JOURNAL OF THE AMERICAN GERIATRICS SOCIETY Copyright © 1975 by the American Geriatrics Society
Vol. XXIII. No. 12 Printed in U.S.A.
Membranous Nephropathy: An Overview MARDOQUEO I. SALOMON, SeD, MD*, KONRAD HSU, PhDt and VICTOR TCHERTKOFF, MD:j:
New York Medical College-Metropolitan Medical Center, and the College of Physicians and Surgeons, Columbia University, New York, NY
ABSTRACT: Membranous nephropathy (MN) accounts for about 20 percent of cases of the nephrotic syndrome. The importance of renal biopsy in establishing the diagnosis is emphasized. In the great majority of MN patients, no etiologic factor can be discerned. In a significant minority, MN appears to be a manifestation of sarcoidosis, diabetes, lupus, syphilis, malaria, or toxicity from heavy metals or drugs. In some cases the "cause" is neoplasia (including lymphoma) or a viral infection. Massive proteinuria, hypoproteinemia and edema are the principal manifestations of MN, finally resulting in renal failure. Treatment consists chiefly of diet and diuretic drugs. In the more pronounced cases, corticosteroids may have a favorable effect and in very resistant cases, cyclophosphamide is indicated. Judicious use of these modalities if often associated with the diminution or disappearance of the clinical signs of MN.
The last two decades have witnessed remarkable progress in nephrology from both diagnostic and therapeutic viewpoints. The advances in diagnosis have been largely associated with the popularization of renal biopsy and with notable refinements in biopsy interpretation, particularly in the fields of electron microscopy and immunofluorescence. The advances in therapeutics have been largely based on the judicious use of antibiotics, immunosuppressive agents, dialysis and transplantation. As a direct consequence of this progress, a precise diagnostic appraisal of nephropathies has ceased to be an exercise in academic futility. It has become imperative for the physician to try to classify the patient's illness on a strict scientific basis. With these advances,
the problem of prognosis in renal disease has had to undergo a thorough re-evaluation. In the realm of the nephrotic syndromes, the foregoing aspects are of the utmost importance. A precise histologic diagnosis should be established whenever possible in these diseases. In our experience and that of many nephrologists, the membranous variety of nephrosis accounts for about 20 percent of nephrotic syndromes. Even though several papers dealing with membranous nephropathy have appeared in the recent medical literature (1-5) and it may seem otiose to add one more, this article is presented because of the somewhat unorthodox approach to the subject and especially because of some new developments in the rapidly evolving field. The nephrotic syndrome is difficult to define in terms that would encompass all of its variants and nothing but these. We are inclined to apply the following definition: a renal disease involving massive proteinuria (usually more than 5 mg per day and sometimes 12 gm or more) leading to hypoproteinemia (below 3 gm per 100 ml) and as a corollary, to edema of renal origin. It should be emphasized that we omit two alleged characteris-
* Clinical Professor of Medicine and Attending Physician. New York Medical College-Metropolitan Medical Center; Attending Physician, Arthur C. Logan Memorial Hospital. New York, NY. Address for correspondence: Mardoqueo I. Salomon. MD. 1350 Madison Avenue, New York, NY 10028. t Professor of Microbiology. College of Physicians and Surgeons. Columbia University, New York, NY. t Professor of Pathology, "lew York Medical College; Director of Laboratories, Metropolitan Hospital, New York, NY.
535
SALOMON, HSU AND TCHERTKOFF
tics of nephrosis, i.e., hypercholesterolemia and selective proteinuria. ETIOLOGY In contrast to the situation in proliferative glomerulonephritis, the cause of membranous nephropathy (MN) remains unknown in most cases. In a considerable number, however, there appears to be a cause-and-effect relationship between MN and systemic diseases. For example, MN occurs in association with some collagen diseases, mainly lupus and occasionally rheumatoid arthritis (6). Ironically, many a case of MN seemingly is caused by the therapeutic agents used in the treatment of rheumatoid arthritis, especially penicillamin (7) but also gold. The withdrawal of some of these therapeutic agents usually leads to the disappearance of MN. Moreover, the prolonged administration of heavy metals, even in small amounts, may cause the disease. Kibukamusoke et al (8) recently described a case of MN due to skin-lightening cream; this instructive report illustrates the diligence required in the search for etiologic factors. In several cases of epilepsy, the use of trimethadione has been followed by MN. This form of nephropathy may be caused not only by syphilis per se but also by the old-fashioned method of treatment, especially with bismuth. Malaria, insect stings, and some esoteric disorders have contributed their share to the growing list of etiologic factors inMN. In the renal tissue of several MN patients, electron microscopy has revealed virus-like particles. The meaning of this finding is still uncertain. Nevertheless, a viral cause seems plausible, especially in cases associated with hepatitis B virus. Much more ominous is the association between MN and neoplasms, including lymphomas. Indeed, it has been claimed that in 6 percent of patients with MN such a substratum can be found. Hence, in the process of diagnosis, it is mandatory to search for a possible neoplasm. This problem unfortunately is complicated by the fact that MN may not appear during the course of an already diagnosed neoplasm but may precede it by weeks or months. In our experience the percentage of co-existence has been much lower, but its importance is undeniable. Couser et al (9) recently reported a case of MN in which tumor antigen was deposited in the renal glomeruli; moreover, the particular antigen was reactive with the antibody found in association with the
536
Vol. XXIII
colonic carcinoma. When the tumor was resected and a renal biopsy performed four months later, the immune complexes in the glomeruli showed evidence of resolution and the antigen was no longer detectable in the glomeruli, but the edema persisted. Thus, once triggered, the nephrotic syndrome may persist indefinitely (10-12). Other systemic diseases not infrequently associated with MN are sarcoidosis (13) and diabetes. Diabetes should always be kept in mind because renal involvement in this disease is practically universal (14); yet the high incidence of MN in known diabetic patients may be overlooked. The prognosis and the results of treatment in MN are quite different from the gloomy outlook in diabetic nephropathy. However, nothing short of a renal biopsy can establish the true nature of the renal involvement. PATHOLOGY The kidneys are slightly enlarged and pale in the initial stages of MN. When the disease is more advanced, and especially when renal failure sets in, the size of the kidneys diminishes, though they always remain symmetrical. The histologic examination is crucial for diagnosis. There is no hypercellularity, and the mesangium is only minimally increased. The characteristic deposits appear in the basement membrane or, more exactly, in the epithelial surface of the lamina densa externa. These deposits contain IgG and C3 complement, in a granular pattern. As if endeavoring to separate the deposits by "fences," the lamina densa externa produces perpendicular spikes. At a later stage these spikes are joined by basement membrane-like material which eng lobes the deposits, giving the impression of a thickened basement membrane (Fig. 1). Electronmicroscopy confirms the foregoing findings and is especially valuable in demonstrating the deposits and the spikes, i.e., the true nature of the apparent thickening of the basement membrane (Fig. 2). It cannot be overemphasized that the characteristic structure of the basement membrane and the adventitious tissue is often missed by the routine stains employed for simple microscopy; Special stains (CSM or Jones) must be used. Immunof1uorescence is valuable in the microscopic study of MN because it demonstrates both the granular and the chemical nature of the deposits, thus confirming their role as part of the immune complex. Occasionally, however, the de-
MEMBRANOUS NEPHROPATHY
Decemb er 1975
Fig : I . A. Capillary loops showing thickened wall. open lumina. and outlines of spikes. B. Spikes clearly visible. ( x 1000.)
posits may fade away or. when very dense. not be impregnated by the fluorescent sta in (Fig. 3) . The term membranous nephropathy is certainly preferable to the multitude of other terms suggested. The disease is not a glomerulonephritis . The tubular changes are modest, i.e., some degree of atrophy and an occasional foamy appearance. The interstitium is edematous. As the disease advances, the glomerular capillary wall encroaches on the hitherto patent lumen. This obstruction usually is associated with the clinical appearance of renal insufficiency. CLINICAL COURSE The majority of patients with MN consult a physician because they notice edema, beginning in either the legs or the eyelids but gradually involving the whole body . The onset usually is insidious and often the edema is first brought to the patient's attention by a family member or a friend. Sometimes, although the patient may not notice the edema. he may consult a physician because he wants to "go on a diet to lose that excessive weight." Extreme anasarca was common in past decades before the availability of modern drugs, but now it is rare. Perhaps in one-third of all nephrotic patients there is practically no edema despite severe proteinuria and
even hypoproteinemia. In general, hypertension and hematuria are not features of MN; however, Gartner et al (15) observed these manifestations rather frequently in their series of cases . The outstanding feature is proteinuria, with a daily excretion between 5 and 12 gm; lower or higher outputs are not uncommon since the proteinuria may either fade or increase for days or even months for no obvious reason. The urinary sediment contains small to moderate amounts of casts, leukocytes and erythrocytes. Blood urea nitrogen levels, creatinine, and creatinine clearance are normal. In most cases there is no antecedent history of such ailments as " colds" or " throa t infections." The antistreptolysin-O titer and the complement are within normal limits. The evolution of MN is capricious. Usually there are no signs of renal failure for several years. Repeated biopsies may show similar findings, even in untreated patients. Under judicious therapy, the renal findings may remain virtually unchanged for 10 or more years in many cases. MN occasionally is found in children but it is much more common in adults, particularly in those of the 50-70 age group. In many cases, it does not seem to shorten the lifespan. In about 20 percent of patients, deterioration sets in after a few years . Some of these cases evolve into focal glomerulosclerosis, and some
537
SALOMON, HSU AND TCHERTKOFF
Vol. XXIII
into "anti-glomerular-basement-membrane glomerulonephritis" [Klassen et al (16)]. In others the progressive thickening of the basement membrane leads to eventual obsolescence of the glomeruli. An interesting feature of MN is hypovolemia. The roles of renin, aldosterone, and many other factors are still not clear. Clinically. two rare occurrences should be kept in mind: 1) oligemic shock, and 2) collapse after renal biopsy. We have observed neither phenomenon, and we consider renal biopsy particularly easy and safe in MN. Renal vein thrombosis is another problem, discussed in the next section. DIFFERENTIAL DIAGNOSIS
FiF? 2. Capillary loop showing subendothelial deposits and fusion of processes. (Reduced from x 9000.)
After evaluation of nonrenal causes (e.g., cardiac or hepatic disease), at least two other aspects should be considered. First, the general diagnosis of the nephrotic syndrome has to be established. Usually this is not difficult, especially if the outstanding criteria are present, i.e., massive proteinuria, hypoproteinemia, and probably edema. However, the subspecies of the nephrotic
Fig. 3. Immunofluorescent outline of a segment of a glomerulus stained with fluoresceinated antihuman IgG. Granular pattern apparent. (x 720.)
538
December 1975
MEMBRANOUS NEPHROPATHY
syndrome present the main problem in diagnosis. Thus, in a young child the diagnosis is likely to be lipoid nephrosis whereas in an adult it is likely to be MN. Since exceptions occur in both directions, age does not provide a guaranteed basis for making the correct diagnosis. The presence of an underlying predisposing factor may raise the possibility of amyloidosis. Diabetes is a "predisposing" factor, and important precautions are needed in distinguishing diabetic nephropathy from MN. Nothing short of renal biopsy will establish the diagnosis firmly. Several authors have tried to circumvent the necessity for renal biopsy by resorting to certain ancillary studies, especially with regard to the so-called "selectivity" of proteinuria, which is high in the lipoid type of nephrosis, low in the proliferative type and often intermediate in MN. In view of the numerous exceptions, this criterion is unreliable. It has been claimed that a normal blood cholesterol level is the rule in lupus, thus enabling the physician to distinguish lupus nephrosis from MN. Again, there are too many exceptions. Moreover, the status of hypercholesterolemia in MN is very obscure (17). The same applies to the diagnostic value of the level of complement. These statements constitute a plea for more frequent use of renal biopsy in the nephrotic syndrome. In our private and consultant practices, we have reached the conclusion that only renal biopsy can give the physician any feeling of certainty in diagnosis. Renal vein thrombosis (unilateral or bilateral) poses a different problem; it is almost impossible to determine whether it is a cause of MN or a complication. A sudden deterioration in the clinical course of MN should lead one to suspect such a disaster, and a thorough search should be undertaken. Not all cases of thrombosis are lethal; sometimes recanalization takes place and the patient survives. Renal vein thrombosis can occur in one of two forms. In the acute form the patient complains of lower back or flank pains, increased edema of the legs, accentuation of proteinuria, and the appearance of hematuria. Sometimes a mass can be palpated in the kidney region. X-ray examination is invaluable in such cases as it often shows enlargement of the affected kidney (more in width than in length) and may also reveal complications such as pulmonary embolism. Chronic renal vein thrombosis is more difficult to diagnose. Flank pain is usually less pronounced
and the increases in leg edema and proteinuria are more surreptitious and therefore less easy to detect. Great attention should be paid to the finding of a palpable mass. TREATMENT AND PROGNOSIS In this field, significant progress has been made in the last two decades. Previously the prognosis had always been considered gloomy, and this is still the attitude of some physicians. In our experience, the prognosis has definitely improved. We prescribe rest initially if the edema is marked. Otherwise, although physical activity has to be curtailed in order to diminish the catabolism of proteins, the degree and duration of rest are regulated more by the weakness of the patient than by any therapeutic wisdom. In the diet we routinely prescribe an abundant supply of proteins of high nutritive value. Carbohydrates are given freely. Although the question of the special susceptibility of MN patients to coronary and cerebral atheromatosis is still controversial, we curtail the ingestion of fats, especially those of the saturated type. Sometimes it is difficult to convince patients (even apparently intelligent ones) that there is no reason to curtail the drinking of liquids ad libitum as long as renal failure is not severe. Patients with MN should be given a low-salt diet, but this dictum is no longer as draconic as it used to be. At present we limit the dietary deletions to bacon, herring, anchovies and other salt-rich foods. The availability of efficient diuretics permits the more liberal use of salt. Many patients respond favorably to the relatively mild thiazides, and these occasionally can be combined with aminophylline to increase the glomerular filtration rate. When hypokalemia threatens, the use of spironolactone or a similar drug is indicated. Not infrequently, the more potent diuretics such as ethacrynic acid or furosemide have to be used in order to achieve adequate diuresis and combat otherwise intractable edema. (In these cases hypokalemia is more apt to occur.) The proteinuria often disappears under the impact of a potent diuretic, but the mechanism of action is unknown. In many patients, more drastic methods of treatment should be employed. Outstanding among them is the use of corticosteroids. In contrast to the experience of many authors, we
539
Vol. XXlII
SALOMON, HSU AND TCHERTKOFF
have found the judicious use of these agents to be helpful in eliminating or diminishing the proteinuria and hypoproteinemia. The risks inherent in such a therapeutic measure should be weighed against its usefulness. We have not observed any increased tendency toward coronary thrombosis under these circumstances, but we cannot tell whether this is due to good luck, to the fact that we use the smallest possible dose on "alternate days," or to a combination of these factors. In some cases in which the response to the foregoing treatment is suboptimal, cyclophosphamide is added. The side effects must be kept in mind. Hemorrhagic cystitis can be readily prevented by the ingestion of generous amounts of water. Sterility is more of a problem in young people than in middle-aged and older people. Weekly blood counts are indicated in view of the occasional depressing effect of the drug on the hematopoietic system. The long-range possibility of the oncogenic effect of immunosuppression has to be carefully weighed. Nevertheless, when used cautiously and for only a few weeks, cyclophosphamide is both efficacious and relatively safe. In about 60 percent of MN patients the response to these therapeutic measures is favorable; life seems to be prolonged, suffering is diminished, and in many cases there is apparently a "cure" lasting several years (17). Unfortunately, no matter how energetic the treatment, some patients do not respond. In this group, the prognosis is poor; after four or five years, renal failure intervenes. Between the two extremes there is a "gray zone" of intermediate therapeutic results in a significant percentage of patients, and hence an intermediate prognosis. However, even in this group, marked amelioration of the disease is frequently observed. Of late, our attention has been focused on a relatively new agent, dipyridamole. Kan et al (18) have recently surveyed its use for the suppression of proteinuria. The drug is said to reduce platelet adhesiveness and thrombus formation, and hence to be effective in preventing some glomerular lesions. We have tried it on 3 patients, with dubious results. Volume expanders are rarely used today. Injections of human albumin are given occasionally for the purpose of combating hypoproteinemia, and thus the edema. However, the advent of better therapeutic modalities has made these measures obsolete.
540
COMMENT Again, we stress the importance of renal biopsy in making the diagnosis. The clinical manifestations of MN often can be greatly diminished and life apparently prolonged by the use of diet and diuretics; severe cases of MN call for the judicious use of corticosteroids and even cyclophosphamide in addition.
Acknowledgment The authors gratefully acknowledge the kind cooperation of Drs. Gloria Gallo, Artemis Nash and R. H. Heptinstall, and the technical assistance of Mrs. Dolores Quencro.
REFERENCES 1. Gluck MC et al: Membranous glomerulonephritis. Evolution of clinical and pathologic features. Ann Int Med 78: 1. 1973. 2. Hept.inst all RH: Pathology of membranous glomerulonephritis. in Glomerulonephritis. ed. by P Kincaid-Smith. TH Mathew and EL Becker. New York, John Wiley. 197:3, p 415. 3. Pollak VE, Pi rani CL and Clyne DH: The natural history of membranous glomerulonephropathy, Ibid p 423. 4. Laver MC and Kincaid-Smith P: The natural history and treatment of membranous glomerulonephritis. Ibid p 461. 5. Allison AC et al: Immune complexes in the nephrotic syndrome of African children. Lancet 1: 1232. 1969. 6. Salomon MI et al: The kidney in rheumatoid arthritis. A study based on renal biopsies. Nephron 12: 297. 1974. 7. Jaffe IA et al: Nephropathy induced by D-penicillamine. Ann Int Med 69: .549. 1968. 8. Kibukamusoke JW. Davies DR and Hutt MSR: Membranous nephropathy due to skin-lightening cream. Brit Med J 2: 646. 1974. 9. Couser WG et al: Glomerular deposition of tumor antigen in membranous nephropathy associated with colonic carcinoma, Am .J Med .57: 962. 1974. 10. Combes B et al: Glomerulonephritis with deposition of Australia antigen-antibody complexes in glomerular basement membrane, Lancet 2: 234. 1971. 11. Sutherland JC and Mardiney MR Jr: Immune complex disease in the kidneys of lymphoma-leukemia patients. The presence of an oncornavirus-related antigen, J Nat Cancer lnst 50: 633, 1973. 12. Lewis MB. Loughridge LW and Phillips TM: Immunological studies in nephrotic syndrome associated with extrarenal maligant disease. Lancet 2: 1:34. 1971. 13. Salomon MI et al: Membranous glomerulopathy in sarcoidosis, Arch Path 99: 479, 1975. 14. Salomon, MI: Diabetic nephropathy: clinicopathologic correlation. A study based on renal biopsies, Metabolism 12: 687, 196:l. 15. Gartner HV et al: Comparison of clinical and morphological features of peri-j Epi-Extra) membranous glomerulonephritis. Nephron 13: 288, 1974. 16. Klassen .J et al: Evolution of membranous nephropathy into anti-glomerular- basement -mem brane glomerulonephritis, N England .J Med 290: 1340, 1974. 17. Robson J: The nephrotic syndrome, in Renal Disease. ed. by D Black. Oxford. Blackwell. 1972. pp 331-3:l6. 18. Kan K et al: Dipyridamole for proteinuria suppression, Use in a patient with proliferative glomerulonephritis. JAMA 229: .557. 1974.
Vol. XXIII. No. 12 Printed in U.S.A.
Membranous Nephropathy: An Overview MARDOQUEO I. SALOMON, SeD, MD*, KONRAD HSU, PhDt and VICTOR TCHERTKOFF, MD:j:
New York Medical College-Metropolitan Medical Center, and the College of Physicians and Surgeons, Columbia University, New York, NY
ABSTRACT: Membranous nephropathy (MN) accounts for about 20 percent of cases of the nephrotic syndrome. The importance of renal biopsy in establishing the diagnosis is emphasized. In the great majority of MN patients, no etiologic factor can be discerned. In a significant minority, MN appears to be a manifestation of sarcoidosis, diabetes, lupus, syphilis, malaria, or toxicity from heavy metals or drugs. In some cases the "cause" is neoplasia (including lymphoma) or a viral infection. Massive proteinuria, hypoproteinemia and edema are the principal manifestations of MN, finally resulting in renal failure. Treatment consists chiefly of diet and diuretic drugs. In the more pronounced cases, corticosteroids may have a favorable effect and in very resistant cases, cyclophosphamide is indicated. Judicious use of these modalities if often associated with the diminution or disappearance of the clinical signs of MN.
The last two decades have witnessed remarkable progress in nephrology from both diagnostic and therapeutic viewpoints. The advances in diagnosis have been largely associated with the popularization of renal biopsy and with notable refinements in biopsy interpretation, particularly in the fields of electron microscopy and immunofluorescence. The advances in therapeutics have been largely based on the judicious use of antibiotics, immunosuppressive agents, dialysis and transplantation. As a direct consequence of this progress, a precise diagnostic appraisal of nephropathies has ceased to be an exercise in academic futility. It has become imperative for the physician to try to classify the patient's illness on a strict scientific basis. With these advances,
the problem of prognosis in renal disease has had to undergo a thorough re-evaluation. In the realm of the nephrotic syndromes, the foregoing aspects are of the utmost importance. A precise histologic diagnosis should be established whenever possible in these diseases. In our experience and that of many nephrologists, the membranous variety of nephrosis accounts for about 20 percent of nephrotic syndromes. Even though several papers dealing with membranous nephropathy have appeared in the recent medical literature (1-5) and it may seem otiose to add one more, this article is presented because of the somewhat unorthodox approach to the subject and especially because of some new developments in the rapidly evolving field. The nephrotic syndrome is difficult to define in terms that would encompass all of its variants and nothing but these. We are inclined to apply the following definition: a renal disease involving massive proteinuria (usually more than 5 mg per day and sometimes 12 gm or more) leading to hypoproteinemia (below 3 gm per 100 ml) and as a corollary, to edema of renal origin. It should be emphasized that we omit two alleged characteris-
* Clinical Professor of Medicine and Attending Physician. New York Medical College-Metropolitan Medical Center; Attending Physician, Arthur C. Logan Memorial Hospital. New York, NY. Address for correspondence: Mardoqueo I. Salomon. MD. 1350 Madison Avenue, New York, NY 10028. t Professor of Microbiology. College of Physicians and Surgeons. Columbia University, New York, NY. t Professor of Pathology, "lew York Medical College; Director of Laboratories, Metropolitan Hospital, New York, NY.
535
SALOMON, HSU AND TCHERTKOFF
tics of nephrosis, i.e., hypercholesterolemia and selective proteinuria. ETIOLOGY In contrast to the situation in proliferative glomerulonephritis, the cause of membranous nephropathy (MN) remains unknown in most cases. In a considerable number, however, there appears to be a cause-and-effect relationship between MN and systemic diseases. For example, MN occurs in association with some collagen diseases, mainly lupus and occasionally rheumatoid arthritis (6). Ironically, many a case of MN seemingly is caused by the therapeutic agents used in the treatment of rheumatoid arthritis, especially penicillamin (7) but also gold. The withdrawal of some of these therapeutic agents usually leads to the disappearance of MN. Moreover, the prolonged administration of heavy metals, even in small amounts, may cause the disease. Kibukamusoke et al (8) recently described a case of MN due to skin-lightening cream; this instructive report illustrates the diligence required in the search for etiologic factors. In several cases of epilepsy, the use of trimethadione has been followed by MN. This form of nephropathy may be caused not only by syphilis per se but also by the old-fashioned method of treatment, especially with bismuth. Malaria, insect stings, and some esoteric disorders have contributed their share to the growing list of etiologic factors inMN. In the renal tissue of several MN patients, electron microscopy has revealed virus-like particles. The meaning of this finding is still uncertain. Nevertheless, a viral cause seems plausible, especially in cases associated with hepatitis B virus. Much more ominous is the association between MN and neoplasms, including lymphomas. Indeed, it has been claimed that in 6 percent of patients with MN such a substratum can be found. Hence, in the process of diagnosis, it is mandatory to search for a possible neoplasm. This problem unfortunately is complicated by the fact that MN may not appear during the course of an already diagnosed neoplasm but may precede it by weeks or months. In our experience the percentage of co-existence has been much lower, but its importance is undeniable. Couser et al (9) recently reported a case of MN in which tumor antigen was deposited in the renal glomeruli; moreover, the particular antigen was reactive with the antibody found in association with the
536
Vol. XXIII
colonic carcinoma. When the tumor was resected and a renal biopsy performed four months later, the immune complexes in the glomeruli showed evidence of resolution and the antigen was no longer detectable in the glomeruli, but the edema persisted. Thus, once triggered, the nephrotic syndrome may persist indefinitely (10-12). Other systemic diseases not infrequently associated with MN are sarcoidosis (13) and diabetes. Diabetes should always be kept in mind because renal involvement in this disease is practically universal (14); yet the high incidence of MN in known diabetic patients may be overlooked. The prognosis and the results of treatment in MN are quite different from the gloomy outlook in diabetic nephropathy. However, nothing short of a renal biopsy can establish the true nature of the renal involvement. PATHOLOGY The kidneys are slightly enlarged and pale in the initial stages of MN. When the disease is more advanced, and especially when renal failure sets in, the size of the kidneys diminishes, though they always remain symmetrical. The histologic examination is crucial for diagnosis. There is no hypercellularity, and the mesangium is only minimally increased. The characteristic deposits appear in the basement membrane or, more exactly, in the epithelial surface of the lamina densa externa. These deposits contain IgG and C3 complement, in a granular pattern. As if endeavoring to separate the deposits by "fences," the lamina densa externa produces perpendicular spikes. At a later stage these spikes are joined by basement membrane-like material which eng lobes the deposits, giving the impression of a thickened basement membrane (Fig. 1). Electronmicroscopy confirms the foregoing findings and is especially valuable in demonstrating the deposits and the spikes, i.e., the true nature of the apparent thickening of the basement membrane (Fig. 2). It cannot be overemphasized that the characteristic structure of the basement membrane and the adventitious tissue is often missed by the routine stains employed for simple microscopy; Special stains (CSM or Jones) must be used. Immunof1uorescence is valuable in the microscopic study of MN because it demonstrates both the granular and the chemical nature of the deposits, thus confirming their role as part of the immune complex. Occasionally, however, the de-
MEMBRANOUS NEPHROPATHY
Decemb er 1975
Fig : I . A. Capillary loops showing thickened wall. open lumina. and outlines of spikes. B. Spikes clearly visible. ( x 1000.)
posits may fade away or. when very dense. not be impregnated by the fluorescent sta in (Fig. 3) . The term membranous nephropathy is certainly preferable to the multitude of other terms suggested. The disease is not a glomerulonephritis . The tubular changes are modest, i.e., some degree of atrophy and an occasional foamy appearance. The interstitium is edematous. As the disease advances, the glomerular capillary wall encroaches on the hitherto patent lumen. This obstruction usually is associated with the clinical appearance of renal insufficiency. CLINICAL COURSE The majority of patients with MN consult a physician because they notice edema, beginning in either the legs or the eyelids but gradually involving the whole body . The onset usually is insidious and often the edema is first brought to the patient's attention by a family member or a friend. Sometimes, although the patient may not notice the edema. he may consult a physician because he wants to "go on a diet to lose that excessive weight." Extreme anasarca was common in past decades before the availability of modern drugs, but now it is rare. Perhaps in one-third of all nephrotic patients there is practically no edema despite severe proteinuria and
even hypoproteinemia. In general, hypertension and hematuria are not features of MN; however, Gartner et al (15) observed these manifestations rather frequently in their series of cases . The outstanding feature is proteinuria, with a daily excretion between 5 and 12 gm; lower or higher outputs are not uncommon since the proteinuria may either fade or increase for days or even months for no obvious reason. The urinary sediment contains small to moderate amounts of casts, leukocytes and erythrocytes. Blood urea nitrogen levels, creatinine, and creatinine clearance are normal. In most cases there is no antecedent history of such ailments as " colds" or " throa t infections." The antistreptolysin-O titer and the complement are within normal limits. The evolution of MN is capricious. Usually there are no signs of renal failure for several years. Repeated biopsies may show similar findings, even in untreated patients. Under judicious therapy, the renal findings may remain virtually unchanged for 10 or more years in many cases. MN occasionally is found in children but it is much more common in adults, particularly in those of the 50-70 age group. In many cases, it does not seem to shorten the lifespan. In about 20 percent of patients, deterioration sets in after a few years . Some of these cases evolve into focal glomerulosclerosis, and some
537
SALOMON, HSU AND TCHERTKOFF
Vol. XXIII
into "anti-glomerular-basement-membrane glomerulonephritis" [Klassen et al (16)]. In others the progressive thickening of the basement membrane leads to eventual obsolescence of the glomeruli. An interesting feature of MN is hypovolemia. The roles of renin, aldosterone, and many other factors are still not clear. Clinically. two rare occurrences should be kept in mind: 1) oligemic shock, and 2) collapse after renal biopsy. We have observed neither phenomenon, and we consider renal biopsy particularly easy and safe in MN. Renal vein thrombosis is another problem, discussed in the next section. DIFFERENTIAL DIAGNOSIS
FiF? 2. Capillary loop showing subendothelial deposits and fusion of processes. (Reduced from x 9000.)
After evaluation of nonrenal causes (e.g., cardiac or hepatic disease), at least two other aspects should be considered. First, the general diagnosis of the nephrotic syndrome has to be established. Usually this is not difficult, especially if the outstanding criteria are present, i.e., massive proteinuria, hypoproteinemia, and probably edema. However, the subspecies of the nephrotic
Fig. 3. Immunofluorescent outline of a segment of a glomerulus stained with fluoresceinated antihuman IgG. Granular pattern apparent. (x 720.)
538
December 1975
MEMBRANOUS NEPHROPATHY
syndrome present the main problem in diagnosis. Thus, in a young child the diagnosis is likely to be lipoid nephrosis whereas in an adult it is likely to be MN. Since exceptions occur in both directions, age does not provide a guaranteed basis for making the correct diagnosis. The presence of an underlying predisposing factor may raise the possibility of amyloidosis. Diabetes is a "predisposing" factor, and important precautions are needed in distinguishing diabetic nephropathy from MN. Nothing short of renal biopsy will establish the diagnosis firmly. Several authors have tried to circumvent the necessity for renal biopsy by resorting to certain ancillary studies, especially with regard to the so-called "selectivity" of proteinuria, which is high in the lipoid type of nephrosis, low in the proliferative type and often intermediate in MN. In view of the numerous exceptions, this criterion is unreliable. It has been claimed that a normal blood cholesterol level is the rule in lupus, thus enabling the physician to distinguish lupus nephrosis from MN. Again, there are too many exceptions. Moreover, the status of hypercholesterolemia in MN is very obscure (17). The same applies to the diagnostic value of the level of complement. These statements constitute a plea for more frequent use of renal biopsy in the nephrotic syndrome. In our private and consultant practices, we have reached the conclusion that only renal biopsy can give the physician any feeling of certainty in diagnosis. Renal vein thrombosis (unilateral or bilateral) poses a different problem; it is almost impossible to determine whether it is a cause of MN or a complication. A sudden deterioration in the clinical course of MN should lead one to suspect such a disaster, and a thorough search should be undertaken. Not all cases of thrombosis are lethal; sometimes recanalization takes place and the patient survives. Renal vein thrombosis can occur in one of two forms. In the acute form the patient complains of lower back or flank pains, increased edema of the legs, accentuation of proteinuria, and the appearance of hematuria. Sometimes a mass can be palpated in the kidney region. X-ray examination is invaluable in such cases as it often shows enlargement of the affected kidney (more in width than in length) and may also reveal complications such as pulmonary embolism. Chronic renal vein thrombosis is more difficult to diagnose. Flank pain is usually less pronounced
and the increases in leg edema and proteinuria are more surreptitious and therefore less easy to detect. Great attention should be paid to the finding of a palpable mass. TREATMENT AND PROGNOSIS In this field, significant progress has been made in the last two decades. Previously the prognosis had always been considered gloomy, and this is still the attitude of some physicians. In our experience, the prognosis has definitely improved. We prescribe rest initially if the edema is marked. Otherwise, although physical activity has to be curtailed in order to diminish the catabolism of proteins, the degree and duration of rest are regulated more by the weakness of the patient than by any therapeutic wisdom. In the diet we routinely prescribe an abundant supply of proteins of high nutritive value. Carbohydrates are given freely. Although the question of the special susceptibility of MN patients to coronary and cerebral atheromatosis is still controversial, we curtail the ingestion of fats, especially those of the saturated type. Sometimes it is difficult to convince patients (even apparently intelligent ones) that there is no reason to curtail the drinking of liquids ad libitum as long as renal failure is not severe. Patients with MN should be given a low-salt diet, but this dictum is no longer as draconic as it used to be. At present we limit the dietary deletions to bacon, herring, anchovies and other salt-rich foods. The availability of efficient diuretics permits the more liberal use of salt. Many patients respond favorably to the relatively mild thiazides, and these occasionally can be combined with aminophylline to increase the glomerular filtration rate. When hypokalemia threatens, the use of spironolactone or a similar drug is indicated. Not infrequently, the more potent diuretics such as ethacrynic acid or furosemide have to be used in order to achieve adequate diuresis and combat otherwise intractable edema. (In these cases hypokalemia is more apt to occur.) The proteinuria often disappears under the impact of a potent diuretic, but the mechanism of action is unknown. In many patients, more drastic methods of treatment should be employed. Outstanding among them is the use of corticosteroids. In contrast to the experience of many authors, we
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have found the judicious use of these agents to be helpful in eliminating or diminishing the proteinuria and hypoproteinemia. The risks inherent in such a therapeutic measure should be weighed against its usefulness. We have not observed any increased tendency toward coronary thrombosis under these circumstances, but we cannot tell whether this is due to good luck, to the fact that we use the smallest possible dose on "alternate days," or to a combination of these factors. In some cases in which the response to the foregoing treatment is suboptimal, cyclophosphamide is added. The side effects must be kept in mind. Hemorrhagic cystitis can be readily prevented by the ingestion of generous amounts of water. Sterility is more of a problem in young people than in middle-aged and older people. Weekly blood counts are indicated in view of the occasional depressing effect of the drug on the hematopoietic system. The long-range possibility of the oncogenic effect of immunosuppression has to be carefully weighed. Nevertheless, when used cautiously and for only a few weeks, cyclophosphamide is both efficacious and relatively safe. In about 60 percent of MN patients the response to these therapeutic measures is favorable; life seems to be prolonged, suffering is diminished, and in many cases there is apparently a "cure" lasting several years (17). Unfortunately, no matter how energetic the treatment, some patients do not respond. In this group, the prognosis is poor; after four or five years, renal failure intervenes. Between the two extremes there is a "gray zone" of intermediate therapeutic results in a significant percentage of patients, and hence an intermediate prognosis. However, even in this group, marked amelioration of the disease is frequently observed. Of late, our attention has been focused on a relatively new agent, dipyridamole. Kan et al (18) have recently surveyed its use for the suppression of proteinuria. The drug is said to reduce platelet adhesiveness and thrombus formation, and hence to be effective in preventing some glomerular lesions. We have tried it on 3 patients, with dubious results. Volume expanders are rarely used today. Injections of human albumin are given occasionally for the purpose of combating hypoproteinemia, and thus the edema. However, the advent of better therapeutic modalities has made these measures obsolete.
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COMMENT Again, we stress the importance of renal biopsy in making the diagnosis. The clinical manifestations of MN often can be greatly diminished and life apparently prolonged by the use of diet and diuretics; severe cases of MN call for the judicious use of corticosteroids and even cyclophosphamide in addition.
Acknowledgment The authors gratefully acknowledge the kind cooperation of Drs. Gloria Gallo, Artemis Nash and R. H. Heptinstall, and the technical assistance of Mrs. Dolores Quencro.
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