D. Gwyn Williams

Idiopathic mesangiocapillary glomerulonephritis: Comparison of types I and II in children and adults and long-term prognosis

Of 104 patients with idiopathic mesangiocapillary glomerulonephritis studied for at least two years, 69 patients had type I disease and 35 had type II. Forty-five patients were children, and 59 were adults. Type II mesangiocapillary glomerulonephritis was more common in children than in adults, but no other clinical feature distinguished the two types at onset. Complement studies revealed that patients with type II had lower serum C3 concentrations and more frequently showed C3-splitting activity (C3 nephritic factor) in the serum. Children had hypertension or a lowered glomerular filtration rate less frequently at onset than did adults, but children had a higher incidence of a hematuric onset; C3 nephritic factor was also more frequent in the children. During a follow-up period of two to 21 years (mean eight years), only seven patients (five with type I and two with type II) showed clinical remission, whereas 38 percent of patients with type I and 49 percent of patients with type II died or required dialysis; a further 23 percent of patients with type I and 16 percent of patients with type II had continuing disease and reduced glomerular filtration rate. Only the presence and persistence of a nephrotic syndrome in type I predicted renal failure. In both types, the presence of sclerosis or crescents in the initial renal biopsy specimen was associated with a poorer prognosis, but no other feature was of major prognostic value.

Recurrence of focal segmental glomerulosclerosis in transplanted kidneys: Analysis of incidence and risk factors in 59 allografts

Fifty-nine allografts were placed in 43 patients with renal failure from focal segmental glomerulosclerosis (FSGS): 27 allografts were put into 16 children aged less than 15 years, and 32 allografts into 27 adolescents and adults. Recurrence of FSGS was noted histologically in 13 allografts, 10 in 8 children and 3 in adults. None of the 9 children and 24 adults who never developed an allograft nephrotic syndrome showed FSGS in their allograft biopsies. The age of onset was a strong risk factor for recurrence: recurrent FSGS developed in 8 of 16 children (50%) but only in 11% of adolescents and adults (3 of 27 patients). Although the time from apparent onset to renal replacement treatment was shorter in those with recurrence than those without in the children, there was no difference in the time spent on dialysis prior to transplantation. Mesangial prominence was observed in the original biopsy in 12 of 13 patients with recurrence, and recurrence rate was similar in living and cadaver donor allografts; class I MHC matching was similar in those with and without recurrence. Three allografts treated with cyclosporin A as well as 9 with azathioprine showed recurrence. Of 9 second or subsequent allografts placed in those with recurrence in the first allograft, only 3 showed further recurence. rence. In 3 re-grafted after 13, 11 and 5 years, normal function was seen.

DIFFERENTIATION BETWEEN ALLOGRAFT REJECTION AND CYCLOSPORIN NEPHROTOXICITY IN RENAL-TRANSPLANT RECIPIENTS

In a retrospective study of 60 renal-transplant patients immunosuppressed with cyclosporin no specific clinical features differentiated allograft dysfunction responsive to anti-rejection therapy from dysfunction responsive to reduction in cyclosporin dosage. Histologically, allograft dysfunction responsive to anti-rejection therapy was strongly associated with diffuse interstitial infiltration by mononuclear cells, oedema, and haemorrhage, vascular endothelial-cell proliferation, and infiltration of arterial walls by mononuclear cells. Arteriolar medial hypertrophy and hyalinosis were more commonly found in biopsy specimens from allografts with dysfunction responsive to reduction in cyclosporin dose than in those with dysfunction responsive to anti-rejection therapy and those with stable or improving function. Whole-blood cyclosporin concentrations were significantly lower in patients with dysfunction reversed by anti-rejection therapy than in those with dysfunction reversed by reduction in cyclosporin dose or in those with stable function. There was, however, considerable overlap between these groups, so that individual cyclosporin measurements were of little diagnostic value.

LONG-TERM IMPAIRMENT OF SUPPRESSOR-CELL FUNCTION BY CYCLOPHOSPHAMIDE IN MINIMAL-CHANGE NEPHROPATHY AND ITS ASSOCIATION WITH THERAPEUTIC RESPONSE

Lymphocyte suppressor-cell function was studied by induction with concanavalin A in 31 patients with minimal-change nephropathy (MCN) in remission. 21 patients had been treated with cyclophosphamide 0.5--12.0 years previously (mean 6.5 years) and had been in remission for 0.5--9.0 years (mean 5.1 years). The remaining 10 patients had never received cyclophosphamide and had been in remission for 1--10 years (mean 5.3 years). The cyclophosphamide-treated group had significantly less suppressor-cell function than either the controls or the non-cyclophosphamide-treated group, the latter being not significantly different from normal. When patients who had received cyclophosphamide were divided into those who had relapsed after taking this drug (10 patients) and those who had not (11 patients), suppressor-cell function was significantly impaired in the non-relapsing group. This association of impaired suppressor-cell function with failure to relapse may indicate that suppressor cells have a pathogenetic role in MCN and that the therapeutic effect of cyclophosphamide in this disease is to diminish their function. Alternatively, the impaired suppressor-cell function in the non-relapsing group may be simply a marker of effective treatment with cyclophosphamide. The finding of long-term suppression of lymphocyte function after cyclophosphamide coupled with this drugs risks of causing malignancy and gonadal dysfunction reinforces the need for caution in its use in MCN.

A common anti-DNA antibody idiotype and anti-phospholipid antibodies in sera from patients with schistosomiasis and filariasis with and without nephritis.

The serum concentration of a public idiotype (16/6 ID), originally identified on a human hybridoma-derived monoclonal anti-DNA antibody, was raised in patients with S. mansoni and filariasis with or without nephritis, compared to patients with S. haematobium (in which nephritis does not occur) or idiopathic nephritis not associated with infection. There was no significant difference in 16/6 ID levels between patients with or without renal disease, whether associated with S. mansoni or filarial infection. The 16/6 ID-positive antibodies did not bind to native or denatured DNA, using competitive fluid-phase inhibition studies. Anti-cardiolipin antibody (ACA) concentration was increased in patients with either S. mansoni or filarial infection. In filariasis, both IgG and IgM ACA isotypes were elevated, irrespective of the presence of nephritis. In S. mansoni infection, IgA ACA were limited to patients with renal disease, and IgG ACA isotype to patients without overt nephritis. Both isotypes of anti-cardiolipin antibody correlated with levels of the 16/6 ID in patients with S. mansoni or filariasis. The 16/6 idiotype was therefore a feature of chronic helminthic infection, but was not related to anti-DNA antibody levels or specificity. The occurrence of nephritis as a complication of these infections was not related to the prevalence of the 16/6 idiotype.

Pathogenesis of idiopathic IgA nephropathy

Despite a prodigious amount of work on the physiology of IgA production in man, and many studies on the immunopathology of IgA nephropathy, ranging from the immunogenetics to the immune response to chemical characteristics of the IgA, we are hardly any nearer to defining the pathogenesis of this disease. One of the main changes in our understanding has been to recognise that the bone marrow, now known to produce normally one-third of the bodys IgA, overproduces this immunoglobulin in IgA nephropathy. This alters the previous notion that IgA nephropathy was due simply to IgA production in the mucosa, although a mucosal component is not excluded. Certain characteristics of the IgA in the diseased kidney and the circulation have been defined: it is of subclass IgA1 and has a higher proportion of λ light chains and negative charge than in normal subjects. The specificities of the IgA, either in the kidney or in complexes, have not helped to clarify the pathogenesis. They have been found for a wide range of endogenous and exogenous antigens, suggesting that the antibody activity represents polyclonal B cell activation. These findings have not helped to confirm the prevailing theory that IgA nephropathy is an immune complex disease. Other theories put forward are that IgA nephropathy is an autoimmune disease, glomerular components or IgA itself being among the candidate antigens, or that there is primary dysregulation of the IgA immune system. At this stage of development in our understanding of this common nephropathy, it is important to guard against the assumption that idiopathic IgA nephropathy is one disease and is the result of a single pathogenetic mechanism.

Idiotypes of DNA-Binding Autoantibodies:Mapping by Epitope Scanning and Molecular Modelling

One of the cardinal features of systemic lupus erythematosus (SLE) is the production of autoantibodies against a range of intracellular autoantigens. The spectrum of antibodies, and their fine specificities, may vary between individuals with SLE reflecting the varied nature of the aetiologial and pathogenic processes that contribute to the SLE syndrome. One relatively constant feature of the serology of SLE, however, is the production of antibodies that react with DNA and these are found both in humans and also in mice that develop the disease. It is generally accepted that these antibodies play a significant role in the developing pathology, especially that associated with nephritis. For example, transfusion of some DNA-binding antibodies into healthy BALB/c mice (Vlahakos et al., 1992) or young MRL/lpr mice in early stages of disease (Lake & Staines 1988) will cause significant changes in kidney function. It is quite likely, if not certain, that other autoantibodies also contribute significantly to lupus nephritis and the dominant role ascribed to the DNA antibodies may to an extent be a result of the concentration of research effort directed at them.

The treatment of immune glomerular disease

ConclusionsAlthough the outcome of severe forms of glomerulonephritis has improved over recent years, there has to be a realistic sense of disappointment related to the lack of immunologically specific treatment available, reflected in the overall similarity of the management of these patients. The sense of disappointment is heightened by the lack of properly conducted trials containing an adequate number of subjects to answer the relatively simple questions posed in everyday nephrological practice. With the advent of the more specific immunological therapies outlined above and the development in some diseases of particular immunopathogenetic markers, there are reasons for an optimistic view of the future; this must be tempered by the hope that new forms of therapy will be properly assessed.

Hereditary and Congenital Diseases

This chapter describes a number of conditions which, although they may vary in their pathogenesis, are inherited or congenital or both. Some hereditary disorders have already been described in other sections, e.g. tubular defects (Chapter 6).

Pregnancy and the Kidney

The pregnant woman is at risk of developing several renal complications, some of which may be fatal. Asymptomatic bacteriuria is common, and with it a higher risk of overt urinary tract infection, including pyelonephritis. Obstruction may occur due to the gravid uterus per se, or because there is some fetal malformation, e.g. hydrocephalus.