TRPM7 contributes to progressive nephropathy.

TRPM7 belongs to the Transient Receptor Potential Melastatin family of ion channels and is a divalent cation-conducting ion channel fused with a functional kinase. TRPM7 plays a key role in a variety of diseases, including neuronal death in ischemia, cancer, cardiac atrial fibrillation, malaria invasion. TRPM7 is aberrantly over-expressed in lung, liver and heart fibrosis. It is also overexpressed after renal ischemia-reperfusion, an event that induces kidney injury and fibrosis. However, the role of TRPM7 in kidney fibrosis is unclear. Using the unilateral ureteral obstruction (UUO) mouse model, we examined whether TRPM7 contributes to progressive renal damage and fibrosis. We find that TRPM7 expression increases in UUO kidneys. Systemic application of NS8593, a known TRPM7 inhibitor, prevents kidney atrophy in UUO kidneys, retains tubular formation, and reduces TRPM7 expression to normal levels. Cell proliferation of both tubular epithelial cells and interstitial cells is reduced by NS8593 treatment in UUO kidneys, as are TGF-ß1/Smad signaling events. We conclude that TRPM7 is upregulated during inflammatory renal damage and propose that pharmacological intervention targeting TRPM7 may prove protective in progressive kidney fibrosis.

MicroRNA-34a Promotes Renal Fibrosis by Downregulation of Klotho in Tubular Epithelial Cells.

Renal fibrosis is the main pathological characteristic of chronic kidney disease (CKD), whereas the underlying mechanisms of renal fibrosis are not clear yet. Herein, we found an increased expression of microRNA-34a (miR-34a) in renal tubular epithelial cells of patients with renal fibrosis and mice undergoing unilateral ureteral obstruction (UUO). In miR-34a-/- mice, miR-34a deficiency attenuated the progression of renal fibrosis following UUO surgery. The miR-34a overexpression promoted epithelial-to-mesenchymal transition (EMT) in cultured human renal tubular epithelial HK-2 cells, which was accompanied by sharp downregulation of Klotho, an endogenous inhibitor of renal fibrosis. Luciferase reporter assay revealed that miR-34a downregulated Klotho expression though direct binding with the 3' UTR of Klotho. Conversely, overexpression of Klotho prevented miR-34a-induced EMT in HK-2 cells. Furthermore, results showed that miR-34a was induced by transforming growth factor ß1 (TGF-ß1) through p53 activation, whereas dihydromyricetin could inhibit TGF-ß1-induced miR-34a overexpression. Accordingly, dihydromyricetin administration dramatically restored the aberrant upregulation of miR-34a and Klotho reduction in obstructed kidney, and markedly ameliorated renal fibrosis in the Adriamycin nephropathy and UUO model mice. These findings suggested that miR-34a plays an important role in the progression of renal fibrosis, which provides new insights into the pathogenesis and treatment of CKD.

Acute bilateral ureteral obstruction secondary to guaifenesin toxicity.

Several medications or their metabolites have been associated with urolithiasis, although overall they remain an infrequent cause of urolithiasis. Guaifenesin stones were originally reported as complexed with ephedrine, and subsequent reports have demonstrated pure guaifenesin stones, occurring after long term abuse. We report a case of a 23-year-old male who ingested a large, one time dose of guaifenesin, resulting in acute bilateral ureteral obstruction, which, to our knowledge, is the first such reported case in the literature.

Sulphadiazine-induced obstructive renal failure complicating treatment of HIV-associated toxoplasmosis.

A patient with newly-diagnosed HIV infection and biopsy-proven cerebral toxoplasmosis was treated with sulphadiazine and pyrimethamine. Despite adequate hydration and daily examination of urine for sulphadiazine crystals obstructive uropathy due to bilateral ureteric stones with hydronephrosis occurred, resulting in rapid onset renal failure. Sulphadiazine was discontinued and clindamycin was substituted. With intravenous fluid hydration and bilateral nephrostomies the urolithiasis resolved. This case serves to remind clinicians of the need for vigilance when treating cerebral toxoplasmosis with sulphadiazine, in order to avoid this potentially serious complication of treatment.

[Distal and late ureteral obstruction: a rare complication following dextranomer/hyaluronic acid injection for vesicoureteral reflux in children]. / L'obstruction urétérale distale secondaire : une complication rare du traitement endoscopique par Deflux(®) du reflux vésico-urétéral de l'enfant.

Surgically relevant obstruction after dextranomer/hyaluronic acid injection (Dx/Ha, Deflux(®)) for the treatment of vesicoureteral reflux (VUR) is rare with a 0.6% incidence. It occurs usually during the early postoperative period. We report here the case of a 9-year-old boy with a history of VUR who was previously treated with Deflux(®) and was referred more than 2 years later with acute flank pain (as he already did 2 weeks after surgery with a spontaneous relief under medical treatment). Initial radiological investigations showed hydronephrosis caused by distal ureteral obstruction which required open surgery removal of the Dx/Ha and Cohen procedure. This is the second case of delayed symptomatic obstruction due to Dx/Ha reported in the literature.

Ureteral obstruction following injection of dextranomer/hyaluronic acid copolymer: an infrequent but relevant complication.

PURPOSE: To report our experience with ureteral obstruction after injection of dextranomer/hyaluronic acid copolymer (Dx/Ha) to treat vesicoureteral reflux, and analyze its possible causes, management and outcome. MATERIALS AND METHODS: Retrospective review of patients undergoing injection of Dx/Ha. The charts of patients with clinically relevant ureteral obstruction were evaluated for indications, prior interventions, technique of injection and volume injected. Video recordings obtained during injection were analyzed to detect possible technical errors. RESULTS: Fifty-four patients (87 ureters) were treated with Dx/Ha injection in a 5-year period. Five ureters (5.7%) in five patients (9.3%) developed significant ureteral obstruction requiring intervention. Manifestations of obstruction included pain in two patients, urinary tract infections in one and loss of function in one. Increased serum creatinine was observed in a patient with a transplanted kidney. Four obstructions resolved spontaneously (two after percutaneous nephrostomy, two after placement of a ureteral stent) and one required reimplantation. Review of the videos did not reveal any deviation from the usual technique. The volumes injected in the obstructed cases (0.7-1.2 ml) were in the usual range. CONCLUSIONS: In this series, the incidence of post Dx/Ha ureteral obstruction was higher than previously reported. Although 4/5 cases resolved spontaneously, they required drainage to relieve symptoms or to improve renal function. Surgeons need to be aware of this complication and include its possible occurrence in the informed consent obtained prior to injection.

The optimal dose of Adriamycin to create a viable rat model potentially applicable to congenital obstructive uropathy.

PURPOSE: The Adriamycin rat model is an established model for different organ anomalies including congenital obstructive uropathy. In the current study, we carried out a dose-response analysis to find out the optimal dose of Adriamycin to create a viable rat model of obstructive uropathy. METHODS: Thirty time-mated Sprague-Dawley rats were divided into 5 groups including 1 control group and 4 different treatment groups. The 4 Adriamycin dosage regimens investigated in this study were 1.25, 1.5, 1.75, and 2 mg/(kg d). Experimental rats (n = 24) were injected intraperitoneally with different doses of Adriamycin on gestational days 7 to 9 (6 rats in each group). Control rats (n = 6) were injected with an equivalent volume of saline on the same days. Viable term fetuses were harvested on gestational day 21 by cesarean delivery and dissected under a dissecting microscope. Serial transverse sections from urinary tract system were obtained for histological examination. RESULTS: One hundred thirty-three viable fetuses were recovered from Adriamycin-treated rats, and 50 were from rats in the control group. There were no resorptions in the control group; however, 52 resorptions were recorded in Adriamycin groups. The rates of hydronephrosis and resorptions were 60% and 0%, 80.5% and 5.8%, 100% and 17.3%, and 100% and 76.9% at doses of 1.25, 1.50, 1.75, and 2 mg/(kg d), respectively. Histologic examination of the kidneys in the treated groups showed a significant decrease in renal parenchyma compared with the control group. CONCLUSIONS: The dosage of 1.5 mg/(kg d) of Adriamycin yielded the highest number of viable hydronephrotic fetuses. At this dose, urinary abnormalities are milder; but the highest number of viable fetuses is provided, which is necessary to create a reproducible and viable animal model.

Postoperative ureteral obstruction after subureteral injection of dextranomer/hyaluronic Acid copolymer.

PURPOSE: Subureteral injection of dextranomer/hyaluronic acid copolymer is widely accepted for the treatment of primary vesicoureteral reflux. Few studies document the incidence of surgically relevant postoperative obstruction or the characteristics of patients at risk. MATERIALS AND METHODS: Four institutions had reported surgically relevant postoperative obstruction to representatives of Q-Med Scandinavia, the manufacturers of Deflux (dextranomer/hyaluronic acid). All children undergoing dextranomer/hyaluronic acid injection at these institutions were evaluated in this study. Patients requiring postoperative stenting were retrospectively reviewed for pertinent history, volume injected, technique of injection, duration of symptoms before intervention, duration of intervention and final outcome. RESULTS: A total of 745 patients (1,155 ureters) underwent injection. Five patients (6 renal units, 7 ureters) required stenting for obstructive symptoms and hydronephrosis, of whom 4 immediately became symptomatic. All patients had been injected with up to 1 ml dextranomer/hyaluronic acid. Four patients (80%) had either a neurogenic bladder or dysfunctional voiding. All stents were placed and removed without complications, with complete resolution of symptoms in all patients. Length of stenting ranged from 2 to 6 weeks. No patient required open surgery. One of 2 patients undergoing postoperative voiding studies had development of recurrent vesicoureteral reflux. CONCLUSIONS: Dextranomer/hyaluronic acid injection is associated with a small risk of postoperative ureteral obstruction requiring endoscopic intervention, with an overall incidence of less than 0.7% of patients injected. Patients with voiding dysfunction or neurogenic bladder may be at increased risk. Intervention with temporary ureteral stenting is effective, technically simple and curative.

Wilm's tumor in a solitary kidney complicated by chemotherapy induced obstructive uropathy.

A three-year-old male child with Wilm's tumor of left kidney and right sided unilateral renal agenesis is reported. The left renal vein was located posterior to the aorta. He was managed with medical measures alone. The initial phase of treatment was complicated by chemotherapy induced dislodgment of the tumor fragment and subsequent distal obstruction.

Distal ureteral stenosis after early adjuvant intravesical mitomycin C application for superficial bladder cancer.

We report a case of distal ureteral stenosis after transurethral resection of a small bladder tumor near the left ureteral orifice and early postoperative mitomycin C instillation for prevention of recurrence. The patient developed late recurrent stenosis of the ureteral orifice with histologic evidence of localized, severe benign inflammatory reaction. The recurrent stenosis was successfully managed by transurethral resection of the scar tissue and ureteric stenting. Although ureteral stenosis does occur after transurethral resection, the severity and time course of the stenosis in this case suggest an influence of the intravesical chemoprophylaxis used.

Bilateral ureteric obstruction secondary to the prolonged use of tiaprofenic acid.

There is increasing awareness that the long-term use of the non-steroidal anti-inflammatory agent tiaprofenic acid (Surgam) is associated with a severe form of cystitis. The condition is usually reversible with complete resolution of symptoms on stopping the drug. We present a case of tiaprofenic acid-induced cystitis resulting in bilateral hydronephrosis suggesting ureteric obstruction. The previous reported cases are reviewed and the risks of delay in withdrawal of the drug and of permanent ureteric damage are discussed.

[Obstructive renal insufficiency caused by amoxicillin crystalluria]. / Insuffisance rénale obstructive par cristallurie à l'amoxicilline.

A 76-year-old woman was admitted to the ICU for a meningitis with rhombencephalitis due to Listeria monocytogenes. The treatment included amoxicillin (250 mg.kg-1.day-1) and gentamicin (3 mg.kg-1.day-1 over 6 days). Neurological outcome was favourable. However at the 14th day, an acute renal failure occurred, following macroscopic haematuria and milkiness urine. CT scan and sonography confirmed the diagnosis of obstructive renal failure with bilateral ureteral obstruction. Crystalluria caused by amoxicillin was suspected. Endoscopic ureteral insertion of double-J catheters permitted the recovery of a normal renal function.

Segmental stenosis of ureter: a late complication of intra-arterial chemotherapy for bladder cancer.

A 54-year-old Japanese male was treated with a single shot of cisplatin-phosphatidylcholine-lipiodol (CPL) suspension due to bladder tumour (stage T2N0M0). Seven months later, a right lower ureteral stenosis developed. The possible cause of ureteral stenosis due to intra-arterial chemotherapy is discussed.

Drug-induced renal disease.

The clinical manifestations of drug-induced renal disease may include all the manifestations attributed to natural or spontaneous renal diseases such as acute renal failure, chronic renal failure, acute nephritic syndrome, renal colic, haematuria, selective tubular defects, obstructive nephropathy, etc. It is therefore vital in any patient with renal disease whatever the clinical manifestations might be, to obtain a meticulous drug and toxin inventory. Withdrawal of the offending drug may result in amelioration or cure of the renal disorder although in the case of severe renal failure it may be necessary to utilise haemodialysis or peritoneal dialysis to tide the patient over the period of acute renal failure. Analgesic nephropathy is an important cause of terminal chronic renal failure and it is therefore vital to make the diagnosis as early as possible. The pathogenesis of some drug-induced renal disorders appears to be immunologically mediated. There are many other pathogenetic mechanisms involved in drug-induced renal disorders and some drugs may under appropriate circumstances be responsible for a variety of different nephrotoxic effects. For example, the sulphonamides have been incriminated in examples of crystalluria, acute interstitial nephritis, acute tubular necrosis, generalised hypersensitivity reactions, polyarteritis nodosa and drug-induced lupus erythematosus.

Ureteral involvement in genitourinary tuberculosis: review of 20 cases encountered over three years.

Genitourinary tuberculosis continues to be a significant worldwide problem. In the southwestern United States, this is particularly true among Indians and Spanish-Americans who, in the experience of the authors, frequently present with advanced and neglected disease. The possibility of silent development or progression of ureteral strictures while on antituberculous medication demands routine urographic evaluation of all patients in whom pulmonary tuberculosis is diagnosed. A large percentage of patients with ureteral tuberculosis undergo stricture formation or progression while on chemotherapy, and require reconstructive ureteral surgery if renal destruction is to be avoided.

Analgesic abuse, ureteric obstruction, and retroperitoneal fibrosis.

We report two cases of unusual ureteric obstruction in patients with an excessive consumption of analgesics. In a retrospective survey of seven cases of non-malignant retroperitoneal fibrosis seen in the last 15 years it was found that four had taken excessive amounts of analgesics. A careful drug history should be taken in all patients with restroperitoneal fibrosis and ureteric obstruction.