- Email: [email protected]
Complications In Nephrotic Syndrome In Children
Review Article
COMPLICATIONS IN NEPHROTIC SYNDROME IN CHILDREN RN Srivastava and A Vasudev Senior Consultant, Pediatric Nephrologist, Apollo Indraprastha Hospitals, Sarita Vihar, New Delhi 110076, India. e-mail: [email protected], [email protected] Correspondence to: Dr R N Srivastava, Senior Consultant, Pediatric Nephrologist, Apollo Indraprastha Hospitals, Sarita Vihar, New Delhi 110076, India. A variety of complications are often encountered in children with nephrotic syndrome. Some result from treatment with drugs, notably corticosteroids and other immunosuppressive agents, which may have to be used for prolonged periods. The side effects of drugs can be avoided or minimized with their judicious application and careful clinical and laboratory monitoring. Uncontrolled nephrotic state (with heavy proteinuria, hypoalbuminemia and hyperlpidemia) makes the child susceptible to infections, hypovolemia, acute kidney injury and thrombotic complications, which are occasionally serious and life threatening. Expert management of nephrotic syndrome, explanation to parents and close follow up care are important to prevent and treat such complications. Key words: Complications in nephrotic syndrome, Thrombotic complications, Hypovolemia.
NEPHROTIC syndrome is a frequent renal disorder in children. Most cases are idiopathic and of these about 90% are of the “minimal lesion – steroid responsive” variety. The remainder (that also includes genetic and congenital cases) have siginificant glomerular abnormalities and usually do not respond to corticosteroids. “Secondary” nephrotic syndrome with glomerular involvement being due to a systemic condition (e.g., systemic lupus erythematosus, Henoch Schonlein vasculitis, renal polyangiitis, IgA nephropathy) is uncommon in pediatric age group [1]. Nephrotic syndrome is a recurrent (having remissions and relapses) or persistent condition, of varying severity and requires long-term management with agents that may have serious side effects. Uncontrolled nephrotic state with heavy proteinuria, hypoalbuminemia and hyperlpidemia makes the child susceptible to complications that may be life threatening. Proper management is aimed at preventing various complications and ensuring their optimal treatment [2]. The aim is to keep nephrotic syndrome in remission or at least keep the child edema free in steroid resistant group.
severity of hypoalbuminemia, and therefore particularly common in steroid resistant nephrotic syndrome and congenital nephrotic syndrome. Important complications are listed in Table 1. Infections Several factors predispose the child with a severe nephrotic state to infections, which can be mild or serious and life threatening [3]. These include edema, ascitis and effusions in serous cavities. Massive edema causes
Table 1. Complications in nephrotic syndrome with massive proteinuria and hypoalbuminemia (I)
Infections Bacterial. Peritonitis, cellulitis, sepsis, pneumonia, meningitis, urinary tract infections Viral, Varicella, measles
(ii) Hypovolemia and acute kidney injury (acute renal failure) (iii) Thromboembolic complications
COMPLICATIONS IN NEPHROTIC SYNDROME Various complications can be considered as those (i) resulting from the nephrotic state, and (ii) from toxicity of the drugs used in its management [1]. Complications as a consequence of massive proteinuria and hypoalbuminemia The risk of various complications is related with the 129
Venous. Deep veins in extremities, cerebral venous sinuses, renal vein Arterial. Pulmonary, cerebral, extremities (iv) Loss of binding proteins. Vitamin D binding globulin, insulin like growth factor I -II , thyroid binding protein, Transferin, ceruloplasmin, cortisol binding protein (v) Hyperlipdemia and risk of cardiovascular disease.
Apollo Medicine, Vol. 6, No. 2, June 2009
Review Article
stretching and devitalisation of skin, which breaks with minor trauma. Blood levels of IgG and factor B are reduced because of increased urinary loss. The latter adversely affect the alternative pathway of complement activation, which is responsible for opsonization of encapsulated bacteria such as S. pneumoniae. Impaired Tlymphocyte function and reduced concentrations of zinc and transferrin may also have a role. Peritonitis is a common infection and usually associated with vague clinical features such as mild fever and abdominal pain, whereas characteristic abnormalities and localising signs may be absent [4]. S. Pneuomniae is the commonest causative organism but Gram negative organisms (E. Coli, H. influenzae B) may also be responsible. Ascitic fluid should be obtained and treatment started with broad spectrum antibiotics. Pneumococcal vaccine is advised for children with nephrotic syndrome. Cellulitis is also frequently observed and may progress with alarming rapidity. Thigh and perineal region are common sites. Initially it may be mistaken for insect bite or allergic rash. Aggressive antibiotic therapy is necessary. The importance of skin care and local hygiene should be explained to the parents. Varicella and measles. Varicella and measles can be particularly severe in a child with nephrotic syndrome receiving corticosteroids or other immunosuppressive agents. Varicella vaccine should promptly be administered if there is a history of contact. Acyclovir is used for treatment.
Whereas hypovolemia is readily reversed by infusion of colloid (or even 0.9% saline as an emergency measure), acute kidney injury (ARF) may occasionally develop. Presence of an underlying infection, tubulointerstitial edema, blockage of tubules by casts and use of nephrotoxic drugs (interstitial nephritis is a common complication of furosemide) may be contributory factors. After hypovolemia has been corrected, 1-2 mg/kg of furosemide may be given IV. If renal function is not restored, standard regimen for management of ARF is instituted [1]. Thromboembolic complications [4] Several abnormalities of coagulation mechanism have been observed in nephrotic syndrome. However, despite presence of a hypercoagulable state, serious thromboembolic complications are uncommon. The predisposing factors include hypovolemia and hemoconcentation, hyperviscosity, low levels of antithrombin III (due to increased urinary losses), factors XI and XII and raised concentrations pf protein C and S, platelet hypercoagulability, decreased fibrinolysis and hyperlipidemia. Thrombosis is usually venous involving deep veins of extremities and cerebral venous sinuses and occasionally renal vein. Pulmonary and cerebral arteries may be affected. Unless clinically suspected and promptly diagnosed by appropriate imaging, such complications can become life threatening. Asymmetric edema of legs or arms (Fig.1), severe headache, seizures, visual impairment, sudden dyspnea, flank pain and gross hematuria should be carefully assessed.
Hypovolemia and acute kidney injury (acute renal failure) Children with significant edema and hypoalbuminemia are usually hypovolemic. An acute loss of fluid from diarrhea or vomiting or overzealous use of diuretics may lead to a rapid fall in renal perfusion and “pre renal” ARF. Hypovolemia is suggested by anorexia, abdominal pain, vomiting, cold peripheries with poor capillary refill, oliguria and tachycardia. Blood pressure may be normal (occasionally elevated from release of vasoconstrictors) or hypotension in late stages. Core –toe temperatures difference is >3 degrees C. Blood examination shows hemoconcentration, increased levels of urea and to a lesser extent creatinine. Urinary sodium is <5 mEq/L (unless the child has received diuretics). Hypovolemia can be rapidly corrected with infusion of 20% albumin, 0.5-1 g/kg body weight over a period of 4 hours with close monitoring of pulse and BP and evidence of pulmonary congestion. Apollo Medicine, Vol. 6, No. 2, June 2009
Fig.1. Child having nephrotic syndrome showing edema of right arm. The left arm does not have any edema. Ultrasound Doppler study disclosed thrombosis of brachial and subclavian veins.
130
Review Article
Treatment. Heparin 75 U/kg is administered IV as a slow bolus and thereafter 20 U/kg infused/hour. Activated thromboplastin time (APTT) is maintained at 1.5 to twice the basal value. Low molecular weight heparin may be more effective. Fibrinolytic agents such as urokinase and tissue plsaminogen activator (0.1 mg/kg/hour) would be indicated for major thrombosis (pulmonary, renal arteries). Following recovery from acute stage, warfarin (0.2 mg/kg, modified according to INR values) is administered for 3-6 months.
Table 2. Complications due to side effects and toxicity of drugs used in the management of nephrotic syndrome
Loss of binding proteins Increased urinary losses of various binding proteins individually do not appear to be clinically important (with the exception of thyroid binding protein in congenital nephrotic syndrome), but could contribute to various problems. Hyperlipidemia [5] Extremely high levels of blood cholesterol are not uncommon in nephrotic syndrome, especially at the onset when the diagnosis is often delayed. In steroid responsive cases (comprising about 90%), institution of corticosteroids therapy promptly induces a remission with resolution of proteinuria and the raised lipid levels rapidly return to normal. However, in steroid resistant nephritic syndrome (with underlying non-minimal lesions on renal histology), heavy proteinuria, hypoalbuminemia and hyperlipidemia (elevated cholesterol, triglycerides, VLDL, and LDL) may persist. Hyperlipidemia increases the risk of atheromatous vascular disease. Dietary restriction of fats appears to be insufficient to control elevated lipid levels. The use of statins, well established in adults, has recently been recommended in children [6]. Complications due to use of medications [1] Significant and occasionally troublesome complications are frequently observed in children with nephrotic syndrome that can be related to use of several agents in the management (Table 2). With judicious use of these drugs, detailed explanation provided to the parents and careful observation, most of them can be avoided.
(i)
Corticosteroids. Cushingoid features (moon facies, hirsutism, shoulder hump, massive obesity, striae, reduction of muscle mass, thinning of skin), hypertension, behaviour disorders, osteoporosis, growth retardation, glucose intolerance, posterior subcapsular cataracts, myopathy, pseudotumor cerebri
(ii)
Cyclophosphamide. Alopecia, hemorrhagic cystitis, bone marrow suppression, neutropenia, gonadal toxicity (azoospermia, ovarian fibrosis)
(iii)
Levamisole. Neutropenia, vasculitis
(iv)
Mycophenolate. Bone marrow suppression
(v)
Cyclosporine. Hirsutism, gingival hypertrophy, hypertension, nephrotoxicity
(vi)
Tacrolimus. Diabetes, nephrotoxicity
Prompt medical consultation should be sought for any acute problem. Regular follow up evaluation of linear growth is essential. Serious corticosteroid toxicity must be avoided and steroid sparing agents introduced as indicated [2]. Strict guidelines while using cyclophosphamide and calcineurin inhibitors should be followed in the management of steroid sensitive as well as steroid resistant nephrotic syndrome [7]. CONCLUSION Nephrotic syndrome in children is the most frequent recurrent or chronic condition. In most cases complete cure is the expected outcome. The disorder requires expert, long-term management. Serious complications are occasionally observed and require prompt detection and aggressive treatment. Most drug-related complications are avoidable. REFERENCES
Treatment related complications Nephrotic syndrome in children is usually a recurrent condition requiring expert management, which should be carried out jointly by the child’s pediatrician and the pediatric nephrologist. At the outset the family is given detailed information of the condition and the expected outcome. Compliance with treatment and avoidance of other forms of treatment should be emphasized. They should be aware of the side effects of the drug being used. 131
1. Srivastava RN, Bagga A. Nephrotic syndrome. In Pediatric Nephrology, 4th Ed. Jaypee Brothers Med Publishers, New Delhi, 2005, 161-200. 2. Indian Pediatric Nephrology Group, IndianAcademy of Pediatrics. Management of steroid sensitive nephritic syndrome : Revised guidelines. Indian Pedaitr 2008; 45: 203-214. 3. Srivastava RN, Moudgil A, Khurana O. Serious infections and mortality in nephrotic syndrome. Indian Pediatr 1987; 24: 1077-1080. 4. Hoyer PF, Gonda S, Barthels M, et al. Thromboembolic complications in children with nephrotic syndrome. Acta Pediatr Scand 1986; 75: 804-810. Apollo Medicine, Vol. 6, No. 2, June 2009
Review Article 5. Thabet MA, Salcedo JR, Chan JCM. Hyperlipidemia in nephrotic syndrome. Pediatr Nephrol 1993; 7: 559556. 6. Prescott WA, Streetman DA, Streetman DS. The potential role of HMG-CoA reductase inhibitors in
Apollo Medicine, Vol. 6, No. 2, June 2009
132
pediatric nephritic syndrome. Ann Pharmacother 2004; 38: 2105-2114. 7. Indian Society of Pediatric Nephrology. Management of steroid resistant nephrotic syndrome. Indian Pediatr 2009; 46: 35-47.
COMPLICATIONS IN NEPHROTIC SYNDROME IN CHILDREN RN Srivastava and A Vasudev Senior Consultant, Pediatric Nephrologist, Apollo Indraprastha Hospitals, Sarita Vihar, New Delhi 110076, India. e-mail: [email protected], [email protected] Correspondence to: Dr R N Srivastava, Senior Consultant, Pediatric Nephrologist, Apollo Indraprastha Hospitals, Sarita Vihar, New Delhi 110076, India. A variety of complications are often encountered in children with nephrotic syndrome. Some result from treatment with drugs, notably corticosteroids and other immunosuppressive agents, which may have to be used for prolonged periods. The side effects of drugs can be avoided or minimized with their judicious application and careful clinical and laboratory monitoring. Uncontrolled nephrotic state (with heavy proteinuria, hypoalbuminemia and hyperlpidemia) makes the child susceptible to infections, hypovolemia, acute kidney injury and thrombotic complications, which are occasionally serious and life threatening. Expert management of nephrotic syndrome, explanation to parents and close follow up care are important to prevent and treat such complications. Key words: Complications in nephrotic syndrome, Thrombotic complications, Hypovolemia.
NEPHROTIC syndrome is a frequent renal disorder in children. Most cases are idiopathic and of these about 90% are of the “minimal lesion – steroid responsive” variety. The remainder (that also includes genetic and congenital cases) have siginificant glomerular abnormalities and usually do not respond to corticosteroids. “Secondary” nephrotic syndrome with glomerular involvement being due to a systemic condition (e.g., systemic lupus erythematosus, Henoch Schonlein vasculitis, renal polyangiitis, IgA nephropathy) is uncommon in pediatric age group [1]. Nephrotic syndrome is a recurrent (having remissions and relapses) or persistent condition, of varying severity and requires long-term management with agents that may have serious side effects. Uncontrolled nephrotic state with heavy proteinuria, hypoalbuminemia and hyperlpidemia makes the child susceptible to complications that may be life threatening. Proper management is aimed at preventing various complications and ensuring their optimal treatment [2]. The aim is to keep nephrotic syndrome in remission or at least keep the child edema free in steroid resistant group.
severity of hypoalbuminemia, and therefore particularly common in steroid resistant nephrotic syndrome and congenital nephrotic syndrome. Important complications are listed in Table 1. Infections Several factors predispose the child with a severe nephrotic state to infections, which can be mild or serious and life threatening [3]. These include edema, ascitis and effusions in serous cavities. Massive edema causes
Table 1. Complications in nephrotic syndrome with massive proteinuria and hypoalbuminemia (I)
Infections Bacterial. Peritonitis, cellulitis, sepsis, pneumonia, meningitis, urinary tract infections Viral, Varicella, measles
(ii) Hypovolemia and acute kidney injury (acute renal failure) (iii) Thromboembolic complications
COMPLICATIONS IN NEPHROTIC SYNDROME Various complications can be considered as those (i) resulting from the nephrotic state, and (ii) from toxicity of the drugs used in its management [1]. Complications as a consequence of massive proteinuria and hypoalbuminemia The risk of various complications is related with the 129
Venous. Deep veins in extremities, cerebral venous sinuses, renal vein Arterial. Pulmonary, cerebral, extremities (iv) Loss of binding proteins. Vitamin D binding globulin, insulin like growth factor I -II , thyroid binding protein, Transferin, ceruloplasmin, cortisol binding protein (v) Hyperlipdemia and risk of cardiovascular disease.
Apollo Medicine, Vol. 6, No. 2, June 2009
Review Article
stretching and devitalisation of skin, which breaks with minor trauma. Blood levels of IgG and factor B are reduced because of increased urinary loss. The latter adversely affect the alternative pathway of complement activation, which is responsible for opsonization of encapsulated bacteria such as S. pneumoniae. Impaired Tlymphocyte function and reduced concentrations of zinc and transferrin may also have a role. Peritonitis is a common infection and usually associated with vague clinical features such as mild fever and abdominal pain, whereas characteristic abnormalities and localising signs may be absent [4]. S. Pneuomniae is the commonest causative organism but Gram negative organisms (E. Coli, H. influenzae B) may also be responsible. Ascitic fluid should be obtained and treatment started with broad spectrum antibiotics. Pneumococcal vaccine is advised for children with nephrotic syndrome. Cellulitis is also frequently observed and may progress with alarming rapidity. Thigh and perineal region are common sites. Initially it may be mistaken for insect bite or allergic rash. Aggressive antibiotic therapy is necessary. The importance of skin care and local hygiene should be explained to the parents. Varicella and measles. Varicella and measles can be particularly severe in a child with nephrotic syndrome receiving corticosteroids or other immunosuppressive agents. Varicella vaccine should promptly be administered if there is a history of contact. Acyclovir is used for treatment.
Whereas hypovolemia is readily reversed by infusion of colloid (or even 0.9% saline as an emergency measure), acute kidney injury (ARF) may occasionally develop. Presence of an underlying infection, tubulointerstitial edema, blockage of tubules by casts and use of nephrotoxic drugs (interstitial nephritis is a common complication of furosemide) may be contributory factors. After hypovolemia has been corrected, 1-2 mg/kg of furosemide may be given IV. If renal function is not restored, standard regimen for management of ARF is instituted [1]. Thromboembolic complications [4] Several abnormalities of coagulation mechanism have been observed in nephrotic syndrome. However, despite presence of a hypercoagulable state, serious thromboembolic complications are uncommon. The predisposing factors include hypovolemia and hemoconcentation, hyperviscosity, low levels of antithrombin III (due to increased urinary losses), factors XI and XII and raised concentrations pf protein C and S, platelet hypercoagulability, decreased fibrinolysis and hyperlipidemia. Thrombosis is usually venous involving deep veins of extremities and cerebral venous sinuses and occasionally renal vein. Pulmonary and cerebral arteries may be affected. Unless clinically suspected and promptly diagnosed by appropriate imaging, such complications can become life threatening. Asymmetric edema of legs or arms (Fig.1), severe headache, seizures, visual impairment, sudden dyspnea, flank pain and gross hematuria should be carefully assessed.
Hypovolemia and acute kidney injury (acute renal failure) Children with significant edema and hypoalbuminemia are usually hypovolemic. An acute loss of fluid from diarrhea or vomiting or overzealous use of diuretics may lead to a rapid fall in renal perfusion and “pre renal” ARF. Hypovolemia is suggested by anorexia, abdominal pain, vomiting, cold peripheries with poor capillary refill, oliguria and tachycardia. Blood pressure may be normal (occasionally elevated from release of vasoconstrictors) or hypotension in late stages. Core –toe temperatures difference is >3 degrees C. Blood examination shows hemoconcentration, increased levels of urea and to a lesser extent creatinine. Urinary sodium is <5 mEq/L (unless the child has received diuretics). Hypovolemia can be rapidly corrected with infusion of 20% albumin, 0.5-1 g/kg body weight over a period of 4 hours with close monitoring of pulse and BP and evidence of pulmonary congestion. Apollo Medicine, Vol. 6, No. 2, June 2009
Fig.1. Child having nephrotic syndrome showing edema of right arm. The left arm does not have any edema. Ultrasound Doppler study disclosed thrombosis of brachial and subclavian veins.
130
Review Article
Treatment. Heparin 75 U/kg is administered IV as a slow bolus and thereafter 20 U/kg infused/hour. Activated thromboplastin time (APTT) is maintained at 1.5 to twice the basal value. Low molecular weight heparin may be more effective. Fibrinolytic agents such as urokinase and tissue plsaminogen activator (0.1 mg/kg/hour) would be indicated for major thrombosis (pulmonary, renal arteries). Following recovery from acute stage, warfarin (0.2 mg/kg, modified according to INR values) is administered for 3-6 months.
Table 2. Complications due to side effects and toxicity of drugs used in the management of nephrotic syndrome
Loss of binding proteins Increased urinary losses of various binding proteins individually do not appear to be clinically important (with the exception of thyroid binding protein in congenital nephrotic syndrome), but could contribute to various problems. Hyperlipidemia [5] Extremely high levels of blood cholesterol are not uncommon in nephrotic syndrome, especially at the onset when the diagnosis is often delayed. In steroid responsive cases (comprising about 90%), institution of corticosteroids therapy promptly induces a remission with resolution of proteinuria and the raised lipid levels rapidly return to normal. However, in steroid resistant nephritic syndrome (with underlying non-minimal lesions on renal histology), heavy proteinuria, hypoalbuminemia and hyperlipidemia (elevated cholesterol, triglycerides, VLDL, and LDL) may persist. Hyperlipidemia increases the risk of atheromatous vascular disease. Dietary restriction of fats appears to be insufficient to control elevated lipid levels. The use of statins, well established in adults, has recently been recommended in children [6]. Complications due to use of medications [1] Significant and occasionally troublesome complications are frequently observed in children with nephrotic syndrome that can be related to use of several agents in the management (Table 2). With judicious use of these drugs, detailed explanation provided to the parents and careful observation, most of them can be avoided.
(i)
Corticosteroids. Cushingoid features (moon facies, hirsutism, shoulder hump, massive obesity, striae, reduction of muscle mass, thinning of skin), hypertension, behaviour disorders, osteoporosis, growth retardation, glucose intolerance, posterior subcapsular cataracts, myopathy, pseudotumor cerebri
(ii)
Cyclophosphamide. Alopecia, hemorrhagic cystitis, bone marrow suppression, neutropenia, gonadal toxicity (azoospermia, ovarian fibrosis)
(iii)
Levamisole. Neutropenia, vasculitis
(iv)
Mycophenolate. Bone marrow suppression
(v)
Cyclosporine. Hirsutism, gingival hypertrophy, hypertension, nephrotoxicity
(vi)
Tacrolimus. Diabetes, nephrotoxicity
Prompt medical consultation should be sought for any acute problem. Regular follow up evaluation of linear growth is essential. Serious corticosteroid toxicity must be avoided and steroid sparing agents introduced as indicated [2]. Strict guidelines while using cyclophosphamide and calcineurin inhibitors should be followed in the management of steroid sensitive as well as steroid resistant nephrotic syndrome [7]. CONCLUSION Nephrotic syndrome in children is the most frequent recurrent or chronic condition. In most cases complete cure is the expected outcome. The disorder requires expert, long-term management. Serious complications are occasionally observed and require prompt detection and aggressive treatment. Most drug-related complications are avoidable. REFERENCES
Treatment related complications Nephrotic syndrome in children is usually a recurrent condition requiring expert management, which should be carried out jointly by the child’s pediatrician and the pediatric nephrologist. At the outset the family is given detailed information of the condition and the expected outcome. Compliance with treatment and avoidance of other forms of treatment should be emphasized. They should be aware of the side effects of the drug being used. 131
1. Srivastava RN, Bagga A. Nephrotic syndrome. In Pediatric Nephrology, 4th Ed. Jaypee Brothers Med Publishers, New Delhi, 2005, 161-200. 2. Indian Pediatric Nephrology Group, IndianAcademy of Pediatrics. Management of steroid sensitive nephritic syndrome : Revised guidelines. Indian Pedaitr 2008; 45: 203-214. 3. Srivastava RN, Moudgil A, Khurana O. Serious infections and mortality in nephrotic syndrome. Indian Pediatr 1987; 24: 1077-1080. 4. Hoyer PF, Gonda S, Barthels M, et al. Thromboembolic complications in children with nephrotic syndrome. Acta Pediatr Scand 1986; 75: 804-810. Apollo Medicine, Vol. 6, No. 2, June 2009
Review Article 5. Thabet MA, Salcedo JR, Chan JCM. Hyperlipidemia in nephrotic syndrome. Pediatr Nephrol 1993; 7: 559556. 6. Prescott WA, Streetman DA, Streetman DS. The potential role of HMG-CoA reductase inhibitors in
Apollo Medicine, Vol. 6, No. 2, June 2009
132
pediatric nephritic syndrome. Ann Pharmacother 2004; 38: 2105-2114. 7. Indian Society of Pediatric Nephrology. Management of steroid resistant nephrotic syndrome. Indian Pediatr 2009; 46: 35-47.