Mild Renal Failure Research Articles

Assessing Renal Function From Creatinine Measurements in Adults With Chronic Renal Failure

Abstract Measurement of glomerular filtration rate (GFR) following the injection of one of several suitable marker substances remains the best method to determine the severity of renal insufficiency as well as its rate of progression. However, the expense of these procedures continues to restrict their use. A second alternative is the determination of creatinine clearance (CCr) after oral administration of cimetidine. This drug blocks tubular secretion of creatinine almost completely, and CCr measured under these conditions is reported to be nearly identical to GFR in mild or severe renal failure. The optimal dose and timing of cimetidine for this purpose is still uncertain, but a single 1,200-mg dose 2 hours before beginning urine collection is probably suitable. A third alternative is simply the measurement of serum or plasma creatinine (PCr) concentration. However, it is well established that substantial reductions in renal function may occur before PCr becomes abnormal. GFR in adults with chronic renal failure can be approximately estimated from PCr, provided it is greater than 2 mg/dL, with the aid of additional demographic and biochemical variables. Gender, height, weight, age, and race should be taken into account. Further study is needed to derive the best formula for predicting GFR from PCr and other variables. Finally, CCr (without cimetidine) is still in use. This is unfortunate because it has been established that rather than improving on the estimation of GFR from PCr, CCr (determined from urinary creatinine measurements as well as PCr) is a less reliable guide to GFR than PCr alone. The CCr/GFR ratio is almost always greater than unity and increases with decreasing GFR to a maximum of approximately 1.7 at a GFR of approximately 20 mL/min. Furthermore, the variability of CCr is greater than that of PCr. Measurement of CCr (without cimetidine) is an anachronism and should be abandoned. (Am J Kidney Dis 1998 Jul;32(1):23-31)

Treatment of hypertension in patients with comorbidities: Results from the study of hypertensive prescribing practices (SHyPP)

Approximately 50 million people have hypertension. Many agents with differing efficacy, side effects, dosing schedules, and costs are available to treat hypertension. Joint National Committee (JNC) guidelines attempt to simplify this decision by recommending specific agents based on special considerations such as comorbidities. The objective of this study was to survey primary care physicians’ antihypertensive prescribing practices and their treatment recommendations for patients with comorbidities. A direct mail survey was sent to a national random sample of 500 office-based primary care internists, family practitioners, and general practitioners. There were no significant differences between initial treatment recommendations at the time of the survey and those recommended before the survey. However, there were several therapeutic classes whose reported utilization for specific comorbidities significantly changed over 18 months. Angiotensin converting enzyme (ACE) inhibitors reportedly increased in patients with congestive heart failure and diabetes. In addition, the reported use of selective β-blockers increased for patients with a history of myocardial infarction. Physicians did not follow JNC recommendations when initiating treatment in black patients, older patients, or those with mild renal failure. Younger physicians were more likely than older physicians to select agents consistent with guideline recommendations. Physicians did not adhere to JNC guidelines when initiating treatment in patients with comorbidities; however, more physicians are prescribing recommended agents today as compared to 18 months ago. Younger physicians were more likely to prescribe agents consistent with the guidelines. More direct efforts are needed to ensure awareness and compliance with these guidelines.

Renal failure predisposes patients to adverse outcome after coronary artery bypass surgery

More than 600,000 coronary artery bypass graft (CABG) procedures are done annually in the United States. Some data indicate that 10 to 20% of patients who are undergoing a CABG procedure have a serum creatinine of more than 1.5 mg/dl. There are few data on the impact of a mild increase in serum creatinine concentration on CABG outcome. We analyzed a Veterans Affairs database obtained prospectively from 1992 through 1996 at 14 of 43 centers performing heart surgery. We compared the outcome after CABG in patients with a baseline serum creatinine of less than 1.5 mg/dl (median 1.1 mg/dl, N = 3271) to patients with a baseline serum creatinine of 1.5 to 3.0 mg/dl (median 1.7, N = 631). Univariate analysis revealed that patients with a serum creatinine of 1.5 to 3.0 mg/dl had a higher 30-day mortality (7% vs. 3%, P < 0.001) requirement for prolonged mechanical ventilation (15% vs. 8%, P = 0.001), stroke (7% vs. 2%, P < 0.001), renal failure requiring dialysis at discharge (3% vs. 1%, P < 0.001), and bleeding complications (8% vs. 3%, P < 0.001) than patients with a baseline serum creatinine of less than 1.5 mg/dl. Multiple logistic regression analyses found that patients with a baseline serum creatinine of less than 1.5 mg/dl had significantly lower (P < 0.02) 30-day mortality and postoperative bleeding and ventilatory complications than patients with a serum creatinine of 1.5 to 3.0 mg/dl when controlling for all other variables. These results demonstrate that mild renal failure is an independent risk factor for adverse outcome after CABG.

Behavioural deficits during the acute phase of mild renal failure in mice.

Partially nephrectomized (NX) and sham-operated mice were biochemically and behaviourally compared, 10 days, 1 month and 1 year post-surgery. Plasma urea and creatinine concentrations were mildly increased in all NX groups, but creatinine clearance was significantly decreased, 10 days post-surgery only. NX mice showed lower body weights and reduced growth. Wire suspension and rotarod indicated unaffected motor functions, but NX mice did show reduced ambulation and swimming velocity, 10 days post-surgery. Hidden-platform water maze indicated a spatial learning impairment in NX mice, 10 days post-surgery, which could not be entirely reduced to motor incapacity. The acute behavioural deficits in these mildly uremic mice may relate to analogous symptoms in uraemic encephalopathy, a poorly understood brain syndrome occurring in uraemic patients.

Direct effect of phosphate on parathyroid function.

Patients with chronic renal failure develop secondary [18,19]. These findings are further evidence of the hyperparathyroidism (HPT-2). Decreased calcitriol important role of phosphorus in HPT-2 which, in endproduction, hypocalcaemia and phosphate retention stage renal disease, may not be overcome by the are the main pathogenic factors involved in the develadministration of calcitriol. opment of HPT-2 in these patients. Hernandez et al. [20] have analysed the changes in The accumulation of phosphate favours HPT-2 serum PTH and PTH mRNA in rats after a meal with through indirect and direct mechanisms [1]. High a high phosphorus content. The serum PTH increased phosphate inhibits calcitriol production [2–5] which in after the high phosphorus meal with a peak at 8 h and turn causes hypocalcaemia; furthermore uraemia may serum calcium and calcitriol remained unchanged. The directly affect the function of calcitriol and parathyroid increase in serum PTH was associated with an increase (PTH ) receptors [6,7]. High phosphate also impairs in the PTH mRNA. In a different study the same the calcaemic action of PTH [8,9] which is another authors showed that the high phosphate meal did not cause of hypocalcaemia in renal patients. change the parathyroid cell calcium receptor mRNA Recent studies in animals and patients have con[21]. These results demonstrate that an oral phosfirmed the beneficial effect of dietary phosphorus phorus load can directly stimulate the synthesis of restriction for the control of HPT-2. Furthermore PTH. animal experiments and clinical observations have sugRecent in vitro studies at this hospital and by others gested that high phosphate may have a direct effect on have demonstrated that high phosphate in the medium parathyroid glands. These studies demonstrate that stimulates PTH secretion and synthesis [22–24]. dietary phosphorus modulates serum PTH independent Interestingly, the in vitro effect of phosphate on PTH of the severity of renal failure and this effect is observed secretion is observed in parathyroid tissue preparations even with no changes in serum calcitriol. In rats with and not in dispersed parathyroid cells. This suggests surgically induced renal failure, a high phosphorus diet that in order to prove the effect of phosphate, cell to induces severe HPT-2 compared with a moderate phoscell contact or cell to cell communication may be phorus diet [10]. Lopez-Hilker et al. [11] showed that required. Another possibility is that in isolated parareduction of dietary phosphorus reduced PTH indethyroid cells, the phosphate sensing mechanism is pendently of calcium and calcitriol, suggesting that damaged. control of HPT-2 was a direct effect of the decrease in Using intact rat parathyroid glands incubated with serum phosphorus. In different studies by Bover et al. 1.25 mM calcium and 1, 2, 3, and 4 mM phosphate, [12] and by Yi et al. [13] restriction of dietary phoswe observed that with phosphate concentrations of 3 phorus prevented HPT-2. In patients with moderate and 4 mM, the PTH concentration in the medium was renal failure, the serum PTH directly correlated with increased twoand threefold respectively when comserum phosphorus in patients with mild renal failure pared with 1 or 2 mM phosphate (Figure 1); the suggesting a predominant effect of phosphorus on stimulatory effect of phosphate on PTH secretion was HPT-2 [14]. Furthermore, reduction of dietary phosmaintained despite high calcium in the medium; similar phorus has been shown to be highly effective in reduresults were obtained in bovine parathyroid tissue [24]. cing PTH [15–17]. Although reduction of dietary The effect of phosphate was also tested in human phosphorus is effective in the control of HPT-2, poor parathyroid tissue in vitro [25]. The study includes nutrition as a consequence of protein restriction must parathyroid glands obtained from patients with primnot be allowed. ary adenomas and from haemodialysis and kidney Past and recent reports on calcitriol treatment of transplant patients with diffuse and nodular secondary HPT-2 have shown that the PTH response to calcitriol hyperplasia. The decrease in PTH secretion induced treatment is poor when serum phosphorus is high by high extracellular calcium was less in adenomas than in secondary hyperplasia and nodular hyperplasia Correspondence and offprint requests to: M. Rodriguez, Servicio de was less responsive than diffuse hyperplasia. In diffuse Nefrologia, Unidad de Investigacion, Hospital Reina Sofia, Cordoba, Spain. hyperplasia, high extracellular phosphate (3 and

Mirtazapine oral single dose kinetics in patients with different degrees of renal failure

To investigate pharmacokinetic parameters, as well as safety of mirtazapine in patients with renal failure, an open-labelled, single oral dose study was performed in normal healthy controls and in patients with mild, moderate and severe renal failure, as distinguished by glomerular filtration rates (GRFs) of Cr-EDTA (values corrected per 1·73 m2 body surface area). Each group comprised of 10 volunteers (5 males and 5 females). The results show that after a single oral morning dose of 15 mg of mirtazapine, the area under the curve (AUC) for the plasma concentration of this racemic compound was increased in patients with moderate (GFR 22±6 ml/min) and severe (GFR 2±5 ml/min) renal failure compared to controls. The AUCs were, however, unaffected by mild renal failure (GFRs 61±14 ml/min). The oral clearance was found to be lower in patients with moderate or severe renal failure, as well as in females compared to males irrespective of degree of renal failure. The magnitude of renal failure was found not to influence the elimination half-life of mirtazapine (overall mean±SD=36·3±8·1 h). The adverse experiences (AEs) were reported with similar incidences in all groups, and described as being mild or moderate in nature. The most commonly reported AEs were somnolence and tiredness occurring in one half and one third of the subjects, respectively. The single morning 15 mg/day dose of mirtazapine was well tolerated by patients with renal failure, irrespective of degree of severity. Further research is needed to evaluate repeated dose pharmacokinetics and tolerability of mirtazapine in patients with renal failure. An additional option to optimize treatment of an individual, medically compromised patient is to apply Therapeutic Drug Monitoring (TDM) routines for dose adjustments. Such a pharmacokinetic postmarketing surveillance program is currently under development for mirtazapine. © 1998 John Wiley & Sons, Ltd.

The Relation between the Ultrafiltrable Calcium Fraction and Blood pH and Concentrations of Total Plasma Calcium, Albumin, and Globulin

With the advent of various micropartition systems, typically as developed by Amicon, it became simple to ultrafilter serum and to obtain an apparent measure of the ultrafiltrable calcium fraction (UFCa). In studies of this type, evidence of strict monitoring of serum pH, known to affect calcium binding, was not generally reported (1)(2)(3)(4). An earlier study (5), attempted to control temperature and P co2, but in our hands the study was difficult to reproduce (unpublished). We have determined the UFCa values of 54 samples of whole blood at 37 °C at or near physiologic pH and sought an empirical relationship with more readily measured biochemical variables, which might enable us to predict UFCa from routine laboratory results. We were particularly interested in data in mild renal failure. Although any aqueous solution is subject to control by the Henderson-Hasselbach relation, the relatively low p K (6.1) means that the buffering capacity near pH 7.4 is poor. Furthermore, modest changes in the P co2 have a minor effect on the HCO3 concentration, for a marked effect on the pH. We found that the buffering capacity of whole blood allowed confidence in our procedure because the pH remained stable during handling. The Millipore® UFU 4 system allowed lateral filtration without the erythrocytes obstructing the membrane such that an ultrafiltrate of whole blood could be obtained. We used Millipore UFU 4 10KNML systems, shortened to 20 mm by cutting off part of the upper reservoir. Initially, we loaded 1 mL of plasma, but in our final work, we used 1 mL of heparinized venous blood. In pilot experiments, we took 1-mL aliquots of a pooled serum sample (five specimens) and altered the pH by adding 0.1 mol/L HCl or 0.1 mol/L NaOH. The volumes added …

Assessing renal function from creatinine measurements in adults with chronic renal failure

Measurement of glomerular filtration rate (GFR) following the injection of one of several suitable marker substances remains the best method to determine the severity of renal insufficiency as well as its rate of progression. However, the expense of these procedures continues to restrict their use. A second alternative is the determination of creatinine clearance (CCr) after oral administration of cimetidine. This drug blocks tubular secretion of creatinine almost completely, and CCr measured under these conditions is reported to be nearly identical to GFR in mild or severe renal failure. The optimal dose and timing of cimetidine for this purpose is still uncertain, but a single 1,200-mg dose 2 hours before beginning urine collection is probably suitable. A third alternative is simply the measurement of serum or plasma creatinine (PCr) concentration. However, it is well established that substantial reductions in renal function may occur before PCr becomes abnormal. GFR in adults with chronic renal failure can be approximately estimated from PCr, provided it is greater than 2 mg/dL, with the aid of additional demographic and biochemical variables. Gender, height, weight, age, and race should be taken into account. Further study is needed to derive the best formula for predicting GFR from PCr and other variables. Finally, CCr (without cimetidine) is still in use. This is unfortunate because it has been established that rather than improving on the estimation of GFR from PCr, CCr (determined from urinary creatinine measurements as well as PCr) is a less reliable guide to GFR than PCr alone. The CCr/GFR ratio is almost always greater than unity and increases with decreasing GFR to a maximum of approximately 1.7 at a GFR of approximately 20 mL/min. Furthermore, the variability of CCr is greater than that of PCr. Measurement of CCr (without cimetidine) is an anachronism and should be abandoned. (Am J Kidney Dis 1998 Jul;32(1):23-31)

Low Nitric Oxide Production in Patients with Chronic Renal Failure

Background: Rats with chronic renal failure have a low nitric oxide (NO) production and a diminished NO excretion. The supplementation of L-arginine has an inhibitory effect on the progression of renal insufficiency. Methods: The present study was designed to determine whether chronic renal failure patients have a low NO production. Plasma and urine nitrate (NO₃) and nitrite (NO₂), stable metabolites of NO, were measured in 83 consecutive patients with chronic renal failure. The 83 chronic renal failure patients were divided into three groups: group 1, mild renal failure (creatinine clearance >60 ml/min/1.73 m²); group 2, moderate renal failure (creatinine clearance >30 <60 ml/min/1.73 m²), and group 3, severe renal failure (creatinine clearance <30 ml/min/1.73 m²). Thirty-three healthy volunteers served as controls. Results: The daily urinary NO excretion was significantly lower in patients with moderate and severe renal failure as compared with those with mild renal failure and normal controls. The lowest values were found in the severe renal failure group. When the 24-hour urinary NO excretion or NO per milligram creatinine and the NO clearance were correlated with the renal function in all patients as a group, these parameters were directly correlated with the creatinine clearance and inversely correlated with the serum creatinine level. The plasma NO concentration was not different between the three chronic renal failure groups, but higher than in the controls. Plasma NO in renal failure patients was not correlated with the creatinine clearance or serum creatinine levels. Conclusions: Chronic renal failure is a state of NO deficiency. Treatment strategies to increase NO production (L-arginine supplementation or other NO compounds) may prove to be useful in maintaining the renal function and slow the progression of renal disease.

Sodium-dependent [formula omitted] exchange in patients with chronic renal failure: Correlation with renal function

To investigate the effects of uremia on cellular function the activity of the sodium-dependent chloride-bicarbonate exchanger (sodium-dependent Cl-/HCO3- exchanger) and the sodium-independent chloride-bicarbonate exchanger (sodium-independent Cl-/HCO3- exchanger) were examined in lymphocytes from 25 patients with mild chronic renal failure, 9 patients with end-stage chronic renal failure on regular hemodialysis, and from 25 age-matched healthy control subjects. Cytosolic pH (pHi) and the activity of the sodium-dependent Cl-/HCO3- exchanger and the sodium-independent Cl-/HCO3- exchanger were measured spectrophotometrically using the pH-sensitive fluorescent dye 2'7'-bis-carboxyethyl-5 [6]-carboxyfluorescein acetoxy-methylester (BCECF-AM). The activation of the sodium-dependent Cl-/HCO3- exchanger by removal of extracellular chloride was prevented in the presence of 500 micromol/liter 4,4' diisothiocyanostilbene-2,2'-disulfonic acid (DIDS) or in the absence of extracellular sodium, but was not affected by the specific inhibitor of the sodium/proton exchanger, ethyl isopropyl amiloride (EIPA). The sodium-dependent Cl-/HCO3- exchangers were significantly different in lymphocytes from healthy control subjects, patients with mild chronic renal failure, and patients with end-stage chronic renal failure (X2 = 6.43, P = 0.040 by Kruskal-Wallis-test). The sodium-dependent Cl-/HCO3- exchanger was significantly lower in patients with end-stage chronic renal failure compared to patients with mild chronic renal failure or compared to healthy control subjects (each P < 0.05). In patients with chronic renal failure a significantly negative correlation between sodium-dependent Cl-/HCO3- exchanger and the serum creatinine concentration (r = -0.507; P = 0.0022) could be observed. On the other hand, resting pHi in lymphocytes and sodium-independent Cl-/HCO3- exchanger were not significantly different in lymphocytes from healthy control subjects, patients with mild chronic renal failure or patients with end-stage chronic renal failure. The present study suggests that the activity of the sodium-dependent Cl-/HCO3- exchanger is progressively impaired in chronic renal failure.

Ischemic nephropathy: an important cause of renal disease in the elderly.

RAOD is an important cause of progressive renal failure in the elderly population. We can expect to see an increasing incidence of this disease as the population ages. A non-invasive test for detecting this condition with a high degree of sensitivity and specificity has been developed, although the technique is sufficiently difficult that it is currently available in only a few specialized centers. Indications for intervention to preserve renal function are not clear. Application of stenting to renal artery lesions has lead some to advocate treatment of these lesions empirically when they are detected much as is done with coronary artery lesions in patients with ischemic heart disease. Given the present state of knowledge, this is not an unreasonable approach. However, not all lesions progress and their role in causing renal failure is not clear in all cases. Furthermore, intervention can cause worsening of renal failure in some cases and actually precipitate the need for dialysis. Several recommendations are reasonable based on this review. Patients over 50 starting dialysis with renal failure of unknown etiology should be screened for RAOD. Those with bilateral lesions should be offered an intervention. Patients with mild or moderate renal failure of unknown etiology over age 50 should also be screened. Those with bilateral lesions should be offered an intervention with conservative management for those with unilateral lesions. The later group should be monitored on a yearly basis for the development of contralateral lesions or significant bilateral renal atrophy. If either of these eventualities develop, intervention should be offered. These recommendations would have to be considered in the light of the possible need to perform an intervention for the treatment of hypertension.

Determination of Antipyrine and Metabolites in Plasma of a Patient With Mild Renal Failure

A method has been developed for the simultaneous determination of antipyrine and its three major metabolites in plasma of patients with renal failure. Plasma samples (500 microl) were hydrolyzed with beta-glucuronidase/aryl sulphatase. The compounds, after addition of sodium chloride, were extracted with chloroform:ethanol (90:10, v/v) in acidic medium. Chromatographic conditions comprise a C18 column, a mobile phase with 30% methanol and 70% 0.25N sodium acetate buffer (pH 5.0), a total run time of 10 minutes, and ultraviolet absorbance detection at 254 nm. Confidence limits showed 0.5 to 40.0 microg/ml(-1) linearity (r2 = 0.999); 0.1 microg/ml(-1) HMA, 0.05 microg/ml(-1) antipyrine and NORA, and 0.5 microg/ml(-1) OHA sensitivity and absolute recovery >95%. Interprecision and intraprecision expressed as coefficient of variation were <10% for all compounds investigated. The assay shows to be suitable for pharmacokinetics and drug metabolism studies after administration of a single oral dose of 500 mg of antipyrine to a patient with hypertension and chronic renal failure (CL(CR) = 34.17 ml/min(-1); 1.73 m(-2)).

Thin GBM nephropathy: Premature glomerular obsolescence is associated with hypertension and late onset renal failure

Thin glomerular basement membrane (GBM) nephropathy, also called familial benign hematuria, is characterized by chronic hematuria and uniform thinning of the lamina densa of the glomerular basement membrane. It generally holds an excellent renal prognosis. Alport syndrome in early stages can also show attenuation of the GBM; conversely, renal insufficiency has been reported in familial benign hematuria. To discern early Alport syndrome from thin GBM nephropathy, we carried out a prospective epidemiological study in which 19 normotensive and non-azotemic adult patients with chronic microscopic (18 of 19) and macroscopic (1 of 19) hematuria and biopsy-proven thin GBM nephropathy were followed for a median of 12 years (range 9 to 15 years). Renal biopsies of thin GBM patients at entry showed an increased incidence of focal global glomerulosclerosis when compared to disease controls as IgA nephropathy (P = 0.047) and normal renal tissue (P = 0.0075). All renal biopsies showed the presence of the Goodpasture antigen when tested immunohistochemically. Presence of Alport syndrome was excluded clinically as none of the patients had complaints of hearing loss or abnormalities by audiography and ophthalmology. At the end of follow-up, the incidence of hypertension in thin GBM nephropathy (35%) exceeded that of healthy clinical controls (P = 0.048), and one hypertensive patient developed mild renal failure. In the normotensive patients, the glomerular filtration rate at follow-up as measured by inulin clearance was reduced in three out of seven; these were over 50 years of age. Although no family members were known to have renal disease at inclusion, within four families six elderly first degree relatives had developed unexplained renal insufficiency at the end of follow-up. Thus, thin GBM nephropathy predisposes to premature glomerular obsolescence, leading in time to increased incidences of hypertension and late onset renal insufficiency.

Secondary hyperparathyroidism and vitamin D receptor binding to vitamin D response elements in rats with incipient renal failure.

The pathogenesis of secondary hyperparathyroidism in early renal failure is poorly understood. In the study presented here, parathyroid hormone and GFR in rats with mild renal failure of various durations are evaluated. Parathyroid hormone increased significantly 3 days after nephrectomy and peaked at 2 wk, despite reduction in GFR of < 50%. Parathyroid hormone remained elevated, but there was no difference in serum levels of calcium, phosphorus, and calcitriol between the nephrectomized and sham-operated rats. There were also no differences in both intestinal and kidney vitamin D receptor concentrations between the two groups. Histomorphometric analysis of bone at 6 wk revealed significant increase in osteoid thickness, osteoblast number, erosion surface with osteoclasts, and erosion depth. Employing electrophoretic mobility shift assay, we consistently observed a significant reduction in kidney calcitriol-receptor complex binding to mouse osteopontin vitamin D response element (-70.2 +/- 4.9%, P < 0.001). Western blot analysis also revealed a significant reduction in at least one retinoid X receptor isoform. In conclusion, biochemical and histological evidence of secondary hyperparathyroidism develops in rats with mild renal failure, despite normal calcium, phosphorus, calcitriol, and vitamin D receptor concentrations. These rats also have evidence of reduced renal vitamin D receptor binding to nuclear response elements. This finding, possibly an important early factor in the pathogenesis of secondary hyperparathyroidism, could also play a role in the development of compensatory renal growth of the remnant kidney.

Emergency Treatment of Lithium-Induced Diabetes Insipidus with Nonsteroidal Anti-Inflammatory Drugs

Thiazides and amiloride are the most often suggested treatment for nephrogenic diabetic insipidus. We found this ineffectual in a patient with acute problems and reviewed the literature to see if there were other more efficient approaches. A 47-year-old woman on lithium had polyuria. When inadvertently fasted for 48 h she became confused, had a seizure, and her sodium was 170 mmol/L. Urinary output was 24 L/day. Large volumes of intravenous fluids were given but sodium remained >170 mmol/L. Treatment with DDAVP, thiazides, and amiloride did not decrease urinary output. Indomethacin 150 mg was started and urine volume immediately fell to one-half. However, because of persistent high urine output the patient was then fluid depleted, with further reduction to normal in urine volume, and Na decreased to 140 mmol/L. Creatinine rose from 135 μmol/L to 173 μmol/L, but decreased to 152 μmol/L when indomethacin was decreased to 75 mg q.d.; urinary output remained stable around 2 L/day. The literature described 22 patients with nephrogenic diabetes insipidus (16 congenital, 6 lithium) treated with nonsteroidal anti-inflammatory drugs. Urine flow was reduced to 1/3, within hours. Rarely, mild renal failure ensued, improving in all but one case when nonsteroidal anti-inflammatory drugs were reduced. Indomethacin (and controlled volume reduction if continued high urine output), while observing renal function, appears the emergency treatment of choice for serious complications of nephrogenic diabetes insipidus.

Role of intravenous cyclophosphamide in lupus nephritis patients with renal impairment

Summary: Twenty‐three patients with lupus nephritis (21 diffuse proliferative glomerulonephritis and two with focal proliferative glomerulonephritis) with impaired renal functions were evaluated for their response to pulse cyclophosphamide. Diagnosis of lupus nephritis was based on American rheumatism association criteria or on the basis of renal manifestations with high anti dsDNA antibody titres. Cyclophosphamide was given in dosage of 900mg/m2 as infusion in 500 mL of 5% dextrose (reduced by 25% if serum creatinine was more than 6 mg/dL) once every month for 6 months then 3 monthly for a minimum of 3 years. Response was defined by 24h protein excretion less than 500mg and serum creatinine less than 1.4mg/dL. Nine patients (group I) had normal function (serum creatinine 1.16 ± 0.21mg/dL) and 14 patients (group II) had impaired renal function at presentation (serum creatinine 3.72 ± 4.06 mg/dL). Both groups were compared for response to therapy. All patients in group I were in complete remission at last follow up of 44.6 ± 8.3 months (serum creatinine 1.14 ± 0.2mg/dL, 24h proteinuria 0.3 ± 0.3g). While in group 2, 13 patients showed improvement. Two patients were in complete remission, seven in partial remission, one patient died and four patients had mild renal failure at last follow up of 40.2 ± 10.4 months (serum creatinine 1.81 ± 0.74, 24h proteinuria 2.19 ± 2.54g). the side effects of therapy included infection, transient leucopenia and vomiting. We conclude that intravenous (I.V) cyclophosphamide is an effective therapy in severe lupus nephntis with renal impairment.

Rhabdomyolysis and anesthesia: A report of two cases and review of the literature

Rhabdomyolysis occurred in two apparently healthy boys aged 9.5 and 5.5 years after general anesthesia with suxamethonium. Mild hyperkalemia and renal failure were observed in the first patient, who was subsequently diagnosed with Becker dystrophy. In the second patient, the clinical presentation was not classic for malignant hyperthermia and a muscle biopsy failed to disclose any pathological finding. A review of the literature revealed 66 pediatric cases (56 boys and 10 girls) of anesthesia-associated rhabdomyolysis. Fortynine (74 %) cases were caused by an underlying, mostly unrecognized congenital muscle disease, and 14 (21%) cases were caused by malignant hyperthermia susceptibility. Hyperkalemia (23 patients), cardiac arrhythmias (38 patients), renal failure (4 patients), and death (11 patients) were the most serious complications of anesthesia-associated rhabdomyolysis. The neuromuscular blocking agent suxamethonium had been used in at least 43 of the patients reported in the literature.

24R, 25‐Dihydroxyvitamin D3 ameliorates the high‐turnover bone diseases without suppressing parathyroid function in chronic renal failure in rats

Summary: To evaluate the effect of 24R,25‐dihydroxyvitamin D3 (24,25D) on uraemic bone disease, we treated the model rats of mild renal failure either with 0.5 μg/kg bodyweight (BW) of 24,25D, or with 5 μg/kg BW of 24,25D, or with 0.01 μg/kg BW of 1,25‐dihydroxyvitamin D3 (1,25D), or with 0.01 μg/kg BW of 1,25D and 0.5 μg/kg BW of 24,25D, or with vehicle alone, given orally for 16 weeks. the examination of bone histology revealed extreme acceleration of bone turnover and decreased trabecular bone volume with elevated serum parathyroid hormone (PTH) level in vehicle‐treated uraemic rats compared with those of sham‐operated rats. Treatment with 24,25D (5 μg/kg BW) not only ameliorated high‐turnover bone disease as with 1,25D, but also prevented the reduction of trabecular bone volume without any changes of serum PTH levels, suggesting the possible direct effect of 24,25D on the bone. Our data suggest 24,25D may be another useful agent for the treatment of high‐turnover bone disease caused by secondary hyperparathyroidism in chronic renal failure, with less suppression of parathyroid function.

Isolation of "myocardial depressant factor(s)" from the ultrafiltrate of heart failure patients with acute renal failure.

Cardiac function improvement seen with hemofiltration may be attributable to "cardiac depressant factor(s)" removal. The authors have attempted "factor" isolation. Initial 12 hr hemofiltrate was obtained from: 4 patients with acute congestive heart failure (cardiac index: 2.02 +/- 0.48) and acute renal failure (blood urea nitrogen [BUN] 97.7 +/- 32.7; serum creatinine [SCr] 6.2 +/- 3.4 mg%) (Group I); 8 patients with chronic congestive heart failure (CI: 2.69 +/- 1.3) and mild renal failure (BUN 48.8 +/- 31.4; SCr 3.5 +/- 2.4 mg%) (Group II); and 8 patients with end-stage renal disease and no congestive heart failure (Group III). Crude samples were passed through C18Sep-Pak, and eluted with methanol/water mixtures, and 50% methanol samples were fractionated by high pressure liquid chromatography. Inotropic response was studied by injecting samples (in Krebs-Hensleit buffer) into a Langendorff rat heart preparation. The effect of pH, acetate, salts, and adding propranolol on the inotropic response also was tested. Myocardial depression followed all vehicle and preparatory elements: 0.1 M HCl (-47%); 0.08 M acetic acid (-75%); Na acetate (-25%); 0.1 M NaHCO3 (-11%); Na citrate (-84%); and Na glutarate (-14%). Group I had biphasic responses, the positive inotropism accorded to catecholamines, whereas negative inotropism was equal in each patient (-40.3%). Group II had a biphasic response with negative (-15%) inotropism noted. Group III was weakly biphasic. The data indicate there was myocardial depressive activity, most pronounced in Groups I and II, after method interference was corrected.

Diclofenac-Induced Rhabdomyolysis

A case is described in which, after administration of diclofenac for 13 days for arthritis attributed to gout, the patient experienced erythema multiforme followed by muscle weakness, elevation of serum creatine phosphokinase (CPK) level from 101 to 83,770 U/L, 100% muscle isoenzyme, blood urea nitrogen (BUN) level from 15 to 87 mg/dL, creatinine level from 1.0 to 2.1 mg/dL and urine myoglobin level to 1,190 micrograms/dL (N < 1.2). The diagnosis was rhabdomyolysis due to diclofenac, with myoglobinuria resulting in mild renal failure. Treatment consisted of discontinuing diclofenac and administering sufficient fluids to prevent progression of myoglobinuric renal failure. Serum CPK level gradually returned to normal by day 50, BUN and creatinine levels by day 28, and muscle strength between day 90 and 180. Rhabdomyolysis due to diclofenac or to other nonsteroidal antiinflammatory drugs has not been reported.