Cisplatin in children: hearing loss correlates with iris and skin pigmentation.

Pigmentation is reported to affect cisplatin-induced ototoxicity in adult humans. The hearing loss is worse in people with brown irises, than in those with blue irises. We assessed the hypothesis that cisplatin-treated children with dark irises suffer more deterioration in auditory thresholds than do those with less pigmentation. For the 19 children whose data met the requirements of this observational retrospective study, we found a weak correlation (Spearman's r = 0.50; p < 0.05) of high frequency hearing loss (at 4000 Hz) and pigmentation. Blue or hazel-eyed children averaged 2.9 dB worsening at 4000 Hz, in contrast to 14.2 dB worsening for brown or black-eyed children. Pigmentation may account for some of the individual susceptibility to cisplatin ototoxicity. We suggest that iris colour be included in future reports of cisplatin-related hearing loss.

Axonal damage in Crohn's disease is frequent, but non-specific.

We have attempted to confirm the claim by Dvorak and Silen that 'Crohn's disease is accompanied by a severe and extensive necrosis of gut axons...[which] may serve to differentiate Crohn's disease from other inflammatory conditions'. In this electron microscope study the diagnoses were withheld until the assessment of axonal damage was completed. We assessed the axonal damage in ileostomy biopsies in 13 cases of Crohn's disease, four cases of ulcerative colitis, and two 'controls'. In Crohn's disease we found a mean per cent of abnormal axons of 29.85, in ulcerative colitis of 21.25 per cent, and in the two 'controls' of 12.11 and 10.63 per cent, respectively. The difference between the 13 cases of Crohn's disease and the six cases of non-Crohn's disease is not significant. We found considerable numbers of abnormal, very small axons of uncertain nature but probably related to regeneration following surgery. Including or excluding such axons did not significantly alter the incidence of abnormal axons. We conclude that axonal damage is common in chronic inflammatory bowel disease and is not specifically related to Crohn's disease.

Cyclosporin A and anti-glomerular basement membrane antibody glomerulonephritis in rats.

In a telescoped model of antiglomerular basement membrane (GBM) antibody induced nephritis, Lewis strain rats were injected in the footpad with rabbit IgG on day 0 and then given a single intravenous injection of rabbit anti-rat GBM antibody on day 5. Proteinuria developed within 24 h and renal histology 7 days later showed a focal or diffuse proliferative glomerulonephritis. In this study rats treated as above were given Cyclosporin A (CyA) 20 mg/kg daily by intraperitoneal injection from day 0 or from day 5. Rats given CyA plus anti-GBM antibody developed extensive glomerular infiltration with polymorphs and glomerular thrombosis, lesions not seen with unmodified anti-GBM nephritis or in rats who received CyA alone. The mechanism by which CyA given prior to or at the onset of immunological insult in this model worsens glomerular injury is unclear.

Proteinuric glomerular disease in adults: cumulative life tables over twenty years.

Outcome in 425 patients with persistent proteinuria has been assessed over a period of five to 20 years. Nephrotics and non-nephrotics are analysed separately. Clinical and laboratory findings do not correlate with renal histology. Seventy-eight patients had minimal histological lesions and four died (only one in renal failure). Fifty-one patients had endothelial cell proliferation, and 20-year survival was 70 per cent; renal failure occurred within five years in all 17 who progressed, and was independent of nephrotic status. In both membrano-proliferative disease (98 patients) and membranous glomerulopathy (59 patients) 20-year survival was 20 to 30 per cent. Epithelial cell proliferation (85 patients) had the worst prognosis, and survival after 12 years was negligible. In these last three groups decay in survival was almost linear against time and independent of nephrotic status. In focal proliferative disease 20-year survival in nephrotics (31 patients) was only 30 per cent, contrasting with non-nephrotics (23 patients) with 80 per cent survival. Of 105 patients presenting with proteinuria without symptoms, in 30 the proteinuria was postural and biopsies were not done. The other 75 showed a range of histological changes and prognosis similar to the group with symptoms.

Further studies on the glomerular tip lesion: early and late stages and life table analysis.

The glomerular tip lesion is a distinctive abnormality of the kidney associated with steroid-responsive proteinuria. It was first recognized at the stage at which there is a group of intracapillary foam cells adherent to Bowman's capsule next to the tubular origin. Late stages were investigated by studying changes to the lesion with time in seven patients known to have the foam cell stage in their first renal biopsy, and by identifying 13 patients whose biopsies had similar changes. Early stages were investigated by the study of biopsies from three patients who at some time had evidence of the tip lesion. The lesion appears to begin with leak of protein through glomeruli that are normal on light microscopy, with damage to proximal tubular epithelium. Adhesion of the glomerular tuft to Bowman's capsule and the development of foam cells then follows. The lesion is permanent but evolves either into a thin tip adhesion or into a larger area of hyalinosis and sclerosis, at first segmental and then global. The lesion can be specifically identified at all stages except the earliest. Actuarial analysis of 37 patients with the tip lesion indicated a 10-year survival of 55 per cent. The only factor identified that appeared to have an influence on survival was satisfactory control of proteinuria.

Increased albumin and normal dextran clearances in protein-overload proteinuria in the rat.

Female Wistar rats were made heavily proteinuric by daily intraperitoneal injections of bovine serum albumin over 5 days. The size and charge permeability characteristics of the glomerular filter in this condition were determined by studying the renal handling of poly-dispersed uncharged dextran over the range of molecular radii 2-6 nm (albumin 3.6 nm), and of endogenous rat serum albumin over the same clearance period. In proteinuric rats the clearance of rat serum albumin was significantly increased with a resultant reduction in the circulating levels of rat serum albumin. The clearance of uncharged dextran was not significantly different in proteinuric rats compared with control animals. There does not appear to be any size selective defect of the glomerular filtration barrier in this condition. This suggests that the observed increase in the clearance of the negatively charged endogenous albumin may be due to a reduction in the glomerular charge barrier.

The glomerular ultrastructural distribution of immunoglobulin G in hyperalbuminaemic (protein-overload) proteinuria.

Female Munich-Wistar rats were given intraperitoneal injections either of bovine serum albumin to induce proteinuria or of water as a control. Their kidneys were fixed in situ. An ultrastructural technique was used to demonstrate IgG antiperoxidase antibodies either injected from a heterologous species or autologous, induced by immunization with horseradish peroxidase. Photometry of electron micrographic negative was used to determine the distribution of antiperoxidase antibodies. In glomeruli of control animals IgG was present in the basement membrane. There were three sites at which the passage of IgG across the basement membrane was hindered: between blood plasma and the lamina rara interna, between the lamina densa and the lamina rara externa, and between the lamina rara externa and the urinary space. Glomeruli of proteinuric animals were variable in appearance, some showing little structural damage and others showing marked changes with loss of epithelial foot processes and accumulation of vacuoles and protein droplets in epithelial cells. Both types of glomeruli contained IgG in the urinary space. The distribution of IgG in the basement membrane of both types was similar. Compared with control animals there was less IgG in the basement membrane and IgG was distributed uniformly across the basement membrane. The proteinuria in hyperalbuminaemia (protein-overload) is associated with a diffuse change in the barrier function of the glomerular basement membrane to IgG which is, at least in the initial stages, not related to structural changes in glomerular epithelial cells.

Glomerular lysozyme binding in protein-overload proteinuria.

Binding of the cationic molecule lysozyme to the glomerular basement membrane and to the glomerular epithelial cell coat was investigated in the glomerulus of normal female Wistar rats and in rats in which heavy proteinuria was induced by the daily administration of 1 g of bovine serum albumin. In normal rats the binding of lysozyme to the anionic groups in the glomerular basement membrane and the cell coat had no effect on the ultrastructure of the glomerular epithelial cell, in particular the foot processes were unchanged. In the proteinuric rats the lysozyme-binding to the glomerular basement membrane and the epithelial cell coat was completely lost in the damaged glomeruli. In the apparently normal glomeruli present in these proteinuric animals binding was similar to that seen in normal rats. These results suggest that in protein-overload proteinuria there is a loss of glomerular anion and hence a reduction in the glomerular charge barrier. This may account, at least in part, for the increased glomerular leak of negatively charged serum albumin in this experimental model of proteinuria.

Cortical microcystic disease of the kidney with dominant inheritance: a previously undescribed syndrome.

We report a family in which the father and all three children had symptomless chronic renal failure and, in the case of the children, normocytic, normochromic anaemia. None had hypertension, proteinuria, or abnormality of urinary deposit. Renal biopsy specimens showed microcysts confined to the renal cortex; some cysts contained vestigial glomerular tufts. This family appears to represent the first known example of hereditary cortical microcystic disease. The distribution of the disease suggests dominant inheritance without sex linkage.

Ultrastructural localization of anionic and cationic ferritin in the rat glomerular basement membrane in protein-overload proteinuria.

The penetration into the glomerular basement membrane of anionic and cationic ferritin has been studied in rats made proteinuric by intraperitoneal administration of bovine serum albumin. In comparison with control animals anionic ferritin penetrated the glomerular basement membrane to a much greater extent in proteinuric rats. Some ferritin particles were observed in small invaginations of the epithelial cell membrane adjacent to the glomerular basement membrane and incorporated in pinocytotic vesicles within the epithelial cell cytoplasm. This was not seen in control animals. Cationic ferritin distribution in the glomerular basement membrane was similar in control and proteinuric rats suggesting that the increased anionic ferritin penetration observed occurs without any reduction in fixed anionic charge.

A study of glomerular basement membrane anionic sites and glomerular visceral epithelial cell coat in protein overload proteinuria in the rat.

The presence and distribution of anionic sites in the glomerular basement membrane and visceral epithelial cell coat has been demonstrated. No definite decrease in intensity or periodicity of staining of basement membrane particulate sites was seen in protein overload proteinuric animals and only one staining technique employed for electron microscopy (alcian blue 8GX) demonstrated a focal decrease in visceral epithelial cell coat staining in severely damaged glomeruli. A decrease in overall glomerular staining was also demonstrated by quantitative analysis of colloidal iron staining by light microscopy. The findings differ from those described in puromycin aminonucleoside nephropathy and nephrotoxic nephritis. Staining was demonstrated also in other basement membranes, in Bowman's capsule and along interstitial collagen fibres.

The glomerular tip lesion: a previously undescribed type of segmental glomerular abnormality.

We describe a distinctive and previously undescribed abnormality of the kidney. It consists of a combination of changes in the glomerulus and in the proximal convoluted tubule. The glomerular abnormality consists of a well-localized collection of intracapillary foam cells and marked vacuolation of the adjacent glomerular epithelial cells. The abnormality is always situated in the same position in the glomerular tuft namely adjacent to the origin of the proximal convoluted tubule, with adhesion to Bowman's capsule. The rest of the tuft appears normal by light microscopy but shows foot-process fusion by electron microscopy. The abnormality of the proximal convoluted tubular cells invariably affects the first part of the tubule adjacent to the glomerulus but in some cases involves the tubules more extensively in the cortex. Study of a series of 100 2-micron serial sections from one case indicated that probably every glomerulus had a lesion at the origin of the tubule. A study of 185 renal biopsies nearly all with segmental lesions revealed biopsies from 20 patients with this distinctive abnormality. There were 14 males, age 20-57, median 44 years, and six females age 19-65, median 22 years, all presenting with proteinuria, nearly all with the nephrotic syndrome. All except four were treated with steroids and in all those treated the proteinuria improved. Only one patient not treated with steroids had progressive renal impairment. Four patients died, none from renal failure. This lesion, the glomerular tip lesion, as we have called it, seems to be a well-defined and specific pathological entity. It has some similarities to minimal change nephropathy but there are clear and important differences. Previously it may have been included in series of cases of 'focal glomerulosclerosis' but that term is imprecise and is generally taken to have an unfavourable clinical course. For these reasons it is inappropriate to use 'focal glomerulosclerosis' as a name for the glomerular tip lesion.

Effect of molecular charge on the induction of proteinuria and glomerular ultrastructural damage in hyperalbuminaemic female Wistar rats.

Intraperitoneal injection of anionic carbamylated bovine albumin derivatives induced glomerular epithelial cell foot process loss and increased urinary protein excretion, the severity of which rose with the dose administered. The effects induced at a given albumin dose were significantly lower than those previously measured after the administration of normal bovine albumin. The amount of epithelial cell foot process loss induced after the injection of carbamylated bovine albumin derivatives correlated well with the level of induced proteinuria but, at a given level of proteinuria, the amount of foot process was lower in these rats compared with those given normal bovine albumin. The results obtained are consistent with the interpretation that the more anionic carbamylated bovine albumin derivatives were not only filtered less readily at the glomerulus than their less negatively charged counterparts but were also reabsorbed to a lesser extent by the tubular epithelium.

Glomerular ultrafiltration and tubular reabsorption of bovine serum albumin and derivatives with increased negative charge in the normal female Wistar rat.

Urinary clearances of bovine albumin derivatives rose with their increasing negative charge. A mathematical model has been developed to assess the relative contributions of glomerular ultrafiltration and tubular reabsorption to overall urinary protein clearance. This model indicates that the increased urinary clearance seen with negatively charged bovine albumin derivatives was due to a large reduction in the amount of protein absorbed by the proximal tubular epithelium, which swamped the effects of a small decrease in glomerular ultrafiltration. Derivatives of bovine albumin with increasing negative charge were also cleared with correspondingly greater rapidity from the blood stream.

An electron microscopic study of the effects of vinblastine sulphate on the ultrastructure of the kidney, trachea, liver, peripheral nerve and small intestine of the rat.

The effects of vinblastine in high doses on the kidney, liver, trachea, peripheral nerve and small intestine of rats have been studied by scanning and transmission electron microscopy. Dramatic structural changes were seen in glomerular visceral epithelial cells, hepatocytes and small intestinal epithelial cells which appear to be due to the effect of vinblastine on microtubules and possibly also on other proteins and cell membranes. Ciliary microtubules appeared resistant to vinblastine effects.

Extra-tubular deposits of Tamm-Horsfall protein in renal allografts.

Sections from 266 renal allografts that had been transplanted and removed were studied to determine the prevalence of deposits of Tamm-Horsfall protein outside tubules and resulting from tubular rupture, detected by the periodic acid-Schiff (PAS) reaction. The PAS-positive material was shown to be Tamm-Horsfall protein by an indirect immunoperoxidase method. Deposits were found in 152 kidneys (57.1 per cent.), and were commonest at the cortico-medullary junction and in arcuate veins. Deposits were rarely associated with thrombosis or an inflammatory response, and often contained tubules that were reforming. The lesions were rare in grafts totally infarcted from occlusion of the main vessels. Deposits were mostly found in kidneys that had tubular damage from acute rejection reactions, often with ureteric damage, but a few had ureteric obstruction alone. Old deposits were identified in kidneys showing chronic vascular rejection. No features of the deposits themselves could separate cases with ureteric obstruction alone from the other cases. Not every case with ureteric obstruction had the lesions. Extra-tubular deposits of Tamm-Horsfall protein are common in renal allografts and only rarely indicate a specific, surgically-correctable cause of graft dysfunction, namely ureteric obstruction.