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SPLENECTOMY FOR ANAEMIA
367
Focal Glomerulosclerosis
nephrotic syndrome is associated with " minimal changes " on biopsy, a good response to corticosteroid therapy is to be expected in both adults and children.1-3 But exceptions have been reported. A few patients who did not respond to treatment and progressed to renal failure were found to have developed sclerotic glomerular changes with a characteristically focal and segmental disWHEN the
HABIB tribution.4-9 abnormalities in biopsy
al.10
observed similar specimens obtained at onset of the nephrotic syndrome, and subsequent work has amply confirmed their findings. 2. 3,5, 11-13 Within this group of patients two distinct diseases can be identified. In the first and larger group, of composed mainly children (and more often boys than girls), hypertension and hxmaturia are absent or transient, while the proteinuria is generally highly selective and readily abolished by corticosteroids.l--3 Renal-biopsy specimens show either optically normal cells glomeruli or the slight increase of mesangial and matrix which is accepted as " minimal changes ".2,10,11 In the other group, known as "focal glomerulosclerosis" , the sex incidence is roughly equal,2,9.13 hypertension and hxmaturia are common, and proteinuria is usually non-selective,2,12,13 while a complete response to steroid or cytotoxic therapy is unlikely.2, 3,’-2,’3 The renal lesion is distinguishable bythe segmental distribution of glomerular sclerosis with overlying adhesions, inconspicuous proliferation, and associated tubular atrophy. 2-6, 10-133 In his original description of this disease, RICH4 pointed out that the juxtamedullary glomeruli are first affected, the disease spreading centrifugally, and that, in children dying from early complications of the nephrotic syndrome rather than chronic renal failure, they may be the only glomeruli involved. The paper by Dr. HOYER and his colleagues at the front of this week’s issue throws new light on the nature of focal glomerulosclerosis. 3 out of 4 patients who received renal transplants had recurrence of the nephrotic syndrome. Focal glomerular lesions were demonstrated in all 3 patients before transplantation, and post-mortem examination of the 1. 2. 3. 4. 5. 6. 7.
8. 9.
10.
11. 12. 13.
et
Cameron, J. S. Br. med. J. 1968, iv, 352. White, R. H. R., Glasgow, E. F., Mills, R. J. Lancet, 1970, i, 1353. White, R. H. R. in Recent Advances in Paediatrics (edited by D. Gairdner and D. Hull); p. 281. London, 1971. Rich, A. R. Bull. Johns Hopk. Hosp. 1957, 100, 173. McGovern, V. J. Australas. Ann. Med. 1964, 13, 306. Heptinstall, R. H. Pathology of the Kidney; p. 374. Boston, 1966. Hayslett, J. P., Krassner, L. S., Bensch, K. G., Kashgarian, M., Epstein, F. H. New Engl. J. Med. 1969, 281, 181. Duffy, J. L., Cinque, T., Chrishman, E., Churg, J. J. clin. Invest. 1970, 49, 251. Hopper, J., Jr., Ryan, P., Lee, J. C., Rosenau, W. Medicine, Baltimore, 1970, 49, 321. Habib, R., Michielsen, P., de Montera, E., Hinglais, N., Galle, P., Hamburger, J. in Ciba Foundation Symposium on Renal Biopsy edited by G. E. W. Wolstenholme and M. P. Cameron); p. 70. London, 1961. Churg, J., Habib, R., White, R. H. R. Lancet, 1970, i, 1299. Habib, R., Gubler, M. C. Nephron, 1971, 8, 382. Glasgow, E. F., White, R. H. R. ibid. p. 403.
homografts of the 2 who subsequently died showed identical lesions, affecting predominantly the juxtamedullary glomeruli and suggesting recurrence of the original disease rather than a chronic rejection process. The fact that the disease appears to attack the host kidneys and homograft in an identical
despite immunosuppressive therapy and previous bilateral nephrectomy, makes the Minneapolis workers’ suggestion of a humoral factor an attractive possibility. Thus, focal glomerulosclerosis emerges as a progressive disease for which renal transplantation may be contraindicated, leaving dialysis as probably the only means of prolonging life. Accurate diagnosis is therefore of considerable importance. Why do some patients with this disease show only minimal changes when first investigated ? If a humoral mechanism is operative, it may well antedate the glomerular structural changes, making a morphological diagnosis impossible, by current techniques, in the earliest stage. An equally likely explanation is to be found in the unique juxtamedullary distribution of early lesions,4 which could easily be missed in a small or superficial renal-biopsy specimen.2,11 Moreover, when the lesions are slight they may, with the best intentions, be classified pathologically as " minimal changes", just as they are apt to be called " chronic glomerulonephritis "6 in an advanced stage even though the characteristic combination of normal, partly sclerosed, and completely sclerosed manner,
In glomeruli 2,3,11-13 may still be discernible. interpreting the prognostic significance of a morphological diagnosis of minimal changes " the clinical and laboratory findings and the steroid response "
therefore be taken into account.3 This new information about the nature of focal glomerulosclerosis makes the practice of lumping steroidsensitive and steroid-resistant patients together under the common heading " lipoid " or " idiopathic " must
nephrosis
no
longer justifiable.
SPLENECTOMY FOR ANAEMIA EVERY now and then the physician whose special interest is haematology will have to decide whether or not to recommend splenectomy for a patient with anaemia. The decision is straightforward only in one condition-hereditary spherocytosis. In this haemolytic anaemia splenectomy is always successful, and the only decision required is the choice of the right time for the operation. In children it is usual to postpone splenectomy, unless the anaemia is very severe, till after the 5th birthday because of the risk of infection in young children. In patients over 60 the disease is sometimes discovered by chance when they come under investigation for some other condition; here, unless the splenomegaly is serious or the anaemia causing symptoms, splenectomy is rarely recommended, since there is always some risk attached to the operation. In all other types of anaemia with splenomegaly, such
368
autoimmune haemolytic anaemia, anxmia associated with portal hypertension, anaemia in Felty’s syndrome, or myelosclerosis, the decision has often had to be made on quite empirical grounds, such as increasing need for blood-transfusion or the mechanical effect of In the past few years, the large abdominal mass. however, radioactive tagging techniques have provided some useful tests to help assess the probable benefit of splenectomy in a particular case. A combined team from the departments of clinical haematology and surgery at University College Hospital and Medical School, London,l have now reported their experience of these tests and full details are given of the results in 41 patients who had splenectomy for various hxmatological conditions. The tests were determination of the rate of intrasplenic red-cell destruction, the size of the red-cell splenic pool, and estimation of possible expansion of plasma-volume. For the first two tests red cells were tagged with radioactive chromium e1Cr), and for the plasma-volume measurements 131I-tagged humanserum-albumin was injected. In normal persons the half-life of red blood-cells tagged with SlCr is 22-30 days; a half-life of less than 10 days together with a climbing splenic-uptake curve, and a count over the spleen at least twice that over the liver at half-life time, was regarded as one indication for splenectomy. Another was the presence of anaemia and an enlarged spleen more than 4 cm. below the costal margin combined with a plasma-volume of more than 50% in excess of normal. The estimates of splenic pooling were found to be less helpful; changes depended more on the pathology of the different conditions than on anything that gave a guide to the value of splenectomy; increases in the splenic pool were usually found when the basic disease was a red-cell abnormality, but they were less often found when the spleen itself was the source of the disease, as in congestive splenomegaly. Their 41 patients included 5 with hereditary spherocytosis, in whom the splenectomy was predictably entirely successful, though the red-cell survival did not always return to normal; these patients all showed striking shortening of red-cell-survival times, a spleen count increasing to over twice that of the liver count, and an increased splenic red-cell pool; but plasma-volume measurements were normal. Patients with autoimmune haemolytic anxmia gave very similar results, but experience proved that, even when the splenic uptake was favourable for splenectomy, the operation did not always give the expected result. 3 patients with anaemia due to pyruvate-kinase deficiency in the red cells showed decreased red-cell survival, increased spleen/liver ratios, some degree of increased splenic pooling, and again no increase in plasmavolume ; these patients had their spleens removed with benefit even though their anaemia was not entirely relieved. 10 patients had " proliferative conditions, including myeloid metaplasia and chronic myeloid and lymphatic leukxmias; 4 had"congestive splenomegaly; and 7 had a miscellaneous group of diseases (2 with Felty’s syndrome): in all these patients red-cell survival was less shortened or even normal, the spleen/liver ratio was not significantly raised, and the main change
as
"
in the plasma-volume, which was considerably raised and fell towards normal after splenectomy. But it was observed that this fall was not permanent and, despite the absence of the spleen, the figures for plasma and total-blood volumes tended to rise again over the subsequent few years. 3 patients with thalassaemia were investigated before and after splenectomy. Before the operation the red-cell survival was shortened to 12-14 days, the spleen/liver ratio was not raised above 2 in 2 patients and only reached 2-2 in the 3rd, and the plasma-volume figures were raised. However, splenectomy did not alter their hxmatocrit values or diminish their reticulocyte-counts, so the operations were unsuccessful in relieving the anaemia, though the patients will have benefited from removal of their abdominal was
masses.
Nightingale and co-workers also state that in the past splenectomies have been performed on their patients for hxmatological reasons, with only 3 postoperative deaths. This is an excellent record and shows what can be done by close cooperation between surgical and haematological teams. Assessing the results of the isotope tests in their whole series of 104 patients, they conclude that, while these tests are undoubtedly valuable, they do not provide the complete answer. In some patients, when tests are favourable, the splenectomy is not followed by the expected relief of the anaemia; in others good results follow, though the tests gave equivocal results. They believe that the tests provide a significantly better assessment of the value of splenectomy than has been obtained using other bases for assessment in idiopathic acquired haemolytic anaemia ". On the other hand, the results of splenectomy in the conditions in which increased plasmavolume is the only abnormality still seem to be unpredictable. Splenectomy for the relief of anaemia 7 years 104
"
should
not
therefore be advised before
tests
have been
performed-any properly equipped hasmatological laboratory can undertake them today. At the same time, the physician will weigh other factors such as the degree of disability that the anasmia causes, the frequency of the need for blood-transfusion, the burden of the abdominal mass, and the patient’s occupation and home circumstances. Nor should the operative risk be entirely discounted; with the best care this risk is now down to 3%; but weeks of disability may follow the operation, especially in older patients.
HYPOCOMPLEMENTAEMIC NEPHRITIS AFTER Bordet’s description ofhaemolytic complement in 1898,1 there appeared a series of papers reporting low levels of complement (which the authors attributed to urxmia 2-6) in patients with renal disease. Gunn7 reported 4 cases of acute poststreptococcal nephritis with depressed complement levels, and it is now known that serum-haemolytic-complement is reduced in most such patients. Kellettseems to have been the
"
1.
Nightingale, D., Prankerd, T.
A. J., Richards, D. Q. Jl Med. 1972, 41, 261.
J. D. M., Thompson,
1. Bordet, J. Ann. Inst. Pasteur, Paris, 1898, 12, 688. 2. Neisser, E., Doering, H. Berl. klin. Wschr. 1901, 38, 593. 3. Laqueur, A. Dt. med. Wschr. 1901, 27, 744. 4. Hedinger, E. Dt. Arch. klin. Med. 1902, 74, 24. 5. Longcope, W. T. J. Hyg., Camb. 1903, 3, 28. 6. Wolze, E. Zentbl. inn. Med. 1903, 24, 649. 7. Gunn, W. C. J. Path. Bact. 1914, 19, 155. 8. Kellett, C. E. Lancet, 1936, ii, 1262.
Focal Glomerulosclerosis
nephrotic syndrome is associated with " minimal changes " on biopsy, a good response to corticosteroid therapy is to be expected in both adults and children.1-3 But exceptions have been reported. A few patients who did not respond to treatment and progressed to renal failure were found to have developed sclerotic glomerular changes with a characteristically focal and segmental disWHEN the
HABIB tribution.4-9 abnormalities in biopsy
al.10
observed similar specimens obtained at onset of the nephrotic syndrome, and subsequent work has amply confirmed their findings. 2. 3,5, 11-13 Within this group of patients two distinct diseases can be identified. In the first and larger group, of composed mainly children (and more often boys than girls), hypertension and hxmaturia are absent or transient, while the proteinuria is generally highly selective and readily abolished by corticosteroids.l--3 Renal-biopsy specimens show either optically normal cells glomeruli or the slight increase of mesangial and matrix which is accepted as " minimal changes ".2,10,11 In the other group, known as "focal glomerulosclerosis" , the sex incidence is roughly equal,2,9.13 hypertension and hxmaturia are common, and proteinuria is usually non-selective,2,12,13 while a complete response to steroid or cytotoxic therapy is unlikely.2, 3,’-2,’3 The renal lesion is distinguishable bythe segmental distribution of glomerular sclerosis with overlying adhesions, inconspicuous proliferation, and associated tubular atrophy. 2-6, 10-133 In his original description of this disease, RICH4 pointed out that the juxtamedullary glomeruli are first affected, the disease spreading centrifugally, and that, in children dying from early complications of the nephrotic syndrome rather than chronic renal failure, they may be the only glomeruli involved. The paper by Dr. HOYER and his colleagues at the front of this week’s issue throws new light on the nature of focal glomerulosclerosis. 3 out of 4 patients who received renal transplants had recurrence of the nephrotic syndrome. Focal glomerular lesions were demonstrated in all 3 patients before transplantation, and post-mortem examination of the 1. 2. 3. 4. 5. 6. 7.
8. 9.
10.
11. 12. 13.
et
Cameron, J. S. Br. med. J. 1968, iv, 352. White, R. H. R., Glasgow, E. F., Mills, R. J. Lancet, 1970, i, 1353. White, R. H. R. in Recent Advances in Paediatrics (edited by D. Gairdner and D. Hull); p. 281. London, 1971. Rich, A. R. Bull. Johns Hopk. Hosp. 1957, 100, 173. McGovern, V. J. Australas. Ann. Med. 1964, 13, 306. Heptinstall, R. H. Pathology of the Kidney; p. 374. Boston, 1966. Hayslett, J. P., Krassner, L. S., Bensch, K. G., Kashgarian, M., Epstein, F. H. New Engl. J. Med. 1969, 281, 181. Duffy, J. L., Cinque, T., Chrishman, E., Churg, J. J. clin. Invest. 1970, 49, 251. Hopper, J., Jr., Ryan, P., Lee, J. C., Rosenau, W. Medicine, Baltimore, 1970, 49, 321. Habib, R., Michielsen, P., de Montera, E., Hinglais, N., Galle, P., Hamburger, J. in Ciba Foundation Symposium on Renal Biopsy edited by G. E. W. Wolstenholme and M. P. Cameron); p. 70. London, 1961. Churg, J., Habib, R., White, R. H. R. Lancet, 1970, i, 1299. Habib, R., Gubler, M. C. Nephron, 1971, 8, 382. Glasgow, E. F., White, R. H. R. ibid. p. 403.
homografts of the 2 who subsequently died showed identical lesions, affecting predominantly the juxtamedullary glomeruli and suggesting recurrence of the original disease rather than a chronic rejection process. The fact that the disease appears to attack the host kidneys and homograft in an identical
despite immunosuppressive therapy and previous bilateral nephrectomy, makes the Minneapolis workers’ suggestion of a humoral factor an attractive possibility. Thus, focal glomerulosclerosis emerges as a progressive disease for which renal transplantation may be contraindicated, leaving dialysis as probably the only means of prolonging life. Accurate diagnosis is therefore of considerable importance. Why do some patients with this disease show only minimal changes when first investigated ? If a humoral mechanism is operative, it may well antedate the glomerular structural changes, making a morphological diagnosis impossible, by current techniques, in the earliest stage. An equally likely explanation is to be found in the unique juxtamedullary distribution of early lesions,4 which could easily be missed in a small or superficial renal-biopsy specimen.2,11 Moreover, when the lesions are slight they may, with the best intentions, be classified pathologically as " minimal changes", just as they are apt to be called " chronic glomerulonephritis "6 in an advanced stage even though the characteristic combination of normal, partly sclerosed, and completely sclerosed manner,
In glomeruli 2,3,11-13 may still be discernible. interpreting the prognostic significance of a morphological diagnosis of minimal changes " the clinical and laboratory findings and the steroid response "
therefore be taken into account.3 This new information about the nature of focal glomerulosclerosis makes the practice of lumping steroidsensitive and steroid-resistant patients together under the common heading " lipoid " or " idiopathic " must
nephrosis
no
longer justifiable.
SPLENECTOMY FOR ANAEMIA EVERY now and then the physician whose special interest is haematology will have to decide whether or not to recommend splenectomy for a patient with anaemia. The decision is straightforward only in one condition-hereditary spherocytosis. In this haemolytic anaemia splenectomy is always successful, and the only decision required is the choice of the right time for the operation. In children it is usual to postpone splenectomy, unless the anaemia is very severe, till after the 5th birthday because of the risk of infection in young children. In patients over 60 the disease is sometimes discovered by chance when they come under investigation for some other condition; here, unless the splenomegaly is serious or the anaemia causing symptoms, splenectomy is rarely recommended, since there is always some risk attached to the operation. In all other types of anaemia with splenomegaly, such
368
autoimmune haemolytic anaemia, anxmia associated with portal hypertension, anaemia in Felty’s syndrome, or myelosclerosis, the decision has often had to be made on quite empirical grounds, such as increasing need for blood-transfusion or the mechanical effect of In the past few years, the large abdominal mass. however, radioactive tagging techniques have provided some useful tests to help assess the probable benefit of splenectomy in a particular case. A combined team from the departments of clinical haematology and surgery at University College Hospital and Medical School, London,l have now reported their experience of these tests and full details are given of the results in 41 patients who had splenectomy for various hxmatological conditions. The tests were determination of the rate of intrasplenic red-cell destruction, the size of the red-cell splenic pool, and estimation of possible expansion of plasma-volume. For the first two tests red cells were tagged with radioactive chromium e1Cr), and for the plasma-volume measurements 131I-tagged humanserum-albumin was injected. In normal persons the half-life of red blood-cells tagged with SlCr is 22-30 days; a half-life of less than 10 days together with a climbing splenic-uptake curve, and a count over the spleen at least twice that over the liver at half-life time, was regarded as one indication for splenectomy. Another was the presence of anaemia and an enlarged spleen more than 4 cm. below the costal margin combined with a plasma-volume of more than 50% in excess of normal. The estimates of splenic pooling were found to be less helpful; changes depended more on the pathology of the different conditions than on anything that gave a guide to the value of splenectomy; increases in the splenic pool were usually found when the basic disease was a red-cell abnormality, but they were less often found when the spleen itself was the source of the disease, as in congestive splenomegaly. Their 41 patients included 5 with hereditary spherocytosis, in whom the splenectomy was predictably entirely successful, though the red-cell survival did not always return to normal; these patients all showed striking shortening of red-cell-survival times, a spleen count increasing to over twice that of the liver count, and an increased splenic red-cell pool; but plasma-volume measurements were normal. Patients with autoimmune haemolytic anxmia gave very similar results, but experience proved that, even when the splenic uptake was favourable for splenectomy, the operation did not always give the expected result. 3 patients with anaemia due to pyruvate-kinase deficiency in the red cells showed decreased red-cell survival, increased spleen/liver ratios, some degree of increased splenic pooling, and again no increase in plasmavolume ; these patients had their spleens removed with benefit even though their anaemia was not entirely relieved. 10 patients had " proliferative conditions, including myeloid metaplasia and chronic myeloid and lymphatic leukxmias; 4 had"congestive splenomegaly; and 7 had a miscellaneous group of diseases (2 with Felty’s syndrome): in all these patients red-cell survival was less shortened or even normal, the spleen/liver ratio was not significantly raised, and the main change
as
"
in the plasma-volume, which was considerably raised and fell towards normal after splenectomy. But it was observed that this fall was not permanent and, despite the absence of the spleen, the figures for plasma and total-blood volumes tended to rise again over the subsequent few years. 3 patients with thalassaemia were investigated before and after splenectomy. Before the operation the red-cell survival was shortened to 12-14 days, the spleen/liver ratio was not raised above 2 in 2 patients and only reached 2-2 in the 3rd, and the plasma-volume figures were raised. However, splenectomy did not alter their hxmatocrit values or diminish their reticulocyte-counts, so the operations were unsuccessful in relieving the anaemia, though the patients will have benefited from removal of their abdominal was
masses.
Nightingale and co-workers also state that in the past splenectomies have been performed on their patients for hxmatological reasons, with only 3 postoperative deaths. This is an excellent record and shows what can be done by close cooperation between surgical and haematological teams. Assessing the results of the isotope tests in their whole series of 104 patients, they conclude that, while these tests are undoubtedly valuable, they do not provide the complete answer. In some patients, when tests are favourable, the splenectomy is not followed by the expected relief of the anaemia; in others good results follow, though the tests gave equivocal results. They believe that the tests provide a significantly better assessment of the value of splenectomy than has been obtained using other bases for assessment in idiopathic acquired haemolytic anaemia ". On the other hand, the results of splenectomy in the conditions in which increased plasmavolume is the only abnormality still seem to be unpredictable. Splenectomy for the relief of anaemia 7 years 104
"
should
not
therefore be advised before
tests
have been
performed-any properly equipped hasmatological laboratory can undertake them today. At the same time, the physician will weigh other factors such as the degree of disability that the anasmia causes, the frequency of the need for blood-transfusion, the burden of the abdominal mass, and the patient’s occupation and home circumstances. Nor should the operative risk be entirely discounted; with the best care this risk is now down to 3%; but weeks of disability may follow the operation, especially in older patients.
HYPOCOMPLEMENTAEMIC NEPHRITIS AFTER Bordet’s description ofhaemolytic complement in 1898,1 there appeared a series of papers reporting low levels of complement (which the authors attributed to urxmia 2-6) in patients with renal disease. Gunn7 reported 4 cases of acute poststreptococcal nephritis with depressed complement levels, and it is now known that serum-haemolytic-complement is reduced in most such patients. Kellettseems to have been the
"
1.
Nightingale, D., Prankerd, T.
A. J., Richards, D. Q. Jl Med. 1972, 41, 261.
J. D. M., Thompson,
1. Bordet, J. Ann. Inst. Pasteur, Paris, 1898, 12, 688. 2. Neisser, E., Doering, H. Berl. klin. Wschr. 1901, 38, 593. 3. Laqueur, A. Dt. med. Wschr. 1901, 27, 744. 4. Hedinger, E. Dt. Arch. klin. Med. 1902, 74, 24. 5. Longcope, W. T. J. Hyg., Camb. 1903, 3, 28. 6. Wolze, E. Zentbl. inn. Med. 1903, 24, 649. 7. Gunn, W. C. J. Path. Bact. 1914, 19, 155. 8. Kellett, C. E. Lancet, 1936, ii, 1262.