Antiviral medications for the treatment of hepatitis B and C infection and their effects on kidney function.

Over the last decade, treatment options for chronic hepatitis B and hepatitis C infection have markedly evolved. Several Food and Drug Administration-approved drugs are now available for the treatment of chronic hepatitis B, including immunomodulators (standard and pegylated interferon alpha), nucleoside analogues (lamivudine, entecavir and telbivudine) and nucleotide analogues (adefovir dipivoxil and tenofovir). For hepatitis C, the FDA-approved therapies include peginterferon-α, ribavirin, boceprevir, telaprevir, simeprevir and sofosbuvir with expected approval of more agents in the foreseeable future. Some of these antiviral medications have been reported to have nephrotoxic effects, particularly with long-standing therapy, although the exact mechanism has not been fully elucidated. Secondary forms of glomerulonephritis that can be associated with hepatitis B and hepatitis C viral infection can further complicate the evaluation of renal failure in this population. Knowledge of the different antiviral medications and their potential nephrotoxic effects is crucial, since early identification and substitution to a different agent with withdrawal of the offending medication, may result in recovery or stabilization of renal function. Close monitoring of renal function while taking new antiviral medications is recommended, as some of the nephrotoxic effects may only appear after long-term use.

Clinical and basic science advances in the treatment of HIV-1 and its associated kidney disease.

With improved survival in the post-highly active antiretroviral therapy (HAART) era, we have witnessed an increase in the incidence of both acute and chronic kidney disease among patients with human immunodeficiency virus (HIV-1) infection. Much has been learned in the past three decades about the pathophysiological concepts of HIV-1 infection and its association with kidney disease. The extent of HIV-1 associated kidney disease is vast and represents a variety of clinical and histopathological conditions. While HIV-associated nephropathy (HIVAN) remains the most sinister kidney disease related to the direct effects of HIV-1, there are other contributors to kidney disease such as toxic effects of antiviral therapy, high prevalence of hepatitis C, cigarette, and injection drug use. This review presents the pathophysiological principles behind HIV-1 associated kidney diseases, with particular attention to thrombotic microangiopathy, drug-related kidney disease and HIVAN. Therapeutic options such as HAART, corticosteroids and angio-tensin-converting enzyme inhibitors are discussed. Advances in basic science medicine provided some insights into the role of cyclin-dependent kinase inhibitors as a potential therapeutic option for HIVAN. The emerging role of organ transplantation in HIV patients with kidney disease is also presented. Emphasis is placed on early diagnosis and timely treatment of kidney disease and heightened awareness particularly among the vulnerable population that bears most of the disease burden.

Outpatient vancomycin use and vancomycin-resistant enterococcal colonization in maintenance dialysis patients.

BACKGROUND: Although outpatient vancomycin is widely used as empiric therapy for dialysis-associated infections, its relationship with vancomycin-resistant enterococcal (VRE) colonization is not established. METHODS: During a two-year prospective cohort study, rectal swabs obtained from patients at the start and finish of the study period and during interim hospitalizations were cultured for VRE. RESULTS: Ten of 124 patients initially grew VRE. Twenty-four of the remaining patients had no follow-up cultures because of patient death (62%), transfer to another dialysis facility (17%), patient's refusal (7%), and transplantation (4%), and were thus excluded. The remaining patients (N = 90) had a median age of 54.3 years and were 92% African American and 50% male. Fifty-eight percent were treated by hemodialysis. They received 403 g of intravenous vancomycin over 157.2 patient-years of follow-up, 73% as outpatients. Sixteen of 90 patients (17.8%) became colonized with VRE, an incidence rate of one case per 9.8 patient-years of follow-up. None of the 29 patients who did not receive vancomycin developed VRE compared with 26% of those treated with vancomycin (P = 0.001). The odds ratio (95% CI) for the association of outpatient vancomycin (g per year) with VRE colonization was 1.23 (1.05, 1.44, P = 0.008). The association remained significant following adjustment in separate logistic regression analyses for relevant demographic, clinical, antimicrobial (inpatient vancomycin, oral or intravenous cephalosprins, aminoglycosides, quinalones, or antianaerobics), and hospitalization exposures. The unadjusted relative risk of death in patients growing VRE was significantly higher than in those not colonized with VRE (P = 0.005). CONCLUSIONS: VRE colonization is a relatively common and under recognized problem among chronic dialysis patients. It is strongly and independently associated with the outpatient use of vancomycin, which should be avoided whenever possible.

Tyrosine kinase inhibitors and immunosuppressants perturb the myo-inositol but not the betaine cotransporter in isotonic and hypertonic MDCK cells.

BACKGROUND: The sodium/myo-inositol cotransporter (SMIT) and the betaine cotransporter (BGT1) are essential for the accumulation of myo-inositol and betaine, and hence cell survival in a hypertonic environment. The underlying molecular mechanism involves an increase in transcription of the SMIT and BGT1 genes through binding of a trans-acting factor to enhancer elements in the 5' flanking region of both genes, resulting in increased mRNA abundance and increased activity of the cotransporters. Current evidence regarding transcriptional and post-transcriptional regulation indicates that both cotransporters are regulated in parallel. METHODS: To investigate the signal transduction of hypertonic stress, we examined the effect of tyrosine kinase inhibitors and immunosuppressants on the hypertonicity-induced activity of the two cotransporters in Madin-Darby canine kidney (MDCK) cells. RESULTS: None of the agents studied affected BGT1 activity in isotonic or hypertonic conditions. Treatment of MDCK cells with genistein, a tyrosine kinase inhibitor, increased SMIT activity in hypertonic but not isotonic conditions. The stimulation of SMIT by genistein was accompanied by a parallel increase in mRNA abundance. In contrast, treating cells with tyrphostin A23, another tyrosine kinase inhibitor, or cyclosporine A, an immunosuppressant, inhibited SMIT activity in hypertonic cells. FK506, another immunosuppressant, increased SMIT activity, but only in isotonic conditions. CONCLUSIONS: These results provide the first evidence of divergent regulatory pathways modulating SMIT and BGT activity.

Transcription of the sodium/myo-inositol cotransporter gene is regulated by multiple tonicity-responsive enhancers spread over 50 kilobase pairs in the 5'-flanking region.

The sodium/myo-inositol cotransporter is a plasma membrane protein responsible for concentrative cellular accumulation of myo-inositol in a variety of tissues. When cells in kidney and brain are exposed to a hyperosmolar salt condition (hypertonicity) due to the operation of urinary concentration mechanism and pathological conditions, respectively, they survive the stress of hypertonicity by raising the cellular concentration of myo-inositol. Transcription of the sodium/myo-inositol cotransporter gene is markedly stimulated in response to hypertonicity, leading to an increase in the activity of the cotransporter, which in turn drives the osmoprotective accumulation of myo-inositol. To understand the molecular mechanisms by which hypertonicity stimulates transcription, we analyzed the 5'-flanking region of the cotransporter gene for cis-acting regulatory sequences. We identified five tonicity-responsive enhancers that are scattered over 50 kilobase pairs. All the enhancers are variations of the same type of enhancer interacting with the transcription factor named tonicity-responsive enhancer binding protein. In vivo methylation experiments demonstrated that exposure of cells to hypertonicity increases the binding of tonicity-responsive enhancer binding protein to the enhancer sites, indicating that all of these enhancers are involved in the transcriptional stimulation. We conclude that the sodium/myo-inositol cotransporter gene is regulated by a large region (approximately 50 kilobase pairs) upstream of the gene.

Acute renal papillary necrosis induced by ibuprofen.

Several specific renal syndromes may be induced by the interaction of nonsteroidal anti-inflammatory drugs (NSAIDs) upon renal function. We report an NSAID-induced form of acute renal failure that represents a dual mechanism of impact on renal function involving direct parenchymal damage at a renal papillary level and mechanical outflow ureteric obstruction consequent to acute papillary necrosis. This form of NSAID-related acute renal failure has been reported very infrequently. We suspect the syndrome is not often recognized clinically. Clinicians and health care workers need to remind constantly the general public concerning the standard steps to be taken to ensure the proper and safe use of over-the-counter drugs. This is especially important considering the recent FDA approval of the over-the-counter sale of naproxen sodium, ketoprofen, and ibuprofen.

The structural organization of the human Na+/myo-inositol cotransporter (SLC5A3) gene and characterization of the promoter.

The genomic structure, transcription start site, polyadenylation signals, and promoter of the human Na+/ myo-inositol cotransporter (SLC5A3) gene have been elucidated through cloning, sequencing, mRNA analyses, and reporter gene assays. The gene consists of one promoter and two exons spanning approximately 26 kb. Exon 1 contains 175 bp of 5' untranslated sequence and is 15 kb upstream of exon 2. The 9.5-kb exon 2 contains the entire 2157-bp open reading frame and a large 3' untranslated sequence with seven putative polyadenylation signals. Multiple messages with different-sized 3' untranslated regions can be detected on Northern blots. Hypertonic stress caused mRNA levels, and primarily that of the full-length 9.5-kb transcript, to increase in cultured melanoma cells; ribonuclease protection analysis demonstrated that the transcription start site was the same in stressed as in control cells. The SLC5A3 gene functions in cellular osmoregulation and is expressed in many human tissues including the brain, kidney, and placenta. It is localized to chromosome 21q22.1. An overexpression of the SLC5A3 gene deserves consideration as a factor in the pathophysiology of Down syndrome.

Effect of erythropoietin on sexual potency in chronic haemodialysis patients. A preliminary study.

Six male dialysis patients were submitted to a Doppler study of the deep penile arteries and intracavernosal injection of 30 mg papaverine under basal conditions before and after erythropoietin therapy. Penile tumescence was recorded after 15 min by measuring the length and the circumference of the penis as well as the erectile angle between the penis and the legs with the patient in standing position. Haematocrit was raised by erythropoietin therapy from 19.3 +/- 4.5 to 31.2 +/- 5.5 within 3 months. Five patients completed the study. We encountered a significant improvement in the frequency of sexual intercourse per month from 1.3 +/- 0.5 to 2.3 +/- 0.8 (p = 0.014). Furthermore, an increase was observed in the penile brachial index (from 0.87 +/- 0.1 to 0.91 +/- 0.1) and in the papaverin induced increase in penile length (4.6 +/- 1.4 cm versus 5.2 +/- 1.1 cm), penile circumference (2.7 +/- 0.14 cm versus 2.7 +/- 0.27 cm) as well as in the erectile angle (61.7 +/- 37.1 versus 80 +/- 23.5 degrees). These changes were not statistically significant. There was a significant correlation between the increase in the erectile angle and the increase in frequency of intercourse (p = 0.04). In conclusion, erythropoietin treatment could improve the sexual potency in uraemic patients under chronic haemodialysis therapy.

Effect of treatment of anaemia with erythropoietin on neuromuscular function in patients on long term haemodialysis.

To study the effect of treatment of anaemia with recombinant human erythropoietin (r-HUEPO) on neuromuscular function in patients undergoing haemodialysis for chronic renal failure, six patients were given r-HUEPO in an initial dose of 50 u/kg three times a week and their haemoglobin concentration was measured. The dose was increased by 25 u/kg every four weeks if the response was not satisfactory. In five patients anaemia had been corrected within 12 weeks of initiation of treatment. Neuromuscular function was evaluated before treatment, half way through, and after correction of anaemia by clinical examination and neurophysiological studies including motor nerve conduction velocity, distal latency, electromyography and test for neuromuscular fatigue. After correction of anaemia there was a significant increase in motor nerve conduction velocity, a decrease in the duration of motor unit action potential, and a lessening of neuromuscular fatigue. We conclude that treatment of anaemia with r-HUEPO in patients with chronic renal failure undergoing haemodialysis may improve neuromuscular function.