Hypertensive nephrosclerosis: wider kidney biopsy indications may be needed to improve diagnostics.

BACKGROUND: Hypertensive nephrosclerosis is the presumed underlying cause in many end-stage kidney disease (ESKD) patients, but the diagnosis is disputed and based on clinical criteria with low diagnostic accuracy. OBJECTIVE: To evaluate and improve the diagnostic process for nephrosclerosis patients. METHODS: We included adults from the population-based HUNT study (n = 50 552), Norwegian CKD patients referred for kidney biopsy 1988-2012 (n = 7261), and unselected nephrology clinic patients (n = 193) used for matching. Decision tree analysis and ROC curve-based methods of optimal cut-offs were used to improve clinical nephrosclerosis criteria. RESULTS: Nephrosclerosis prevalence was 2.7% in the general population, and eGFR decline and risk for kidney-related hospital admissions and ESKD were comparable to patients with diabetic kidney disease. In the biopsy cohort, current clinical criteria had very low sensitivity (0.13) but high specificity (0.94) for biopsy-verified arterionephrosclerosis. A new optimized diagnostic algorithm based on proteinuria (<0.75 g d-1 ), systolic blood pressure (>155 mm Hg) and age (>75 years) only marginally improved diagnostic accuracy (sensitivity 0.19, specificity 0.96). Likewise, there were still false-positive cases with treatable diagnoses like glomerulonephritis, interstitial nephritis and others (40% of all test positive). Decision curve analysis showed that the new criteria can lead to higher clinical utility, especially for patients considering the potential harms to be close to the potential benefits, while the more risk-tolerant ones (harm:benefit ratio < 1:4) should consider kidney biopsy. CONCLUSION: Further improvements of the current clinical criteria seem difficult, so risks and benefits of kidney biopsy could be more actively discussed with selected patients to reduce misclassification and direct treatment.

Outcome in biopsy-proven Lupus nephritis: Evaluation of biopsies from the Norwegian Kidney Biopsy Registry.

Objective To evaluate long-term mortality and end-stage renal disease (ESRD) in a cohort of Norwegian patients with biopsy-proven lupus nephritis (LN). Methods Renal biopsies were obtained from 178 patients with LN from 1988 until 2007. Mortality rate and death causes were provided by Statistics Norway and ESRD data were provided by the Norwegian Renal Registry. Risk factors for all-cause mortality were evaluated by Cox regression. Standardized mortality ratio (SMR) was compared to observed deaths in a matched general population sample. Results Mean age was 37.6 (±14.4) years, and median time of follow-up was 8.5 years (0-26.2). Thirty-six patients (20.2%) died during follow-up. The SMR for all-cause mortality was 5.6 (Confidence interval [CI] 3.7-7.5). In an adjusted multivariate analysis proliferative glomerulonephritis (LN class IV) was independently associated with all-cause mortality; hazard ratio (HR) 2.6 (Confidence interval [CI] 1.2-5.7 p = 0.017). Main causes of death were infections (47.2%) and cardiovascular events 8 (22.2%). Thirty-six patients (20.2%) reached ESRD. Conclusions Biopsy-proven LN is associated with increased mortality compared to the general population. LN class IV is associated with all-cause mortality. Infections and cardiovascular events were the most common causes of death. Patients with LN have a high incidence of ESRD.

Pharmacokinetics of intraperitoneally instilled aminophylline, terbutaline and tobramycin in pigs.

INTRODUCTION: Venous catheters are sometimes difficult or even impossible to insert and may also be associated with serious complications. This study was carried out to investigate whether intraperitoneal administration of drugs may be an alternative to the intravenous route in patients with limited vascular access. MATERIALS AND METHODS: Three drugs commonly in use in clinical practise, aminophylline, terbutaline and tobramycin, were administered to pigs intravenously and intraperitoneally in small volumes. Serum concentrations were analysed over a period of 6 h and pharmacokinetic key variables for each drug were calculated. RESULTS: Aminophylline (theophylline), terbutaline and tobramycin were absorbed from the peritoneal space and into systemic circulation. For theophylline, the concentration/time profiles after intraperitoneal and after intravenous administration were almost identical, and the intraperitoneal bioavailability was calculated to 0.94. For terbutaline and tobramycin, the intraperitoneal absorption was delayed without any initial peak. Moreover, the intraperitoneal bioavailability was lower than for theophylline (0.71 and 0.65, respectively). CONCLUSION: The pharmacokinetic properties after intraperitoneal administration differed among the three drugs, but the results are encouraging and provide a basis for further investigation in humans.

Intraperitoneal fluid therapy: an alternative to intravenous treatment in a patient with limited vascular access.

We describe a 58-year-old female with Crohn's disease and short bowel syndrome after repeated intestinal resections, with only 90 cm of small intestine left. She had been dependent on vascular access for total parenteral nutrition for 16 years. Due to intravascular complications after numerous long-term central venous catheters, her vascular accessibility became limited. During the course of a year she was fed enterally through a gastrostomy, but required supplementary fluid therapy through peripheral venous route. Because of extremely limited venous access, we decided to implant an intraperitoneal catheter for administration of crystalloid fluid. The first intraperitoneal catheter had to be removed because of a postoperative infection, but after antibiotic treatment, a second intraperitoneal catheter was implanted without complications, through which the patient is now fully provided with crystalloid fluid (Ringer's acetate). Abdominal ultrasound examination shows good absorption of the fluid, and for the first time in 16 years the patient does not need intravascular access. We suggest that intraperitoneal administration of fluid may be an alternative for patients with limited vascular access.

Circulatory responses to hypoglycaemia in diabetic and non-diabetic children.

The purpose of this study was to investigate the circulatory responses to hypoglycaemia in diabetic and non-diabetic children and to determine whether these changes were associated with hormone levels or clinical variables. Plasma glucose levels in 18 diabetic and 15 control children were gradually lowered to 2.5 (0.3) mmol/L (mean (SD)) and 2.9 (0.2) mmol/L, respectively. Blood pressure and heart rate were recorded at 10-min intervals, and blood samples were taken for hormone analysis. Systolic pressure increased from 110.1 (10.0) to 115.0 (11.2) mmHg (p = 0.008) in the diabetic children and from 116.9 (12.0) to 121.6 (12.7) mmHg (p = 0.049) in the controls. Diastolic pressure decreased from 61.9 (6.7) to 55.5 (7.6) mmHg (p < 0.001) in the diabetic children and from 66.5 (6.3) to 55.1 (5.1) mmHg (p < 0.001) in the controls. The increase in pulse pressure during hypoglycaemia was significantly smaller in the diabetic children (10.6 (5.5) vs. 15.7 (7.7) mmHg, p = 0.04). The final systolic and pulse pressure correlated with the final adrenaline level in the controls (r = 0.66, p = 0.008 and r = 0.70, p = 0.003, respectively). In the non-diabetic as well as the diabetic group, the increase in pulse pressure correlated with the increase in adrenaline (r = 0.66, p = 0.008 and r = 0.50, p = 0.03, respectively). It is concluded that systolic pressure increases and diastolic pressure decreases during hypoglycaemia in children. The smaller increase in pulse pressure observed in the diabetic children is probably related to a significantly smaller increase in adrenaline in this group.

Renal histopathology and clinical course in 94 patients with Wegener's granulomatosis.

BACKGROUND: The main purpose of this study was to examine histopathological changes seen in renal biopsies from patients with Wegener's granulomatosis (WG) with varying degrees of renal involvement and to study possible correlations between the morphological variables and the severity of the disease. METHODS: Ninety-four patients with WG and active renal disease were included in this retrospective study. All patients had a percutaneous renal biopsy taken on their first admission to the hospital and 14 patients had a second biopsy. The patients were followed for a median of 42.5 months (range 0.5-184). RESULTS: Segmental necrotizing glomerulonephritis and extracapillary proliferation were present in 85.1 and 91.5% respectively. Of seven patients (7.4%) with normal serum creatinine and urinary protein excretion <0.5 g/day, all had crescents and six had segmental glomerular necrosis. Serum creatinine at biopsy correlated significantly with the percentage of glomeruli with crescents (rho=0.52, P=0.0004), with necrosis (rho=0.36, P=0.002) and with the percentage of normal glomeruli (rho=-0.55, P=0.0003). On a multivariate analysis, only the percentage of normal glomeruli was significantly associated with renal function and development of end-stage renal disease. In 14 second biopsies after a mean of 41.2 (+/-26) months, chronicity scores had increased significantly in 13 biopsies in spite of full immunosuppressive treatment. CONCLUSION: Although renal biopsy is of value in defining renal involvement in WG, it is of limited help in the early stage of the disease in predicting renal outcome for the individual patient. A follow-up biopsy can be useful in revealing the degree of activity and chronicity and hence be of importance for the choice of further therapy.

Wegener's granulomatosis: inflammatory cells and markers of repair and fibrosis in renal biopsies--a clinicopathological study.

OBJECTIVE: This study aimed to quantitate inflammatory cells in renal biopsies from patients with Wegener's granulomatosis (WG) and to identify cells participating in early fibrogenesis. The goal was to determine whether these cells correlated with the severity of renal disease and whether their presence had a bearing on renal prognosis. MATERIAL AND METHODS: Sixty-one patients with WG who had a renal biopsy taken at the time of diagnosis were included in the study. Immunostaining with monoclonal antibodies towards macrophages (CD68), T- and B-lymphocytes, alpha-smooth muscle actin (alpha-SMA) and vimentin was done. RESULTS: The dominating intraglomerular leucocytes were macrophages (29.9 +/- 15 cells/glomerular cross-section) and to a lesser extent T-cells (2.57 +/- 1.8 cells/glomerular cross-section). No B-lymphocytes were detected in the glomeruli. More than two-thirds of the T-cells were CD8+ (cytotoxic) cells. Macrophages and T-lymphocytes were distributed equally in the renal interstitium and were numerous around crescentic glomeruli. Glomerular and interstitial macrophages and interstitial T-cells correlated significantly with serum (S-) creatinine at the time of biopsy but not after 1 year. S-creatinine at the time of biopsy and after 1 year differed significantly among the three levels of interstitial alpha-SMA staining. S-creatinine at biopsy was highest when tubular vimentin staining was strongest, and tubular vimentin staining was strongest in patients with acute tubular damage. CONCLUSIONS: Evidence was found for a cellular type IV immune response in WG, with CD8+ T-lymphocytes and macrophages dominating the cellular infiltrate. The detection of interstitial alpha-SMA, probably staining myofibroblasts implicated in renal fibrogenesis, indicated a low glomerular filtration rate 1 year after renal biopsy.

Single- and multiple-dose pharmacokinetics, kidney tolerability and plasma protein binding of tenoxicam in renally impaired patients and healthy volunteers.

The 20 mg single-dose and 12 days repeated-dose pharmacokinetics of tenoxicam and the 5-OH-tenoxicam metabolite have been evaluated in healthy volunteers and two groups of patients with different degree of renal impairment, in total 20 persons. Concomitantly, the plasma protein binding of tenoxicam and the effects of treatment on renal function were evaluated. No differences were found between the investigated groups in the pharmacokinetics of total tenoxicam and the 5-OH metabolite did not interfere either with the pharmacokinetics or with the plasma protein binding of tenoxicam. A positive correlation was found between an increase in the free fraction (% F) of tenoxicam in plasma and a decrease in the plasma elimination half-life in the low creatinine clearance group (40-20 ml/min.) both after the single-dose and at steady-state. At steady-state, a non-linear correlation was demonstrated between a decrease in the urinary excretion of the 5-OH metabolite and a decrease in creatinine clearance from 130 to 20 ml/min. An increase in the plasma level of the 5-OH metabolite by three times was found in the low creatinine clearance group as compared to healthy subjects. 14C-Impurities of tenoxicam, as low as 1.2%, were shown to greatly influence the determination of the plasma protein binding (equilibrium dialysis) of the highly protein-bound tenoxicam due to a non-binding ability of the impurities to plasma proteins. No significant changes in renal parameters were found during the study. It can be concluded that the pharmacokinetics and plasma protein binding of tenoxicam and the pharmacokinetics of the 5-OH-tenoxicam metabolite are increasingly changed in subjects with a creatinine clearance below 40 ml/min. A decreased binding of tenoxicam to plasma proteins in low clearance patients is probably the reason for a faster elimination of tenoxicam in this group rather than a higher intrinsic hepatic metabolic activity. This study conducted in a low number of patients did not bring forward any new data indicating any adverse effects of tenoxicam on renal function.

Wegener's granulomatosis: clinical course in 108 patients with renal involvement.

BACKGROUND: The aim of this study was to evaluate the clinical course of patients with Wegener's granulomatosis and renal involvement, with special reference to relapse rate, renal and patient survival and morbidity from serious infections. METHODS: A retrospective analysis was carried out of 108 patients presenting with Wegener's granulomatosis and active renal disease in eight hospitals in Norway between 1988 and 1998. Multivariate analysis was used to investigate whether selected variables predicted relapse, renal and patient survival and serious infections. RESULTS: Median follow-up was 41.5 months. Twenty-two patients (20.4%) were admitted with a need for dialysis. Complete remission was obtained in 81.5% after a median of 4 months, and 54.7% relapsed after a median of 22. 5 months. Two- and five-year renal survival was 86 and 75%, respectively, and 22.8% developed end-stage renal disease (ESRD). Two- and five-year patient survival was 88 and 74%, respectively, and the cumulative mortality was 3.8 times higher than expected. The relative risk of relapse increased with the use of intravenous pulse cyclophosphamide compared with daily oral cyclophosphamide. Initial renal function predicted renal survival, and low serum albumin and high age at treatment start increased the mortality risk. Thirty one per cent of the patients were hospitalized for serious infections during follow-up. Old age increased the risk of having an infection. CONCLUSIONS: The current treatment of Wegener's granulomatosis does not prevent relapse, development of ESRD and serious treatment-induced infections in a considerable fraction of the patients. Alternative strategies for the management of this disease will be an important objective for further studies.

Renal involvement in primary Sjögren's syndrome.

Renal involvement was evaluated in 62 patients with primary Sjögren's syndrome, classified according to criteria proposed by The European Classification Criteria Group. Urine concentration capacity was tested using intranasal 1-desamino-8-D-arginine-vasopressin. For patients with urine pH>5.5 without metabolic acidosis (n=28), an acidification test with ammonium chloride was performed. Urinary citrate, albumin, NAG, ALP and beta2-microglobulin were measured and creatinine clearance was calculated. Maximum urine concentration capacity and creatinine clearance were reduced in 13 (21%). Albumin excretion was >30 microg/min in only one patient (1.6%). Seven patients (11.3%) had complete or incomplete distal renal tubular acidosis (dRTA), four had reduced creatinine clearance and five had reduced maximum urine concentration capacity. The ratio of citrate/creatinine in spot urine was below the 2.5 percentile in all patients with complete or incomplete dRTA. The prevalence of dRTA was lower than in previous studies. There were also few patients with signs of glomerular disease (1.6%). The use of citrate:creatinine ratio in spot urine can be a helpful method in identifying patients with complete or incomplete dRTA.

A comparison of solute clearance and ultrafiltration volume in peritoneal dialysis with total or fractional (50%) intraperitoneal volume exchange with the same dialysate flow rate.

BACKGROUND: The most efficient way to perform automated peritoneal dialysis (APD) has not yet been defined. Tidal peritoneal dialysis (TPD) has been claimed to be more efficient than traditional intermittent peritoneal dialysis (IPD), but few comparative studies have been done keeping dialysate flow the same in the two treatment techniques. METHODS: Six patients were treated with 10, 14 and 24 litres total dialysis fluid volume during 9 h (flow rate 18.5, 25.9 and 44.4 ml/min), receiving the treatments both as IPD and TPD. Glucose concentration in the fluid was held constant during all treatments. Transperitoneal clearances (ml/min) for urea, creatinine and uric acid and ultrafiltration volume was calculated, and comparisons made between TPD and IPD. The total intraperitoneal dwell time was calculated for each treatment session. A peritoneal equilibration test was also done for each patient. RESULTS: The ratio of the creatinine concentration in dialysate to the concentration in plasma at 4 h obtained with the peritoneal equilibration test (PET) averaged 0.77 (range 0.69-0.82). Urea clearance was higher for IPD than for TPD with 10 litres: 14.3 +/- 2.4 and 13.3 +/- 2.7 (P = 0.0092). For 14 and 24 litres urea clearance for IPD and TPD was 16.9 +/- 2.3 and 15.9 +/- 3.5 (n.s.) and 20.9 +/- 3.6 and 19.9 +/- 5.6 (n.s.) respectively. Creatinine clearance was higher for IPD than for TPD with 10 litres: 9.6 +/- 1.3 and 8.9 +/- 1.3 (P = 0.0002). For 14 and 24 litres creatinine clearance for IPD and TPD was 11.0 +/- 0.7 and 9.9 +/- 2.0 (n.s.) and 12.3 +/- 1.2 and 12.4 +/- 2.2 (n.s.) respectively. Uric acid clearance was higher for IPD than for TPD with 10 litres: 8.4 +/- 1.3 and 7.7 +/- 1.0 (P = 0.0054). For 14 and 24 litres uric acid clearance for IPD and TPD was 9.3 +/- 1.7 and 8.9 +/- 2.2 (n.s.) and 11.3 +/- 2.9 and 10.6 +/- 2.6 (n.s.) respectively. IPD gave significantly higher ultrafiltration volume (ml) than IPD for both 10 and 14 litres: 944 +/- 278 and 783 +/- 200 (P = 0.0313) and 1147 +/- 202 and 937 +/- 211 (P = 0.0478). For 24 litres there was no significant difference between IPD and TPD: 1220 +/- 224 and 1253 +/- 256. CONCLUSION: With the lowest dialysate flow rate (18.5 ml/min), solute clearance and ultrafiltration volume was higher on IPD than on TPD. With the intermediate flow rate (25.9 ml/min) the ultrafiltration volume was higher on IPD, but no difference was found for solute clearance. With the highest flow rate (44.4 ml/min) there was no difference neither for ultrafiltration nor for solute clearances.

[Diagnosis and treatment of high blood pressure. How to invest?]. / Diagnostikk og behandling av høyt blodtrykk. Hvordan investere?

High blood pressure is a major risk factor for development of cardiovascular diseases. During 1992 and 1993, several national consensus reports about treatment of arterial hypertension have been published. There are discrepancies between the recommendations contained in the reports, which has caused uncertainty among physicians. We discuss the basic problems connected to evaluation and recommendation, and the demand for standardization and organization of the health service programme for patients with high blood pressure. It is possible to learn from, and thereby achieve better quality of medical practice, through a continuous registration of our routines and results. The Trondheim model is designed to depict specific information from the primary health services in a follow-up programme. This information is sampled in a data base from which primary physicians can obtain feedback on statistical evaluations twice a year. This is defined as a quality assurance programme to secure and improve the quality of the medical service to patients with high blood pressure.

[Chloroquine poisoning]. / Klorokinforgiftning.

Chloroquine poisoning has profound effects, chiefly on contractility and conduction of the heart. No treatment has been proven effective, and most cases of serious poisoning are fatal. We describe one case of chloroquine poisoning and discuss its treatment.

[Hypercalcemia in malignant diseases. Physiopathology and treatment]. / Hyperkalsemi ved maligne sykdommer. Patofysiologi og behandling.

About 10% of cancer patients develop hypercalcemia. The mechanisms behind the development of hypercalcemia are complex, but the most important facts seems to be increased osteoclastic bone resorption. Several cellular mediators play a part in creating and sustaining hypercalcemia. The article discusses these mechanisms, and reviews the principles of treatment. Emphasis is placed on rehydration and on inhibition of bone resorption. The use of diphosphonates (bisphosphonates), a group of potent osteoclast inhibitors, is discussed in some detail.