Nephrotic syndrome natural history, complications and prognosis

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Yazan Daaboul, Serge Korjian


Complications of nephrotic syndrome include infections, thrombotic events, and renal failure. Mortality and overall prognosis depends on the occurrence of complications and adherence to medications.

Natural History

In children, the mean age for presentation of nephrotic syndrome is approximately 1-8 years. According to Madani and colleagues[1], who studied nephrotic syndrome in 502 pediatric patients, 67% of patients were in the range of 1-5 years of age. Other studies showed similar age distribution in children.[2][3][4][5] The mean age among adults is much more difficult to calculate because unlike children whose primary disease is almost always minimal change disease, secondary etiologies of nephrotic syndrome, such as HIV and diabetes, are much more common and corresponding age distribution is very wide.[6]



Patients with nephrotic syndrome are at increased risk of infections due to several mechanisms:

Patients with nephrotic syndrome who complain of abdominal pain must always be assessed for peritonitis that requires paracentesis. The rate of spontaneous bacterial peritonitis is 2-6%[8] which contributes to 1-2% of mortality in these patients. In addition to encapsulated bacteria, gram-negative bacterial organisms, such as E. coli, are also especially important infectious agents in patients with nephrotic syndrome.[9] Pneumonias, urinary tract infections, and skin infections, such as cellulitis, erysipelas, and lymphangitis are also common.[6] Since patients are often treated with immunosuppressants, the susceptibility to bacterial and viral infections is further heightened in these patients.[10][7]


The rate of thromboembolism may be as high as 40% in adults; whereas it is much lower in children at a rate of 2-5%.[11] Several factors contribute to thromboembolism in nephrotic syndrome[11]:

Thromboembolism is considered the second most important cause of mortality in nephrotic syndrome. The risk of thromboembolism increases as other risk factors of thrombosis are also present, such as immobility, indwelling catheters, use of diuretics or steroids.[6] Thromboembolism may occur at any site; common locations include deep veins of the extremities, cerebral veins, renal veins, and pulmonary veins. Although arterial occlusion is much less common, its prognostic significance is much graver than venous thromboembolism and is associated with mortality.[11] Considerably, the use of heparin may not be as efficient in nephrotic syndrome due to the insufficiency of antithrombin III required by the drug for anticoagulation.[12]

Cardiovascular Disease

The clinical presentation of nephrotic syndrome per represents a high-risk profile for cardiovascular disease. Patients may present with hypertension, hyperlipidemia, anemia, renal disease, and exposure to steroids, all of which are considered risk factors for the development of cardiovascular disease and cardiovascular events.[13][14]

Acute Renal Failure

Acute renal failure, in as early as within 4 weeks of nephrotic syndrome, is a more common complication in adult males > 60 years.[15] Additional cardiovascular risk factors, like hypertension, and iatrogenic causes, like fluid withdrawal and surgeries, are also important in the development of acute renal failure.[15] Renal failure in nephrotic syndrome is due to multiple factors. Acute tubular necrosis (ATN) corresponds to approximately 60% of acute renal failure in nephrotic syndrome. Interstitial edema, especially due to medications given for patients, like diuretics and steroids, are responsible for the remainder of cases.[15]


Osteoporosis is generally a complication of corticosteroid use in nephrotic syndrome. However, medication-induced osteoporosis is not the only factor that predisposes patients to loss of bone density. Urinary loss of components required for osteogenesis, such as vitamin D-binding protein is also involved.[16][17][18]


Anemia is commonly seen in patients with nephrotic syndrome but has been poorly evaluated. Recent studies have shown that perhaps the association between anemia and nephrotic syndrome are exaggerated and may not be as important as once believed.[19] Anemia be present even without the presence of worsening kidney function. Several reasons predispose patients with nephrotic syndrome to the development of anemia, but the true pathogenesis has not been revealed yet. Some hypothesize that urinary loss of erythropoietin (EPO) and abnormal physiological response to EPO are the culprit of anemia.[20][13] Nonetheless, these claims have not been validated in the literature and are still prone to debate.[21][22][23][24] Additionally, iron stores are thought to be depleted in nephrotic syndrome with urinary loss of transferrin, contributing to the pathogenesis as an iron-resistant microcytic hypochromic anemia. Similarly, some researchers noted that ferritin is in fact increased in patients with nephrotic syndrome, not decreased as once postulated.[25][19] The reason behind such elevation in ferritin remains unclear. Generally, administration of EPO resolves the anemia in these patients.[13]

Growth Retardation

Urinary loss of insulin-like growth factor (IGF) binding proteins may cause a decrease in serum concentration of IGF-I and IGF-II. Corticosteroids, often used in the treatment of nephrotic syndrome, may also suppress growth.[11]



  1. Kirpekar R, Yorgin PD, Tune BM, Kim MK, Sibley RK (2002). "Clinicopathologic correlates predict the outcome in children with steroid-resistant idiopathic nephrotic syndrome treated with pulse methylprednisolone therapy". Am J Kidney Dis. 39 (6): 1143–52. doi:10.1053/ajkd.2002.33382. PMID 12046024.
  2. Kumar J, Gulati S, Sharma AP, Sharma RK, Gupta RK (2003). "Histopathological spectrum of childhood nephrotic syndrome in Indian children". Pediatr Nephrol. 18 (7): 657–60. doi:10.1007/s00467-003-1154-9. PMID 12743793.
  3. Kari JA (2002). "Changing trends of histopathology in childhood nephrotic syndrome in western Saudi Arabia". Saudi Med J. 23 (3): 317–21. PMID 11938425.
  4. Mattoo TK, Mahmood MA, al-Harbi MS (1990). "Nephrotic syndrome in Saudi children clinicopathological study of 150 cases". Pediatr Nephrol. 4 (5): 517–9. PMID 2242321.
  5. Vande Walle JG, Donckerwolcke RA, Koomans HA (1999). "Pathophysiology of edema formation in children with nephrotic syndrome not due to minimal change disease". J Am Soc Nephrol. 10 (2): 323–31. PMID 10215332.
  6. 6.0 6.1 6.2 6.3 6.4 6.5 6.6 Eddy AA, Symons JM (2003). "Nephrotic syndrome in childhood". Lancet. 362 (9384): 629–39. doi:10.1016/S0140-6736(03)14184-0. PMID 12944064.
  7. 7.0 7.1 7.2 Patiroglu T, Melikoglu A, Dusunsel R (1998). "Serum levels of C3 and factors I and B in minimal change disease". Acta Paediatr Jpn. 40 (4): 333–6. PMID 9745775.
  8. Feinstein EI, Chesney RW, Zelikovic I (1988). "Peritonitis in childhood renal disease". Am J Nephrol. 8 (2): 147–65. PMID 3293444.
  9. Tain YL, Lin G, Cher TW (1999). "Microbiological spectrum of septicemia and peritonitis in nephrotic children". Pediatr Nephrol. 13 (9): 835–7. PMID 10603131.
  10. Goldstein SL, Somers MJ, Lande MB, Brewer ED, Jabs KL (2000). "Acyclovir prophylaxis of varicella in children with renal disease receiving steroids". Pediatr Nephrol. 14 (4): 305–8. PMID 10775074.
  11. 11.0 11.1 11.2 11.3 Roth KS, Amaker BH, Chan JC (2002). "Nephrotic syndrome: pathogenesis and management". Pediatr Rev. 23 (7): 237–48. PMID 12093934.
  12. Andrew M, Michelson AD, Bovill E, Leaker M, Massicotte MP (1998). "Guidelines for antithrombotic therapy in pediatric patients". J Pediatr. 132 (4): 575–88. PMID 9580753.
  13. 13.0 13.1 13.2 Feinstein S, Becker-Cohen R, Algur N, Raveh D, Shalev H, Shvil Y; et al. (2001). "Erythropoietin deficiency causes anemia in nephrotic children with normal kidney function". Am J Kidney Dis. 37 (4): 736–42. PMID 11273873.
  14. Vaziri ND (2001). "Erythropoietin and transferrin metabolism in nephrotic syndrome". Am J Kidney Dis. 38 (1): 1–8. doi:10.1053/ajkd.2001.25174. PMID 11431174.
  15. 15.0 15.1 15.2 Loghman-Adham M, Siegler RL, Pysher TJ (1997). "Acute renal failure in idiopathic nephrotic syndrome". Clin Nephrol. 47 (2): 76–80. PMID 9049453.
  16. Auwerx J, De Keyser L, Bouillon R, De Moor P (1986). "Decreased free 1,25-dihydroxycholecalciferol index in patients with the nephrotic syndrome". Nephron. 42 (3): 231–5. PMID 3753749.
  17. Freundlich M, Bourgoignie JJ, Zilleruelo G, Abitbol C, Canterbury JM, Strauss J (1986). "Calcium and vitamin D metabolism in children with nephrotic syndrome". J Pediatr. 108 (3): 383–7. PMID 3485195.
  18. Malluche HH, Goldstein DA, Massry SG (1979). "Osteomalacia and hyperparathyroid bone disease in patients with nephrotic syndrome". J Clin Invest. 63 (3): 494–500. doi:10.1172/JCI109327. PMC 371978. PMID 429568.
  19. 19.0 19.1 Mähr N, Neyer U, Prischl F, Kramar R, Mayer G, Kronenberg F; et al. (2005). "Proteinuria and hemoglobin levels in patients with primary glomerular disease". Am J Kidney Dis. 46 (3): 424–31. doi:10.1053/j.ajkd.2005.06.002. PMID 16129203.
  20. Zhou XJ, Vaziri ND (1992). "Erythropoietin metabolism and pharmacokinetics in experimental nephrosis". Am J Physiol. 263 (5 Pt 2): F812–5. PMID 1443172.
  21. Shibasaki T, Misawa T, Matsumoto H, Abe S, Nakano H, Matsuda H; et al. (1994). "Characteristics of anemia in patients with nephrotic syndrome". Nihon Jinzo Gakkai Shi. 36 (8): 896–901. PMID 7933664.
  22. Gansevoort RT, Vaziri ND, de Jong PE (1996). "Treatment of anemia of nephrotic syndrome with recombinant erythropoietin". Am J Kidney Dis. 28 (2): 274–7. PMID 8768925.
  23. Ishimitsu T, Ono H, Sugiyama M, Asakawa H, Oka K, Numabe A; et al. (1996). "Successful erythropoietin treatment for severe anemia in nephrotic syndrome without renal dysfunction". Nephron. 74 (3): 607–10. PMID 8938689.
  24. Misaizu T, Matsuki S, Strickland TW, Takeuchi M, Kobata A, Takasaki S (1995). "Role of antennary structure of N-linked sugar chains in renal handling of recombinant human erythropoietin". Blood. 86 (11): 4097–104. PMID 7492766.
  25. Branten AJ, Swinkels DW, Klasen IS, Wetzels JF (2004). "Serum ferritin levels are increased in patients with glomerular diseases and proteinuria". Nephrol Dial Transplant. 19 (11): 2754–60. doi:10.1093/ndt/gfh454. PMID 15316097.
  26. Wynn SR, Stickler GB, Burke EC (1988). "Long-term prognosis for children with nephrotic syndrome". Clin Pediatr (Phila). 27 (2): 63–8. PMID 3338230.