Acute renal failure from complete uterine prolapse: role of polycystic kidney disease.

A 48-year-old female developed acute renal failure from obstruction caused by a complete uterine prolapse. She had polycystic kidney disease (ADPKD) with previously stable mild renal impairment. She presented with rapidly declining renal function and oliguria which reversed following manual reduction of the prolapse and insertion of a ring pessary. None of the usual risk factors for uterine prolapse were present, however ADPKD may have contributed to the prolapse. Rapid deterioration of renal function in female patients with ADPKD should prompt gynecological examination to exclude a uterine prolapse as a cause.

Renal tubular peptide catabolism in chronic vascular rejection.

Chronic vascular rejection (CR) is the commonest cause of renal transplant loss, with few clues to etiology, but proteinuria is a common feature. In diseased native kidneys, proteinuria and progression to failure are linked. We proposed a pathogenic role for this excess protein at a tubular level in kidney diseases of dissimilar origin. We demonstrated in both nephrotic patients with normal function and in those with failing kidneys increased renal tubular catabolism and turnover rates of a peptide marker, Aprotinin (Apr), linked to increased ammonia excretion and tubular injury. These potentially injurious processes were suppressed by reducing proteinuria with Lisinopril. Do similar mechanisms of renal injury and such a linkage also occur in proteinuric transplanted patients with CR, and if so, is Lisinopril then of beneficial value? We now examine these aspects in 11 patients with moderate/severe renal impairment (51CrEDTA clearance 26.2+/-3.3 mL/min/1.73 m2), proteinuria (6.1+/-1.5 g/24 h) and biopsy proven CR. Lisinopril (10-40 mg) was given daily for 2 months in 7 patients. Four others were given oral sodium bicarbonate (Na HCO3) for 2 months before adding Lisinopril. Renal tubular catabolism of intravenous 99mTc-Apr (Apr* 0.5 mg, 80MBq), was measured before and after Lisinopril by gamma-ray renal imaging and urinary radioactivity of the free radiolabel over 26 h. Fractional degradation was calculated from these data. Total 24 h urinary N-acetyl-beta-glucoaminidase (NAG) and ammonia excretion in fresh timed urine collections were also measured every two weeks from two months before treatment. After Lisinopril proteinuria fell significantly (from 7.8+/-2.2 to 3.4+/-1.9 g/24 h, p<0.05). This was associated with a reduction in metabolism of Apr* over 26 h (from 0.5+/-0.05 to 0.3+/-0.005% dose/h, p < 0.02), and in fractional degradation (from 0.04+/-0.009 to 0.02+/-0.005/h, p<0.01). Urinary ammonia fell, but surprisingly not significantly and this was explained by the increased clinical acidosis after Lisinopril, (plasma bicarbonate fell from 19.1+/-0.7 to 17.4+/-0.8 mmol/L, p < 0.01), an original observation. Total urinary NAG did fall significantly from a median of 2108 (range 1044-3816) to 1008 (76-2147) micromol/L, p < 0.05. There was no significant change in blood pressure or in measurements of glomerular hemodynamics. In the 4 patients who were given Na HCO3 before adding Lisinopril, both acidosis (and hyperkalemia) were reversed and neither recurred after adding Lisinopril. These observations in proteinuric transplanted patients after Lisinopril treatment have not been previously described.

Pregnancy does not adversely affect renal transplant function.

Women with functioning transplanted kidneys often become fertile again. Indeed, renal function, endocrine status and libido rapidly improve after renal transplantation, and 1:50 women of childbearing age become pregnant. However, there is concern regarding the haemodynamic changes of pregnancy, which could lead to a decline in graft function (temporary or permanent). We examined obstetric data and renal parameters in 29 patients and 33 pregnancies. Mean serum creatinine and creatinine clearance remained stable throughout pregnancy and 1 year postpartum. However, there was a significant increase in proteinuria from a mean of 0.45 g/24 h around the time of conception to 1.11 g/24 h at delivery (p<0.05). The proteinuria resolved to baseline levels at 3 months postpartum. We highlight certain parameters to be considered before conception to allow a good obstetric outcome and prolong stable renal function: serum creatinine <150 micromol/l, proteinuria <1 g/day, absence of histological evidence of chronic allograft rejection, controlled blood pressure (140/90) and stability of maintenance immunosuppression.

Urinary catecholamine excretion in relation to renal function.

The urinary excretions of the free catecholamines noradrenaline, adrenaline and dopamine were measured in 50 patients (33 men and 17 women) with chronic renal failure. Stability studies showed that the catecholamines were stable in unacidified urine as long as the pH was not greater than 7.5 and the urine was acidified within 2-3 h of collection. The outputs of noradrenaline and dopamine correlated positively with creatinine clearance and in patients with clearances above 40 mL/min were similar to those in healthy volunteers (n = 20). However, adrenaline output was not correlated with creatinine clearance although it was lower in patients with renal failure compared with healthy volunteers. The urinary free catecholamine output during the first 10 days after a renal transplant was significantly less than normal, presumably because renal function was still impaired. However, in patients treated with cyclosporin A (CyA) combined with prednisolone the catecholamine excretion was lower compared with those treated with CyA and azathioprine. Impairment in renal function can have a marked effect on the output of free catecholamines and must be borne in mind when interpreting values that may have pathological significance.

Tubular peptide hypermetabolism and urinary ammonia in chronic renal failure in man: a maladaptive response?

Excessive renal tubular peptide uptake and degradation reflecting hypercatabolism may be a maladaptive response in chronic renal failure (CRF). It may also offer an explanation for the increased ammoniagenesis, per surviving nephron, observed in CRF but as yet unexplained. Neither has been explored in man. We have shown in patients with normal renal function and heavy (>5.0 g/24 h) proteinuria that tubular catabolism of a technetium-labelled peptide marker, aprotinin, and urinary ammonia were increased compared to others with less proteinuria. We now measure tubular kinetics of aprotinin and urinary ammonia in 16 CRF patients with variable proteinuria. Metabolism and turnover of aprotinin and ammonia excretion were increased, corrected for glomerular filtration rate, to levels found in patients with normal function and heavy proteinuria.

Proximal renal tubular peptide catabolism, ammonia excretion and tubular injury in patients with proteinuria: before and after lisinopril.

1. Progression to renal failure may be linked to the degree of proteinuria through tubulo-interstitial mechanisms. However, there are no data in man on the kinetics of proximal renal tubular protein catabolism or markers of tubular injury before and after lisinopril. We developed a method to allow such studies, and found increased tubular catabolism of 99mTc-labelled aprotinin (Trasylol) in patients with nephrotic range proteinuria which was associated with increased ammonia excretion. 2. In this study, 10 patients with mild renal impairment (51Cr-EDTA clearance 63.7 +/- 8.3 ml.min-1.1.73 m-2) and heavy proteinuria (8.2 +/- 2.3 g/ 24 h) were given lisinopril (10-20 mg) for 6 weeks. Renal tubular catabolism of intravenous aprotinin was measured before and after lisinopril by renal imaging and urinary excretion of the free radiolabel over 26 h. Fractional degradation was calculated from these data. Fresh timed urine collections were also analysed for ammonia excretion every fortnight from 6 weeks before treatment. Total urinary N-acetyl-beta-D-glucosaminidase and the more tubulo-specific N-acetyl-beta-D-glucosaminidase 'A2' isoenzyme were also measured. 3. After lisinopril proteinuria fell significantly as expected (from 9.5 +/- 1.6 to 4.5 +/- 1.0 g/24 h, P < 0.01). This was associated with a reduction in metabolism over 26 h (from 1.7 +/- 0.1 to 1.2 +/- 0.1% dose/h, P < 0.01) and in fractional degradation of aprotinin (from 0.08 +/- 0.02 to 0.04 +/- 0.007/h, P < 0.04). Ammonia excretion also fell significantly (from 1.2 +/- 0.1 to 0.6 +/- 0.1 mmol/h, P < 0.0001), as did both total urinary N-acetyl-beta-D-glucosaminidase (P < 0.0001) and the N-acetyl-beta-D-glucosaminidase 'A2' isoenzyme (P < 0.015). These observations after lisinopril treatment have not been described previously. There was no significant change in blood pressure nor in glomerular haemodynamics.

Proteinuria and renal tubular damage: urinary N-acetyl-beta-D-glucosaminidase and isoenzymes in dissimilar renal disease.

Markers of renal tubular injury are difficult to interpret in patients with proteinura. The 24-hour urinary N-acetyl-beta-D-glucosaminidase (NAG) concentration was measured in 167 patients with dissimilar renal disease, function, and proteinuria. NAG isoenzymes were also separated in 69 patients, using a modified fast protein liquid chromatography technique. The 'A2' isoenzyme predominated at all levels of renal function and in all diagnostic groups. Urinary NAG and proteinuria were well correlated at all levels of renal function, as was NAG 'A2' isoenzyme. Proteinuria and urinary NAG were similarly correlated in patients with different glomerulonephritides, hypertensive nephrosclerosis, and chronic pyelonephritis, but not in those with diabetic nephropathy.

Oral sodium bicarbonate reduces proximal renal tubular peptide catabolism, ammoniogenesis, and tubular damage in renal patients.

Oral sodium bicarbonate (NaHCO3) is widely used to treat acidosis in patients with renal failure. However, no data are available in man on the effects on proximal renal tubular protein catabolism or markers of tubular injury. We have developed methods to allow such studies, and both increased tubular catabolism of 99mTc-labelled aprotinin (Apr*), as well as tubular damage were found in association with increased ammonia (NH3) excretion in patients with nephrotic range proteinuria. We now examine the effects of reducing renal ammoniogenesis, without altering proteinuria, using oral NaHCO3 in 11 patients with mild/moderate renal impairment and proteinuria. Renal tubular catabolism of Apr* was measured before and after NaHCO3 by renal imaging (Kidney uptake, K% of dose) and urinary excretion of free 99mTcO4- (metabolism, Met% of dose/h) over 26 h. Fractional degradation (Frac) was calculated from Met/K (/h). Fresh urine was also analyzed for NH3 excretion every fortnight from 6/52 before treatment. Total urinary N-acetyl-beta-D-glucose-aminidase (NAG) and the more tubulo-specific NAG "A2" were measured. 51CrEDTA clearance and 99mTc-MAG 3 TER were also assessed. After NaHCO3 Met over 26 h was significantly reduced (from 1.3 +/- 0.2% of dose/h to 0.9 +/- 0.1% dose/hr, p < 0.005), as was Frac of Apr* (from 0.06 +/- .006/h to 0.04 +/- 0.005/hr, p < 0.003). NH3 excretion also fell significantly (from 0.9 +/- 0.2 mmol/h to 0.2 +/- 0.05 mmol/h, p < 0.007), as did both total urinary NAG (from 169 mumol/24 h, 74-642 mumol/24 h to 79 mumol/ 24 h, 37-393 mumol/24 h, p < 0.01), and the NAG 'A2' isoenzyme (from 81.5 mumol/24 h, 20-472 mumol/24 h to 35.0 mumol/24 h, 6-388 mumol/24 h, p < 0.001). Proteinuria remained unaltered, and there was no change in blood pressure nor in glomerular haemodynamics. Oral NaHCO3 may thus pro-tect the proximal renal tubule and help delay renal disease progression.

Chronic bronchiectasis and anti-myeloperoxidase antibody related rapidly progressive necrotizing glomerulonephritis.

We reported two cases of chronic bronchiectasis and rapidly progressive necrotizing glomerulonephritis/severe renal failure which were also positive for anti-myeloperoxidase antibody, and followed their treatment and outcome. Immunosuppressive therapy was complicated by superimposed chest infection in both cases. Nonetheless, cautious use of immunosuppressive and antibiotic therapy reversed dialysis-dependent renal failure in one of the two cases.

Microvascular endothelial activation in the skeletal muscles of patients with multiple organ failure.

The relationship between microvascular damage and the presence of muscle fibre atrophy and necrosis has been investigated in skeletal muscle biopsies taken from 57 patients with multiple organ failure. Immunohistochemical studies showed no loss of capillaries and no luminal thrombosis, while neutrophil leucocytes were more prevalent in the patients' biopsies than in controls. Deposition of the complement membrane attack complex (C5-9MAC) in capillaries was observed in 41% of cases. Endothelial activation was suggested by an increased intensity of expression of ICAM-1, and by an increased proportion of capillaries expressing P selectin and E selectin, although this was not directly associated with neutrophil accumulation. Endothelial swelling was present in many biopsies with 38% of the biopsies having larger capillary profiles on immunohistochemical labelling for von Willebrand factor (vWF), thrombomodulin and CD34, and on Ulex europaeus agglutinin 1 binding. Endothelial swelling was confirmed by image analysis and morphometric evaluation of capillary ultrastructure, however, the capillary luminal area was not reduced as the capillaries were dilated. Increased vWF labelling was associated with C5-9MAC deposition and with fibre necrosis, but the vascular changes were not related to fibre atrophy nor to clinical indices of the severity of the patients' illness. The results suggest that microvascular damage and ischaemia may not be major factors in the pathogenesis of muscle fibre damage in multiple organ failure, but that endothelial activation is a common occurrence. The variability in the patterns of markers of endothelial activation, and the small proportion of capillaries affected, may reflect the complexity of the endothelial response to circulating or locally produced cytokines.

Plasma thrombomodulin in renal disease: effects of renal function and proteinuria.

Plasma thrombomodulin (PTM) may be a marker of vascular endothelial damage and is increased in active vasculitis. However, since PTM is a mixture of glycoproteins (MW between 28 to 105 kD), some may be variably excreted by the kidney. PTM level thus may be affected both renal impairment and proteinuria. This study examines patients with varied renal pathology and relates PTM levels to renal function and proteinuria. PTM levels were measured in eighty nine renal patients with varied renal pathology: 23 patients on hemodialysis (HD), 66 with variable renal function (from normal to severe renal impairment), and proteinuria from insignificant to nephrotic range. PTM levels rose as renal function declined and were highest in HD patients. PTM levels also seemed to rise with increasing proteinuria. Indeed, this relationship appeared to be exaggerated in patients with hypertensive and diabetic nephropathy compared to those with primary glomerulonephritis. Measurements of PTM are clearly affected both by renal function and proteinuria. Thus the confidence limits above which an abnormal level is recognised should be increased as renal function declines.

Muscle fibre atrophy in critically ill patients is associated with the loss of myosin filaments and the presence of lysosomal enzymes and ubiquitin.

Muscle wasting and weakness are common features of patients with critical illnesses, and may impair their recovery. This study examines whether cytoskeletal and contractile proteins are damaged, and which proteolytic mechanisms might be involved, in the muscle fibre atrophy or necrosis associated with the acute myopathy of critically ill patients. Ninety-eight muscle biopsies were obtained by the conchotome method from 57 critically ill patients and examined morphometrically and by immunohistochemical labelling. Sequential biopsies showed a mean reduction in fibre cross-sectional areas of 3-4% per day. More intense immunolabelling for desmin was seen in the smaller fibres of 52% of the biopsies, while immunolabelling for dystrophin, actin and myosin heavy chains was maintained. Myosin ATPase activity was weak in the smaller fibres in some biopsies, and electron microscopy showed the loss of myosin filaments in atrophic fibres. These changes suggest that loss of the filamentous structure of myosin, without degradation of the immunolabelled epitopes, leads to the collapse of the intermyofibrillar desmin network. Fibres with abnormal desmin labelling showed increased cathepsin B, lysozyme and ubiquitin immunolabelling. Nine cases showed increased immunolabelling for heat shock protein 72. The changes in desmin immunolabelling were more prevalent in patients with higher APACHE II scores on admission, but were not related to other clinical features. The results indicate that fibre atrophy is associated with myosin filament depolymerization and the presence of several proteolytic enzymes. In our study, these changes occurred in patients who were critically ill but who did not receive large doses of steroids or neuromuscular blocking agents.

Physiological abnormalities of skeletal muscle in dialysis patients.

BACKGROUND: Muscle weakness is a common but unexplained feature of dialysis patients. This study investigated the prevalence and causes of muscle weakness in dialysis patients by examining the quadriceps muscle force and contractile properties. METHODS: The quadriceps femoris was studied in terms of force, force-frequency curve, and speed of muscle relaxation in 49 dialysis patients and 27 healthy subjects. In addition nutritional, haematological, biochemical, and histological assessments were performed, and steps of force generation were analysed to reach the possible mechanisms leading to the observed weakness. RESULTS: Muscle weakness, though invariable as a symptom, was subtle or absent on clinical examination. Quadriceps force measurements, however, revealed unequivocal weakness in most of the patients (71%). The quadriceps muscle was weaker (317 +/- 115 versus 460 +/- 159 N, P < 0.01) compared to healthy individuals, but there was no evidence of impaired excitation-contraction coupling (0.79 +/- 0.05 versus 0.76 +/- 0.07, P = 0.1). Among dialysis patients the older and the malnourished (n = 23) were the weaker but there was no relationship to the type or duration of dialysis. The serum albumin was the only biochemical parameter related to the muscle force (r = 0.6, P = 0.01). The other most prominent abnormality of quadriceps muscle function observed in this study was slowing of relaxation (patients versus controls; 8.7 +/- 1.8% versus 10.8 +/- 1.1% force loss/10 ms, P < 0.0001) particularly in the malnourished group (malnourished versus well nourished; 8.3 +/- 2.1 versus 9.4 +/- 0.95, P = 0.03). Muscle histology was investigated (n = 12) and revealed that type II fibres were mildly atrophic in 40% of the biopsies in most areas, but predominantly type IIB. Although type IIB fibre areas are slightly smaller in the dialysis patients compared to the controls, this was not statistically significant (3025 +/- 578 versus 4406 +/- 1582, P = 0.1) except in the malnourished group compared to the well-nourished dialysis patients (2092 +/- 304 versus 4346 +/- 1496, P = 0.04), and in the malnourished dialysis patients type IIB fibre area was significantly correlated to the strength (r = 0.6, P = 0.02). CONCLUSIONS: The only significant predictor of loss of muscle strength and abnormality of relaxation in this study was the nutritional state. A regular assessment of the nutritional state is required to ensure adequate nutrition to prevent the observed abnormalities of the skeletal muscles.

'Progressive' versus 'indolent' idiopathic membranous glomerulonephritis.

There is still controversy about safe and effective therapy for idiopathic membranous glomerulonephritis (MGN). Over 20 years, we have simply observed our patients clinically after diagnosis, and only used aggressive therapy with steroids in high dosage and azathioprine for 21 patients with progressive renal failure. The other 42 were thus classified as 'indolent' MGN. Those with 'progressive' MGN had heavier proteinuria and worse renal function on presentation, but the overlap was considerable. Patients with progressive MGN were treated after 1-4 years. All responded promptly, and 5 years after presentation all were alive, and only one was on dialysis. By 10 years, most were still alive, and of these most were off dialysis. In five patients, dialysis was delayed by several years. There were two deaths on dialysis, and three other deaths, mostly in older patients. All but one patient with indolent MGN remained stable on symptomatic treatment only, for at least 5 years after presentation. In many, proteinuria fell to insignificant levels over 4 years. In these remitting patients, there was a prevalence of thyroid disease (7), rheumatoid disease (3) and nephrotic presentation in pregnancy (4). After 6-10 years three patients developed worsening proteinuria and renal failure. Five older patients died from unrelated causes.

Origin and significance of urinary N-acetyl-beta, D-glucosaminidase (NAG) in renal patients with proteinuria.

In patients with proteinuria, indices of tubular damage are unreliable since filtered plasma enzymes could contribute to tubular enzymuria. Previous work has suggested the existence of various forms of the 'A' isoenzyme of N-acetyl-beta, D-glucosaminidase (NAG), one of which could be kidney specific and thus a useful marker of renal tubular damage. By using fast protein liquid chromatography, two forms of the 'A' isoenzyme, 'A1' and 'A2' were separated in human urine, plasma and kidney tissue. The isoenzyme profile in pathological urine resembled that seen in kidney tissue, the 'A2' isoenzyme predominating. The ratio A2/A1 in the urine of renal patients was significantly greater than in the plasma of renal patients, end-stage renal failure patients and healthy volunteers. There was no difference in the plasma ratios of the three groups studied. The clearances of total NAG, 'A1' and 'A2' isoenzymes were all greater than that of the lower molecular weight protein transferrin. This indicates that the origin of urinary NAG in patients with proteinuria is from the kidney itself. Thus, analysis of urinary NAG and its isoenzymes may be of benefit as an early predictor of renal tubular damage and may also be useful as a non-invasive indicator of disease progression.