Downregulation of hepatic cytochrome P450 in chronic renal failure

Chronic renal failure (CRF) is associated with a decrease in drug metabolism. The mechanism remains poorly understood. The present study investigated the repercussions of CRF on liver cytochrome P450 (CYP450). Three groups of rats were defined: control, control paired-fed, and CRF. Total CYP450 activity, protein expression of several CYP450 isoforms as well as their mRNA, and the in vitro N-demethylation of erythromycin were assessed in liver microsomes. The regulation of liver CYP450 by dexamethasone and phenobarbital was assessed in CRF rats. Compared with control and control paired-fed rats, creatinine clearance was reduced by 60% (P: < 0.01) in CRF rats. Weight was reduced by 30% (P: < 0.01) in control paired-fed and CRF rats, compared with control animals. There was no difference in the CYP450 parameters between control and control paired-fed. Compared with control paired-fed rats, total CYP450 was reduced by 47% (P: < 0.001) in CRF rats. Protein expression of CYP2C11, CYP3A1, and CYP3A2 were considerably reduced (>40%, P: < 0.001) in rats with CRF. The levels of CYP1A2, CYP2C6, CYP2D, and CYP2E1 were the same in the three groups. Northern blot analysis revealed a marked downregulation in gene expression of CYP2C11, 3A1, and 3A2 in CRF rats. Although liver CYP450 was reduced in CRF, its induction by dexamethasone and phenobarbital was present. N-demethylation of erythromycin was decreased by 50% in CRF rats compared with control (P: < 0.001). In conclusion, CRF in rats is associated with a decrease in liver cytochrome P450 activity (mainly in CYP2C11, CYP3A1, and 3A2), secondary to reduced gene expression.     

Role of parathyroid hormone in the downregulation of liver cytochrome P450 in chronic renal failure

Chronic renal failure (CRF) is associated with a decrease in drug metabolism secondary to a decrease in liver cytochrome P450 (P450). The predominant theory to explain this decrease is the presence of factors in the blood of uremic patients. This study tested the hypothesis that parathyroid hormone (PTH) could be this factor. The objectives of this study were to determine (1) the role of PTH in the downregulation of hepatocyte P450 induced by rat uremic serum, (2) the role of PTH in the downregulation of liver P450 in rats with CRF, and (3) the effects of PTH on P450 in hepatocytes. For this purpose, (1) hepatocytes were incubated with serum from rat with CRF that was depleted with anti-PTH antibodies or with serum from parathyroidectomized (CRF-PTX) rat with CRF, (2) the effect of PTX on liver P450 was evaluated in rats with CRF, and (3) the effects of PTH on P450 in hepatocytes were determined. The depletion of PTH from CRF serum completely reversed the downregulating effect of CRF serum on P450 in hepatocytes. Addition of PTH (10(-9) M) to depleted CRF serum induced a decrease in P450 similar to nondepleted CRF serum. The serum of CRF-PTX rats had no effect on P450 in hepatocytes compared with CRF serum. Adding PTH to CRF-PTX serum induced a similar decrease in P450 as obtained with CRF serum. Finally, PTX prevented the decrease of liver P450 in rats with CRF. In summary, PTH is the major mediator implicated in the downregulation of liver P450 in rats with CRF.     

Small intestinal function and structure in patients with chronic renal failure

We studied 24 patients with end-stage chronic renal failure not treated with hemodialysis (CRF1) and 16 patients on regular hemodialysis (CRF2), to investigate the digestive, absorptive and morphological aspects of the small intestinal mucosa. Serum d-xylose test and biochemical parameters of absorption (serum calcium and proteins) were determined. Jejunal mucosal biopsies were obtained and tissue homogenates assayed for disaccharidases (sucrase, maltase and lactase) and dipeptidases (glycyl-glycinase, leucyl-glycinase and leucyl-aminopeptidase). Histological changes were classified according to the severity of abnormality and compared with biopsies obtained from control subjects. Serum d-xylose test, calcium and proteins were normal in patients with CRF. Maltase specific activity was higher in CRF1 than in controls (p less than 0.05). Lactase and leucyl-aminopeptidase showed a tendency to decrease in CRF, but this difference did not reach statistical significance. Sucrase, glycyl-glycinase and leucyl-glycinase specific activity in CRF was similar to the control group. Histological changes of the small intestinal mucosa of mild to moderate degree were noted in 68% of patients with CRF vs 36% in control subjects (p less than 0.01). No significant difference was noted in the incidence of absorptive, enzymatic (with the exception of maltase) and histological changes between the two groups of patients with CRF. These changes are not influenced by hemodialysis, a long-term treatment averaging 6 months, they appear to represent primary manifestations of CRF and may be related to the nutritional status of patients with CRF.     

Changes in intestinal flora and its correlation with renal function in chronic renal failure patients

Objective To investigate changes in intestinal bacteria in chronic renal failure (CRF), their diagnostic value for CRF, and correlations between specific bacterial genera and renal function. Methods Fecal specimens were collected from 56 patients with CRF and 38 healthy controls in the Nephrology Department and Medical Examination Center of Shanxi People's Hospital between August 2017 and January 2018. High-throughput sequencing analysis of 16S rDNA V3-V4 hypervariable regions was performed for intestinal bacteria. Intestinal bacteria in CRF patients and healthy subjects were analyzed for alpha, beta diversity, species composition analysis, and differential species analysis. The diagnostic value of the presence of specific intestinal bacteria for CRF was analyzed using a receiver operating characteristic curve (ROC). Pearson's correlation analysis was used to analyze the correlation between the presence of specific genera and the estimated glomerular filtration rate (eGFR). Results The alpha and beta diversity in the CRF group was different from that in the control group (P﹤0.05). At the phylum level, Verrucomicrobia were significantly less abundant in the CRF group than that in the control group (0.70% vs 3.09%, P﹤0.001). The abundance of Actinobacteria was significantly greater in the CRF group than that in the control group (1.48% vs 1.14%, P=0.036). At the genus level, the abundance of Akkermansia (0.96% vs 3.90%), Parasutterella (0.47% vs 0.93%), and Lactobacillus (0.07% vs 0.48%) in the CRF group was significantly less than those in the control group (all P﹤0.01). The abundance of Alloprevotella (0.41% vs 0.04%) and Clostridium IV (0.6% vs 0.1%) was significantly greater than those in the control group (all P﹤0.05). The diagnostic value of CRF for the area under the ROC curve (AUC) for Akkermansia was 0.753, and that for Lactobacillus diagnostic value of CRF was 0.792. The combined AUC diagnostic value of CRF for detection of Akkermansia and Lactobacillus was 0.830, with high disease prediction value. Lactobacillus abundance was positively correlated with eGFR (R=0.29, P=0.029). Conclusions The diversity and structure of intestinal bacteria are altered in patients with CRF. The abundance of Akkermansia and Lactobacillus has diagnostic value for CRF. The abundance of Lactobacillus is positively correlated with eGFR.     

The renal cytochrome P-450 arachidonic acid system

In addition to cyclooxygenase and lipoxygenase, arachidonic acid (AA) is metabolized by the cytochrome P-450 monooxygenase system. The kidney is one of the major extrahepatic tissues that display cytochrome P-450 enzyme activities, in particular the cortex, specifically the proximal tubule demonstrate the highest concentration. AA is metabolized by the renal cytochrome P-450 epoxygenase and /-1 hydroxylases to epoxyeicosatrienoic acids and /-1 alcohols (20- and 19-mono-hydroxyeicosatetraenoic acids), respectively. These metabolites possess a broad spectrum of biological and renal effects which include: vasodilation, vasoconstriction, inhibition and stimulation of Na⁺–K⁺-ATPase, inhibition of ion transport mechanisms, natriuresis, inhibition of renin release and stimulation of cell growth. These metabolites are endogenous constituents of the kidney and are present in urine with increasing concentration under pathological conditions such as pregnancy-induced hypertension. The cytochrome P-450-dependent metabolism of AA is specifically localized to the proximal tubule and exhibits developmental changes, i.e., renal production of metabolites is very low in the fetus, newborn and up to 3 weeks of age, after which a remarkable increase in enzyme activities is observed. These characteristics call attention to the importance of this enzyme system in producing cellular mediators for regulating renal function in normal and diseased states.     

Parathyroidectomy in chronic renal failure

Parathyroidectomy was carried out in 26 patients over a 14-year period. Excellent results were obtained in patients with severe hyperparathyroidism. Vascular calcification, hypercalcaemia and pruritus did not justify surgery unless associated with unequivocal hyperparathyroidism. 13 patients required intravenous calcium infusion for up to 2 weeks to control post-operative hypocalcaemia. Calcium requirements could be predicted from the pre-operative plasma alkaline phosphatase level. Following operation continued treatment with vitamin D was necessary to prevent hypocalcaemia. Hyperparathyroidism recurred in 1 patient after 8 years and 4 patients developed osteomalacia. Since parathyroid hormone may have toxic effects other than those on bone, maintenance of normal levels should be a long-term objective in the treatment of patients with chronic renal failure. Where large parathyroid glands are present, surgical reduction in gland mass is a logical prelude to long-term suppression of parathyroid hormone with vitamin D and phosphate-binding agents.     

Parathyroidectomy in chronic renal failure

Between 1978 and 1984, 19 patients at Royal Perth Hospital (RPH) underwent parathyroidectomy for secondary (renal) hyperparathyroidism. This represented 6.0% of the overall dialysis population treated at RPH during this period of time. The mean duration of pre-operative dialysis for these 19 patients was 48 months, compared with a mean duration of 30 months for the overall dialysis population. The principal indications for parathyroidectomy were symptomatic hyperparathyroid bone disease (10), hypercalcaemia (six), progressive lower limb ischaemia (two) and painful peri-articular calcification (one). The complications of chronic renal failure that were most consistently improved by parathyroidectomy were the clinical, radiological and biochemical manifestations of hyperparathyroid bone disease and hypercalcaemia. Features such as pruritus, soft tissue calcification, vessel wall calcification and peripheral ischaemia responded less predictably. Hyperparathyroid bone disease and hypercalcaemia remain the principal indications for parathyroidectomy in chronic renal failure. Profound postoperative hypocalcaemia was the major early postoperative management problem (seven patients) and was closely linked with the severity of pre-operative hyperparathyroid bone disease. It was also seen more frequently in those patients undergoing total parathyroidectomy with immediate autotransplantation of parathyroid tissue (TP-A), than in those in whom residual parathyroid tissue was left in situ (subtotal parathyroidectomy or STP). Recurrent hyperparathyroidism (four patients) was the major late postoperative complication, but was more frequently the result of a supernumerary or previously overlooked fourth parathyroid gland (three), than due to hyperplasia of residual parathyroid tissue (one). STP and TP-A were equally effective in controlling or reversing renal hyperparathyroidism, but the former was associated with a lower incidence of postoperative management problems and should be the preferred operation in this group of patients.     

Endotoxemia in chronic renal failure

In the past years dialyzers have been improved, and consequently pyrogenic reactions have become rare. However, some patients in our dialysis unit have shown symptoms during hemodialysis which we suspected could be caused by endotoxins. These patients, as well as controls without similar symptoms, had elevated levels of circulating endotoxin. We therefore measured endotoxin in blood from patients with chronic renal failure and different kinds of treatment. Serum samples were analyzed with a sensitive method described in the literature, using a chromogenic substrate and Limulus amebocyte lysate. In patients on hemodialysis (mean +/- SEM) the endotoxin value in samples taken immediately before dialysis was 40 +/- 4.7 ng/l and significantly elevated (p less than 0.001) compared with the endotoxin value (7 +/- 0.6 ng/l) found in the healthy reference group. Increased endotoxin levels were also seen in patients on hemofiltration (19 +/- 7.5 ng/l) and in patients with conservative treatment and various degrees of renal insufficiency (17 +/- 2.5 ng/l). Patients on peritoneal dialysis and renal-transplanted patients had levels not different from the controls. The mechanism behind endotoxemia in uremia is unknown but may partly be explained by reduced endotoxin elimination due to impaired liver macrophage function. The differences in endotoxin levels in patients on peritoneal or hemodialysis treatment may reflect that extracorporeal circulation enhances endotoxin entrance to the circulation and/or that endotoxin clearance is dependent on the dialysis regimen.     

Myoglobinuria in chronic renal failure

Serum and urine myoglobin levels were determined on 14 patients with stable chronic renal failure. Serum myoglobin ranged from 38 to 350 ng/mL. Eleven patients had myoglobinuria between 15 and 250 ng/mL; none developed myoglobinuric renal failure. Fractional excretion of myoglobin in the myoglobinuric patients increased as creatinine clearance decreased, although there was no correlation between filtered load and excretion rate of myoglobin. This confirms that renal failure leads to hypermyoglobinemia and usually to myoglobinuria. Surviving nephrons tend to reabsorb less of the filtered load of myoglobin as renal function diminishes.     

Value of renal biopsy in chronic renal failure

A total of 120 patients with chronic renal failure secondary to parenchymatous kidney disease were biopsied. Percutaneous approach was tried and open technique was employed when there was contraindication to or failure of the percutaneous technique. In 72 cases the histopathologic lesions were identified, in 30 cases it was not possible to identify them and in 18 cases there was no sufficient kidney tissue. The diagnosis was very critical in at least 10 cases: there were 3 cases of primary oxalosis, one case of haemolytic uraemic syndrome, one case of necrotizing glomerulonephritis, one case of Wagner's granulomatosis, 3 cases of focal segmental glomerulosclerosis and one case of Fabry's disease. All but one of these were not diagnosed clinically. There was no patient mortality, and morbidity was significantly higher after open approach. We concluded that kidney biopsy in patients with chronic renal failure is mandatory especially if they are going to be transplanted and it is relatively safe especially when the percutaneous technique is employed.     

Fluoride-induced chronic renal failure

Renal fluoride toxicity in human beings is difficult to assess in the literature. Although experimental studies and research on methoxyflurane toxicity have shown frank renal damage, observations of renal insufficiency related to chronic fluoride exposure are scarce. We report a case of fluoride intoxication related to potomania of Vichy water, a highly mineralized water containing 8.5 mg/L of fluoride. Features of fluoride osteosclerosis were prominent and end-stage renal failure was present. The young age of the patient, the long duration of high fluoride intake, and the absence of other cause of renal insufficiency suggest a causal relationship between fluoride intoxication and renal failure.     

Progression of chronic renal failure

Rates of progression of renal failure were calculated for a group of 277 patients who had five or more clinic visits. The goals of therapy in the absence of ongoing immunological processes were control of blood pressure to diastolic pressures less than 85 mm Hg and serum phosphate less than 1.60 mmol/L (5 mg/dL). The mean rate of progression expressed as the slope of the reciprocal creatinine versus time was -0.0054 +/- 0.0009 dL/mg/mo (mean +/- SEM), and the median was -0.00315 dL/mg/mo. Approximately 25% of these patients had rates of progression less than -0.001 dL/mg/mo. The rate of progression was inversely correlated with the creatinine concentration at entry (P less than 0.004) and with the frequency of clinic visits (P less than 0.01). The "renal survival" time from a creatinine of 880 mumol/L (10 mg/dL) to dialysis was 10.0 +/- 1.2 months (mean +/- SEM). These data provide rates of progression for a group of patients without specific dietary intervention but with vigorous control of blood pressure and phosphorus.     

Perspectives of chronic renal failure

SUMMARY: End-stage renal disease (ESRD) is a major source of morbidity and the increasing number of chronic dialysis patients is a significant health-care issue in many developed as well as developing countries. In the present brief review the current status of chronic dialysis is discussed; and Japan and the USA, two major countries in which chronic dialysis programmes are well developed, are compared. Also discussed is the economic impact, the status of renal transplantation and its future possibilities, recent efforts to halt progression of chronic renal disease, in particular, diabetic nephropathy (which has become the major cause of ESRD in many developed countries), and future perspectives in renal research. It is hoped that, in the future, perhaps by the mid-21 st century, chronic dialysis may become the exception in therapy through our efforts.     

Cardiac anomalies in chronic renal failure

PRINCIPAL CARDIOVASCULAR COMPLICATIONS IN END STAGE RENAL DISEASE: Cardiovascular diseases are the leading causes of morbidity and mortality in end stage renal disease patients. Very often, complications observed are left ventricular hypertrophy and various forms of arterial degenerative lesions involving coronary arteries, less frequently pericarditis and calcifying valvulopathy are diagnosed. THE REASONS ARE COMPLEX: Risk factors can be either specific of uremia per se such as anemia, overhydration, fistula or the same as in the general population. Hemodynamic alterations including tensile stress or blood flow play a major role associated to various locally or generally generated substances whose role remains currently to be determined. THEIR TREATMENTS: Treatments of cardiovascular complications are not specific in this end stage renal disease population but are more often the treatment of the etiology: reduction of fistula blood flow, increase of hemoglobin, best control of weight gain between two hemodialysis sessions or blood pressure control.