (CINAC) its etiology remains unknown. To help define this we examined 34 renal biopsies from Sri Lanka, El Salvador, India and France of patients with chronic kidney disease 2-3 and diagnosed with CINAC by light and electron microscopy. In addition to known histopathology, we identified a unique constellation of proximal tubular cell findings including large dysmorphic lysosomes with a light-medium electron-dense matrix containing dispersed dark electron-dense non-membrane bound "aggregates". These aggregates associated with varying degrees of cellular/tubular atrophy, apparent cell fragment shedding and no-weak proximal tubular cell proliferative capacity. Identical lysosomal lesions, identifiable by electron microscopy, were observed in 9% of renal transplant implantation biopsies, but were more prevalent in six month (50%) and 12 month (67%) protocol biopsies and in indication biopsies (76%) of calcineurin inhibitor treated transplant patients. The phenotype was also found associated with nephrotoxic drugs (lomustine, clomiphene, lithium, cocaine) and in some patients with light chain tubulopathy, all conditions that can be directly or indirectly linked to calcineurin pathway inhibition or modulation. One hundred biopsies of normal kidneys, drug/toxin induced nephropathies, and overt proteinuric patients of different etiologies to some extent could demonstrate the light microscopic proximal tubular cell changes, but rarely the electron microscopic lysosomal features. Rats treated with the calcineurin inhibitor cyclosporine for four weeks developed similar proximal tubular cell lysosomal alterations, which were absent in a dehydration group. Overall, the finding of an identical proximal tubular cell (lysosomal) lesion in CINAC and calcineurin inhibitor nephrotoxicity in different geographic regions suggests a common paradigm where CINAC patients undergo a tubulotoxic mechanism similar to calcineurin inhibitor nephrotoxicity.

Human health risk associated with the management of phosphorus in freshwaters using lanthanum and aluminium.

The use of geo-engineering materials to manage phosphorus in lakes has increased in recent years with aluminium and lanthanum based materials being most commonly applied. Hence the potential impact of the use of these compounds on human health is receiving growing interest. This review seeks to understand, evaluate and compare potential unintended consequences on human health and ecotoxicological risks associated with the use of lanthanum- and aluminium-based materials to modify chemical and ecological conditions in water bodies. In addition to their therapeutic use for the reduction of intestinal phosphate absorption in patients with impaired renal function, the phosphate binding capacity of aluminium and lanthanum also led to the development of materials used for water treatment. Although lanthanum and aluminium share physicochemical similarities and have many common applications, their uptake and kinetics within the human body and living organisms importantly differ from each other which is reflected in a different toxicity profile. Whilst a causal role in the development of neurological pathologies, skeletal lesions, hematopoietic disorders and respiratory effects has unequivocally been demonstrated with increased exposure to aluminium, studies until now have failed to find such a clear association after exposure to lanthanum although caution is warranted. Our review indicates that lanthanum and aluminium have a distinctly different profile with respect to their potential effects on human health. Regular monitoring of both aluminium and lanthanum concentrations in lanthanum-/aluminium-treated water by the responsible authorities is recommended to avoid acute accidental or chronic low level accumulation.

Metformin: A Candidate Drug for Renal Diseases.

Over the past decades metformin has been the optimal first-line treatment for type 2 diabetes mellitus (T2DM). Only in the last few years, it has become increasingly clear that metformin exerts benign pleiotropic actions beyond its prescribed use and ongoing investigations focus on a putative beneficial impact of metformin on the kidney. Both acute kidney injury (AKI) and chronic kidney disease (CKD), two major renal health issues, often result in the need for renal replacement therapy (dialysis or transplantation) with a high socio-economic impact for the patients. Unfortunately, to date, effective treatment directly targeting the kidney is lacking. Metformin has been shown to exert beneficial effects on the kidney in various clinical trials and experimental studies performed in divergent rodent models representing different types of renal diseases going from AKI to CKD. Despite growing evidence on metformin as a candidate drug for renal diseases, in-depth research is imperative to unravel the molecular signaling pathways responsible for metformin's renoprotective actions. This review will discuss the current state-of-the-art literature on clinical and preclinical data, and put forward potential cellular mechanisms and molecular pathways by which metformin ameliorates AKI/CKD.

Short-term dexamethasone treatment transiently, but not permanently, attenuates fibrosis after acute-to-chronic kidney injury.

BACKGROUND: Acute kidney injury (AKI) is an underestimated, yet important, risk factor for the development of chronic kidney disease (CKD). Persistence of inflammation after a renal ischemic injury has been observed, both in experimental models and patients, and is thought to be an important mechanisms underlying progression of acute-to-chronic renal injury. Temporary suppression of inflammation immediately after AKI might therefore be a good first-line therapeutic strategy towards a better long term outcome. METHODS: Male C57Bl/6 J mice (Charles River, 10-12 weeks of age) underwent warm (36 °C body temperature) unilateral ischemia-reperfusion of the kidney for 21 min, after which treatment with intraperitoneal injection of the corticosteroid dexamethasone (10 mg/kg) was initiated for 3 weeks. Both at that time point and after an additional 3 week post-treatment follow up period, fibrosis was quantified by collagen I gene expression and immunostaining, as well as gene expression analysis of fibrosis-related genes Tgfß, Ccn2 (Ctgf), Pai-1 and Ccn3. Furthermore, inflammation was evaluated by Tnfα gene expression and protein expression of the F4/80 macrophage marker and the α-SMA fibroblast marker. Lastly, renal histopathology was quantified by a morphometric analysis of the tubulointerstitial area. RESULTS: Treatment with dexamethasone attenuated development of fibrosis, as evidenced by reduced collagen I gene expression and immunostaining, in combination with reduced gene expression of the pro-fibrotic Ccn2 and increased expression of the anti-fibrotic Ccn3. The effects of dexamethasone on renal fibrosis persisted during the 3 week follow up period, as evidenced by stagnation of collagen I deposition in the ischemic kidney, in contrast to vehicle-treatment, where progression of fibrosis was observed. However, expression levels of the pro-fibrotic genes re-approached those of vehicle-treated injured kidneys suggesting that the effects of dexamethasone on fibrosis beyond the treatment period are temporary. CONCLUSION: A short term anti-inflammatory therapy with dexamethasone only transiently attenuates ischemia induced fibrosis. Prolonged or persistent anti-inflammatory treatment seems warranted to achieve long term benefit.

Epithelial Cell Cycle Behaviour in the Injured Kidney.

Acute kidney injury (AKI), commonly caused by ischemia-reperfusion injury, has far-reaching health consequences. Despite the significant regenerative capacity of proximal tubular epithelium cells (PTCs), repair frequently fails, leading to the development of chronic kidney disease (CKD). In the last decade, it has been repeatedly demonstrated that dysregulation of the cell cycle can cause injured kidneys to progress to CKD. More precisely, severe AKI causes PTCs to arrest in the G1/S or G2/M phase of the cell cycle, leading to maladaptive repair and a fibrotic outcome. The mechanisms causing these arrests are far from known. The arrest might, at least partially, be attributed to DNA damage since activation of the DNA-damage response pathway leads to cell cycle arrest. Alternatively, cytokine signalling via nuclear factor kappa beta (NF-κß) and p38-mitogen-activated protein kinase (p38-MAPK) pathways, and reactive oxygen species (ROS) can play a role independent of DNA damage. In addition, only a handful of cell cycle regulators (e.g., p53, p21) have been thoroughly studied during renal repair. Still, why and how PTCs decide to arrest their cell cycle and how this arrest can efficiently be overcome remain open and challenging questions. In this review we will discuss the evidence for cell cycle involvement during AKI and development of CKD together with putative therapeutic approaches.

Environmental toxin-induced acute kidney injury.

Human beings are exposed to various potentially toxic agents and conditions in their natural and occupational environments. The kidney, due to its concentrating ability and excretory function, is highly vulnerable to the effects of environmental toxins. Identifying the precise cause and mechanisms of environmentally induced renal injury remains a challenge for which various scientific disciplines need to be involved. Investigations in this field are confronted with the apparent infinite types of toxins, their mutual interaction, handling/metabolization by the body, ways of exposure, etc. Although interdisciplinary efforts and persistence are required to identify, mechanistically unravel and tackle environmental toxin-induced pathologies, research eventually pays off in ameliorated working/living conditions and development of preventive/therapeutic strategies. This review was compiled to particularly emphasize the need for a maintained awareness of environmental threats in general and those targeting the kidney. Different mechanisms of renal toxicity are illustrated and discussed, thereby focusing on three types of environmental toxins, namely aristolochic acid, melamine and heavy metals.

Untargeted DNA-Demethylation Therapy Neither Prevents Nor Attenuates Ischemia-Reperfusion-Induced Renal Fibrosis.

BACKGROUND: Current treatment options for chronic kidney disease (CKD) are limited and their focus is on slowing its progression by addressing comorbidities. Fibrosis, the common histopathological process in CKD, is a major therapeutic research target. In CKD, fibroblasts are terminally activated due to alterations in their DNA-methylation pattern, particularly hypermethylation. Preventing the copying of pathological DNA-methylation patterns in proliferating fibroblasts could be a new effective therapeutic strategy for treating CKD. METHODS: To evaluate the therapeutic effect of short-term treatment with the DNA-methyltransferase (DNMT)-inhibitor decitabine on fibrosis (either developing or already established), male C57Bl/6 mice underwent warm unilateral ischemia-reperfusion injury. Respectively 3 days, 3 and 6 weeks after surgery, decitabine treatment (0.25 mg/kg) was initiated for 10 days after which animals were followed up to 12 weeks after ischemia. The efficacy of therapy on fibrosis was evaluated by collagen I and tgfß gene expression and histological quantification of collagen I staining. In addition, the effect of decitabine treatment on tubular injury (Kim-1, Ngal), inflammation (TNFa, IL6), DNA-methyltransferases (Dnmt1, 3a, and 3b), and global methylation status was determined. RESULTS: Following ischemia there was a significant increase in fibrotic, injury, and inflammatory markers as well as an increase of the various dnmts. Although decitabine treatment transiently increased renal injury and had a moderately decreasing effect on dnmt expression and on global DNA-methylation upon immediate treatment, none of the treatment regimens succeeded in preventing, attenuating, or diminishing fibrosis in the long run. CONCLUSION: Administration of untargeted nucleoside analogues seems unsuitable as a first-line treatment option in developing or established CKD.

Unilateral Renal Ischemia-Reperfusion as a Robust Model for Acute to Chronic Kidney Injury in Mice.

Acute kidney injury (AKI) is an underestimated, yet important risk factor for development of chronic kidney disease (CKD). Even after initial total recovery of renal function, some patients develop progressive and persistent deterioration of renal function and these patients are more likely to progress to end-stage renal disease (ESRD). Animal models are indispensable for unravelling the mechanisms underlying this progression towards CKD and ESRD and for the development of new therapeutic strategies in its prevention or treatment. Ischemia (i.e. hypoperfusion after surgery, bleeding, dehydration, shock, or sepsis) is a major aetiology in human AKI, yet unilateral ischemia-reperfusion is a rarely used animal model for research on CKD and fibrosis. Here, we demonstrate in C57Bl/6J mice, by both histology and gene expression, that unilateral ischemia-reperfusion without contralateral nephrectomy is a very robust model to study the progression from acute renal injury to long-term tubulo-interstitial fibrosis, i.e. the histopathological hallmark of CKD. Furthermore, we report that the extent of renal fibrosis, in terms of Col I, TGFß, CCN2 and CCN3 expression and collagen I immunostaining, increases with increasing body temperature during ischemia and ischemia-time. Thus, varying these two main determinants of ischemic injury allows tuning the extent of the long-term fibrotic outcome in this model. Finally, in order to cover the whole practical finesse of ischemia-reperfusion and allow model and data transfer, we provide a referenced overview on crucial technical issues (incl. anaesthesia, analgesia, and pre- and post-operative care) with the specific aim of putting starters in the right direction of implementing ischemia in their research and stimulate them, as well as the community, to have a critical view on ischemic literature data.

Evaluation of intestinal phosphate binding to improve the safety profile of oral sodium phosphate bowel cleansing.

Prior to colonoscopy, bowel cleansing is performed for which frequently oral sodium phosphate (OSP) is used. OSP results in significant hyperphosphatemia and cases of acute kidney injury (AKI) referred to as acute phosphate nephropathy (APN; characterized by nephrocalcinosis) are reported after OSP use, which led to a US-FDA warning. To improve the safety profile of OSP, it was evaluated whether the side-effects of OSP could be prevented with intestinal phosphate binders. Hereto a Wistar rat model of APN was developed. OSP administration (2 times 1.2 g phosphate by gavage) with a 12h time interval induced bowel cleansing (severe diarrhea) and significant hyperphosphatemia (21.79 ± 5.07 mg/dl 6h after the second OSP dose versus 8.44 ± 0.97 mg/dl at baseline). Concomitantly, serum PTH levels increased fivefold and FGF-23 levels showed a threefold increase, while serum calcium levels significantly decreased from 11.29 ± 0.53 mg/dl at baseline to 8.68 ± 0.79 mg/dl after OSP. OSP administration induced weaker NaPi-2a staining along the apical proximal tubular membrane. APN was induced: serum creatinine increased (1.5 times baseline) and nephrocalcinosis developed (increased renal calcium and phosphate content and calcium phosphate deposits on Von Kossa stained kidney sections). Intestinal phosphate binding (lanthanum carbonate or aluminum hydroxide) was not able to attenuate the OSP induced side-effects. In conclusion, a clinically relevant rat model of APN was developed. Animals showed increased serum phosphate levels similar to those reported in humans and developed APN. No evidence was found for an improved safety profile of OSP by using intestinal phosphate binders.

Lanthanum carbonate inhibits intestinal oxalate absorption and prevents nephrocalcinosis after oxalate loading in rats.

PURPOSE: Increased intestinal oxalate absorption leads to increased urinary oxalate excretion (secondary hyperoxaluria) and calcium oxalate crystal formation, contributing to nephrocalcinosis/lithiasis. Lanthanum carbonate is an intestinal phosphate binder that is orally administered to patients on dialysis to treat hyperphosphatemia. It is hypothesized that lanthanum can also bind oxalate, in addition to phosphate. We evaluated this in vitro and in vivo. MATERIALS AND METHODS: In vitro oxalate binding was evaluated by oxalate precipitation from a solution by lanthanum. In vivo oxalate absorption kinetics and the effect of lanthanum carbonate on nephrocalcinosis development were assessed in male Sprague-Dawley® rats that received 1) 1,000 mg lanthanum carbonate and oxalate, 2) carboxymethylcellulose and oxalate or 3) carboxymethylcellulose by gavage for up to 12 hours (kinetics) or 7 days (nephrocalcinosis). Plasma and urinary oxalate concentrations were measured at several time points after gavage. The degree of nephrocalcinosis was assessed histomorphometrically on von Kossa stained sections and by measuring total calcium content in renal tissue. RESULTS: In vitro lanthanum bound oxalate in a pH range comparable to the range of the intestine. In vivo oxalate administration in untreated animals resulted in a biphasic pattern of increased plasma oxalate levels, which was almost abolished in lanthanum treated rats. In the urine of treated rats oxaluria and calcium oxalate crystalluria were blunted. Moreover, significantly decreased nephrocalcinosis was observed compared with that in untreated rats. CONCLUSIONS: Lanthanum carbonate is a promising agent for the future prevention/treatment of secondary hyperoxaluria.