Renal disease and drug metabolism: an overview

Renal disease will perturb the disposition of drugs that primarily depend upon renal excretory function for elimination. While changes in drug half-life (T1/2) are often cited as evidence of altered drug disposition, it must be remembered that T1/2 is a dependent variable whose magnitude varies directly with volume of distribution (Vd) and indirectly with total body clearance (ClT). ClT is the one term that succinctly describes drug elimination. ClT is defined as the sum of the renal (ClR) and nonrenal (ClNR), or metabolic, clearances of a drug. Renal failure has been shown to alter the hepatic microsomal mixed-function oxidase system of drug metabolizing enzymes. Therefore, in end-stage renal failure, the potential exists for the modification of the disposition of drugs whose elimination is primarily hepatic. The kidneys themselves contain many of the enzymes important in hepatic drug metabolism. Drugs such as morphine, paracetamol, and p-aminobenzoic acid are metabolized in the kidney and experimental renal disease has been shown to reduce drug metabolism in the diseased kidney compared with the contralateral normal kidney. Renal disease, then, has the potential to alter not only the renal clearance of unchanged drug but also may substantially modify the metabolic transformation of drugs in both the liver and the kidneys. It can no longer be assumed that the pharmacokinetics of drugs that are disposed mainly by metabolism will be unaltered in renal failure.     

代谢组学在骨质疏松症中的应用进展

骨质疏松症好发于中老年人群,是一种危害巨大的全身代谢性骨骼疾病。代谢组学是近年来兴起的科学,可以对生物样本中的全部代谢产物进行定量测量分析,从而直观、全面地反映生物体内的代谢物变化。将代谢组学运用到骨质疏松症中或有一定优势,目前已成为研究热点之一。基于代谢组学在骨质疏松症中的应用,本文综述了将代谢组学运用于骨质疏松症的早期诊断及中药干预机制等方面的研究文献,初步总结部分可能可用于诊断骨质疏松症的特异性代谢标志物,展望代谢组学在骨质疏松症的中药干预机制研究及临床应用方面的前景。     

Intracellular organelles in health and kidney disease

Subcellular organelles consist of smaller substructures called supramolecular assemblies and these in turn consist of macromolecules. Various subcellular organelles have critical functions that consist of genetic disorders of organelle biogenesis and several metabolic disturbances that occur during non-genetic diseases e.g. infection, intoxication and drug treatments. Mitochondrial damage can cause renal dysfunction as ischemic acute renal injury, chronic kidney disease progression. Moreover, mitochondrial dysfunction is an early event in aldosterone-induced podocyte injury and cardiovascular disease due to oxidative stress in chronic kidney disease. Elevated production of reactive oxygen species could be able to activate NLRP3 inflammasome representing new deregulated biological machinery and a novel therapeutic target in hemodialysis patients. Peroxisomes are actively involved in apoptosis and inflammation, innate immunity, aging and in the pathogenesis of age related diseases, such as diabetes mellitus and cancer. Peroxisomal catalase causes alterations of mitochondrial membrane proteins and stimulates generation of mitochondrial reactive oxygen species. High concentrations of hydrogen peroxide exacerbate organelles and cellular aging. The importance of proper peroxisomal function for the biosynthesis of bile acids has been firmly established. Endoplasmic reticulum stress-induced pathological diseases in kidney cause glomerular injury and tubulointerstitial injury. Furthermore, there is a link between oxidative stress and inflammations in pathological states are associated with endoplasmic reticulum stress. Proteinuria and hyperglycemia in diabetic nephropathy may induce endoplasmic reticulum stress in tubular cells of the kidney. Due to the accumulation in the proximal tubule lysosomes, impaired function of these organelles may be an important mechanism leading to proximal tubular toxicity.     

Antihypertensive therapy and the progression of chronic renal disease. Are there renoprotective drugs?

The pathogenesis of hypertensive glomerular injury is complex, involving both hemodynamic and nonhemodynamic factors. One can therefore confidently predict that a wide variety of disparate therapeutic interventions, pharmacologic and nonpharmacologic, may be effective in arresting or slowing progressive glomerular injury. Based on the experimental and clinical literature available to date, it is clear that glomerular capillary hypertension is an important pathogenetic factor in this disease and that lowering of Pgc with antihypertensive drugs is associated with prevention of glomerular injury. Furthermore, the CEI may have a special renoprotective effect compared to other antihypertensive agents, most likely due to their unique renal hemodynamic actions. Pending the results of well-designed clinical trials, converting enzyme inhibitors represent the antihypertensive agents most likely to arrest the progressive decline in renal function observed in patients with hypertension and chronic renal failure. The calcium channel blockers are effective antihypertensive agents in patients with chronic renal failure, but whether they confer specific renoprotective effects remains uncertain. Since a large number of patients with chronic renal failure require more than one antihypertensive drug for adequate blood pressure control it may be of interest to evaluate the benefits of drug combinations. In this regard, it is possible that a combination of a CEI and a CCB may have complimentary effects in protecting the kidney. The development of these new classes of antihypertensive agents has had a major impact on the treatment of patients with chronic progressive renal failure. Future studies will hopefully clarify the optimal antihypertensive therapeutic regimen and allow us to move closer to the goal of eliminating end-stage renal failure.     

Metabolic disorders following kidney transplantation

Kidney transplantation in patients suffering from end-stage renal disease, although beneficial, may result in potential complications increasing cardiovascular risk of mortality. Common metabolic problems after surgery are weight gain, hypertension, hyperlipidemia, and insulin resistance. Immunosuppressant therapy can enhance comorbidity progression. Early identification and treatment of these abnormalities can promote transplant function. Lifestyle modifications have shown to be promising in the reduction of the metabolic syndrome symptoms, but there remain limited trials focusing on this area. This article reflects a comprehensive review of the available research of each of the?potential metabolic complications within the renal transplant population. Immunosuppressant medication effects, biochemical values, and medical nutrition therapy intervention are also included with regard to their influence with these metabolic disorders. Methods for review completion included a MEDLINE search for peer-reviewed research, using the following keywords: transplant, chronic kidney disease, nutrition, metabolic syndrome, and diet after transplantation.     

Perioperative Pharmacologic Management of Patients with End Stage Renal Disease

The pharmacokinetics of numerous medications used in the perioperative period are altered in patients with end‐stage renal disease. Clearance of drugs, or their metabolites, that are normally excreted by the kidney is markedly reduced in ESRD. In addition, patients with ESRD may also have alterations in gastrointestinal absorption, volume of distribution, protein binding, and metabolic clearance of pharmacologic agents. Finally, drug removal may be augmented during dialysis. All of these factors contribute to the need for dose adjustment of medications, including analgesics, anesthetics, neuromuscular blockers, and antimicrobial agents, which may be used in the perioperative management of the ESRD patient.     

Drug-induced renal calculi

Drug-induced renal calculi represent 1-2% of all renal calculi. They include two categories: those resulting from the urinary crystallisation of a highly excreted, poorly soluble drug or metabolite, and those due to the metabolic effects of a drug. Indinavir, used in HIV-infected patients, sulfonamides, especially sulfadiazine, and triamterene, which is less prescribed today, are the most frequent. Besides these drugs, about twenty other molecules, among them silicate-containing drugs and some antibiotics have been reported in patients receiving high doses or long-term treatments. Calculi analysis by physical methods such as infrared spectroscopy or x-ray diffraction can demonstrate the presence of the drug or its metabolites inside the calculi. In those calculi due to the metabolic effects of a drug, diagnosis relies on both stone analysis and clinical inquiry. Incidence of such calculi is probably underestimated, especially those due to calcium/vitamin D supplements or carbonic anhydrase inhibitors. Drug-induced calculi occur more often during high-dose or long term treatments, but there are also patient-related risk factors in relation to urine pH, urine output and other parameters, which can provide a basis for preventive treatment of such calculi. A better knowledge of these lithogenic complications of treatments and of solubility characteristics of drugs should reduce the incidence of drug-induced nephrolithiasis, especially in patients with identified risk factors.     

The renal biopsy in the genomic era

Renal biopsy was introduced in the 1950s. By 1980 the pathologic diagnostic criteria for the majority of medical kidney diseases known today, including pediatric diseases, were established using light, electron microscopy and immunohistochemistry. However, it has become clear that there are limitations in the morphologic evaluation, mainly because a given pattern of injury can be caused by different aetiologies and, conversely, a single aetiology may present with more than one histological pattern. An explosion in kidney disease research in the last 20–30 years has brought new knowledge from bench to bedside rapidly and resulted in new molecular and genetic tools that enhance the diagnostic and prognostic power of the renal biopsy. Genomic technologies such as polymerase chain reaction (PCR), in situ hybridization and oligonucleotide microarrays, collectively known as genomics, detect single or multiple genes underscoring the pathologic changes and revealing specific causes of injury that may require different treatment. The aims of this review are to (1) summarize current recommendations for diagnostic renal biopsies encompassing light microscopy, immunofluorescence or immunohistochemistry and electron microscopy; (2) address the limitations of morphology; (3) show current contributions of genomic technologies adjunct to the renal biopsy, and provide examples of how these may transform pathologic interpretation into molecular disease phenotypes.     

Pathogenesis of perinatal programming

PURPOSE OF REVIEW: In recent years, there has been an increase in research designed to delineate the underlying causes of perinatal programming. Starting with epidemiological observations that birth weight was inversely associated with cardiovascular disease, a variety of studies both in humans and in experimental models have begun to demonstrate how the perinatal milieu can subtly alter vasculogenesis and nephrogenesis. Additionally, rates of prenatal and postnatal growth each appear to contribute to future vascular, renal and metabolic function. The purpose of this review is to discuss recent reports that have begun to elucidate factors that initiate perinatal programming as it affects renal disease and cardiovascular disease in later life. RECENT FINDINGS: Nephrogenesis per se is affected by changes in maternal nutrition and health, and recent data more specifically linking these changes with renal function and hypertension are presented. Additionally, renal functional changes in later life may be influenced by changes in renal tubular transporters noted early when maternal nutrition is compromised. Various hormonal systems affected by maternal nutrition in utero may effect subsequent changes in renal function via subtle alterations in renal function and structure initiated during nephrogenesis. SUMMARY: Current research is beginning to clarify certain aspects of perinatal programming and indicates that broad educational programmes might ultimately lessen both perinatal risks and long-term outcomes by encouraging therapeutic interventions in at-risk persons.     

Effect of arachidonic acid metabolic inhibitors on hypoxia/reoxygenation-induced renal cell injury

The present study was undertaken to examine the role of arachidonic acid (AA) metabolites in hypoxia/reoxygenation (H/R)-induced renal cell injury in rabbit renal cortical slices using AA metabolic inhibitors. Inhibitors of cyclooxygenase (indomethacin and diclofenac sodium) and lipoxygenase pathways (nordihydroguaiaretic acid, caffeic acid, and eicosapentaenoic acid) reduced H/R-induced LDH release in a dose-dependent manner, whereas an inhibitor of cytochrome P-450 monooxygenase pathway ethoxyresorufin was not effective. AA increased LDH release in control slices, and the effect was not altered by indomethacin and nordihydroguaiaretic acid. The protective effect of indomethacin was not affected by addition of PGE2, a main product of cyclooxygenase pathway in the kidney. H2O2-induced LDH release was prevented by inhibitors of lipoxygenase but not by inhibitors of cyclooxygenase and cytochrome P-450 monooxygenase H/R-induced LDH release was not altered by iron chelators, phenanthroline and deferoxamine, and a potent antioxidant, N,N'-diphenyl-p-phenylenediamine, suggesting that the H/R-induced cell injury is not attributed to a generation of reactive oxygen species. Morphological studies showed that H/R-induced structural changes including cell necrosis were significantly prevented by indomethacin. These results suggest that inhibitors of cyclooxygenase and lipoxygenase pathways exert a direct protective effect against the H/R-induced cell injury in renal tubules. Whether these effects are mediated by alterations of AA metabolic pathways is not certain.     

Review: Serum and urine biomarkers of kidney disease: A pathophysiological perspective

The use of reliable biomarkers is becoming increasingly important for the improved management of patients with acute and chronic kidney diseases. Recent developments have identified a number of novel biomarkers in serum or urine that can determine the potential risk of kidney damage, distinguish different types of renal injury, predict the progression of disease and have the potential to assess the efficacy of therapeutic intervention. Some of these biomarkers can be used independently while others are more beneficial when used in combination with knowledge of other clinical risk factors. Advances in gene expression analysis, chromatography, mass spectrometry and the development of sensitive enzyme-linked immunosorbent assays have facilitated accurate quantification of many biomarkers. This review primarily focuses on describing new and established biomarkers, which identify and measure the various pathophysiological processes that promote kidney disease. It provides an overview of some of the different classes of renal biomarkers that can be assessed in serum/plasma and urine, including markers of renal function, oxidative stress, structural and cellular injury, immune responses and fibrosis. However, it does not explore the current status of these biomarkers in terms of their clinical validation.     

Epithelial-mesenchymal transition and its implications for the development of renal tubulointerstitial fibrosis

Despite a lot of research efforts, the origin of renal fibroblasts is still matter of debate. Epithelial-mesenchymal transition (EMT) of tubular epithelial cells could be at least one of the mechanisms by which renal fibroblasts are generated. Every kind of renal injury is potentially able to induce renal tubular cells to go through the various steps of EMT and generate fibroblasts, as it has been demonstrated by experimental models, in vitro experiments, and renal biopsy studies. It means that, if EMT is a common process of progression of renal failure, further studies and a better understanding of this process can lead us to envisage specific treatments to counteract the progression of renal disease.     

Renal failure and its treatment

Kidney disease can be defined as acute or chronic kidney injury. Acute kidney injury is measured directly via glomerular filtration rate (GFR) and indirectly via urea and electrolyte levels. Acute kidney injury can be classified via the RIFLE criteria.Chronic kidney injury is a progressive and irreversible condition, which is defined as an estimated GFR (eGFR) less than 60 ml/minute/1.73 m² or where there is evidence of chronic kidney damage (irrespective of eGFR) on at least two occasions more than 3 months apart. As chronic kidney injury progresses there are a number of co-morbidities associated with the disease process, cardiovascular, respiratory and endocrine. These co-morbidities must be considered when anaesthetizing a patient with kidney injury.Renal replacement therapy may be necessary for patients who acutely deteriorate to end-stage renal failure or in those with a slow progression to this point. Haemofiltration or haemodiafiltration may be used in the acute setting and haemodialysis or peritoneal dialysis may be used in cases where the deterioration of renal function takes a more progressive course.     

Renal injury in the elderly: diagnosis, biomarkers and prevention

Acute kidney injury (AKI) in the elderly patient is a common iatrogenic complication of major surgery that impacts morbidity, mortality and resource use. Several renal functional and structural changes have been described, including a substantially decreased nephron mass. Loss of renal function defines AKI and is classified by the RIFLE (R: renal risk, I: injury, F: failure, L: Loss and E: End-stage renal disease) criteria; however, it frequently occurs many hours to several days after the injury to the kidney. Therefore, novel biomarkers indicating tubulo-interstitial damage are needed for early AKI diagnosis. The limitations of serum creatinine are much more pronounced in the elderly, including its dependence on muscle mass and the presence of multiple drug use and co-morbidities. Although it is conceivable that earlier AKI diagnosis and application of classical preventive measurements, including postponement of surgery or preference of medical treatment, optimisation of haemodynamics, euvolaemia, aggressive avoidance of nephrotoxic antibiotics or analgesics may translate into better patient outcomes, much more data are needed in this specific cohort.     

The key to halting progression of CKD might be in the produce market, not in the pharmacy

In vitro, experimental, and clinical work suggests that metabolic acidosis, either directly or indirectly, can promote the progression of chronic kidney disease (CKD). Goraya et al. demonstrate that both oral alkali supplementation and a diet rich in fruits and vegetables are equally effective at decreasing urinary excretion of markers of renal injury in patients with stage 2 CKD. Although this study is promising, the short duration and use of only urinary markers as a surrogate outcome weaken the conclusions.     

Comparative clinical pharmacokinetics of tubocurarine, gallamine, alcuronium and pancuronium.

Data about plasma concentration, renal and biliary elimination of tubocurarine, gallamine, alcuronium and pancuronium are taken from the literature for synoptical pharmacokinetic analysis. All plasma concentration curves can be described by triexponential functions according to an open three-compartment pharmacokinetic model in line, the elements of which are an application and measuring compartment, a pharmacologically specific compartment and a non-specific one. The corresponding results for all drugs represent the same range and there is no substantial basis for a further differentiation of clinically significant drug specific characteristics, neither regarding the time course of neuromuscular blockade nor the excretory or metabolic disposition. Thus no particular advantage or disadvantage of any drug can be stated from the kinetic or metabolic point of view and especially none seems to have a striking advantage in patients with impaired renal function. Drug specific peculiarities are more likely to be found in the field of side effects.     

Pharmacokinetics of atorvastatin and its metabolites after single and multiple dosing in hypercholesterolaemic haemodialysis patients.

BACKGROUND: Patients with chronic renal failure commonly suffer from a secondary form of complex dyslipidaemia, and may benefit from lipid-lowering treatment. Atorvastatin has been shown to reduce efficiently the levels of atherogenic lipoproteins also in patients with renal failure, but pharmacokinetic data in haemodialysis patients are lacking. METHODS: In this study, hypercholesterolaemic haemodialysis patients received 40 mg (n=12) or 80 mg (n=11) atorvastatin once daily, first as a single dose and then continuously for 2 weeks. Plasma levels of atorvastatin and its active and inactive metabolites were measured by LC/MS/MS, and pharmacokinetic parameters (C(max), t(max), AUC, t(1/2)) compared between single and multiple dosing, and between the different doses. RESULTS: The pharmacokinetic parameters of the parent drug atorvastatin acid were not significantly different after single and 2-week multiple dosing; they showed dose-proportionality between the 40 and 80 mg dose, and were comparable to findings in healthy volunteers. Dose-proportionality and absence of accumulation was also observed for the major active metabolite ortho-hydroxy-atorvastatin and the inactive metabolites atorvastatin lactone and ortho-hydroxy-atorvastatin lactone, but the levels of the active metabolite were relatively lower, and the inactive metabolites higher, compared with healthy volunteers. The para-hydroxy-metabolites constituted only a minor pathway in atorvastatin's metabolic elimination. Haemodialysis did not cause enhanced clearance of atorvastatin or its metabolites, the drug was well tolerated and there were no serious adverse events. CONCLUSION: While subtle differences may exist in the metabolic processing of atorvastatin in haemodialysis patients, active drug did not accumulate nor did it show enhanced elimination, and levels were comparable to those measured in healthy volunteers. Therefore there is no need to adapt atorvastatin dosage in this particular patient population.     

Comparison of the effects of cyclosporine and its metabolites on the release of prostacyclin and endothelin from mesangial cells.

CsA-induced alterations in mesangial cell production of potent vasoactive substances may be a contributing factor to the decreased renal blood flow and glomerular thrombosis associated with CsA nephrotoxicity. In this study the toxic effects of several CsA metabolites, previously isolated and characterized by mass spectrometry and nuclear magnetic resonance, were investigated in cultured rabbit mesangial cells. AM4N and AM9 were the most cytotoxic metabolites examined, having potency ratios of 0.28-0.56 with respect to CsA for the inhibition of cell growth and DNA synthesis. In addition the effects of several CsA metabolites were examined on the basal release of prostacyclin and endothelin. A concentration-dependent decrease in prostacyclin production, as measured by release of its stable metabolite, 6-keto-PGF1 alpha, was observed in cells treated with CsA and metabolites. CsA metabolites were equipotent as parent drug resulting in a significant (P less than 0.05) 20-40% reduction in prostacyclin production. The dihydroxylated metabolites of CsA, AM19, and AM1c9 resulted in a significantly (P less than 0.05) increased production of endothelin from the cells. In contrast parent drug resulted in a slight decrease in its production. In general CsA metabolites were found to be significantly less cytotoxic than parent drug in mesangial cells. However, the finding that certain CsA metabolites could alter production of vasoactive substances from these cells suggests that CsA metabolites may directly alter the renal hemodynamics, producing alterations consistent to that observed for CsA-induced renal side effects in vivo.