James E. Springate

Renal late effects in patients treated for cancer in childhood: a report from the Children's Oncology Group.

Improvements in childhood cancer therapy have led to increasing numbers of long‐term survivors. These survivors are at risk for a variety of late effects due to the disease itself, treatment exposures (surgery, chemotherapy, and radiotherapy), underlying medical problems, and health behaviors. The COG LTFU Guidelines are risk‐based, exposure‐related recommendations for the identification and management of late effects due to therapies utilized in the treatment of childhood cancer, and are designed for asymptomatic survivors presenting for routine medical follow‐up 2 or more years after completion of cancer therapy. The COG Guidelines Task Force on Urinary Tract Complications conducted an extensive review of the medical literature via MEDLINE. Specific treatment exposures which were reviewed include nephrectomy, chemotherapy regimens known to be nephrotoxic (cisplatin, carboplatin, ifosfamide, and methotrexate), and renal irradiation. Literature sources were ranked according to the strength of evidence and are cited in the review. This review summarizes the literature that supported the recommendations for cancer survivors at risk for nephrotoxicity previously outlined in the Childrens Oncology Group Long‐Term Follow‐Up Guidelines for Survivors of Childhood, Adolescent and Young Adult Cancers (COG LTFU Guidelines). Pediatr Blood Cancer 2008;51:724–731.

Ifosfamide metabolite chloroacetaldehyde causes renal dysfunction in vivo.

Renal injury is a common side‐effect of the chemotherapeutic agent ifosfamide. Current evidence suggests that the ifosfamide metabolite chloroacetaldehyde may be responsible for this nephrotoxicity. The present study examined the effect of increasing amounts of intrarenally infused chloroacetaldehyde on kidney function, glutathione content and malondialdehyde formation. The ability of the uroprotectant medication sodium 2‐mercaptoethanesulfonate (mesna) to prevent chloroacetaldehyde‐induced renal injury was also assessed. Intrarenal chloroacetaldehyde infusion caused dose‐dependent declines in glomerular filtration rate and p‐aminohippuric acid clearance and increases in urine flow rate, sodium, glucose and protein excretion. These abnormalities were associated with progressive kidney glutathione depletion and malondialdehyde accumulation. Mesna infusion did not affect renal function but did cause a significant fall in kidney glutathione content. Simultaneous administration of chloroacetaldehyde and mesna only partially corrected renal functional abnormalities and prevented malondialdehyde accumulation but not glutathione depletion. These results show that the ifosfamide metabolite chloroacetaldehyde causes kidney dysfunction, glutathione depletion and lipid peroxidation in vivo. Mesna provides limited protection against chloroacetaldehyde nephrotoxicity, potentially explaining its inability to completely prevent ifosfamide‐related renal injury in clinical practice. ©u20091997 by John Wiley & Sons, Ltd.

TOXICITY OF IFOSFAMIDE AND ITS METABOLITE CHLOROACETALDEHYDE IN CULTURED RENAL TUBULE CELLS

SummaryRenal injury is a common side effect of the chemotherapeutic agent ifosamide. Current evidence suggests that the ifosfamide metabolite chloroacetaldehyde may contribute to this nephrotoxicity. The present study examined the effects of ifosfamide and chloroacetaldehyde on rabbit proximal renal tubule cells in primary culture. The ability of the uroprotectant medication sodium 2-mercaptoethanesulfonate (mesna) to prevent chloroacetaldehyde-induced renal cell injury was also assessed. Chloroacetaldehyde (12.5–150 µM) produced dose-dependent declines in neutral red dye uptake, ATP levels, glutathione content, and cell growth. Coadministration of mesna prevented chloroacetaldehyde toxicity while pretreatment of cells with the glutathione-depleting agent buthionine sulfoximine enhanced the toxicity of chloroacetaldehyde. Ifosfamide (1000–10 000 µM) toxicity was detected only at concentrations of 4000 µM or greater. Analysis of media collected from ifosfamide-treated cell cultures revealed the presence of several ifosfamide metabolites, demonstrating that renal proximal tubule cells are capable of biotransforming this chemotherapeutic agent. This primary renal cell culture system should prove useful in studying the cause and prevention of ifosfamide nephrotoxicity.

Interstitial nephritis from mesalazine: case report and literature review.

We report a new case of biopsy-confirmed mesalazine-induced interstitial nephritis in an 18-year-old male with ulcerative colitis. His renal function improved with drug discontinuation and corticosteroid treatment. An English literature review revealed an additional 22 cases of this complication that, taken together, showed (1) a male predominance, (2) an absence of specific symptoms or findings on urinalysis, (3) a 61% frequency of residual chronic renal insufficiency with 13% of patients developing end-stage renal disease, and (4) an apparent favorable response to steroid therapy. We conclude that patients receiving 5-aminosalicylates should be routinely monitored with serum creatinine measurements to prevent this uncommon but potentially serious adverse drug reaction.

COMPARATIVE TOXICITY OF IFOSFAMIDE METABOLITES AND PROTECTIVE EFFECT OF MESNA AND AMIFOSTINE IN CULTURED RENAL TUBULE CELLS

Renal injury is a common side effect of the chemotherapeutic agent ifosfamide. Current evidence suggests that the ifosfamide metabolite chloroacetaldehyde contributes to this nephrotoxicity. The present study examined the effects of chloroacetaldehyde and acrolein, another ifosfamide metabolite, on rabbit proximal renal tubule cells in primary culture. The ability of the uroprotectant medications sodium 2-mercaptoethanesulfonate (mesna) and amifostine to prevent chloroacetaldehyde- and acrolein-induced renal cell injury was also assessed. Chloroacetaldehyde and acrolein (25-200 M) produced dose-dependent declines in neutral red dye uptake, glucose transport and glutathione content. Chloroacetaldehyde was a more potent toxin than acrolein. Pretreatment of cells with the glutathione-depleting agent buthionine sulfoximine enhanced the toxicity of both chloroacetaldehyde and acrolein while co-administration of mesna or amifostine prevented metabolite toxicity. These results support the hypothesis that chloroacetaldehyde is responsible for ifosfamide-induced nephrotoxicity. The protective effect of mesna and amifostine in vitro contrasts with clinical experience showing that these medications do not eliminate ifosfamide nephrotoxicity.

THE NEVOID BASAL CELL CARCINOMA SYNDROME

The nevoid basal cell carcinoma syndrome is a rare and complex disease with multiple manifestations. As an example, we present the case of an eight-year-old girl with this syndrome whose initial complaint was acute abdominal pain secondary to torsion of an ovarian fibroma. Because of its multisystem effects, patients with this syndrome can present to any of a number of medical or surgical specialists. Close attention to the family and past medical history and physical examination will alert the clinician to its presence, allowing for appropriate genetic counseling and serial screening for the development of malignancies and other complications.

Regulation of renal proximal tubule Na-K-ATPase by prostaglandins

Prostaglandins (PGs) play a number of roles in the kidney, including regulation of salt and water reabsorption. In this report, evidence was obtained for stimulatory effects of PGs on Na-K-ATPase in primary cultures of rabbit renal proximal tubule (RPT) cells. The results of our real-time PCR studies indicate that in primary RPTs the effects of PGE(2), the major renal PG, are mediated by four classes of PGE (EP) receptors. The role of these EP receptors in the regulation of Na-K-ATPase was examined at the transcriptional level. Na-K-ATPase consists of a catalytic α-subunit encoded by the ATP1A1 gene, as well as a β-subunit encoded by the ATP1B1 gene. Transient transfection studies conducted with pHβ1-1141 Luc, a human ATP1B1 promoter/luciferase construct, indicate that both PGE(1) and PGE(2) are stimulatory. The evidence for the involvement of both the cAMP and Ca(2+) signaling pathways includes the inhibitory effects of the myristolylated PKA inhibitor PKI, the adenylate cyclase (AC) inhibitor SQ22536, and the PKC inhibitors Gö 6976 and Ro-32-0432 on the PGE(1) stimulation. Other effectors that similarly act through cAMP and PKC were also stimulatory to transcription, including norepinephrine and dopamine. In addition to its effects on transcription, a chronic incubation with PGE(1) was observed to result in an increase in Na-K-ATPase mRNA levels as well as an increase in Na-K-ATPase activity. An acute stimulatory effect of PGE(1) on Na-K-ATPase was observed and was associated with an increase in the level of Na-K-ATPase in the basolateral membrane.

Renal injury from valproic acid: case report and literature review.

A child with developmental delay and epilepsy developed glucosuria approximately 16 months after starting valproic acid therapy. Laboratory evaluation revealed global defects in proximal tubule function consistent with the De Toni-Debré-Fanconi syndrome. Discontinuation of valproate led to complete recovery 5 months later. Review of previously reported cases indicates that this complication is unique to children and reversible when the medication is discontinued.

Targeting of renal proximal tubule Na,K-ATPase by salt-inducible kinase

The renal proximal tubule (RPT) is a central locale for Na+ reabsorption, and blood pressure regulation. Na+ reabsorption in the RPT depends upon the Na,K-ATPase, which is controlled by a complex regulatory network, including Salt-Inducible Protein Kinase (SIK). SIKs are recently discovered members of the AMP-activated Protein Kinase (AMPK) family, which regulate salt homeostasis and metabolism in a number of tissues. In the RPT, SIK interacts with the Na,K-ATPase in the basolateral membrane (BM), regulating both the activity and level of Na,K-ATPase in the BM. Thus, Na,K-ATPase activity can be rapidly adjusted in response to changes in Na+ balance. Long-term changes in Na+ intake affect the state of SIK phosphorylation, and as a consequence the phosphorylation of TORCs, Transducers of Regulated CREB (cAMP Regulatory Element Binding Protein). Once phosphorylated, TORCs enter the nucleus, and activate transcription of the ATP1B1 gene encoding for the Na,K-ATPase beta subunit.

Ifosfamide toxicity in cultured proximal renal tubule cells.

Renal injury is a common side effect of the chemotherapeutic agent ifosfamide. Current evidence suggests that ifosfamide metabolites, particularly chloroacetaldehyde, produced within the kidney contribute to nephrotoxicity. The present study examined the effects of ifosfamide and its metabolites, chloroacetaldehyde and acrolein, on rabbit proximal renal tubule cells in primary culture, using a transwell culture system that allows separate access to apical and basolateral cell surfaces. The ability of the uroprotectant medications sodium 2-mercaptoethanesulfonate (mesna) and amifostine to prevent chloroacetaldehyde-and acrolein-induced renal cell injury was also assessed. Ifosfamide (2,000–4,000xa0μM) did not affect transcellular inulin diffusion but caused a modest but significant impairment in organic ion transport; this impairment was greater when ifosfamide was added to the basolateral compartment of the transwell. Chloroacetaldehyde and acrolein (6.25–100xa0μM) produced dose-dependent impairments in transcellular inulin diffusion and organic ion transport. Chloroacetaldehyde was a more potent toxin than acrolein. Co-administration of mesna or amifostine prevented metabolite toxicity. Amifostine was only protective when added to the apical compartment of transwells. These results show that ifosfamide is taken up by renal tubule cells preferentially through their basolateral surfaces, and supports the hypothesis that chloroacetaldehyde is primarily responsible for ifosfamide-induced nephrotoxicity. The protective effect of mesna and amifostine in vitro contrasts with clinical experience showing that these medications do not eliminate ifosfamide nephrotoxicity in vivo.