CASE REPORTS
Decline in Creatinine Clearance in a Patient With Glomerulomegaly Associated With a Congenital Cyanotic Heart Disease Michael T. Hagley, MD, Dale P. Murphy, MD, Diane Mullins, MD, and Joseph Zarconi, MD • Glomerulomegaly is associated with congenital cyanotic heart disease and has heretofore been considered a benign condition. We describe a patient with congenital cyanotic heart disease and glomerulomegaly. Deterioration of renal function was demonstrated by comparison of creatinine clearances measured at the time of kidney biopsy and 4 years later. No alteration in kidney histology other than glomerulomegaly and focal glomerulosclerosis at autopsy could account for this deterioration. This is the first description of deterioration of renal function in a patient with glomerulomegaly and congenital cyanotic heart disease. This observation may influence the management of patients with glornerulomegaly and congenital cyanotic heart disease who are potential recipients of heart or heart-lung allografts. © 1992 by the National Kidney Foundation, Inc. INDEX WORDS: Renal failure; glomerulomegaly; congenital heart disease; cyanotic heart disease.
CASE PRESENTATION A 27-year-old white woman with a congenital cyanotic heart disease (cor biatrium triloculare) was admitted to the hospital with nausea, vomiting, and myalgias. One week earlier, she was hospitalized for 3 days due to similar symptoms. Over the previous 2 years, she had experienced progression of her disease marked by decreasing arterial oxygen saturation, decreased exercise capacity, pain in her lower extremities, and the development of a third heart sound, jugular venous distension, and hepatomegaly. This progression was attributed to progressive pulmonary hypertension with increasing right to left shunt. Her medications included digoxin and procainamide, which were started after an episode of atrial flutter about I year earlier, propranolol for sinus tachycardia, and iron sulfate for iron deficiency related to polycythemia treated by periodic phlebotomy. She denied use of any medications other than those prescribed, including nonsteroidal antiinflammatory drugs. Her blood pressure was 105/70 mm Hg. heart rate 95 bpm, respiratory rate 18 bpm, and oral temperature 36.7°C. She was small in stature, had midface hypoplasia, and had marked cyanosis of her lips, nose, cheeks. and hands. She had jugular venous distension to the angle of the jaw with her head elevated 45 degrees and visible pulsations in the left cervical and right supraclavicular areas. Her precordium was hyperdynamic with a systolic lift. Her heart produced a loud S2. a low-pitched IV IVI holosystolic murmur audible across the entire precordium and loudest at the left sternal border, and a high-pitched IIIVI midsystolic murmur audible at the lower left sternal border. The liver was visibly pulsatile. was palpable 3 cm below the right costal margin, and measured 15 cm by percussion in the right midclavicular line. She had no peripheral edema. She had marked clubbing of the nails of her fingers and toes. The patient was admitted, and supportive care was provided. On her second hospital day. she developed a wide-complex bradycardia followed by asystole. No resuscitation was attempted. An autopsy was performed. The patient had been evaluated for proteinuria 4 years before death. Renal ultrasonography was normal. Blood urea nitrogen (BUN) was 2.9 mmol/L (8.0 mgjdL), creatinine was
71 /Lmol/L (0.8 mgjdL), and creatinine clearance was 1.7 mLI s (102 mL/min). A renal biopsy showed glomerulomegaly (Fig I). One month before death, her BUN was 6.0 mmol/L (17.0 mgjdL). creatinine was 88 /Lmol/L (1 .0 mgjdL), and creatinine clearance on two occasions was 0.7 mL/s (42 mL/min). Postmortem examination showed grossly normal kidneys with glomerulomegaly (Fig 2), hypercellularity, and focal glomerular sclerosis.
DISCUSSION
This patient had a congenital cyanotic heart disease, glomerulomegaly with proteinuria, and deterioration of renal function documented by creatinine clearances measured at the time ofbiopsy and on two occasions 4 years later. She had normal peripheral pulses and no evidence of systemic hypoperfusion. An autopsy showed no kidney abnormalities other than glomerulomegaly and focal glomerular sclerosis. There was no evidence of ischemic necrosis or other abnormalities that could be attributed to poor renal blood flow. Thus, we suspect that the decline in creatinine clearance was due to progressive glomerular sclerosis, rather than decreased renal blood flow . This is the second report of glomerulomegaly documented by percutaneous renal biopsy in a living patient,l and the first case in which deteFrom the Departments of M edicine and Pathology, Akron City Hospital. Akron. OR. R eceived June 12,1991; accepted in revised form March 17. 1992. Address reprint requests to Michael T. Hagley, MD, Department of Internal Medicine. Akron C ity Hospital, 525 E M arket St.Akron. OH 44309. © 1992 by the National Kidney Foundation, Inc. 0272-6386/ 92/2002-0010$3.00/0
American Journal of Kidney Diseases, Vol XX, No 2 (August), 1992: pp 177-179
177
HAGLEY ET AL
178
Fig 1.
Enlarged glomeruli from autopsy specimen (A) compared to control (8). (H&E; original magnification X 40.)
rioration of renal function in a patient with glomerulomegaly has been documented. Glomerulomegaly occurs in patients with hypoxia and polycythemia due to congenital cyanotic heart diseases l -6 and cor pulmonale.? In addition, polycythemia and glomerulomegaly have been induced in rats by intrarenal injections of nickel subsulfide. 8.9 The factors responsible for development of glomerulomegaly are unclear, but several mechanisms are plausible. Meyers et allO demonstrated that isovolemic increase in hematocrit in rats is associated with a slight decrease in single-nephron glomerular filtration, increased filtration fraction, and increases in afferent and efferent arteriolar resistances. The increase in efferent resistance was greater than afferent resistance. The increase in
glomerular transcapillary hydraulic pressure that results could produce ectasia of glomerular capillary walls in chronically polycythemic patients, as previously suggested. 1 A second proposed mechanism by which glomerulomegaly occurs involves hypertrophy or hyperplasia of erythropoietin-producing cells in response to persistent hypoxia. The manner in which glomerulomegaly may be associated with decline in renal function is also unclear, but three plausible explanations are considered. First, our observation may simply reflect decreased cardiac output in the late stages of a congenital cyanotic heart disease. Second, slight reductions in glomerular filtration have been reported with a polycythemia in congenital heart disease, 11 primary polycythemia,12 and ac-
Fig 2. Hypercellularity of glomeruli from a percutaneous renal biopsy performed 4 years before death (A) and from an autopsy specimen (8) (H&E; original magnification X 200.)
GLOMERULOMEGAL Y AND DECLINE IN CREATININE CLEARANCE
climatization to high altitude. 13 These observations may reflect a hypoxia-induced increase in intrarenal adenosine concentrations, which facilitates erythropoiesis l4 and decreases glomerular filtration by concomitantly increasing afferent arteriolar resistance and decreasing efferent arteriolar resistance. 15 Third, hyperperfusion of glomeruli, which appears to occur in polycythemia,lo is associated with progression of renal failure in many diseases. 16 This explanation is appealing, as the single mechanism of hyperperfusion could account for both the development of glomerulomegaly and the progression to renal failure. Proteinuria was present during life in many patients from autopsy series2-6 reported by Ingeifinger et aI, I and in the present case. The cause
179
and significance are unclear. However, it suggests that urinalysis might be a convenient means of screening for glomerulomegaly in patients with congenital cyanotic heart disease. The observation we report suggests that glomerulomegaly, rather than being an innocuous condition as previously suggested, I may lead to progressive renal failure. The diagnosis should be considered when evaluating patients with congenital cyanotic heart disease and proteinuria. Since adequate renal function is necessary to undergo heart or heart-lung transplant, 17,18 renal function should be monitored carefully in patients with glomerulomegaly. Transplantation should be undertaken before prohibitive deterioration in renal function.
REFERENCES 1. Ingelfinger JR, Kissane JM, Robson AM: Glomerulomegaly in a patient with cyanotic congenital heart disease. Am J Dis Child 120:69-71, 1970 2. Bauer WC, Rosenberg F: A quantitative study of glomerular enlargement without an increase in renal mass. Am J PathoI37:695-712, 1960 3. Marinozzi V: Aspetti morfologici del rene nelle cardiopatie congenite cianotizzanti. Policlinico (Med) 66:48-62, 1959 4. Meessen H, Litton MD: Morphology of the kidney in morbus caerulells. Arch Pathol 56:480-487, 1953 5. Spear GS: The glomerulus in cyanotic congenital heart disease and primary pulmonary hypertension: A review. Nephron 1:238-48, 1964 6. Spear GS: Glomerular alterations in cyanotic congenital heart disease. Bull Johns Hopkins Hosp 106:347-367, 1960 7. Klahr S, Schreiner G, Iekuni I: The progression ofrenal disease. N Eng! J Med 318:1657-66, 1990 8. McCully KS, Rinehimer LA, Gillies CG, et a1: Erythrocytosis, g!omerulomegaly, mesangial hyperplasia. sialyl hyperplasia, and arteriosclerosis induced in rates by nickel subsulfide. Virchows Arch [A] 394:207-220, 1982 9. McCully KS, Sunderman FW, Hopfer SM, et al: Effects of unilateral nephrectomy on erythrocytosis and arterioscle-
rosis induced in rats by intrarenal injection of nickel subsulfide. Virchows Arch [A] 397:251-259, 1982 10. Meyers BD, Deen WM, Robertson CR, et al: Dynamics of glomerular filtration in the rat: Effects of hematocrit. Circ Res 36:425-435, 1975 11. Scott HW, Elliott SR: Renal hemodynamics in congenital cyanotic heart disease. Bull Johns Hopkins Hosp 86: 58-71,1950 12. De Wardener HE, McSwiney RR, Miles BE: Renal hemodynamics in primary polycythemia. Lancet 2:204-205, 1951 13. Becker EL, Schilling JA, Arvey RB: Renal function in man acclimatized to high altitude. J Appl Physiol 10:79-80, 1957 14. Paul P, Rothmann SA, Meagher RC: Modulation of erythroprotein production by adenosine. J Lab Clin Med 112: 168-173,1988 15. Gouyon JB, Guignard JP: Theophylline prevents the hypoxia-induced renal hemodynamic changes in rabbits. Kidney Int 33:1078-1083, 1988 16. Klahr S, Schreiner G, Ichikawa I: The progression of renal disease. N Eng! J Med 318:1657-1666, 1988 17. McGregor CGA, Oyer PE, Shamway NE: Heart and heart-lung transplantation. Prog Allergy 38:346-365, 1986 18. Tuna IC, Jamieson SW: Human heart and lung transplantation. Adv Surg 22:251-276,1989
Decline in Creatinine Clearance in a Patient With Glomerulomegaly Associated With a Congenital Cyanotic Heart Disease Michael T. Hagley, MD, Dale P. Murphy, MD, Diane Mullins, MD, and Joseph Zarconi, MD • Glomerulomegaly is associated with congenital cyanotic heart disease and has heretofore been considered a benign condition. We describe a patient with congenital cyanotic heart disease and glomerulomegaly. Deterioration of renal function was demonstrated by comparison of creatinine clearances measured at the time of kidney biopsy and 4 years later. No alteration in kidney histology other than glomerulomegaly and focal glomerulosclerosis at autopsy could account for this deterioration. This is the first description of deterioration of renal function in a patient with glomerulomegaly and congenital cyanotic heart disease. This observation may influence the management of patients with glornerulomegaly and congenital cyanotic heart disease who are potential recipients of heart or heart-lung allografts. © 1992 by the National Kidney Foundation, Inc. INDEX WORDS: Renal failure; glomerulomegaly; congenital heart disease; cyanotic heart disease.
CASE PRESENTATION A 27-year-old white woman with a congenital cyanotic heart disease (cor biatrium triloculare) was admitted to the hospital with nausea, vomiting, and myalgias. One week earlier, she was hospitalized for 3 days due to similar symptoms. Over the previous 2 years, she had experienced progression of her disease marked by decreasing arterial oxygen saturation, decreased exercise capacity, pain in her lower extremities, and the development of a third heart sound, jugular venous distension, and hepatomegaly. This progression was attributed to progressive pulmonary hypertension with increasing right to left shunt. Her medications included digoxin and procainamide, which were started after an episode of atrial flutter about I year earlier, propranolol for sinus tachycardia, and iron sulfate for iron deficiency related to polycythemia treated by periodic phlebotomy. She denied use of any medications other than those prescribed, including nonsteroidal antiinflammatory drugs. Her blood pressure was 105/70 mm Hg. heart rate 95 bpm, respiratory rate 18 bpm, and oral temperature 36.7°C. She was small in stature, had midface hypoplasia, and had marked cyanosis of her lips, nose, cheeks. and hands. She had jugular venous distension to the angle of the jaw with her head elevated 45 degrees and visible pulsations in the left cervical and right supraclavicular areas. Her precordium was hyperdynamic with a systolic lift. Her heart produced a loud S2. a low-pitched IV IVI holosystolic murmur audible across the entire precordium and loudest at the left sternal border, and a high-pitched IIIVI midsystolic murmur audible at the lower left sternal border. The liver was visibly pulsatile. was palpable 3 cm below the right costal margin, and measured 15 cm by percussion in the right midclavicular line. She had no peripheral edema. She had marked clubbing of the nails of her fingers and toes. The patient was admitted, and supportive care was provided. On her second hospital day. she developed a wide-complex bradycardia followed by asystole. No resuscitation was attempted. An autopsy was performed. The patient had been evaluated for proteinuria 4 years before death. Renal ultrasonography was normal. Blood urea nitrogen (BUN) was 2.9 mmol/L (8.0 mgjdL), creatinine was
71 /Lmol/L (0.8 mgjdL), and creatinine clearance was 1.7 mLI s (102 mL/min). A renal biopsy showed glomerulomegaly (Fig I). One month before death, her BUN was 6.0 mmol/L (17.0 mgjdL). creatinine was 88 /Lmol/L (1 .0 mgjdL), and creatinine clearance on two occasions was 0.7 mL/s (42 mL/min). Postmortem examination showed grossly normal kidneys with glomerulomegaly (Fig 2), hypercellularity, and focal glomerular sclerosis.
DISCUSSION
This patient had a congenital cyanotic heart disease, glomerulomegaly with proteinuria, and deterioration of renal function documented by creatinine clearances measured at the time ofbiopsy and on two occasions 4 years later. She had normal peripheral pulses and no evidence of systemic hypoperfusion. An autopsy showed no kidney abnormalities other than glomerulomegaly and focal glomerular sclerosis. There was no evidence of ischemic necrosis or other abnormalities that could be attributed to poor renal blood flow. Thus, we suspect that the decline in creatinine clearance was due to progressive glomerular sclerosis, rather than decreased renal blood flow . This is the second report of glomerulomegaly documented by percutaneous renal biopsy in a living patient,l and the first case in which deteFrom the Departments of M edicine and Pathology, Akron City Hospital. Akron. OR. R eceived June 12,1991; accepted in revised form March 17. 1992. Address reprint requests to Michael T. Hagley, MD, Department of Internal Medicine. Akron C ity Hospital, 525 E M arket St.Akron. OH 44309. © 1992 by the National Kidney Foundation, Inc. 0272-6386/ 92/2002-0010$3.00/0
American Journal of Kidney Diseases, Vol XX, No 2 (August), 1992: pp 177-179
177
HAGLEY ET AL
178
Fig 1.
Enlarged glomeruli from autopsy specimen (A) compared to control (8). (H&E; original magnification X 40.)
rioration of renal function in a patient with glomerulomegaly has been documented. Glomerulomegaly occurs in patients with hypoxia and polycythemia due to congenital cyanotic heart diseases l -6 and cor pulmonale.? In addition, polycythemia and glomerulomegaly have been induced in rats by intrarenal injections of nickel subsulfide. 8.9 The factors responsible for development of glomerulomegaly are unclear, but several mechanisms are plausible. Meyers et allO demonstrated that isovolemic increase in hematocrit in rats is associated with a slight decrease in single-nephron glomerular filtration, increased filtration fraction, and increases in afferent and efferent arteriolar resistances. The increase in efferent resistance was greater than afferent resistance. The increase in
glomerular transcapillary hydraulic pressure that results could produce ectasia of glomerular capillary walls in chronically polycythemic patients, as previously suggested. 1 A second proposed mechanism by which glomerulomegaly occurs involves hypertrophy or hyperplasia of erythropoietin-producing cells in response to persistent hypoxia. The manner in which glomerulomegaly may be associated with decline in renal function is also unclear, but three plausible explanations are considered. First, our observation may simply reflect decreased cardiac output in the late stages of a congenital cyanotic heart disease. Second, slight reductions in glomerular filtration have been reported with a polycythemia in congenital heart disease, 11 primary polycythemia,12 and ac-
Fig 2. Hypercellularity of glomeruli from a percutaneous renal biopsy performed 4 years before death (A) and from an autopsy specimen (8) (H&E; original magnification X 200.)
GLOMERULOMEGAL Y AND DECLINE IN CREATININE CLEARANCE
climatization to high altitude. 13 These observations may reflect a hypoxia-induced increase in intrarenal adenosine concentrations, which facilitates erythropoiesis l4 and decreases glomerular filtration by concomitantly increasing afferent arteriolar resistance and decreasing efferent arteriolar resistance. 15 Third, hyperperfusion of glomeruli, which appears to occur in polycythemia,lo is associated with progression of renal failure in many diseases. 16 This explanation is appealing, as the single mechanism of hyperperfusion could account for both the development of glomerulomegaly and the progression to renal failure. Proteinuria was present during life in many patients from autopsy series2-6 reported by Ingeifinger et aI, I and in the present case. The cause
179
and significance are unclear. However, it suggests that urinalysis might be a convenient means of screening for glomerulomegaly in patients with congenital cyanotic heart disease. The observation we report suggests that glomerulomegaly, rather than being an innocuous condition as previously suggested, I may lead to progressive renal failure. The diagnosis should be considered when evaluating patients with congenital cyanotic heart disease and proteinuria. Since adequate renal function is necessary to undergo heart or heart-lung transplant, 17,18 renal function should be monitored carefully in patients with glomerulomegaly. Transplantation should be undertaken before prohibitive deterioration in renal function.
REFERENCES 1. Ingelfinger JR, Kissane JM, Robson AM: Glomerulomegaly in a patient with cyanotic congenital heart disease. Am J Dis Child 120:69-71, 1970 2. Bauer WC, Rosenberg F: A quantitative study of glomerular enlargement without an increase in renal mass. Am J PathoI37:695-712, 1960 3. Marinozzi V: Aspetti morfologici del rene nelle cardiopatie congenite cianotizzanti. Policlinico (Med) 66:48-62, 1959 4. Meessen H, Litton MD: Morphology of the kidney in morbus caerulells. Arch Pathol 56:480-487, 1953 5. Spear GS: The glomerulus in cyanotic congenital heart disease and primary pulmonary hypertension: A review. Nephron 1:238-48, 1964 6. Spear GS: Glomerular alterations in cyanotic congenital heart disease. Bull Johns Hopkins Hosp 106:347-367, 1960 7. Klahr S, Schreiner G, Iekuni I: The progression ofrenal disease. N Eng! J Med 318:1657-66, 1990 8. McCully KS, Rinehimer LA, Gillies CG, et a1: Erythrocytosis, g!omerulomegaly, mesangial hyperplasia. sialyl hyperplasia, and arteriosclerosis induced in rates by nickel subsulfide. Virchows Arch [A] 394:207-220, 1982 9. McCully KS, Sunderman FW, Hopfer SM, et al: Effects of unilateral nephrectomy on erythrocytosis and arterioscle-
rosis induced in rats by intrarenal injection of nickel subsulfide. Virchows Arch [A] 397:251-259, 1982 10. Meyers BD, Deen WM, Robertson CR, et al: Dynamics of glomerular filtration in the rat: Effects of hematocrit. Circ Res 36:425-435, 1975 11. Scott HW, Elliott SR: Renal hemodynamics in congenital cyanotic heart disease. Bull Johns Hopkins Hosp 86: 58-71,1950 12. De Wardener HE, McSwiney RR, Miles BE: Renal hemodynamics in primary polycythemia. Lancet 2:204-205, 1951 13. Becker EL, Schilling JA, Arvey RB: Renal function in man acclimatized to high altitude. J Appl Physiol 10:79-80, 1957 14. Paul P, Rothmann SA, Meagher RC: Modulation of erythroprotein production by adenosine. J Lab Clin Med 112: 168-173,1988 15. Gouyon JB, Guignard JP: Theophylline prevents the hypoxia-induced renal hemodynamic changes in rabbits. Kidney Int 33:1078-1083, 1988 16. Klahr S, Schreiner G, Ichikawa I: The progression of renal disease. N Eng! J Med 318:1657-1666, 1988 17. McGregor CGA, Oyer PE, Shamway NE: Heart and heart-lung transplantation. Prog Allergy 38:346-365, 1986 18. Tuna IC, Jamieson SW: Human heart and lung transplantation. Adv Surg 22:251-276,1989
