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.

Effects of hydroxyethyl starch 130/0.4 on the kidney tissue of rats with ureteral obstruction.

OBJECTIVE: This study was conducted since the effects of colloid solutions on the renal system remain controversial and need to be adequately studied in animals. We aimed to evaluate the effects of hydroxyethyl starch (Voluven) on the kidney tissue of rats with late renal failure due to ureteral obstruction. MATERIALS AND METHODS: Rats were divided into four groups: Group C, control; Group HES, hydroxyethyl starch solution (HES) 130/0.4 (Voluven®); Group UUO, unilateral ureteral obstruction (UUO); and Group UUO-HES, UUO-HES 130/0.4 (Voluven®). In the groups with ureteral obstruction, the distal part of the right ureter was accessed and sutured through a lower abdominal incision under ketamine anesthesia. Any signs of late-stage renal failure were evaluated after three weeks. Rats in the HES group and the renal failure-HES group were administered with HES 130/0.4 as a single intravenous dose of 20 mL/kg. After a follow-up of 24 hours, intra-abdominal blood sample was collected, and the rats were sacrificed. Biochemical and histopathological parameters were then evaluated. RESULTS: Ureteral obstruction significantly increased urea and creatinine levels. In addition, when the UUO-HES and HES groups were compared, the administration of HES increased urea and creatinine levels in the UUO-HES group. Nitric oxide enzyme activity and malondialdehyde levels have significantly increased in the UUO groups. In addition, HES significantly increased nitric oxide activity and malondialdehyde levels in the UUO-HES group, in comparison with the HES group. The activity of caspases 3 and 8 was significantly increased in the UUO groups. In addition, HES significantly increased the activity of caspases 3 and 8 in the UUO-HES group, in comparison with the HES group. Light microscopy revealed significant changes in the UUO groups, especially in the obstructed kidneys. CONCLUSION: If indicated, HES should be used with caution in cases of UUO, but not in the cases of bilateral ureteral obstruction. Other aspects of these findings, including the clinical significance and practical applications, merit further experimental and clinical investigation.

[Bilateral hydronephrosis as a result of opioid-induced bowel spasm in a patient with an ileal conduit]. / Harnstauungsnieren beidseits infolge opiatinduzierter Darmspastik bei einer Patientin mit Ileumconduit.

A 47-year-old woman with spina bifida and an ileal conduit since childhood presented with left-sided flank pain, bilateral hydronephrosis and oliguria suspicious for a recurrent stenosis at the ureteral implantation site. Her history revealed a recent increase in her pain medication with opioids for treatment of neuropathic pain. After insertion of percutaneous nephrostomy on the left side and confirmation of the stenosis, open reimplantation of the ureter was already discussed with the patient. However after dose reduction of the opioid therapy hydronephrosis resolved. Thus opioid-induced bowel spasm was probably the cause for the obstruction.

Acute renal failure after ingestion of guaifenesin and dextromethorphan.

BACKGROUND: Guaifenesin is a common nonprescription medication that has been implicated in drug-induced nephrolithiasis. Dextromethorphan, a nonprescription antitussive found in some guaifenesin-containing preparations, is increasingly recognized as a substance of abuse by many youth and young adults. Renally excreted medications known to have poor solubility in urine have the potential to precipitate when ingested in large quantity, leading to acute obstruction of the ureters and renal failure. OBJECTIVE: We describe the case of a 22-year-old male who developed severe bilateral flank pain, hematuria, and oliguria after an isolated recreational ingestion of guaifenesin and dextromethorphan. CASE REPORT: The patient was found to have bilateral ureteral obstruction and acute renal failure, suspected to be secondary to precipitation of medication metabolites in the urine. CONCLUSIONS: This case highlights the potential for acute renal failure secondary to guaifenesin and dextromethorphan abuse.

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.

Devastating complication of silver nitrate instillation for the treatment of chyluria.

The passage of milky white urine (chyluria) is an alarming sign. Safety and efficacy of silver nitrate instillation therapy for chyluria has been demonstrated in various studies in literature. Inspite of these, various serious complications following silver nitrate therapy have been reported from the regions where the pathology is prevalent. Even today, no protocol has been standardised for instillation therapy for chyluria about the ideal agent used, exact concentration or amount to be instilled, total number of instillations and doses per instillation to be administered. We presented a devastating complication of silver nitrate instillation therapy resulted in acute renal failure followed by later formation of long ureteric stricture in a patient resulting in long-term morbidity to the patient. There is a need for more vigilant approach and standardisation of protocol for silver nitrate instillation for treatment of chyluria.

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.

[Effect of supplementing Qi-nourishing Yin-dispersing blood stasis-dredging collateral herbs on p38 MAPK signaling pathway in kidney of early diabetic rats].

OBJECTIVE: To study the effect of supplementing Qi-nourishing Yin and dispersing blood stasis-dredging collateral herbs on p38 mitogen activated protein kinase (p38 MAPK) signaling pathway in the kidney of early diabetic rats. METHOD: Dividing SD rats randomly into 6 groups: Simple nephrectomy group, model group, irbesatan group, traditional Chinese medicine (TCM) low dose group, TCM middle dose group and TCM high dose group. Each group of rats was fed with the corresponding dose of medicine. After 6 weeks, detecting 24 h urine protein (UPro) level, renal function, p38 MAPK mRNA and p-p38 MAPK protein level. RESULT: UPro levels of irbesatan group, TCM low group and TCM middle dose group decreased significantly (P < 0.05) , compared with that of the model group. Renal function of the treated groups was improved greatly and their p38 MAPK mRNA and p-p38MAPK protein levels decreased significantly (P < 0.05), compared with those of the model group. CONCLUSION: Supplementing Qi-nourishing Yin-dispersing blood stasis-dredging collateral herbs could treat DN rats effectively by inhibiting the expression of p38 MAPK signaling pathway.

Phenytoin metabolite renal calculus: an index case.

INTRODUCTION: Drugs and their metabolites are known factors in 1% to 2% of all kidney stones. Certain antiepileptic drugs are known to cause stone formation. Phenytoin is used as a first line antiepileptic therapy for many seizure disorders. We present what we believe to be the first report of a phenytoin metabolite urinary stone. METHODS: A 79-year-old woman with a fever and seizure disorder was found to have a right pelvic kidney with hydronephrosis and multiple large calcifications. She had been taking the antiepileptic medication phenytoin for the past 10 years. Average total serum phenytoin level from the year prior was in the normal range. Free phenytoin levels were not routinely monitored, but the one value available was elevated at 5.1 ng/dL. The patient underwent a percutaneous nephrolitomy, ultimately expiring from medical complications after the procedure. Final stone analysis revealed a composition of 35% phenytoin metabolite (5-(para-hydroxyphenyl)-5-phenylhydantoin) and 65% proteinaceous material. An extensive review of literature including PubMed, MedLine, and various internet search engines was performed, searching for any prior reports of urinary calculi formed from phenytoin or its metabolite. RESULTS: No previous reports of phenytoin or phenytoin metabolite urinary stones were found in the medical literature. Phenytoin has many known ill effects on the genitourinary system including acute interstitial nephritis, nephrotic syndrome, acute renal failure, and priapism. Now we can add urinary lithiasis to the list of its potential adverse effects. This article represents the first report of a phenytoin metabolite urinary stone. CONCLUSION: A metabolite of the commonly used antiepileptic medication phenytoin can cause clinically relevant urolithiasis leading to significant morbidity and even mortality. Clinicians should have an increased level of suspicion for metabolite stone formation in symptomatic patients taking antiepileptic medications. Further studies on phenytoin metabolism and its potential for inducing urinary lithiasis should be performed.

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.