Studies of the molecular basis of IgA production, subclass regulation and class-switch recombination in IgA nephropathy patients.

IgA nephropathy (IgAN), the most common form of glomerulonephritis, is characterized by normal to elevated levels of serum IgA. In order to understand the molecular mechanism(s) involved in the production of IgA in IgAN, peripheral blood mononuclear cells (PBMC) from these patients were analysed in this study. IL-10, transforming growth factor-beta 1 (TGF-beta 1) and CD40 have previously been shown to be involved in IgA production. We show here that CD40L expression was increased three-fold in these patients. However, expression of TGF-beta 1 in serum levels was comparable to controls. In vitro stimulation of PBMC with a polyclonal activator resulted in a three-fold increase in synthesis of both IgA subclasses, with a preference for IgA1 RNA. In situ hybridization studies also showed a three-fold increase in the numbers of IgA1- and IgA2-producing cells, but the subclass distribution was similar to the controls. Furthermore, using the nested primer polymerase chain reaction (PCR) for amplifying switch (S mu/S alpha) breakpoints we could demonstrate that in unstimulated PBMC the switch frequency did not differ from that of control donors. Sequence analysis of the amplified switch breakpoints and the I alpha regulatory region from patients showed no structural abnormality. Although we have previously demonstrated a correlation to in vivo germ-line RNA expression and class switching, no I alpha transcripts were detected in unstimulated PBMC from these patients. However, stimulation of PBMC with TGF-beta 1 resulted in I alpha production. Taken together, results from in vivo and in vitro studies suggest that increased cytokine production and hyperresponsiveness to polyclonal stimulation may play an important role in the increased synthesis of IgA. The preference for IgA1 is due to increased production of IgA1 per cell, and the absence of I alpha RNA indicates that additional defect(s) in immune regulation may play an important role in the pathogenesis of IgAN.

Treatment of IgA nephropathy with omega-3-polyunsaturated fatty acids: a prospective, double-blind, randomized study.

In several studies diets supplemented with fish oil containing a high proportion of omega-3-polyunsaturated fatty acids (w-3-PUFA) have been shown to produce beneficial effects, such as a reduction in blood pressure, lipid levels and inflammation, all of which may affect the course of IgA nephropathy. However, the results of hitherto published studies concerning IgA nephropathy have been inconclusive. We therefore carried out a prospective, randomized, placebo-controlled six-month study with a higher daily dose of w-3-PUFA than used in previous studies. Thirty-two adult patients with biopsy-proven IgA nephropathy and proteinuria completed the study: 15 were assigned to a fish-oil product with a high percentage of w-3-PUFA (K 85, with 55% eicosapentenoic and 30% docosahexenoic acid) and 17 to corn oil, 6g daily of either oil. At the start, no significant differences were found between the two groups (K85: 3 females/12 males, mean age 39 years (range 22-64), corn oil: 4 females/13 males, age 42 years (range 26-68). By six months, supplements of K85 resulted in a slight but significant reduction in glomerular filtration rate (GFR) compared to the start: 51Cr-EDTA: 63 +/- 22 to 59 +/- 21 ml/min/1.73 m2 (p < 0.05), creatinine clearance: 91 +/- 31 to 79 +/- 25 ml/min (p < 0.01), s-creatinine: 131 +/- 39 to 139 +/- 39 mumol/l, whereas no change in GFR was observed in the corn oil group. The urinary total protein and red blood cell excretions were not affected in any of the groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Fatal outcome of bilateral nephrectomy in a patient with polycystic kidney disease. Case report.

A 49-year-old woman had polycystic kidneys and liver cysts first diagnosed in 1968. She presented with hepatic and renal failure in 1980 and by 1988 was undergoing regular haemodialysis. In February 1989 she had bilateral nephrectomy (before renal transplantation) but developed septic shock and died. The reported mortality of bilateral nephrectomy before kidney transplantation is about 5%, and patients should be carefully selected and assessed before operation.

Deterioration of GFR in IgA nephropathy as measured by 51Cr-EDTA clearance.

In 191 patients with mesangial IgA nephropathy, GFR was determined as clearance of 51Cr-EDTA. 86 (45%) of them had subnormal renal function 7.3 +/- 4.6 years after renal biopsy. The change in GFR was followed in 153 patients with repeated determinations of 51Cr-EDTA clearance. 50.3% of the patients had a loss of more than 1.1 ml/min/year, which we regard as pathological. The markers of progressive disease were: male sex, high output of urinary protein, severe histological lesions and presence of hypertension. Even patients lacking these markers had a significantly increased incidence of progressive disease. Of 93 patients, with initially normal GFR, 32% will have a subnormal GFR within five years and 25% will develop end-stage renal failure within 20 years. In 38 patients with six or more determinations of 51Cr-EDTA clearance, the predictive value of the first four determinations was calculated. Of 26 with a decrease of more than 1.1 ml/min/year, 13 (50%) developed subnormal GFR during follow-up, while 11 of 12 (91.7%) with a decrease of less than 1.1 ml/min/year (P less than 0.05) remained normal. This shows that repeated determinations of GFR with an accurate method will predict the final outcome early in the disease. We also confirmed that single or repeated determinations of clearance of creatinine are of little value in separating a normal GFR from a slightly decreased one, but more reliable in detecting a markedly reduced GFR.

Deterioration rate in hypertensive IgA nephropathy: comparison of a converting enzyme inhibitor and beta-blocking agents.

The effect of beta-blocking agents and enalapril as antihypertensive drugs has been compared in 47 patients with IgA nephropathy. The deterioration rate was calculated from the regression line of 51Cr-EDTA clearance and expressed in ml/min/year. The annual loss in glomerular filtration rate (GFR) was greater in patients treated with different beta-blocking agents (-4.9 +/- 6.8 ml/min/year) compared to patients treated with Enalapril (1.7 +/- 7.4 ml/min/year), in spite of the fact that these patients had a lower initial GFR. Nine patients were initially treated with beta-blocking agents (-9.5 +/- 9.3 ml/min/year) and then with an angiotensin-converting enzyme inhibitor (5.5 +/- 11.2 ml/min/year). Angiotensin-converting enzyme inhibitors should therefore be preferred in the treatment of hypertension in IgA nephropathy.

Development of hypertension in IgA nephropathy as a marker of a poor prognosis.

We have studied 209 patients with IgA nephropathy. 26 were hypertensive at the time of renal biopsy, and 59 patients developed hypertension during follow-up. Survival statistics show that only 45% of the patients will remain normotensive 10 years after renal biopsy. The presence of hypertension at renal biopsy correlated well with the usual parameters of a poor prognosis. The same markers predicted a later development of hypertension in patients who were normotensive at the time of renal biopsy. When hypertension is established, the prognosis is poor. Three years after diagnosis of hypertension, the renal survival was found to be 70% in the 59 patients we have followed. It is also possible that the markers of a poor prognosis actually predict the progression rate rather than the prognosis, because in time, some patients with initially mild manifestations of the disease will progress to end-stage renal failure.

IGA nephropathy: a retrospective evaluation of prognostic indices in 176 patients.

One hundred and seventy-six patients with mesangial IgA nephropathy have been studied retrospectively. Mean follow up from apparent onset of the disease was 9.3 years and with follow up from the diagnostic renal biopsy of 4.6 years. Our aim was to evaluate the prognostic significance of sex, age and type of symptoms at onset. The degree of proteinuria, presence of hypertension or decreased renal function, histological lesions and IFL pattern at the time of the diagnostic renal biopsy were recorded. 17 of the patients developed End Stage Renal Failure (ESRF) during the study. According to the Logrank test (renal survival) and Cox stepwise proportional hazard model, severity of glomerular mesangial lesions and degree of proteinuria are the most important indicators of a poor prognosis. The significance of all other parameters disappear after correction for histological lesions and degree of proteinuria. Our conclusion is that a semiquantitative light microscopical examination is an excellent prognostic index in IgA nephropathy, as is a simple determination of protein excretion in the urine.

Are beta-haemolytic streptococci involved in the pathogenesis of mesangial IgA-nephropathy?

In retrospect we have found that 38 of 187 patients who fulfilled the criteria of mesangial IgA-nephropathy had possible acute glomerulonephritis at the onset of their disease. We have therefore studied anti-streptococcal antibodies (ASO and ADNAseB) prospectively. Forty-three per cent of the patients had ADNAseB greater than 800 units. Thirty-one per cent of the patients studied more than once had a fourfold or greater change in their ADNAseB titre. Thirty-three per cent of the patients had different groups of beta-haemolytic streptococci isolated from their throats. This indicates a possible role of beta-haemolytic streptococci in the pathogenesis of some cases of mesangial IgA-nephropathy.

Course of renal function in IgA glomerulonephritis in children and adolescents.

The pathophysiology of IgA GN was investigated in different stages of the disease. Seventeen patients who were between 3.5 and 16.5 years of age at the onset were included in the study. Clearance studies were performed repeatedly in 6 patients (in 5 of them over a period extending from the onset to 5-9.5 years) and only once in 9 patients (10-23 years after the onset). Two patients (one with uremia) were only evaluated clinically. CIn, CPAH and UNaV were studied during hydropenia (HP) and 3% isotonic saline volume expansion (VE). Shortly after the onset CIn, CPAH and UNaV were depressed. Renal function was essentially normal and 1 and 2 years after the onset in spite of signs of active disease. A supernormal GFR was found in 7 patients after they had had the condition between 5 and 17 years. After a duration of IgA GN for greater than 9 years 3 of 12 patients had developed hypertension and uremia and 2 had hypertension or labile BP. Three of 10 patients had a normal GFR and BP, but had increased natriuresis during VE. Only 2 of 10 patients were normotensive and had normal renal function. Disturbances in the renal function are thus frequent in all stages of IgA GN and the changes seem to be related to the duration of the disease. Exaggerated natriuresis may indicate progressive disease.

Clinical trial of plasma exchange with a membrane filter in treatment of crescentic glomerulonephritis.

Four patients with rapidly progressive crescentic glomerulonephritis were treated with repeated plasma exchanges, using a disposable plasma filter (PLASMAFLO), combined with immunosuppression and anticoagulation. A definite improvement of renal function was observed in two patients and complete recovery of the severe lung changes of Goodpasture's syndrome was seen in one of them. In another patient rapid progression of renal insufficiency was arrested. One patient with anuria at the start of treatment remained anuric. The filter was capable of removing as large a molecule as IgM, and the plasma concentrations of immunoglobulins and complement factors declined successively after each treatment. Plasma exchange with the filter technique is readily accessible and safe in hands of the hemodialysis staff. Easy availability and simplicity are important advantages over the centrifuge methods, considering that prompt commencement of the treatment is a key issue in success.