Degree Of Renal Failure Research Articles

Thrombophilia in neonatal renal venous and arterial thrombosis

Sirs, Renal venous thrombosis (RVT) is a classical disease in neonates, especially those that are preterm. It is a rare disorder with severe consequences for the affected kidney(s). A recent survey, carried out in Germany over a 2year period, identified 35 proven cases, corresponding to an incidence of 2.2 in 100,000 live births; half of these were premature [1]. Organ scarring was observed in 26 of the 39 affected kidneys. The clinical presentation consists of increased kidney size, macroor microhematuria, reduced urine output, and some degree of renal failure. Renal ultrasonography shows unior bilateral kidney enlargement with little flow and in many cases additional thrombi in the vena cava. The cause of RVT is unclear. The following predisposing factors have been identified in several earlier studies: maternal diabetes, traumatic delivery, prematurity, hyperviscosity, hypovolemia, and hemoconcentration. Recent single case observations have pointed to the association of RVT with activated protein C resistance, especially in bilateral cases [2, 3, 4, 5]. One multicenter case-control study in neonates and infants with abdominal venous thrombosis was published [6]. The odds ratio for RVT was 10.9 in infants with different forms of thrombophilia. Treatment remains controversial in the absence of trials to compare supporting therapy with anticoagulation and/or thrombolysis. Renal artery thrombosis (RAT) in the neonate is far less common than RVT, and there is little information about its incidence. It is strongly associated with umbilical catheters and patent ductus arteriosus [7]. The clinical presentation is rather silent and renal ultrasound findings can be minimal unless Doppler imaging is used. The outcome of the affected kidneys is poor with global atrophy being the rule. To the best of our knowledge, no patients with neonatal RAT and thrombophilia have been reported to date. Thrombophilia is an acquired or genetic state of hypercoagulability; the most common abnormalities being genetic in origin. Established genetic forms predisposing to venous thrombosis are deficiencies of antithrombin, protein C, and protein S, mutations in the promotor of the gene encoding prothrombin and factor V Leiden mutation. Mutations in the gene for methylenetetrahydofolate reductase, which lead to hyperhomocysteinemia, are associated with venous as well as arterial thrombosis. Over the last 25 years, ten patients were followed regularly in our Renal Unit for renal damage as a consequence of renal venous or arterial thrombosis in the neonatal period. There were eight boys and two girls. RVT was diagnosed in five patients, of whom two had bilateral thrombosis. RAT was observed in another five patients and was unilateral in all. The diagnosis of RVT was based on clinical, laboratory, and ultrasound manifestations. All patients had hematuria, thrombocytopenia, and kidney enlargement. The diagnosis of RAT was based on arterial hypertension, reduced kidney size, and poor renal perfusion. The two patients with bilateral RVT developed chronic renal failure. Of the five patients with RAT, three have complete atrophy of the affected kidney and two with a remnant kidney have needed antihypertensive drugs for several years. The investigations for thrombophilia were performed when the patients were aged between 18 months and 22 years. In two patients W. Proesmans · P. van de Wijdeven Renal Unit, Department of Pediatrics, University Hospital, Leuven, Belgium

Oral soft and hard tissue abnormalities in pediatric renal transplant recipients

An increasing number of dental patients are living with the end-stage renal diseases (ESR) or are the recipient of renal transplant. Soft and hard oral tissues may be affected by both renal diseases and also by the therapeutic immunosuppressive medications. Cyclosporin is associated with gingival overgrowth as a result of an interaction between the drug and its metabolites with susceptible gingival fibroblasts. The combined cyclosporine and an antihypertensive nifedipine regime enhances the degree of gingival overgrowth in renal graft recipients compared with cyclosporin alone. Cyclosporine-induced gingival overgrowth may stabilize 6 or 12 months after transplantation depending on the plaque level. Immunosuppression may inhibit periodontal tissue reaction to plaque stimulation and can mask the early signs of oral infection. Fever as the only sign of odontogenic infection has been reported in renal transplant recipients. A case of bilateral mandibular cysts has been reported in an 8-year-old boy treated with cyclosporin A (CsA). CsA might contribute to the cyst genesis by (1) interference with control mechanisms that regulate the reabsorption of gingival stromal tissue, allowing progressive dental eruption, and (2) an increase in the gingival connective tissue components.1 Viral infections, candidacies, large and slow-healing ulcers, lymphoma, Kaposi's sarcoma, carcinoma arising in cyclosporin-induced gingival hyperplasia, hairy leukoplakia, and dental pulp narrowing have been reported. There is an increase in the prevalence of enamel hypoplasia in children with chronic kidney diseases. The severity and extent of this depends on the degree of renal failure and its time of onset. Developmental enamel defects may occur through the period of enamel formation and may include hypoplasia, demarcated and diffuse opacities, and a combination of these defects. Altered vitamin D, calcium, and phosphate metabolism contribute to enamel opacities, loss of lamina dura, teeth mobility, bony fractures, and tumors from secondary hyperthyroidism. The incidence of caries experienced is generally low in these children, and radiographic assessments have shown only a slight delay in dental eruption. More aggressive periodontal treatments, such as periodontal surgery or orthodontics, should be undertaken only after the first year following transplantation. Prophylactic antibiotics are recommended for aggressive dental treatments.

Persistently low serum osteoprotegrin levels during the treatment of multiple myeloma patients predicts worse event-free survival

Osteoprotegrin (OPG) functions as a secreted inhibitor of bone resorption and its serum levels have been reported to be reduced in patients with multiple myeloma (MM). In this study, serum and urine OPG levels were prospectively measured in patients with MM (stage II III) and in patients with other hematologic malignancies (control group) and correlated to response to therapy. Newly diagnosed as well as patients on maintenance therapy were included. The MM and control group were well matched in terms of age and gender, as well as time from diagnosis to enrollment. Seventeen MM patients underwent autologous stem cell transplant while none in the control group were transplanted. Blood and urine samples were collected monthly, cytocentrifuged and stored in frozen aliquots at −20° C until analyzed. OPG was measured using an ELISA. Thus far data on 28 MM patients and 9 patients with other hematologic malignancies (2 AML, 2 CML, 1 CLL, 2 NHL, 2 monoclonal gammopathy of unknown significance) have been analyzed. All patients were treated with monthly intravenous bisphosphonate. The results reveal that OPG is detectable in the urine and its levels correlate significantly (r = 0.77 and two-tailed P = 0.0032) with the degree of renal failure as reflected by serum creatinine. Our results also show that the overall median serum OPG level was lower in MM patients (1181 pg/mL), but not significantly different than that of the control group (1437 pg/mL). However, 4 of 20 (20%) evaluable MM patients with adequate follow-up had OPG serum levels that remained < 1000 pg/mL throughout the treatment. Their median event-free survival (EFS) was 8 months compared with 19 months for the rest of the group (P = 0.023), while no significant difference was detected in the median overall survival. There was no OPG serum levels < 1000 pg/mL during the follow-up of the control group. Among the 10 newly diagnosed MM patients enrolled in the study, only 2 (20%) had low serum OPG at presentation, with no detectable urine OPG. Median OPG serum levels were lower for MM patients during induction therapy (940 pg/mL, n = 7) in comparison to those undergoing maintenance therapy (1536 pg/mL, n = 8; P = 0.16). In conclusion, OPG urine as well as serum levels should be monitored simultaneously since low serum levels may reflect high OPG urinary loss. In addition, persistently low OPG serum levels throughout treatment of MM patients may be a prognostic factor for worse EFS.

Plasma Homocysteine and Insulin in Diabetic Nephropathy: Relationship to Body Mass Index

The data on plasma homocysteine and endogenous insulin in type 2 diabetes mellitus with nephropathy and relationship to body mass index (BMI) is particularly from the Indian subcontinent. A prospective study was carried out in 50 patients of type 2 diabetes mellitus with overt nephropathy (Group A). The results were compared with 25 diabetics without nephropathy (Group B), and 25 age and sex matched healthy controls (Group C). Microenzyme immunoassay and ELISA estimated the plasma homocysteine and insulin, respectively. The mean values of plasma homocysteine were significantly elevated in diabetic nephropathy (21.3 ± 7.2 µmol/L) and diabetics without nephropathy (19.4 ± 7.1) when compared to healthy control (11.5 ± 2.3). The insulin levels and BMI were significantly higher in diabetics as compared to controls. There was no correlation between homocysteine and insulin, homocysteine and BMI, and homocysteine with the degree of renal failure.

The effect of short-term treatment with simvastatin on renal function in patients with peripheral arterial disease.

The objective of this study was to investigate the effects of lipid-lowering treatment on renal function in patients with peripheral arterial disease (PAD). This was a retrospective study of hyperlipidemic claudicants referred to a vascular surgery and risk modification clinic. Serum creatinine and urate concentrations and the fasting lipid profile were measured pretreatment and after 3-4 months of treatment with 20 mg/day simvastatin. In 103 consecutive patients with PAD (57 men; 46 women), median age 67 years (range: 51 to 83) there was a significant decrease in serum creatinine from a mean (SD) of 87 (12) micromol/L pretreatment to 84 (12) micromol/L post-treatment (p<0.0001). This difference was more marked in the tertile of patients with the highest baseline creatinine levels. There was also a significant reduction in serum urate from 0.37 (0.07) mmol/L to 0.35 (0.07) mmol/L (p<0.0001). Both these effects were independent of the degree of total cholesterol (TC) or low-density lipoprotein (LDL) cholesterol reduction. There was a significant reduction in TC from 6.6 (1.0) to 5.2 (0.8) mmol/L and LDL cholesterol from 4.3 (1.0) to 2.8 (0.7) mmol/L; both p<0.0001. Significant improvement also occurred in the high-density lipoprotein cholesterol and triglyceride levels. Cholesterol lowering with simvastatin 20 mg/day improved indices of renal function after 3-4 months of treatment in hyperlipidemic patients with PAD. Further studies are needed to establish and define the clinical relevance of these findings, especially in patients with different degrees of renal failure.

Sevelamer hydrochloride attenuates kidney and cardiovascular calcifications in long-term experimental uremia

In chronic renal failure (CRF), hyperphosphatemia and an elevated calcium-phosphate product are associated with vascular calcification and increased cardiovascular morbidity and mortality. Previous data have demonstrated that 3-month treatment of uremic rats with sevelamer was associated with less nephrocalcinosis compared to calcium carbonate (CaCO3), despite similar control of serum phosphorus, calcium-phosphorus product (Ca x P product), and secondary hyperparathyroidism. There was no evidence of aortic calcification after 3 months of uremia (J Am Soc Nephrol 13:2299-2308, 2002). The present studies explore the influence of sevelamer and CaCO3 on cardiovascular and kidney calcifications in long-term experimental uremia over 6 months. Normal and 5/6 nephrectomized rats (U) were fed a high phosphorus (HP) diet for 6 months. Two phosphate binders, CaCO3 and sevelamer, were administered and their influence on hyperphosphatemia, secondary hyperparathyroidism, kidney/myocardial/aortic calcification, and renal function was compared. All uremic rats began the study with the same degree of renal failure. Sevelamer was as effective as CaCO3 in reducing serum phosphorus, Ca x P product, and attenuating secondary hyperparathyroidism. Despite similar serum cholesterol levels, rats in the U-HP + sevelamer group had markedly lower calcium deposition in the myocardium and aorta (myocardium, 72 +/- 4 microg/g wet tissue; aorta, 736 +/- 156 microg/g wet tissue) compared to rats in either the U-HP + CaCO3 group (myocardium, 179 +/- 48, P < 0.05; aorta, 1308 +/- 343, P < 0.05) or the U-HP group (myocardium, 98 +/- 10, NS; aorta, 2150 +/- 447, P < 0.05). Dual immunohistochemical analysis for calcium and endothelial cell markers demonstrated that myocardial calcium deposition was intravascular within capillaries. Furthermore, calcium deposition in the kidney of uremic rats treated with sevelamer (582 +/- 111 microg/g wet tissue) was lower than that found in uremic rats treated with CaCO3 (1196 +/- 180 microg/g wet tissue). Sevelamer-treated rats had less deterioration in renal function with an associated lower serum creatinine, higher creatinine clearance, and less proteinuria. There was no difference in overall mortality between the three experimental groups. In long-term experimental CRF, in addition to controlling serum phosphorus and secondary hyperparathyroidism as efficiently as CaCO3, treatment with the phosphate-binder sevelamer attenuates vascular and kidney calcification.

Origin and characteristics of an unusual pyridine nucleotide accumulating in erythrocytes: positive correlation with degree of renal failure

Background: Our aim was to identify an unusual nucleotide accumulating, with precursors, in erythrocytes in uraemia and to establish its relationship to the candidate uraemic toxin, N1-methyl-2-pyridone-5-carboxamide (M2Py). Methods: This nucleotide, plasma creatinine and M2Py were measured in four categories of patients: mild chronic renal failure (CRF), end-stage renal failure (ESRF), haemodialysis (HD) and continuous ambulatory peritoneal dialysis (CAPD); also in healthy controls and patients after successful kidney transplantation (Post-Tx). Results: The nucleotide was identified using liquid chromatography and mass spectrometry as 2-pyridone-5-carboxamide ribonucleoside triphosphate (2PyTP). In the patient groups, mean 2PyTP concentrations are lowest in CRF (21.8 μmol/l), increasing with degree of renal failure through ESRF (55.1 μmol/l) and HD patients (70.9 μmol/l) and being highest in CAPD patients (216.7 μmol/l). Following successful transplantation, 2PyTP concentrations fall to the control range. Plasma concentrations of M2Py correlate with 2PyTP in the erythrocytes; both are undetectable in patients lacking molybdenum cofactor, needed to oxidise N-methylnicotinamide. Conclusion: Our evidence indicates that M2Py accumulates in parallel with the nucleotide 2PyTP in renal failure: either may be a uraemic toxin, since both increase with the degree of renal failure. Elevated concentrations of 2PyTP in CAPD patients reflect a longer half-life for erythrocytes than in HD patients.

The risk of developing end-stage renal disease in patients with type 2 diabetes and nephropathy: The RENAAL Study

Diabetic nephropathy has become the single most important cause of end-stage renal disease (ESRD) worldwide. Strategies to slow the rate of loss of renal function in these patients have been developed. We examined the risk factors that predict loss of kidney function (doubling of serum creatinine) or ESRD (dialysis or transplantation) in patients with type 2 diabetes in whom blood pressure was controlled. We evaluated risk factors for doubling of serum creatinine or the development of ESRD in the Reduction of End Points in NIDDM with the Angiotensin II Receptor Antagonist Losartan (RENAAL) study, which included 1513 patients with type 2 diabetes and nephropathy. Univariate analyses demonstrated a group of 23 risk factors that significantly predicted doubling of serum creatinine or ESRD. From these univariate analyses, a multivariate model was developed that demonstrated four independent risk factors: proteinuria, serum creatinine, serum albumin, and hemoglobin level. Proteinuria was the strongest and most consistent risk factor. The multivariate risk model was derived from only the placebo group and was similar to that derived for the total population, suggesting that the risk predictors for progression of kidney disease were independent of therapy. After control of blood pressure in type 2 diabetic patients with nephropathy, proteinuria, degree of renal failure, serum albumin, and hemoglobin level are independent risk factors that predict renal outcomes. The level of proteinuria proved to be the most important risk for progressive kidney injury in these diabetic patients.

Homocysteine metabolism in renal disease.

Hyperhomocysteinemia, a new cardiovascular risk factor, occurs in 85-100% of patients with end-stage renal disease. The exact mechanism by which renal function is linked to plasma homocysteine has not been definitively established. There is reasonably good clinical evidence that hyperhomocysteinemia in itself does not cause renal insufficiency. Two, not mutually exclusive, hypotheses are that in renal failure: i) homocysteine disposal is impaired in the kidneys themselves and ii) extra-renal homocysteine metabolism is defective, possibly due to uremic toxins. Several methods have been applied to investigate kidney and whole-body sulfur amino acid metabolism in healthy subjects and in patients with different degrees of renal failure. Arteriovenous extraction studies have not found a significant homocysteine disposal in the human kidney. Methods to study whole-body homocysteine metabolism have included measurement of plasma metabolites, calculation of plasma homocysteine elimination after oral loading and the use of stable isotope techniques with methionine tracers. The results implicate a decreased homocysteine clearance instead of an increased production as the cause of hyperhomocysteinemia in renal failure, but the exact site of the impaired clearance remains controversial.

Insulin-like growth factor I administration in young rats with acute renal failure.

The outcome of ischemic acute renal failure (IARF) is better in young than adult rats. Insulin-like growth factor I (IGF-I) treatment may increase mortality of adult rats with IARF, probably because of an exaggerated inflammatory response. We report the response to IGF-I therapy in young rats with IARF. Male rats, aged 28+/-1 days, with IARF were given subcutaneous IGF-I, 50 microg/100 g at 0, 8, and 16 h after reperfusion (IGF) or were untreated (ARF). Sham-operated rats were used as controls. At 2 and 7 days after ischemia, serum urea nitrogen and histological damage score, cell proliferation, apoptosis, neutrophil infiltration, and IGF-I receptor mRNA in kidneys were analyzed. The degree of renal failure, mortality rate, histological damage, cell proliferation, and neutrophil infiltration were not different between IGF-I and ARF rats. Hence, short-term IGF-I treatment did not modify the course of IARF in young rats.

Oxidative stress in hemodialysis patients: Is NADPH oxidase complex the culprit?

Oxidative stress results from an imbalance between oxidant production, including reactive oxygen species (ROS), reactive nitrogen species (RNS), chlorinated compounds, and antioxidant defense mechanisms. Most reports prove that oxidative stress is present in ESRD patients. Several studies tend to accreditate the hypothesis by which oxidative stress is a strong co-factor for the development of complications related to long-term HD such as atherosclerosis, amyloidosis, malnutrition, anemia, and infection. In order to evaluate the rationale for curative action against oxidative damage in chronic renal failure patients, we reviewed the putative factors involved in this process. Antioxidant systems are severely impaired in uremic patients and gradually altered with the degree of renal failure. Moreover, the inflammatory state caused by the hemoincompatibility of the dialysis system plays a critical role in the activation of NADPH oxidase, aggravating the pro-oxidant status of uremic patients. Prevention of ROS overproduction by improvement of dialysis biocompatibility, an important component of adequate dialysis, might be completed by antioxidant supplementation.

The role of trace elements in uraemic toxicity

Although most research on uraemic toxicity has focused on the retention or removal of organic solutes, subtle changes in the concentration of inorganic compounds are also of importance because these compounds may have significant clinical consequences. Potential clinical implications include increased risk of cancer, cardiovascular disease, immune deficiency, anaemia, renal function impairment and bone disease. In uraemic patients, the most important factor affecting trace element concentration is the degree of renal failure and modality of renal replacement therapy. Accumulation of trace elements in haemodialysis patients has resulted from dialysate contaminated with aluminium and strontium. Several trace elements have been implicated in the decline of renal function. These include arsenic, cadmium, copper, germanium, lead and mercury. In uraemic patients, aluminium, cadmium, chromium, lanthanum, strontium and zinc have been shown to accumulate in bone. In addition to substantial evidence linking aluminium to renal osteodystrophy, studies have also implicated cadmium, iron and strontium in bone disease. Studies using a rat model of chronic renal failure have demonstrated an association between lanthanum accumulation and mineralization defects characteristic of osteomalacia. Investigations of arsenic accumulation in animal models have demonstrated that speciation of trace elements potentially may alter toxicities of trace elements accumulated in uraemic patients. Conversely, the presence of uraemic toxins may also alter the uptake and toxicity of certain trace elements. Although research in uraemic patients has focused primarily on total concentrations of trace elements, the evolution of both inorganic and organic species should be considered separately.

URATE HOMEOSTASIS IN POLYCYSTIC KIDNEY DISEASE: COMPARISON WITH CHRONIC GLOMERULONEPHRITIC KIDNEY

Autosomal dominant polycystic kidney disease (ADPKD) might affect urate homeostasis and clearance. Renal tubular urate transport was studied by means of probenecid (PB) and pyrazinamide (PZA) tests in individuals with ADPKD and normal renal function as well as various degrees of renal failure (49 patients). Comparisons were made between polycystic and chronic glomerulonephritic kidney (CGNK), as well as with controls (men with normal renal function). Patients with ADPKD and normal renal function showed plasma urate levels within normal range and normal renal urate handling. In contrast higher plasma urate levels comparing to controls were found in patients with CGNK and normal renal function. During the evolution of renal failure ADPKD patients showed lower urate plasma levels and higher renal clearance as well as, fractional urate excretion, comparing to CGNK patients with the same degree of renal failure. In conclusion patients with ADPKD and normal renal function have normal urate handling and plasma urate levels within normal range. With increasing severity of disease and during evolution of renal failure CGNK patients showed higher urate plasma levels and lower clearances comparing to ADPKD patients. When renal disease becomes more advanced there was no difference in renal urate handling between ADPKD and CGNK patients.

Chronic Uremia Induces Permeability Changes, Increased Nitric Oxide Synthase Expression, and Structural Modifications in the Peritoneum

Advanced glycation end products (AGE), growth factors, and nitric oxide contribute to alterations of the peritoneum during peritoneal dialysis (PD). These mediators are also involved in chronic uremia, a condition associated with increased permeability of serosal membranes. It is unknown whether chronic uremia per se modifies the peritoneum before PD initiation. A rat model of subtotal nephrectomy was used to measure peritoneal permeability after 3, 6, and 9 wk, in parallel with peritoneal nitric oxide synthase (NOS) isoform expression and activity and structural changes. Uremic rats were characterized by a higher peritoneal permeability for small solutes and an increased NOS activity due to the up-regulation of endothelial and neuronal NOS. The permeability changes and increased NOS activities correlated with the degree of renal failure. Focal areas of vascular proliferation and fibrosis were detected in uremic rats, in relation with a transient up-regulation of vascular endothelial growth factor and basic fibroblast growth factor, as well as vascular deposits of the AGE carboxymethyllysine and pentosidine. Correction of anemia with erythropoietin did not prevent the permeability or structural changes in uremic rats. Thus, in this rat model, uremia induces permeability and structural changes in the peritoneum, in parallel with AGE deposits and up-regulation of specific NOS isoforms and growth factors. These data suggest an independent contribution of uremia in the peritoneal changes during PD and offer a paradigm to better understand the modifications of serosal membranes in uremia.

Drug dosage in patients with renal failure optimized by immediate concurrent feedback.

To examine the impact of immediate concurrent feedback on dose adjustment in patients with renal failure. Prospective 12-month study in patients with various degrees of renal failure, with comparison to a retrospective control group. A 39-bed unit of a university hospital providing primary and tertiary care. Patients with renal failure (estimated creatinine clearance < or = 50 mL/min) receiving at least 1 pharmacologically active drug. Education of physicians and immediate concurrent feedback on the ward giving estimated creatinine clearance and dose recommendations for renally eliminated drugs adjusted to individual renal function. The percentage of dosage regimens adjusted to renal function and cost assessment of drug therapy were calculated. Overall, 17% of the patients had at least 1 estimated creatinine clearance < or = 50 mL/min. In the intervention group, the dose of 81% of renally eliminated drugs was adjusted to renal function, compared with 33% in the control group ( P <.001). The mean difference in cost between standard and adjusted dose of renally eliminated drugs in the intervention and control groups was 5.3 +/- 12.3 and 0.75 +/- 2.8 Swiss francs (approximately US$3.5 and US$0.5), respectively ( P <.001), accounting for 16.5% and 2.8%, respectively, of daily medication costs of all drugs. The proportion of doses of renally eliminated drugs adjusted to renal function can be substantially increased by immediate concurrent feedback. This saves drug costs and has the potential to prevent adverse drug reactions.

Prevalence of hypertension in renal disease.

Hypertension (HTN) is very frequent in patients with renal disease and its prevalence increases as renal failure progresses. We studied the prevalence of HTN in 1921 patients with different nephropathies. Patients on dialysis and renal transplant patients were not included in the study. HTN was defined as SBP>140 and/or DBP>90 mmHg, or requiring antihypertensive therapy. The prevalence of HTN in the total group of patients with renal diseases was 60.5%, but this prevalence varied widely depending upon the type of underlying nephropathy. The prevalence of HTN was practically universal in patients with renal vascular disease (93%) and in patients with established diabetic nephropathy (87%), and 74% of the patients with polycystic kidney disease, 63% of the patients with chronic pyelonephritis and 54% of the patients diagnosed with glomerulonephritis were hypertensive. The prevalence of HTN in patients with renal insufficiency (80%) is significantly higher than that in patients without renal insufficiency (43% P<0.001). In a multiple logistic regression analysis, the independent risk factors defining HTN in renal patients were: renal failure, age, the presence of diabetes, hypertriglyceridaemia and proteinuria. Antihypertensive treatment consisted of diet alone in 4% of the patients, one drug in 45%, two drugs in 36%, three medications in 13% and more than three drugs in 2.5%. The angiotensin-converting enzyme (ACE) inhibitors were the most frequently prescribed drug (39% of the patients treated in monotherapy) followed by calcium channel blockers (27%), diuretics (18%) and beta-blockers (9%). The most common combined therapy was a diuretic plus an ACE inhibitor. The percentage of patients with BP controlled according to current recommendations for renal patients (BP<130/85) was very low; SBP in only 49% and DBP in 24%. Control of both was only achieved in 10% of the patients. There is a high prevalence of HTN in renal patients, which depends on the type of nephropathy and the degree of renal failure. Other independent risk factors for HTN in patients with renal disease are: advanced age, the presence of diabetes, hypertriglyceridaemia and the severity of proteinuria. BP control in renal patients is quite poor and should be improved to reduce progression of the renal disease.

Chronic metabolic acidosis in azotemic rats on a high-phosphate diet halts the progression of renal disease

Hyperphosphatemia and metabolic acidosis are general features of advanced chronic renal failure (RF), and each may affect mineral metabolism. The goal of the present study was to evaluate the effect of chronic metabolic acidosis on the development of hyperparathyroidism and bone disease in normal and azotemic rats on a high-phosphate diet. Our assumption that the two groups of azotemic rats (acid-loaded vs. non-acid-loaded) would have the same degree of renal failure at the end of the study proved to be incorrect. Four groups of rats receiving a high-phosphate (1.2%), normal-calcium (0.6%) diet for 30 days were studied: (1) normal (N); (2) normal + acid (N + Ac) in which 1.5% ammonium chloride (NH4Cl) was added to the drinking water to induce acidosis; (3) RF, 5/6 nephrectomized rats; and (4) RF + acid (RF + Ac) in which 0.75% NH4Cl was added to the drinking water of 5/6 nephrectomized rats to induce acidosis. At sacrifice, the arterial pH and serum bicarbonate were lowest in the RF + Ac group and were intermediate in the N + Ac group. Serum creatinine (0.76 +/- 0.08 vs. 1.15 +/- 0.08 mg/dL), blood urea nitrogen (52 +/- 8 vs. 86 +/- 13 mg/dL), parathyroid hormone (PTH; 180 +/- 50 vs. 484 +/- 51 pg/mL), and serum phosphate (7.46 +/- 0.60 vs. 12.87 +/- 1.4 mg/dL) values were less (P < 0.05), and serum calcium (9.00 +/- 0.28 vs. 7.75 +/- 0.28 mg/dL) values were greater (P < 0.05) in the RF + Ac group than in the RF group. The fractional excretion of phosphate (FEP) was greater (P < 0.05) in the two azotemic groups than in the two nonazotemic groups. In the azotemic groups, the FEP was similar even though PTH and serum phosphate values were less in the RF + Ac than in the RF group. NH4Cl-induced acidosis produced hypercalciuria in the N + Ac and RF + Ac groups. When acid-loaded (N + Ac and RF + Ac) and non-acid-loaded (N and RF) rats were combined as separate groups, serum phosphate and PTH values were less for a similarly elevated serum creatinine value in acid-loaded than in non-acid-loaded rats. Finally, the osteoblast surface was less in the N + Ac group than in the other groups. However, in the acid-loaded azotemic group (RF + Ac), the osteoblast surface was not reduced. The presence of chronic metabolic acidosis in 5/6 nephrectomized rats on a high-phosphate diet (1) protected against the progression of RF, (2) enhanced the renal clearance of phosphate, (3) resulted in a lesser degree of hyperparathyroidism, and (4) did not reduce the osteoblast surface. The combination of metabolic acidosis and phosphate loading may protect against the progression of RF and possibly bone disease because the harmful effects of acidosis and phosphate loading may be counterbalanced.

Increased Fibrinogen Levels and Hemostatic Abnormalities in Patients with Arteriolar Nephrosclerosis: Association with Cardiovascular Events

Increased plasma fibrinogen levels and hemostatic abnormalities suggestive of a prothrombotic state are present in patients with end-stage renal failure and could contribute to increased cardiovascular morbidity in these patients. We investigated the relationship between abnormalities of the hemostatic system and the degree of renal failure and whether these abnormalities are associated with increased prevalence of cardiovascular events in patients with arteriolar nephrosclerosis. In 425 patients recruited at a hypertension clinic we assessed the renal function by creatinine clearance, urinary protein excretion, and microalbuminuria, the prevalence of atherosclerotic disease, and measured prothrombin time, activated partial thromboplastin time. fibrinogen, prothrombin fragment 1+2 (F1+2), D-dimer, and antithrombin. Early impairment of renal function (creatinine clearance, 30 to 89 ml/min per 1.73 m2 of body surface area) caused by arteriolar nephrosclerosis was found in 172 patients. Patients with early renal failure were significantly older and had significantly greater values of blood pressure, plasma fibrinogen, F1+2, and D-dimer than patients with normal renal function. Elevated D-dimer and fibrinogen levels were independently associated with the presence of decreased creatinine clearance. Log fibrinogen, log F1+2, and log D-dimer were inversely correlated with creatinine clearance. The prevalence of coronary artery, cerebrovascular, and peripheral vascular disease was significantly greater in patients with mild renal failure than in those with normal renal function. Elevated levels of fibrinogen and D-dimer were associated with the presence of atherosclerotic disease independent of renal function and other risk factors. In conclusion, changes in hemostatic parameters occur early in the course of renal failure in patients with arteriolar nephrosclerosis, suggesting a prothrombotic state that may contribute to the risk for atherosclerotic disease at all levels of renal function.

Nutrition for ill neonates.

1. Danna M. Premer, MD* 2. Michael K. Georgieff, MD* 1. 2. *Department of Pediatrics, Division of Neonatology, University of Minnesota, Minneapolis, MN. After completing this article, readers should be able to: 1. List the factors on which the nutritional needs of the neonate depend. 2. Describe the factors that illnesses alter, thereby changing nutrient requirements. 3. Describe the levels of amino acids that can be initiated without causing intolerance or toxicity in most ill infants. 4. Delineate the adverse effects of protein malnutrition following an acute or prolonged illness or insult. From early in this century, investigators have attempted to determine the optimal nutrient delivery for term infants to promote normal growth and development. In the past 25 years, nutritional investigators have concentrated on the needs of the ideal, healthy preterm infant to try to mimic intrauterine growth and body composition. Although great progress has been made in characterizing the needs of healthy preterm and term infants, the needs of ill, physiologically unstable infants largely have been neglected. The primary reasons for this lack of investigation are the assumption that the needs of ill infants are similar to those of healthy infants and the difficulty of studying metabolic needs in ill infants. The persistent efforts of several groups of investigators and the development of new techniques to study metabolism now have begun to delineate the specific nutritional needs of this particular patient population. Drawing on models generated in the adult surgical intensive care literature of the 1980s makes it possible to try to elucidate the effect of common illnesses and conditions (eg, acute pulmonary disease, bronchopulmonary dysplasia[BPD], congenital heart disease[CHD], sepsis, and surgery) on neonatal metabolism and, therefore, nutritional requirements. The assumption is that changes from the norm in metabolism require alterations in substrate delivery (ie, nutrition). As with adults, it is likely that each illness induces characteristic changes in metabolism. The task for the practitioner is to customize nutritional delivery to fit the specific infant’s …

Dynamics of skeletal resistance to parathyroid hormone in the rat: effect of renal failure and dietary phosphorus

Secondary hyperparathyroidism develops in renal failure and is generally ascribed to factors directly affecting parathyroid hormone (PTH) production and/or secretion. These include hypocalcemia, phosphorus retention, and a calcitriol deficiency. However, not often emphasized is that skeletal resistance to PTH is an important factor. Our study evaluated: (1) the relative effects of uremia and dietary phosphorus on the skeletal resistance to PTH; and (2) how, during a PTH infusion, the dynamics of skeletal resistance to PTH were affected by renal failure. Renal failure was surgically induced and, based on serum creatinine, rats were divided into normal, moderate renal failure, and advanced renal failure. In each group, three diets with the same calcium (0.6%) but different phosphorus contents were used: high (1.2%, HPD); moderate (0.6%, MPD); and low (0.2%, LPD) phosphorus. The study diet was given for 14–16 days followed by a 48 h infusion of rat PTH(1-34) (0.11 μg/100 g per hour), a dose five times greater than the normal replacement dose. During the PTH infusion, rats received a calcium-free, low phosphorus (0.2%) diet. In both moderate and advanced renal failure, the PTH level was greatest in the HPD group ( p < 0.05) and, despite normal serum calcium values, PTH was greater in the MPD than the LPD group ( p < 0.05). Despite phosphorus restriction and normal serum calcium and calcitriol levels in the azotemic LPD groups, the PTH level was greater ( p < 0.05) in the LPD group with advanced rather than moderate renal failure. During PTH infusion, the increase in serum calcium was progressively less ( p < 0.05) in all groups as renal function declined. Furthermore, despite normal and similar serum phosphorus values at the end of PTH infusion, the serum calcium concentration was less ( p < 0.05) in the HPD group than the other two groups and similar in the LPD and MPD groups. In conclusion: (1) uremia and phosphorus each had separate and major effects on skeletal resistance to PTH; (2) skeletal resistance to PTH was an important cause of secondary hyperparathyroidism, even in moderate renal failure; (3) during PTH infusion, the dynamics of skeletal resistance to PTH changed because all groups received a low phosphorus diet, and the adaptation to a new steady state was delayed by the degree of renal failure and the previous dietary phosphorus burden; and (4) normal serum phosphorus may not be indicative of body phosphorus stores during states of disequilibrium.