A joint Congress by ERA-EDTA and ISN

NATURAL HISTORY AND PROGNOSTIC FACTORS

Claudio Ponticelli, Milan, Italy

Chair: Dontscho Kerjaschki, Vienna, Austria

Claudio Ponticelli, Milan, Italy

Prof C. Ponticelli IRCCS Istituto Auxologico Italiano Milan, Italy

Slide 1

Professor Kerjaschki, Dear colleagues.

Slide 2

The natural course of membranous nephropathy may be variable with some patients entering spontaneous remission, others showing persistent proteinuria, usually in the nephrotic range and a third group of patients progressing  to ESRD or even dying from extra renal complications.

Slide 3

A number of factors can influence the natural course of this disease and I’ll try in my talk to summarize shortly the most important of them.

Slide 4

In a large review of Doctor Hogan it was shown that about 40% of Caucasians and Black patients enter the ESRD within 10 years from clinical onset. However, the prognosis seems to be better in Japan. In a large multicentre Japanese study almost 1000 patients were enrolled and the renal survival was 90% at 10 years and 81% at 15 years. An excellent renal survival has also been reported in some papers from China although the number of patients enrolled was smaller and the follow up was shorter.

Slide 5

In the past children were considered to have fair prognosis, however recent analysis reported that 25-50% of children with nephrotic syndrome whether treated or untreated progressed to kidney failure and more importantly were also susceptible to vascular thrombosis.

Slide 6

Spontaneous remission and response to therapy are similar in older patients and in younger adults. However older patients usually have lower levels of creatinine clearance at presentation and can therefore, develop renal insufficiency earlier than younger adults. Moreover, elderly patients may have a poor tolerance to treatments and are more vulnerable to the consequences of the nephrotic syndrome.

Slide 7

Spontaneous remission and response to therapy are more frequent in women than in men for unknown reasons.

Slide 8

These data have been confirmed by Doctor Cattran who by reviewing the data of the Toronto Registry showed that the renal survival was significantly better in women than in men although some 20-25% of women eventually entered end stage renal failure after a long-term follow up.

Slide 9

It is well known that patients with persisting nephrotic syndrome have relatively poor outcomes in the long-term while patients with non-nephrotic proteinuria have a better outcome.
However, assessing the prognosis from the amount of proteinuria at presentation may be unreliable, since a number of patients presenting with nephrotic syndrome have spontaneous remission while a number of patients with non-nephrotic proteinuria can eventually develop a nephrotic proteinuria.

Slide 10

Therefore, Pei and Cattran through a sophisticated model suggested to measure the amount of proteinuria over time for at least 6 months. They reported that patients with proteinuria less than 4 g/day over 6 months have a low risk of progression, about 6%. Patients with proteinuria ranging between 4 and 8 g/day over 6 months have a medium risk of developing chronic renal insufficiency at about 55% within 10 years. Patients with abnormal or deteriorating serum creatinine and/or proteinuria more than 8g/day over 6 months have 66-80% probabilities of developing renal insufficiency within 10 years.
A limitation of this study however, is that about ¼ of patients required one year or more to have stable proteinuria. Accordingly,  in some cases we should wait for a relatively long period of time before taking therapeutic decisions.

Slide 11

Doctor Branten reported that an increased urinary excretion of β2 microglobulin or an increased excretion of IgG can be of prognostic value since patients with elevated excretion of IgG have a high probability of having a serum creatinine of more than 1.5 mg/dL. These data however, were obtained in patients either untreated or treated with corticosteroids which are of little efficacy in patients with membranous nephropathy. The results can be better with other treatments.

Slide 12

For example, according to Doctor Fervenza, who kindly provided me this slide, there wasn’t any association between the reduction of proteinuria after rituximab and the baseline values IgG.

Slide 13

Many investigators believe that increased serum creatinine levels at presentation can presage the late development of ESRD. However, in a number of cases with severe nephrotic syndrome, renal insufficiency may be functional and reversible being caused by hypovolemia related to severe hypoalbuminemia or to excessive dosage of diuretics or to a drug-associated acute interstitial nephritis.

Slide 14

A marker of good prognosis over time may be complete remission of proteinuria.
In an old paper Doctor Passerini reported that out of 157 patients who entered complete remission of proteinuria, either spontaneously or after treatment, only one developed ESRD after median follow ups ranging between 38-132 months.

Slide 15

In the same study, we followed for 10 years 45 patients in our unit who had complete remission of proteinuria . The mean serum creatinine maintained almost stable over the time.

Slide 16

Also partial remission of proteinuria can be a sign of a favorable prognosis. According to a definition of partial proteinuria relatively strict (meaning normal serum creatinine and proteinuria ranging between 0.21 and 2 g/day), we followed 37 patients and after a mean follow up of 76 months 89% of them maintained a stable serum creatinine and 11% deteriorated renal function but none of them entered ESRD.

Slide 17

These data have been more recently confirmed by Troyanov and co-workers, they reviewed again the data of the Toronto Registry and they reported that the prognosis in the long-term was excellent for patients who entered complete remission of proteinuria. It was 70% at 15 years for patients who entered a partial remission of proteinuria while it was about 30% at 15 years for patients who did not respond to treatment and remained nephrotic.

Slide 18

What about renal histology? A number of investigators couldn’t find any relationship between the glomerular stages according to Ehrenreich and Churg  classification and the renal outcome.

Slide 19

Instead both univariate and multivariate analyses clearly showed that severe tubulo-interstitial lesions were predictive of renal failure.

Slide 20

More controversial is the role of superimposed focal sclerosis. In a paper of Doctor Dumoulin it was showed that after a mean follow up of 68 months renal survival and remission were significantly lower in patients with superimposed focal sclerosis than in patients without. Pooling their results with those of 3 previous studies of the literature the remission rate was 13% in patients with superimposed focal sclerosis versus 32% for patients without superimposed sclerosis. 

Slide 21

However, these data has been challenged by Heeringa and co-workers who couldn’t find any significant difference in the renal survival rate between patients without focal sclerosis and patients with superimposed focal sclerosis.

Slide 22

By reviewing our data of a multicentre controlled trial we found that no pathological feature was able to reliably predict the presence or absence of a favorable response to a cyclical therapy with steroid-cytotoxic agents.

Slide 23

The role of renal histology has been also partially criticized by Troyanov and co-workers. They found that although the severity of tubulo-interstitial lesions, vascular damage, and secondary FSGS correlated with a reduced renal survival, these parameters did not predict the outcome independently of the baseline serum creatinine and proteinuria, nor did they correlate with the rate of decline in function. Moreover, the severity of tubulo-interstitial and vascular lesions did not preclude remission upon treatment.

Slide 24

But one of the most important predictor factors is time. We looked at the prognosis of a membranous nephropathy taking into consideration only the few papers that reported the outcome for patients who were untreated with any specific therapy. One can see that the prognosis at 5 years seems quite favorable with most patients still alive with kidney functioning. But at 10 years some 40-60% of patients already entered ESRD and the prognosis was quite poor for patients with follow-ups longer than 10 years.

Slide 25

So in conclusion a number of non modifiable factors may influence the natural course of membranous nephropathy. At presentation urinary β2 M and urinary IgG, serum creatinine, interstitial fibrosis and/or FSGS at renal biopsy may be associated with a worse prognosis in untreated patients but a number of patients with these risk factors can respond to an adequate treatment. However,  it must be remembered that apart from the risk of renal progression over time a persistent nephrotic syndrome entails a high risk of extra-renal complications such as vascular thrombosis, cardiovascular disease, infection and malnutrition. These data are often underevaluated by the nephrologists.

Slide 26

So what to do with our patients? I feel that patients who do not have nephrotic proteinuria and who have normal renal function should not be treated with any specific therapy. A wait and see policy can be adopted for patients with proteinuria ranging between 3-4 g/day and for patients who remain asymptomatic. Instead  patients with persistent proteinuria, more than 4 g/day, those symptomatic and those with deterioration of renal function should be given a specific treatment but what kind of treatment will be discussed by my friend Doctor Glassock in a few minutes. Thank you for your attention.