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Massive proteinuria associated with chronic pyelonephritis
EDITORIALS
THE EMPEROR’S
CLOTHES?
Since the inception of antimicrobial therapy, some in vitro methodology has been used both to screen drugs and to select which drug should be most effective clinically. The article on “Correlations Between In Vitro Sensitivity Testing and Therapeutic Response in Urinary Tract Infections,” by Dr. Eudy in this issue, page 519, is of questionable statistical validity, but it casts serious doubts on the usefulness of disk sensitivities to predict the clinical outcome of drug use in urinary tract infections. Although at first glance his data seem to show correlation of in vitro and in vivo results, a small sub-fraction of the sample has heavily weighted the results so that if pseudomonas is excluded, results with other organisms fail to show correlation. Disk sensitivities are convenient, quick, cheap, and popular. They have been enshrined by Dr. Kirby and Dr. Bauer. Even the bacteriologically unsophisticated person knows, however, that sulfonamide and streptomycin sensitivities take special and elaborate media for evaluation. The larger drawbacks and pitfalls of disk sensitivities for other drugs must be pointed out. Simulating the clinical situation in urine, even the patient’s own urine, is relatively simple. The use of concentrations of antibacterials that approximate the levels obtainable in urine with available dosage forms and regulated inoculum of bacteria should yield more significant results. Objections may be made to the author’s criteria for “cure” and equation of infection with a fixed concentration of organisms, but he is to be commended for reminding us that a spontaneous cure rate in urinary infections exists and that not everyone dies of untreated infections. Autopsy data, indeed, show that one out of five persons has had upper urinary tract infections, most of which healed spontaneously unsuspected and untreated.
588
New developments in automated sensitivity testing will supplant disk sensitivities and yield more rapid, accurate, and useful data in the near future. Other ongoing investigations will further show the superiority of tube dilution, and preloaded agar methods will help the clinician to apply the drug of choice. Dr. Eudy’s article should hasten this along. As the methodology now stands we have purchased inexpensively, dubious information of highly questionable usefulness. Hans H. Zinsser, M.D. 620 West 168th Street New York, New York 10032
MASSIVE PROTEINURIA ASSOCIATED WITH CHRONIC PYELONEPHRITIS Massive proteinuria is associated only rarely with vesicoureteral reflux. Zimmerman et al. in their work, “Vesicoureteral Reflux Nephropathy: Evidence for Immunologically Mediated Glomerular Injury,” in this issue, page 534, describe a series of 8 patients with vesicoureteral reflux, heavy proteinuria, interstitial nephritis, and urinary tract infection. The association between vesicoureteral reflux and chronic pyelonephritis has been documented,l but it should be remembered that in a previous report of 3 patients with massive proteinuria and vesicoureteral reflux,2 the pathologic diagnosis was chronic proliferative glomerulonephritis in 2 patients and severe nephrosclerosis in the third. Descriptions of the renal sections from this group contained little which could be interpreted as evidence of chronic infection. Chronic pyelonephritis is characterized by interstitial chronic inflammation and fibrosis with destruction of tubules. This pathologic picture is
UROLOGY
/
NOVEMBER
1973
/
VOLUME
II, NUMBER 5
nonspecific in that it may be caused by various types of injury, such as ischemia, and bacterial antigen may be difficult to demonstrate, even when the pathogenetic role of bacteria seems plausible.3 Putting aside the difficulties in accurate diagnosis and in understanding its pathogenesis, it suffices for our purpose to emphasize that a principal consequence of this interstitial process is the loss of proximal tubules. Indeed, in a report implicating chronic pyelonephritis as a cause of massive proteinuria and the nephrotic syndrome, the proteinuria was ascribed to diminished tubular reabsorption.4 However, glomerular lesions are relatively common in chronic pyelonephritis and typically consist of either periglomerular fibrosis or sclerosis of the glomerular capillary tuft itself.5 The fibrosis and sclerosis may take different forms, but are usually confined in their occurrence to areas of pyelonephritic scarring. Glomerular lesions outside of pyelonephritic scars may also be seen. These may resemble lesions of chronic proliferative glomerulonephritis and when found are associated with uremia and hypertension .6 The pathogenesis of these glomerular lesions has never been clear. Zimmerman et al. in their current report, present evidence that they are immunologically mediated. They found granular deposition of complement and IgM in peripheral capillary loops and mesangial regions of glomeruli by immunofluorescence microscopy and subendothelial dense deposits by electron microscopy. Our own findings concur with the proposed glomerular origin of severe proteinuria in chronic pyelonephritis. We have observed similar glomerular deposition of IgG and complement (IgM was not tested for) in 1 patient with repeated urinary tract infection, severe chronic pyelonephritis, hypertension, uremia, and twenty-four-hour urinary protein excretion ranging from 2.5 to 11 Gm. By contrast, in other patients with chronic pyelonephritis and little or no proteinuria, results of our immunofluorescence studies of the glomerulus have been negative.? The finding of granular deposits of complement and immunoglobulin in the mesangial and subendothelial regions of the glomerulus suggests that we are witnessing deposition of large, poorly soluble complexes of antigen and antibody capable of inducing glomerular damage.8 The important question left unanswered, of course, is the nature of the antigen(s) involved. If we could identify the antigen(s), we would be able to state whether or not the glomerular injury in these patients is directly related to urinary tract
UROLOGY
/
NOVEMBER
1973
I VOLUME
II, NUMBER 5
infection aid chronic pyelonephritis, fir example, if the antigens were of bacterial or nonglomerular renal origin, or is a manifestation of an unrelated, incidentally associated disease. Zimmerman et al. comment on the striking resemblance in many instances to the changes noted in “focal sclerosing glomerulonephropathy with hyalinosis.” Focal sclerosing glomerulonephritis is usually associated with the nephrotic syndrome. Focal glomerular deposits of IgM and complement are found in approximately 50 per cent of patients with this condition.s In children and most adults, its causation is entirely unknown. Similar immunofluorescence findings in heroin addicts suggest that in this special group of adults, the antigen may be heroin or its vehicle.lOJ1 It seems likely that an apparently similar condition may have different causation in different patients. Elution of antibody from resected pyelonephritic kidneys, or attempts to detect by immunofluorescence circumstantially implicated antigens in biopsy material, may prove rewarding. The urologist is a central figure in the elucidation of this question, both in the direct investigation of the patient, perhaps at an earlier stage of the disease than in the past, and in ensuring that the tissue specimens are not simply placed in formalin but are processed in such a way as to allow the requisite special procedures. Anthony D. Nicastri, M.D. Department of Pathology, Downstate Medical Center 450 Clarkson Avenue, Brooklyn, New York 11203
References Chronic pyelonephritis and vesicoureteric reflux, Clin. Radiol. 11:219 (1960).
1. HODSON, C. J., and EDWARDS, D.:
Massive proteinuria associated with vesicoureteral reflux, Lancet 2: 1272 (1969). 3. SCHWARTZ, M., and COTRAN, R. S.: Common enterobacterial antigen in human chronic pyelonephritis and interstitial nephritis, an immunofluorescent study, N. Engl. J. Med. 289: 830 (1973). 4. DELANO, B., et al.: “Chronic pyelonephritis” as a cause of massive proteinuria (? nephrotic syndrome), Arch. Int. Med. 129: 73 (1972). 5. HEPTINSTALL, R. H.: Pathology of the Kidney, Boston, Little, Brown and Co., 1966, pp. 426-431. 6. KIMMELSTIEL, P., and WILSON, C.: Inflammatory lesions in the glomeruli in pyelonephritis in relation to hypertension and renal insufficiency, Amer. J. Path. 12: 99 (1936). 7. NICASTRI, A. D.: Unpublished observations. 8. GERMUTH, F. G., SR., and RODRIGUEZ, E.: Immunopathology of the Renal Glomerulus. Immune Complex Disease and Antibasement Membrane Disease, Boston, Little, Brown and Co., 1973.
2. PILLAY, V. K. G., et al.:
589
9. MOREL-MAROGER, L., LEATHEM, A., and RICHET, G.:
Glomerular abnormalities in nonsystemic diseases, relationship between findings by light microscopy and immunofluorescence in 433 renal biopsy specimens, Amer. J. Med. 53: 170 (1972). 10. KILCOYNE, M., et al.: Nephrotic syndrome in heroin addicts, Lancet 1: 17 (1972). 11. RAW, T. K. S.,NICASTR& A. D., and FRIEDMAN, E. A.: Natural history of heroin associated nephropathy, N. Engl. J. Med., in press.
IS SPLENECTOMY BENEFICIAL TO RENAL ALLOGRAFT RECIPIENTS? After a decade in which renal transplantation has been performed over 16,000 times, those teams with extensive experience are taking a second look at components of the “established” preintra- and postoperative treatment schedule. In “Splenectomy in Renal Transplantation,” in this issue, page 542, Bennett and coworkers report on their results with 99 patients who received 116 renal transplants in which splenectomy was associated with septic and thromboembolic complications while not improving graft function. By contrast, Swanson and the Milwaukee group recently found a marked protective effect against rejection induced by splenectomy prior to, at the time of, or after, kidney transp1antation.l This diametrically different interpretation in two large series of patients underscores the subjective basis for most of the clinical protocols now in use. Surgical procedures de.signed to relieve lifeendangering disease may find widespread application even though the experimental basis for their use is limited and incompletely evaluated. Examples of operations prematurely rushed to clinical practice come easily to mind, and include carotid body removal for asthma, gastric freezing for peptic ulcer, and internal mammary artery ligation for intractable coronary artery disease. In fairness to the surgical pioneers who introduced renal and, later, cardiac transplantation, it
590
must be appreciated that prior to the development of a workable surgical and immunosuppressive regimen in man no consistently successful animal model has been devised. Dogs given azathioprine and methylprednisolone, for example, have only a modest prolongation of renal allograft function although about one in ten hold grafts for six or more months. As reviewed by Opelz and Terasaki,2 splenectomy prolongs mouse skin allograft survival, diminishes antibody response to antigens in mouse and dog, and has a protective effect against nitrogen mustard toxicity. To date no data in dog renal allograft experiments indicates that splenectomy lengthens graft function, Careful reading of Bennett and coworkers’ article reveals how the desire for “hard” information must still be developed from unproved techniques. In their study, for instance, episodic rejection was “documented by open renal bistable histoOPSY," a poor tool for differentiating logic changes from actually evolving graft destruction. Also, rejection was treated by. , . “highdose intravenous methylprednisolone for five to seven days and/or local graft irradiation to 900 r,” both immunosuppressive modalities of questioned efficacy although regularly employed by many groups. An answer to the question of splenectomy is unfortunately not at hand. For the time being, the old saw “when in doubt, don’t” has merit. .We await with much interest the alternate case evaluation by Bennett and associates which is now in progress. Eli A. Friedman, M.D. Department of Medicine, Downstate Medical Center 450 Clarkson Avenue, Brooklyn, New York 11203 References 1. SWANSON, M. K., MCGREGOR, W. R. RODGERS, R. E., and KAUFMANN,H. M., JR.: Timing of splenectomy in human kidney transplantation, Surg. Forum 24: 283 (1973). 2. OPE~Z, G., and TERASAKI,P. I.: Affect of splenectomy on human renal transplants, Transplantation 15: 605 (1973).
UROLOGY
I NOVEMBER1973
I VOLUME
II,NUMBER5
THE EMPEROR’S
CLOTHES?
Since the inception of antimicrobial therapy, some in vitro methodology has been used both to screen drugs and to select which drug should be most effective clinically. The article on “Correlations Between In Vitro Sensitivity Testing and Therapeutic Response in Urinary Tract Infections,” by Dr. Eudy in this issue, page 519, is of questionable statistical validity, but it casts serious doubts on the usefulness of disk sensitivities to predict the clinical outcome of drug use in urinary tract infections. Although at first glance his data seem to show correlation of in vitro and in vivo results, a small sub-fraction of the sample has heavily weighted the results so that if pseudomonas is excluded, results with other organisms fail to show correlation. Disk sensitivities are convenient, quick, cheap, and popular. They have been enshrined by Dr. Kirby and Dr. Bauer. Even the bacteriologically unsophisticated person knows, however, that sulfonamide and streptomycin sensitivities take special and elaborate media for evaluation. The larger drawbacks and pitfalls of disk sensitivities for other drugs must be pointed out. Simulating the clinical situation in urine, even the patient’s own urine, is relatively simple. The use of concentrations of antibacterials that approximate the levels obtainable in urine with available dosage forms and regulated inoculum of bacteria should yield more significant results. Objections may be made to the author’s criteria for “cure” and equation of infection with a fixed concentration of organisms, but he is to be commended for reminding us that a spontaneous cure rate in urinary infections exists and that not everyone dies of untreated infections. Autopsy data, indeed, show that one out of five persons has had upper urinary tract infections, most of which healed spontaneously unsuspected and untreated.
588
New developments in automated sensitivity testing will supplant disk sensitivities and yield more rapid, accurate, and useful data in the near future. Other ongoing investigations will further show the superiority of tube dilution, and preloaded agar methods will help the clinician to apply the drug of choice. Dr. Eudy’s article should hasten this along. As the methodology now stands we have purchased inexpensively, dubious information of highly questionable usefulness. Hans H. Zinsser, M.D. 620 West 168th Street New York, New York 10032
MASSIVE PROTEINURIA ASSOCIATED WITH CHRONIC PYELONEPHRITIS Massive proteinuria is associated only rarely with vesicoureteral reflux. Zimmerman et al. in their work, “Vesicoureteral Reflux Nephropathy: Evidence for Immunologically Mediated Glomerular Injury,” in this issue, page 534, describe a series of 8 patients with vesicoureteral reflux, heavy proteinuria, interstitial nephritis, and urinary tract infection. The association between vesicoureteral reflux and chronic pyelonephritis has been documented,l but it should be remembered that in a previous report of 3 patients with massive proteinuria and vesicoureteral reflux,2 the pathologic diagnosis was chronic proliferative glomerulonephritis in 2 patients and severe nephrosclerosis in the third. Descriptions of the renal sections from this group contained little which could be interpreted as evidence of chronic infection. Chronic pyelonephritis is characterized by interstitial chronic inflammation and fibrosis with destruction of tubules. This pathologic picture is
UROLOGY
/
NOVEMBER
1973
/
VOLUME
II, NUMBER 5
nonspecific in that it may be caused by various types of injury, such as ischemia, and bacterial antigen may be difficult to demonstrate, even when the pathogenetic role of bacteria seems plausible.3 Putting aside the difficulties in accurate diagnosis and in understanding its pathogenesis, it suffices for our purpose to emphasize that a principal consequence of this interstitial process is the loss of proximal tubules. Indeed, in a report implicating chronic pyelonephritis as a cause of massive proteinuria and the nephrotic syndrome, the proteinuria was ascribed to diminished tubular reabsorption.4 However, glomerular lesions are relatively common in chronic pyelonephritis and typically consist of either periglomerular fibrosis or sclerosis of the glomerular capillary tuft itself.5 The fibrosis and sclerosis may take different forms, but are usually confined in their occurrence to areas of pyelonephritic scarring. Glomerular lesions outside of pyelonephritic scars may also be seen. These may resemble lesions of chronic proliferative glomerulonephritis and when found are associated with uremia and hypertension .6 The pathogenesis of these glomerular lesions has never been clear. Zimmerman et al. in their current report, present evidence that they are immunologically mediated. They found granular deposition of complement and IgM in peripheral capillary loops and mesangial regions of glomeruli by immunofluorescence microscopy and subendothelial dense deposits by electron microscopy. Our own findings concur with the proposed glomerular origin of severe proteinuria in chronic pyelonephritis. We have observed similar glomerular deposition of IgG and complement (IgM was not tested for) in 1 patient with repeated urinary tract infection, severe chronic pyelonephritis, hypertension, uremia, and twenty-four-hour urinary protein excretion ranging from 2.5 to 11 Gm. By contrast, in other patients with chronic pyelonephritis and little or no proteinuria, results of our immunofluorescence studies of the glomerulus have been negative.? The finding of granular deposits of complement and immunoglobulin in the mesangial and subendothelial regions of the glomerulus suggests that we are witnessing deposition of large, poorly soluble complexes of antigen and antibody capable of inducing glomerular damage.8 The important question left unanswered, of course, is the nature of the antigen(s) involved. If we could identify the antigen(s), we would be able to state whether or not the glomerular injury in these patients is directly related to urinary tract
UROLOGY
/
NOVEMBER
1973
I VOLUME
II, NUMBER 5
infection aid chronic pyelonephritis, fir example, if the antigens were of bacterial or nonglomerular renal origin, or is a manifestation of an unrelated, incidentally associated disease. Zimmerman et al. comment on the striking resemblance in many instances to the changes noted in “focal sclerosing glomerulonephropathy with hyalinosis.” Focal sclerosing glomerulonephritis is usually associated with the nephrotic syndrome. Focal glomerular deposits of IgM and complement are found in approximately 50 per cent of patients with this condition.s In children and most adults, its causation is entirely unknown. Similar immunofluorescence findings in heroin addicts suggest that in this special group of adults, the antigen may be heroin or its vehicle.lOJ1 It seems likely that an apparently similar condition may have different causation in different patients. Elution of antibody from resected pyelonephritic kidneys, or attempts to detect by immunofluorescence circumstantially implicated antigens in biopsy material, may prove rewarding. The urologist is a central figure in the elucidation of this question, both in the direct investigation of the patient, perhaps at an earlier stage of the disease than in the past, and in ensuring that the tissue specimens are not simply placed in formalin but are processed in such a way as to allow the requisite special procedures. Anthony D. Nicastri, M.D. Department of Pathology, Downstate Medical Center 450 Clarkson Avenue, Brooklyn, New York 11203
References Chronic pyelonephritis and vesicoureteric reflux, Clin. Radiol. 11:219 (1960).
1. HODSON, C. J., and EDWARDS, D.:
Massive proteinuria associated with vesicoureteral reflux, Lancet 2: 1272 (1969). 3. SCHWARTZ, M., and COTRAN, R. S.: Common enterobacterial antigen in human chronic pyelonephritis and interstitial nephritis, an immunofluorescent study, N. Engl. J. Med. 289: 830 (1973). 4. DELANO, B., et al.: “Chronic pyelonephritis” as a cause of massive proteinuria (? nephrotic syndrome), Arch. Int. Med. 129: 73 (1972). 5. HEPTINSTALL, R. H.: Pathology of the Kidney, Boston, Little, Brown and Co., 1966, pp. 426-431. 6. KIMMELSTIEL, P., and WILSON, C.: Inflammatory lesions in the glomeruli in pyelonephritis in relation to hypertension and renal insufficiency, Amer. J. Path. 12: 99 (1936). 7. NICASTRI, A. D.: Unpublished observations. 8. GERMUTH, F. G., SR., and RODRIGUEZ, E.: Immunopathology of the Renal Glomerulus. Immune Complex Disease and Antibasement Membrane Disease, Boston, Little, Brown and Co., 1973.
2. PILLAY, V. K. G., et al.:
589
9. MOREL-MAROGER, L., LEATHEM, A., and RICHET, G.:
Glomerular abnormalities in nonsystemic diseases, relationship between findings by light microscopy and immunofluorescence in 433 renal biopsy specimens, Amer. J. Med. 53: 170 (1972). 10. KILCOYNE, M., et al.: Nephrotic syndrome in heroin addicts, Lancet 1: 17 (1972). 11. RAW, T. K. S.,NICASTR& A. D., and FRIEDMAN, E. A.: Natural history of heroin associated nephropathy, N. Engl. J. Med., in press.
IS SPLENECTOMY BENEFICIAL TO RENAL ALLOGRAFT RECIPIENTS? After a decade in which renal transplantation has been performed over 16,000 times, those teams with extensive experience are taking a second look at components of the “established” preintra- and postoperative treatment schedule. In “Splenectomy in Renal Transplantation,” in this issue, page 542, Bennett and coworkers report on their results with 99 patients who received 116 renal transplants in which splenectomy was associated with septic and thromboembolic complications while not improving graft function. By contrast, Swanson and the Milwaukee group recently found a marked protective effect against rejection induced by splenectomy prior to, at the time of, or after, kidney transp1antation.l This diametrically different interpretation in two large series of patients underscores the subjective basis for most of the clinical protocols now in use. Surgical procedures de.signed to relieve lifeendangering disease may find widespread application even though the experimental basis for their use is limited and incompletely evaluated. Examples of operations prematurely rushed to clinical practice come easily to mind, and include carotid body removal for asthma, gastric freezing for peptic ulcer, and internal mammary artery ligation for intractable coronary artery disease. In fairness to the surgical pioneers who introduced renal and, later, cardiac transplantation, it
590
must be appreciated that prior to the development of a workable surgical and immunosuppressive regimen in man no consistently successful animal model has been devised. Dogs given azathioprine and methylprednisolone, for example, have only a modest prolongation of renal allograft function although about one in ten hold grafts for six or more months. As reviewed by Opelz and Terasaki,2 splenectomy prolongs mouse skin allograft survival, diminishes antibody response to antigens in mouse and dog, and has a protective effect against nitrogen mustard toxicity. To date no data in dog renal allograft experiments indicates that splenectomy lengthens graft function, Careful reading of Bennett and coworkers’ article reveals how the desire for “hard” information must still be developed from unproved techniques. In their study, for instance, episodic rejection was “documented by open renal bistable histoOPSY," a poor tool for differentiating logic changes from actually evolving graft destruction. Also, rejection was treated by. , . “highdose intravenous methylprednisolone for five to seven days and/or local graft irradiation to 900 r,” both immunosuppressive modalities of questioned efficacy although regularly employed by many groups. An answer to the question of splenectomy is unfortunately not at hand. For the time being, the old saw “when in doubt, don’t” has merit. .We await with much interest the alternate case evaluation by Bennett and associates which is now in progress. Eli A. Friedman, M.D. Department of Medicine, Downstate Medical Center 450 Clarkson Avenue, Brooklyn, New York 11203 References 1. SWANSON, M. K., MCGREGOR, W. R. RODGERS, R. E., and KAUFMANN,H. M., JR.: Timing of splenectomy in human kidney transplantation, Surg. Forum 24: 283 (1973). 2. OPE~Z, G., and TERASAKI,P. I.: Affect of splenectomy on human renal transplants, Transplantation 15: 605 (1973).
UROLOGY
I NOVEMBER1973
I VOLUME
II,NUMBER5