Correspondence

The Nephrotic Syndrome

N Engl J Med 1998; 339:772-773September 10, 1998

Article

To the Editor:

In their review article, Orth and Ritz (April 23 issue)1 state that membranous nephropathy is the most common cause of idiopathic nephrotic syndrome in adults, citing as a source data from a book published in 1988.2 According to these data, summarized in Table 1 of the article, minimal-change nephropathy is the second most common cause of adult nephrotic syndrome, and focal segmental glomerulosclerosis is third, accounting for fewer than 15 percent of such cases. However, recent data from three separate groups3-5 indicate that over the past 25 years and particularly during the past decade, there has been a marked increase in the incidence of primary focal segmental glomerulosclerosis in adults, both overall and as a cause of the nephrotic syndrome. In the renal-biopsy practice at my institution, which processes over 500 native renal-biopsy specimens a year from more than 30 hospitals in the midwestern United States, and in the similarly busy practice of D'Agati based in New York City, focal segmental glomerulosclerosis is now the leading cause of idiopathic nephrotic syndrome in adults.3,5 In a recent study of the underlying causes of 233 cases of adult idiopathic nephrotic syndrome diagnosed from 1995 to 1997,5 my colleagues and I found that focal segmental glomerulosclerosis was the cause in 35 percent of cases, membranous nephropathy in 33 percent, and minimal-change disease in 15 percent. Our data are similar to those of Korbet and coworkers.4 Focal segmental glomerulosclerosis is particularly common in blacks, accounting for 56 percent of cases of idiopathic nephrotic syndrome in black adults and two thirds of such cases in black adults under the age of 45 years. In white adults, although membranous nephropathy remains the most common cause of idiopathic nephrotic syndrome (frequency, 38 percent), the relative frequency of focal segmental glomerulosclerosis as a primary nephropathy has more than doubled since the late 1970s, and it is now the second most common cause of idiopathic nephrotic syndrome in this group, accounting for 25 percent of cases.5 The cause of this increase in the frequency of primary focal segmental glomerulosclerosis is not known, though it is not related to a change in the racial composition of our patient population, to changes in our ability as pathologists to diagnose focal segmental glomerulosclerosis, or to changes in the size or processing of renal-biopsy specimens.5

Mark Haas, M.D., Ph.D.
University of Chicago, Chicago, IL 60637-1470

5 References

1
Orth SR, Ritz E. The nephrotic syndrome. N Engl J Med 1998;338:1202-1211
Full Text | Web of Science | Medline

2
Lewis EJ. Management of the nephrotic syndrome in adults. In: Cameron JS, Glasscock RJ, eds. The nephrotic syndrome. New York: Marcel Dekker, 1988;461-521.

3
D'Agati V. The many masks of focal segmental glomerulosclerosis. Kidney Int 1994;46:1223-1241
CrossRef | Web of Science | Medline

4
Korbet SM, Genchi RM, Borok RZ, Schwartz MM. The racial prevalence of glomerular lesions in nephrotic adults. Am J Kidney Dis 1996;27:647-651
CrossRef | Web of Science | Medline

5
Haas M, Meehan SM, Karrison TG, Spargo BH. Changing etiologies of unexplained adult nephrotic syndrome: a comparison of renal biopsy findings from 1976-1979 and 1995-1997. Am J Kidney Dis 1997;30:621-631
CrossRef | Web of Science | Medline

To the Editor:

Orth and Ritz provide a lucid and comprehensive review of the nephrotic syndrome. They recommend the use of ultrafiltration in particularly severe cases. However, they do not include metolazone among the noninvasive treatment options available as an adjunct to loop and potassium-sparing diuretics.

The addition of metolazone to furosemide therapy can be helpful in the treatment of refractory edema in infants and children, leading to greater natriuresis, urinary output, and weight loss than is induced by furosemide alone.2 The use of metolazone is based on the principle of sequential nephron blockade, in which metolazone acts synergistically with a loop diuretic by preventing compensatory sodium retention in the early distal tubule. Thus, we believe there is a place for metolazone in the management of severe edema resistant to loop diuretics before extracorporeal techniques are employed.

Zohar Barzilay, M.D.
Gideon Paret, M.D.
Chaim Sheba Medical Center, Tel-Hashomer 52621, Israel

2 References

1
Garin EH. A comparison of combinations of diuretics in nephrotic edema. Am J Dis Child 1987;141:769-771
Web of Science | Medline

2
Arnold WC. Efficacy of metolazone and furosemide in children with furosemide-resistant edema. Pediatrics 1984;74:872-875
Web of Science | Medline

Author/Editor Response

The authors and a colleague reply:

To the Editor: We are aware of the report by Haas et al.1 and similar reports2-4 of a trend toward an increase in the frequency of focal segmental glomerulosclerosis in recent decades. The report by Haas et al. was published after our article had been completed, and we thought that without some comment and discussion, it might have been misleading to make a global statement about focal segmental glomerulosclerosis as the number-one cause of the nephrotic syndrome. Haas et al.1 reported that in the past two decades the proportion of patients with focal segmental glomerulosclerosis and IgA glomerulonephritis among patients undergoing renal biopsy for the nephrotic syndrome has increased. Among black adults with the nephrotic syndrome, 56 percent had focal segmental glomerulosclerosis, whereas the respective value among white adults was 25 percent.1 The findings of Haas et al.1 are in agreement with our observation that among patients who underwent renal biopsy for the nephrotic syndrome in 1997, 30.5 percent had membranous glomerulonephritis, 19.4 percent had focal segmental glomerulosclerosis, and 11.1 percent had minimal-change glomerulonephropathy.

Drs. Barzilay and Paret correctly point out that natriuresis is enhanced by sequential blockade of the nephron — i.e., of the ascending thick loop of Henle with loop diuretics and the distal tubule with thiazides, possibly in combination with potassium-sparing diuretics. We could show this effect even in patients with advanced renal failure.5 Metolazone, although chemically not characterized by a thiazide ring system, is a diuretic acting at the thiazide-sensitive distal site and thus fits into the scheme of sequential nephron blockade that we had proposed. We thank Drs. Barzilay and Paret, however, since this simple method of increasing diuretic potency is not widely known and is even less widely used.

Stephan R. Orth, M.D.
Ivan Rychlík, M.D.
Eberhard Ritz, M.D.
Ruperto Carola University, 69115 Heidelberg, Germany

5 References

1
Haas M, Meehan SM, Karrison TG, Spargo BH. Changing etiologies of unexplained adult nephrotic syndrome: a comparison of renal biopsy findings from 1976-1979 and 1995-1997. Am J Kidney Dis 1997;30:621-631
CrossRef | Web of Science | Medline

2
Korbet SM, Genchi RM, Borok RZ, Schwartz MM. The racial prevalence of glomerular lesions in nephrotic adults. Am J Kidney Dis 1996;27:647-651
CrossRef | Web of Science | Medline

3
D'Agati V. The many masks of focal segmental glomerulosclerosis. Kidney Int 1994;46:1223-1241
CrossRef | Web of Science | Medline

4
Braden G, Mulhern J, O'Shea M, Germain M, Nash S, Ucci A. Changing incidence of idiopathic glomerular diseases in adults. J Am Soc Nephrol 1995;6:413-413 abstract.
Web of Science

5
Fliser D, Schroter M, Neubeck M, Ritz E. Coadministration of thiazides increases the efficacy of loop diuretics even in patients with advanced renal failure. Kidney Int 1994;46:482-488
CrossRef | Web of Science | Medline

Citing Articles (1)

Citing Articles

1
DANIEL F. JIMENEZ AND, ALICE F. TARANTAL. (2003) Quantitative Analysis of Male Fetal DNA in Maternal Serum of Gravid Rhesus Monkeys (Macaca mulatta). Pediatric Research 53:1, 18-23
CrossRef