Continuing Education Activity

The nephritic syndrome is a clinical syndrome presenting as hematuria, hypertension, oliguria, and edema. It can be due to a primary renal disease or a clinical manifestation of other glomerular renal pathology. The underlying cause must be promptly diagnosed and managed. This activity reviews the evaluation and treatment of nephritic syndrome and highlights the role of the interprofessional team in evaluating and treating patients with this condition.

Objectives:

• Describe the pathophysiology of nephritic syndrome.
• Explain the appropriate steps in the evaluation of nephritic syndrome.
• Outline the management options available for the nephritic syndrome.
• Summarize interprofessional team strategies for improving care coordination and communication to nephritic syndrome and improve outcomes.

Introduction

The nephritic syndrome is a clinical syndrome that presents as hematuria, elevated blood pressure, decreased urine output, and edema. The major underlying pathology is inflammation of the glomerulus that results in nephritic syndrome. It causes a sudden onset of the appearance of red blood cell (RBC) casts and blood cells, a variable amount of proteinuria, and white blood cells in the urine. The primary pathology can be in the kidney, or it can be a consequence of systemic disorders.

Etiology

The nephritic syndrome is a common presentation of most proliferative glomerulonephritides (GN). The nephritic syndrome can be due to acute proliferative glomerulonephritis (postinfectious and infection associated), crescentic glomerulonephritis, and proliferative lupus glomerulonephritis. 

• In children, the most common cause of acute glomerulonephritis is post-streptococcal glomerulonephritis.[1] Sudden onset of the nephritic syndrome occurs seven to ten days after a streptococcal throat or 2-3 weeks after a skin infection (impetigo).[2] The most common pathogen involved is group A-beta hemolytic streptococci. Only a few strains of the bacteria are nephritogenic. Over 90% of the patients show a previous infection with types 12, 4, and 1 Streptococci. These are identified by typing of the M protein of the bacterial cell walls.
• A similar form of glomerulonephritis (infection associated) may occur in association with certain infections, e.g., bacterial infections (meningococcemia, staphylococcal endocarditis, and pneumococcal pneumonia, etc.), viral infections (mainly hepatitis B, hepatitis C, mumps, HIV infection, varicella, and EBV causing infectious mononucleosis), and parasitic infections (malaria and toxoplasmosis).
• Crescentic or rapidly progressive glomerulonephritis (RPGN) is characterized by the nephritic syndrome presenting with the clinical picture of sudden and severe acute renal failure. However, RPGN does not have a specific etiology. It may occur due to:

  • Anti-GBM antibody-mediated disease (e.g., Goodpasture syndrome)
  • Diseases caused by immune complex deposition, with granular deposits of antibodies and complement by immunofluorescence: This results from the complication of any of the immune complex nephritides and includes postinfectious glomerulonephritis, lupus nephritis, IgA nephropathy, and Henoch-Schönlein purpura.
  • Pauci-immune crescentic GN may be associated with systemic or renal vasculitis.
  • In systemic lupus erythematosus (SLE), patients with focal or generalized proliferative glomerular inflammation can present with nephritic syndrome.

Epidemiology

As per the final report by the National Center of Health Statistics, nephritis syndrome, along with nephrotic syndrome, is the 9th leading cause of death in the USA in the year 2017.[3] The reported number of combined deaths due to the nephritic syndrome, nephrotic syndrome, and renal diseases was 50,633 out of a total of 2,813,503 deaths in the year 2017.[3]

The mortality rate increases with advancing age. The deaths due to nephritic and nephrotic syndrome were higher in women, as compared to men, per the report. In women, it was the ninth leading cause accounting for 1.8% of total deaths, while in men, it was not in the top ten causes.[3]

Pathophysiology

The pathophysiology depends on the underlying cause of the nephritic syndrome. In nephritic syndrome, there is a structural disruption of the glomerular basement membrane. Glomerular filtration barrier (GFB) is formed by a meshwork of laminin, proteoglycans, and type IV collagen. It allows the filtration of water and small and medium-sized solutes. The three layers of the glomerular filtration barrier are the endothelium, glomerular basement membrane (GBM), and podocytes. The podocytes are part of the visceral layer of the bowman's capsule, a layer of cuboidal epithelial cells that transform and form cytoplasmic extensions that wrap around the basement membrane of the capillaries. It has a cell body, primary, and secondary foot processes.[2] The foot processes form a slit-like diaphragm which is selective for size and charge of the substances it filters.[4] In nephritic syndrome, the GFB can be damaged by various mechanisms:[5]

• Direct damage to the endothelial cell layer
• Deposition of immune complex in subendothelial, subepithelial, and mesangial space
• Disruption of glomerular basement membrane by primary renal or secondary systemic diseases
• Damage to the podocytes' cellular layer

Poststreptococcal glomerulonephritis occurs after sore throat or skin impetigo by nephritogenic strains of group A streptococcus. The antibodies are produced against nephritogenic antigens of group A streptococcus. The immune complex formed deposits in or around the glomerular basement membrane. It activates complement cascade resulting in the recruitment of immune cells like T cells, plasma cells, and macrophages. The coagulation cascade is also activated, resulting in micro thrombosis.[6]

RPGN patients have a high prevalence of certain HLA alleles, e.g., HLA-DR 14 and HLA-DR 4, suggesting a genetic predisposition to autoimmunity.[7] In Goodpasture syndrome, the autoantibodies are against a glomerular basement membrane (GBM) peptide within the noncollagenous portion of the α3 chain of collagen type IV.[8] The exact mechanism that triggers the formation of these autoantibodies is unclear. However, exposure to viruses or certain hydrocarbon solvents in paints and dyes has been implicated in some patients. Several drugs can also lead to autoantibodies. Additionally, certain malignancies are also implicated.

Henoch-Schönlein purpura (HSP) frequently follows upper respiratory tract infections. Group A streptococcus, parainfluenza virus, and parvovirus B19 are commonly implicated in its pathogenesis.[8] The deposition of IgA containing immune complexes in the mesangium plays a central role in the pathogenesis of HSP. It induces cell proliferation, white blood cell recruitment, and release of large amounts of cytokines and chemokines. The inflammatory reaction causes endothelial and podocyte damage.[9]

In pauci-immune glomerulonephritis, most patients have circulating anti-neutrophil cytoplasmic antibodies (ANCAs) that produce a cytoplasmic (c-ANCA) or perinuclear (p-ANCA) staining pattern. There may be a component of systemic vasculitides such as granulomatosis with polyangiitis (earlier known as Wegener granulomatosis) or microscopic polyangiitis. In many cases, the vasculitis is limited to the kidneys (idiopathic), and about 90% of idiopathic patients have c-ANCAs (specific for the neutrophil granule protein proteinase-3) or p-ANCAs (anti-neutrophil myeloperoxidase) in the serum. The pathogenic potential of ANCA antibodies has been established recently with studies in mice where transferring antibodies against myeloperoxidase (the target antigen of most p-ANCAs) induces a form of RPGN.[10]

The disruption of the glomerular filtration barrier in nephritic syndrome allows red blood cells, albumin, and large molecules to get filtered in the urine resulting in nephritic syndrome.[11] The dysmorphic RBCs- a feature of glomerular hematuria, acanthocytes, and RBC casts are pathognomonic of glomerulonephritis. RBC casts are formed when deformed, and distorted RBCs and white blood cells are encased by the Tamm-Horsfall protein (THP). THP is secreted by renal tubular cells and excreted in urine normally.

Histopathology

The microscopic findings of different etiologies are:

Poststreptococcal Glomerulonephritis: Light microscopy picture shows that the glomeruli are diffusely enlarged with endocapillary proliferation and neutrophil infiltration. The immunofluorescence microscopy shows a "stary sky pattern" due to subepithelial "lumpy" granular deposition of IgG and C3. Electron microscopy will demonstrate the "lumpy" subepithelial immune deposits. Mesangial deposits may also be seen in some patients.[12]

Staphylococcal Glomerulonephritis: The majority of patients have focal endocapillary glomerulonephritis with peripheral capillary occlusion due to endothelial cell proliferation and neutrophil infiltration. Capillary tufts may show necrosis. "Lumpy" subepithelial immune deposits are seen.  In some patients, mesangial proliferative glomerulonephritis (also called membranoproliferative glomerulonephritis or MPGN) may be seen with marked mesangial proliferation and granular immune deposits within the basement membrane.[13]

Crescentic Glomerulonephritis: The crescent is formed by the proliferation of epithelial cells in the parietal layer of the Bowman capsule. Macrophages, fibrin exudates, fibroblasts, complement products may be seen trapped in the mesangium and the Bowman's capsule space.[14] In addition to this, other features of disorder-specific lesions may be seen in different diseases.

• In Goodpasture syndrome, there is a linear deposition of IgG antibodies and C3 along the GBM.
• Lupus nephritis has a "full-house pattern" with IgG, IgM, IgA, C3 immune deposits present diffusely in the mesangium, sub epithelium, and sub-endothelium.[15]
• Anti-GBM antibodies or immune complexes are not detected by immunofluorescence and electron microscopy in pauci-immune crescentic glomerulonephritis. Vasculitis may be seen on renal biopsy.

History and Physical

The classic symptoms of the nephritic syndrome are:

• Periorbital and pedal edema
• Hematuria with red or cola-colored urine
• Proteinuria in non-nephrotic (i.e., less than 3.5 gm/day) range and may cause foamy urine when protein content is high
• Hypertension or poorly controlled blood pressure (BP) in patients with previously controlled BP
• Renal insufficiency characterized by oliguria (reduced urine output), and azotemia, due to decreased glomerular filtration rate (GFR)

The clinical symptoms can have a variable course. They can present with a chronic progressive course causing chronic renal failure (usual adults with postinfectious GN and RPGN) or acute self-limiting illness (usual children with post-streptococcal GN). The acute fulminant course is usually seen in all patients with crescentic glomerulonephritis.

The pertinent questions provider should ask the patients are: [16]

• Periorbital puffiness in the early morning
• Edema in legs in the evening
• The change in color, odor, consistency, and output of urine
• Recent upper respiratory tract or skin infection
• Fever, fatigue
• Ulcers and rash on the extremities to rule out vasculitis
• Hemoptysis and dyspnea may be present in Goodpasture syndrome (due to cross-reacting antibodies to the alveolar epithelium) and Wegener granulomatosis (if lungs are affected). History of viral disease or exposure to hydrocarbons may be elicited in these patients.

On physical examination, the patient may have pallor and anemia. On vital examination, the patients have elevated blood pressure. The signs of fluid overload may be present, including JVP distention, pitting edema, and crackles on chest auscultation.  On cardiovascular examination, a new heart murmur can be auscultated in patients with infective endocarditis. Palpable purpura and painful and swollen joints are present in patients with systemic diseases like vasculitis, Henoch-Schönlein purpura, and SLE.

Evaluation

The urine analysis is the first test done in the evaluation of nephritic syndrome. Exercise, food, or medicines can cause discoloration of urine. There is normal excretion of a small amount of blood in the urine. The upper limit of normal excretion of blood in the urine is 3 RBCs/HPF.[17]

In nephritic syndrome, the urine has greater than 5 RBCs/ HPF along with acanthocytes, dysmorphic RBCs, and red blood cells (RBCs) casts and in a few cases white blood cells (WBCs) casts.[18] The hematuria usually is marked with brownish (cola) colored urine. As the hematuria is glomerular, dysmorphic RBCs are seen, and at least 1 per 20 cells is an acanthocyte in glomerular hematuria.[19] The patients have pyuria in the absence of a urinary tract infection. The cellular casts are less common than acanthocytes in glomerular hematuria as casts are present in severe disease.[20]

The proteinuria usually ranges in the sub nephrotic range (less than 3.5 g/day), but it can go up to the nephrotic range. A 24-hours urinary protein assay is required if the attendant nephrotic syndrome is suspected.

The renal functions should be assessed by measuring plasma creatinine and urea levels. Plasma creatinine levels can estimate GFR to determine the stage of chronic kidney disease.[21] In nephritic syndrome, the excretion of urea and creatinine is impaired due to the disruption of GFB. This results in azotemia, elevated creatine level, and reduced GFR. Blood cultures are obtained in patients with persistent fever and signs of chronic infection.

The kidney biopsy will provide the definite underlying cause for the nephritic syndrome. The histopathological findings of kidney biopsy are described in the histopathology section above.  

Following serological tests should be carried out to rule out the underlying immunological renal disease.[22]

• ANA: Anti-nuclear antibodies to rule out autoimmune disorders
• Serum C3 and C4 Complement Levels: The complement levels are low in diseases in which there is an activation of the inflammatory cascade resulting in deposition of immune complexes in the glomerulus. The conditions include post-streptococcal glomerulonephritis, infective endocarditis, and SLE.
• ASO Titers: High levels of anti-streptolysin O, anti-DNase B antibody titers indicate a recent streptococcal infection
• ANCA: Both cytoplasmic and peripheral anti-neutrophil cytoplasmic antibodies (ANCA) levels are assessed to rule out systemic vasculitis (i.e., granulomatosis with polyangiitis, microscopic polyangiitis)
• Anti-dsDNA Antibodies: Highly sensitive for the diagnosis of systemic lupus erythematosus
• Anti-glomerular Basement Membrane Antibodies: To rule out Goodpasture syndrome
• Hepatitis B Surface Antigen and HCV Antibodies: To rule out hepatitis B and C infection

• Serum Protein Electrophoresis and Serum Immunofixation: To identify plasma cell disorders and levels of monoclonal proteins[23]

• Rheumatoid Factor: To screen for cryoglobulinemia in suspected patients

Treatment / Management

The treatment in nephritic syndrome is mainly supportive. The treatment consists of:

• Antihypertensives: Anti-hypertensives are administered in patients with elevated blood pressure despite dietary salt, fluid restriction, and loop diuretics. In severe cases, hypertension is treated with ACE inhibitors, ARBs, and nifedipine.[6]

• Diuretics: Loop diuretics may be administered to excrete excess sodium and water retained in the body. It helps to decrease fluid retention in the body. The reduced fluid load on kidneys helps speed up the healing process.[24]
• Corticosteroids: Help relieve the inflammation in the kidney and promote healing.
• Immunomodulators: Immunosuppressive drugs reduce and block the antigenic effects of the inciting agents. It is most useful for rapidly progressive glomerulonephritis.[25] The use of corticosteroids and immunomodulators is controversial in certain causes of the nephritic syndrome, including staphylococcal endocarditis. It can aggravate the sepsis and result in increased mortality.[26]
• Antibiotics: Post streptococcal GN patients with evidence of streptococcal infection are administered penicillin. Erythromycin is preferred for patients allergic to penicillin. Early treatment of streptococcal infection with antibiotics reduces the severity and incidence of glomerulonephritis.[27]
• Dialysis: In some cases, the disease has a fulminating course leading to renal failure. In such cases, renal replacement therapy with dialysis is performed.[28]

Differential Diagnosis

The following renal diseases have a clinical presentation similar to the nephritic syndrome:

• Nephrotic syndrome
• Familial nephritis
• Idiopathic hematuria
• Anaphylaxis

Prognosis

The prognosis of the nephritic syndrome depends upon the underlying etiology and age of the patients. Usually, children have an acute self-limiting course of glomerulonephritis, and the prognosis is good. Adults typically have a chronic fulminating course. The disease is not resolved in 20 to 74% of the adults. In these patients, the renal function derangement persists and will result in chronic renal failure.[29]

Complications

The nephritic syndrome can grossly compromise renal function and lead to the following complications.

• Acute renal failure and progression to RPGN
• Uncontrolled hypertension
• Azotemia
• Hyperkalemia
• Hyperphosphatemia
• Hypocalcemia
• Heart failure
• Hypertensive encephalopathy presenting as seizures and altered consciousness

Deterrence and Patient Education

• Diet restriction: Patients should have a diet low in sodium and potassium. The reduced intake of sodium and potassium helps reduce the retention of water.
• Fluid restriction: To relieve the existing edema and minimize the risk of developing edema, fluid restriction is advised.
• Bed rest: Patients are advised to have reduced physical activity along with the treatment.

Pearls and Other Issues

• The nephritic syndrome may have a variable clinical picture depending on the underlying etiology.
• The severity of clinical symptoms at the time of presentation determines the prognosis of the disease. Patients with severe oliguria, azotemia, raised creatinine level at the time of presentation have a worse prognosis.
• The acanthocytes, dysmorphic red blood cells, and RBC casts are pathognomonic of glomerular inflammation. It can be identified in urine analysis.
• Supportive treatment should be initiated immediately along with carrying out the evaluation tests for a specific diagnosis.

Enhancing Healthcare Team Outcomes

• The management of nephritic syndrome involves a multidisciplinary team consisting of internists, nephrologists, immunologists, infectious disease specialists, pharmacists, and nursing staff. Close monitoring of the patient’s hemodynamic status and renal profile should be done to assess the progression of the disease.
• The underlying autoimmune disease can be managed by the administration of corticosteroids and immunomodulatory drugs. The immunologist and pharmacists should educate the patient regarding close monitoring of the adverse effects of these drugs. 
• The patient should follow a restricted diet low in sodium, potassium, and phosphate planned by the dietician.

Review Questions

• Access free multiple choice questions on this topic.
• Click here for a simplified version.
• Comment on this article.

References

1.

Zhang Y, Shen Y, Feld LG, Stapleton FB. Changing pattern of glomerular disease at Beijing Children's Hospital. Clin Pediatr (Phila). 1994 Sep;33(9):542-7. [PubMed: 8001323]

2.

Rodríguez-Iturbe B, Katiyar VN, Coello J. Neuraminidase activity and free sialic acid levels in the serum of patients with acute poststreptococcal glomerulonephritis. N Engl J Med. 1981 Jun 18;304(25):1506-10. [PubMed: 7231488]

3.

Heron M. Deaths: Leading Causes for 2017. Natl Vital Stat Rep. 2019 Jun;68(6):1-77. [PubMed: 32501203]

4.

Reiser J, Kriz W, Kretzler M, Mundel P. The glomerular slit diaphragm is a modified adherens junction. J Am Soc Nephrol. 2000 Jan;11(1):1-8. [PubMed: 10616834]

5.

Yuste C, Gutierrez E, Sevillano AM, Rubio-Navarro A, Amaro-Villalobos JM, Ortiz A, Egido J, Praga M, Moreno JA. Pathogenesis of glomerular haematuria. World J Nephrol. 2015 May 06;4(2):185-95. [PMC free article: PMC4419128] [PubMed: 25949932]

6.

Rodriguez-Iturbe B, Haas M. Post-Streptococcal Glomerulonephritis. In: Ferretti JJ, Stevens DL, Fischetti VA, editors. Streptococcus pyogenes: Basic Biology to Clinical Manifestations [Internet]. University of Oklahoma Health Sciences Center; Oklahoma City (OK): Feb 10, 2016. [PubMed: 26866231]

7.

Phelps RG, Rees AJ. The HLA complex in Goodpasture's disease: a model for analyzing susceptibility to autoimmunity. Kidney Int. 1999 Nov;56(5):1638-53. [PubMed: 10571772]

8.

Kalluri R, Wilson CB, Weber M, Gunwar S, Chonko AM, Neilson EG, Hudson BG. Identification of the alpha 3 chain of type IV collagen as the common autoantigen in antibasement membrane disease and Goodpasture syndrome. J Am Soc Nephrol. 1995 Oct;6(4):1178-85. [PubMed: 8589284]

9.

Wyatt RJ, Julian BA. IgA nephropathy. N Engl J Med. 2013 Jun 20;368(25):2402-14. [PubMed: 23782179]

10.

Gómez-Puerta JA, Bosch X. Anti-neutrophil cytoplasmic antibody pathogenesis in small-vessel vasculitis: an update. Am J Pathol. 2009 Nov;175(5):1790-8. [PMC free article: PMC2774045] [PubMed: 19815703]

11.

Mundel P, Shankland SJ. Podocyte biology and response to injury. J Am Soc Nephrol. 2002 Dec;13(12):3005-15. [PubMed: 12444221]

12.

Sorger K, Gessler M, Hübner FK, Köhler H, Olbing H, Schulz W, Thoenes GH, Thoenes W. Follow-up studies of three subtypes of acute postinfectious glomerulonephritis ascertained by renal biopsy. Clin Nephrol. 1987 Mar;27(3):111-24. [PubMed: 3552342]

13.

Nasr SH, Markowitz GS, Stokes MB, Said SM, Valeri AM, D'Agati VD. Acute postinfectious glomerulonephritis in the modern era: experience with 86 adults and review of the literature. Medicine (Baltimore). 2008 Jan;87(1):21-32. [PubMed: 18204367]

14.

Fischer EG, Lager DJ. Anti-glomerular basement membrane glomerulonephritis: a morphologic study of 80 cases. Am J Clin Pathol. 2006 Mar;125(3):445-50. [PubMed: 16613350]

15.

Devadass CW, Mysorekar VV, Eshwarappa M, Mekala L, Siddaiah MG, Channabasappa KG. Clinical features and histological patterns of lupus nephritis in a single center of South India. Saudi J Kidney Dis Transpl. 2016 Nov-Dec;27(6):1224-1230. [PubMed: 27900970]

16.

Khanna R. Clinical presentation & management of glomerular diseases: hematuria, nephritic & nephrotic syndrome. Mo Med. 2011 Jan-Feb;108(1):33-6. [PMC free article: PMC6188440] [PubMed: 21462608]

17.

Sokolosky MC. Hematuria. Emerg Med Clin North Am. 2001 Aug;19(3):621-32. [PubMed: 11554278]

18.

Rovin BH, Song H, Birmingham DJ, Hebert LA, Yu CY, Nagaraja HN. Urine chemokines as biomarkers of human systemic lupus erythematosus activity. J Am Soc Nephrol. 2005 Feb;16(2):467-73. [PubMed: 15601744]

19.

Chang BS. Red cell morphology as a diagnostic aid in hematuria. JAMA. 1984 Oct 05;252(13):1747-9. [PubMed: 6471304]

20.

Hebert LA, Dillon JJ, Middendorf DF, Lewis EJ, Peter JB. Relationship between appearance of urinary red blood cell/white blood cell casts and the onset of renal relapse in systemic lupus erythematosus. Am J Kidney Dis. 1995 Sep;26(3):432-8. [PubMed: 7645551]

21.

National Collaborating Centre for Chronic Conditions (UK). Chronic Kidney Disease: National Clinical Guideline for Early Identification and Management in Adults in Primary and Secondary Care. Royal College of Physicians (UK); London: Sep, 2008. [PubMed: 21413194]

22.

Hebert LA, Parikh S, Prosek J, Nadasdy T, Rovin BH. Differential diagnosis of glomerular disease: a systematic and inclusive approach. Am J Nephrol. 2013;38(3):253-66. [PMC free article: PMC3842189] [PubMed: 24052039]

23.

Parry HM, Pratt G, Hutchison CA. Monoclonal gammopathy of undetermined significance: an update for nephrologists. Adv Chronic Kidney Dis. 2012 Sep;19(5):291-6. [PubMed: 22920639]

24.

Ali SS, Sharma PK, Garg VK, Singh AK, Mondal SC. The target-specific transporter and current status of diuretics as antihypertensive. Fundam Clin Pharmacol. 2012 Apr;26(2):175-9. [PubMed: 22145583]

25.

Jennette JC. Rapidly progressive crescentic glomerulonephritis. Kidney Int. 2003 Mar;63(3):1164-77. [PubMed: 12631105]

26.

Glassock RJ, Alvarado A, Prosek J, Hebert C, Parikh S, Satoskar A, Nadasdy T, Forman J, Rovin B, Hebert LA. Staphylococcus-related glomerulonephritis and poststreptococcal glomerulonephritis: why defining "post" is important in understanding and treating infection-related glomerulonephritis. Am J Kidney Dis. 2015 Jun;65(6):826-32. [PubMed: 25890425]

27.

Johnston F, Carapetis J, Patel MS, Wallace T, Spillane P. Evaluating the use of penicillin to control outbreaks of acute poststreptococcal glomerulonephritis. Pediatr Infect Dis J. 1999 Apr;18(4):327-32. [PubMed: 10223684]

28.

Beck L, Bomback AS, Choi MJ, Holzman LB, Langford C, Mariani LH, Somers MJ, Trachtman H, Waldman M. KDOQI US commentary on the 2012 KDIGO clinical practice guideline for glomerulonephritis. Am J Kidney Dis. 2013 Sep;62(3):403-41. [PubMed: 23871408]

29.

Montseny JJ, Meyrier A, Kleinknecht D, Callard P. The current spectrum of infectious glomerulonephritis. Experience with 76 patients and review of the literature. Medicine (Baltimore). 1995 Mar;74(2):63-73. [PubMed: 7891544]

Disclosure: Mydah Hashmi declares no relevant financial relationships with ineligible companies.

Disclosure: Jyotsna Pandey declares no relevant financial relationships with ineligible companies.