oxalates and Nephritis

The primary hyperoxalurias (PHs) are inborn errors of glyoxylate metabolism characterized by endogenous oxalate overproduction in the liver, and thus elevated urinary oxalate excretion. The urinary calcium-oxalate (CaOx) supersaturation and the continuous renal accumulation of insoluble CaOx crystals yield a progressive decline in renal function that often ends with renal failure. In PH Type 1 (AGXT mutated), the most frequent and severe condition, patients typically progress to end-stage renal disease (ESRD); in PH Type 2 (GRHPR mutated), 20% of patients develop ESRD, while only one patient with PH Type 3 (HOGA1 mutated) has been reported with ESRD so far. Patients with ESRD undergo frequent maintenance (haemo)dialysis treatment, and finally must receive a combined liver-kidney transplantation as the only curative treatment option available in PH Type 1. In experimental models using oxalate-enriched chow, CaOx crystals were bound to renal tubular cells, promoting a pro-inflammatory environment that led to fibrogenesis in the renal parenchyma by activation of a NACHT, LRR and PYD domains-containing protein 3 (NALP3)-dependent inflammasome in renal dendritic cells and macrophages. Chronic fibrogenesis progressively impaired renal function. Targeting the inflammatory response has recently been suggested as a therapeutic strategy to treat not only oxalate-induced crystalline nephropathies, but also those characterized by accumulation of cystine and urate in other organs. Herein, we summarize the pathogenesis of PH, revising the current knowledge of the CaOx-mediated inflammatory response in animal models of endogenous oxalate overproduction. Furthermore, we highlight the possibility of modifying the NLRP3-dependent inflammasome as a new and complementary therapeutic strategy to treat this severe and devastating kidney disease.

Topics: Adolescent; Adult; Animals; Calcium Oxalate; Child; Child, Preschool; Disease Models, Animal; Humans; Hyperoxaluria, Primary; Infant; Inflammasomes; Kidney; Kidney Failure, Chronic; Kidney Transplantation; Macrophages; Mice; Nephritis; NLR Family, Pyrin Domain-Containing 3 Protein; Oxalates; Renal Dialysis; Renal Insufficiency; RNA Interference; Uric Acid; Young Adult

The identification of a disease entity as one that is the result of a heritable defect offers the physician an opportunity to intervene in a variety of ways. As emphasized, knowledge of the heritable pattern of a particular disease allows the physician an opportunity to counsel family members in personal disease risk and the offspring. Such genetic counseling results in a reduction of affected cases for many inherited diseases. There is every expectation that similar approaches would be effective for inherited renal diseases. The heritable diseases are a favored group for investigative purposes since these diseases result from a single gene defect no matter how plieotropic the effects of that defect. Thus the investigator is capable of constant probing with tools available for identifying that one event or component that lies at the basis of the disease. The emphasis of this chapter is on those inherited renal diseases for which we have reached a high level of understanding of this single defect. In many of these diseases a single enzyme is identified as deficient and is the presumed genetic defect. In others (cystinuria, RTA, and cystinosis) the precise biochemical answers appear close at hand. Thus a variety of therapeutic approaches to overcome either the gene defect or ill effects of the gene defect emerge for diseases involving the kidney and are listed in Table 7. For some of these diseases the new diagnostic technique of prenatal diagnosis can be used (Table 8). This genetic option provides couples at risk for bearing affected offspring with reduced risk. For a number of other diseases that are not identified by amniocentesis, this risk can be effectively lowered to acceptable levels by use of artificial insemination. Thus the inherited diseases of the kidney are amenable to medical intervention at a variety of levels. Such intervention can predictably lead to a lowering of both the incidence and consequences of these gene defects.

Topics: Acidosis, Renal Tubular; Adult; Child; Chromosome Aberrations; Chromosome Disorders; Cystinosis; Cystinuria; Diabetes Insipidus; Fanconi Syndrome; Female; Genes, Dominant; Genes, Recessive; Glycosphingolipids; Humans; Infant, Newborn; Kidney; Kidney Diseases; Kidney Diseases, Cystic; Lesch-Nyhan Syndrome; Lipid Metabolism, Inborn Errors; Male; Metabolism, Inborn Errors; Middle Aged; Nephritis; Orotic Acid; Oxalates; Polycystic Kidney Diseases; Pseudohypoparathyroidism; Sex Chromosome Aberrations; Xanthines

Inflammation worsens oxalate nephropathy by exacerbating tubular damage. The transient receptor potential vanilloid 1 (TRPV1) channel is present in kidney and has a polymodal sensing ability. Here, we tested whether TRPV1 plays a role in hyperoxaluria-induced renal inflammation. In TRPV1-expressed proximal tubular cells LLC-PK

Topics: Acute Kidney Injury; Animals; Hyperoxaluria; Inflammation; Male; Nephritis; Oxalates; Oxidative Stress; Rats; Rats, Wistar; TRPV Cation Channels

Intrarenal crystal formation activates the Nlrp3 inflammasome in myeloid cells and triggers a profound inflammatory response. Here, we studied whether a specific inhibitor of the Nlrp3 inflammasome, CP-456,773, can prevent kidney fibrosis in a murine model of crystal nephropathy induced by diets rich in oxalate or adenine. Inflammasome activation in renal dendritic cells and the resulting interleukin (IL)-1β and IL-18 production were markedly reduced by CP-456,773 treatment both ex vivo and in vivo. We directly visualized intrarenal inflammasome activation and its inhibition by CP-456,773 in vivo by adoptive transfer of bone marrow cells transduced with interleukin-1β-Gaussia luciferase, a proteolytic luciferase-based reporter for inflammasome activation, into irradiated mice. CP-456,773 treatment strongly attenuated kidney fibrosis when given early in the genesis of crystal nephropathy, but was unable to reverse established crystal-induced fibrosis. The urinary IL-18 concentration appeared to be a useful noninvasive biomarker for renal inflammasome activation. Finally, NLRP3 inhibition did not compromise adaptive immune responses as previously reported for the global inhibition of IL-1 signaling. Thus, early NLRP3 inhibition by CP-456,773 may be an effective treatment for crystal nephropathy. Use of iGLuc transfected cells introduces a novel imaging technique for inflammasome activation in mice.

Topics: Adenine; Adoptive Transfer; Animals; Cells, Cultured; Dendritic Cells; Disease Models, Animal; Fibrosis; Furans; Heterocyclic Compounds, 4 or More Rings; Humans; Immunohistochemistry; Indenes; Inflammasomes; Inflammation; Interleukin-18; Interleukin-1beta; Kidney; Mice; Mice, Inbred C57BL; Mice, Knockout; Nephritis; NLR Family, Pyrin Domain-Containing 3 Protein; Oxalates; Primary Cell Culture; Signal Transduction; Sulfonamides; Sulfones

Oxalate nephropathy with renal failure is caused by multiple disorders leading to hyperoxaluria due to either overproduction of oxalate (primary hyperoxaluria) or excessive absorption of dietary oxalate (enteric hyperoxaluria). To study the etiology of renal failure in crystal-induced kidney disease, we created a model of progressive oxalate nephropathy by feeding mice a diet high in soluble oxalate (high oxalate in the absence of dietary calcium). Renal histology was characterized by intratubular calcium-oxalate crystal deposition with an inflammatory response in the surrounding interstitium. Oxalate nephropathy was not found in mice fed a high oxalate diet that also contained calcium. NALP3, also known as cryopyrin, has been implicated in crystal-associated diseases such as gout and silicosis. Mice fed the diet high in soluble oxalate demonstrated increased NALP3 expression in the kidney. Nalp3-null mice were completely protected from the progressive renal failure and death that occurred in wild-type mice fed the diet high in soluble oxalate. NALP3 deficiency did not affect oxalate homeostasis, thereby excluding differences in intestinal oxalate handling to explain the observed phenotype. Thus, progressive renal failure in oxalate nephropathy results primarily from NALP3-mediated inflammation.

Topics: Animals; Carrier Proteins; Disease Models, Animal; Disease Progression; Female; Genotype; Inflammasomes; Inflammation Mediators; Kidney; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Nephritis; NLR Family, Pyrin Domain-Containing 3 Protein; Oxalates; Phenotype; Renal Insufficiency; Signal Transduction; Time Factors

Knauf et al. demonstrate that prolonged activation of the intrarenal inflammasome is responsible for the loss of kidney function in oxalate crystal nephropathy. These findings suggest new therapeutic opportunities for patients suffering from severe hereditary kidney diseases such as primary hyperoxaluria, and reveal a previously unappreciated general mechanism of kidney disease progression that may also contribute to conditions other than crystal nephropathy.

Topics: Animals; Carrier Proteins; Female; Inflammasomes; Inflammation Mediators; Kidney; Male; Nephritis; NLR Family, Pyrin Domain-Containing 3 Protein; Oxalates; Renal Insufficiency

Topics: Adolescent; Adult; Amyloidosis; Child; Cystinosis; Diabetic Nephropathies; Fabry Disease; Female; Gout; Humans; Kidney Diseases; Kidney Failure, Chronic; Kidney Transplantation; Male; Metabolic Diseases; Middle Aged; Nephritis; Nephritis, Hereditary; Oxalates; Renal Dialysis; Retrospective Studies; Transplantation, Homologous

Kidney tissue enzyme patterns from patients with calcium oxalate stone disease were compared to enzyme patterns from healthy and inflamed human kidneys. In the case of oxalate stone disease there was a significantly decreased activity of the glycolytic enzyme aldolase, resulting in a cumulation of oxaloacetate and of oxalic acid. This decrease of the aldolase activity does not completely reveal the cause of calcium oxalate stones but provides a new aspect to the disease.

Topics: Calcium; Carbohydrate Metabolism, Inborn Errors; Fructose-Bisphosphate Aldolase; Glyoxylates; Humans; Kidney; Kidney Calculi; Nephritis; Oxalates

The results of kidney transplantation in a variety of renal diseases have been analyzed. The diseases causing end-stage kidney failure in recipients were Alport syndrome, amyloidosis, cystinosis, diabetes mellitus, Fabry disease, familial nephritis, gout, medullary cystic disease, oxalosis, and systemic lupus erythematosus. The data indicate that renal transplantation is justifiable and parallels functional results for the more common causes of end-stage renal disease in all but Fabry disease and oxalosis. Although Fabry disease did not recur in any grafted kidney, only three patients have a functioning graft one year after transplantation. From a group of ten patients with oxalosis who received a total of 14 kidneys, only one survives. In no other metabolic disease, except one instance of primary amyloidosis, did the metabolic disease notably affect the transplant as it did in oxalosis.

Topics: Adolescent; Adult; Amyloidosis; Cystinosis; Diabetes Complications; Evaluation Studies as Topic; Fabry Disease; Female; Follow-Up Studies; Gout; Humans; International Cooperation; Kidney Diseases; Kidney Transplantation; Lupus Erythematosus, Systemic; Male; Middle Aged; Nephritis; Nephritis, Hereditary; Oxalates; Registries; Transplantation, Homologous

Topics: Angiography; Arteriovenous Shunt, Surgical; Autopsy; Female; Humans; Kidney; Kidney Diseases; Kidney Transplantation; Metabolism, Inborn Errors; Microradiography; Necrosis; Nephritis; Oxalates; Postoperative Complications; Thrombosis; Transplantation, Homologous; Vascular Diseases

Topics: Animals; Brain; Carnivora; Cat Diseases; Cats; Dog Diseases; Dogs; Ethylene Glycols; Glycols; Nephritis; Neurologic Manifestations; Oxalates; Pathology; Poisoning; Toxicology

Topics: Citrates; Humans; Kidney Calculi; Lithiasis; Nephritis; Nephrolithiasis; Oxalates; Phosphates; Uric Acid; Urine