Post-Streptococcal Glomerulonephritis

Post-Streptococcal Glomerulonephritis

I. What every physician needs to know.

Post-streptococcal glomerulonephritis (PSGN) is a condition manifested by development of hematuria, proteinuria, hypertension and edema, which presents several weeks after infection (tonsillopharyngitis or cellulitis/erysipelas) with nephritogenic strains of Group A beta hemolytic streptococcus (GAS). The bacteria produce antigens with high affinity for glomerular sites forming glomerular immune complexes; these glomerular immune complexes activate complement with subsequent inflammation and development of the disease.

II. Diagnostic Confirmation: Are you sure your patient has Post-Streptococcal Glomerulonephritis?

The clinical criteria of PSGN are the development of hematuria with proteinuria of variable degree, with hypertension and dependent edema. In addition there should be documentation of infection with GAS by serology (ASO titers; streptozyme test) or culture (throat or skin).

A. History Part I: Pattern Recognition:

The PSGN usually appears 1 to 3 weeks after GAS tonsillopharyngitis and between 3 and 6 weeks after GAS cellulitis/erysipelas.

The patient can present varying from indolent asymptomatic microscopic hematuria to a well established nephritic syndrome characterized by dark-colored urine, proteinuria of variable range, hypertension, dependent edema and decreased glomerular filtration rate (GFR) with elevation in serum creatinine. It affects male patients more commonly.

A classic presentation is a young male patient (more common in pediatric patients and young adults) who has a history of GAS pharyngitis 3 weeks earlier, who presents with dark colored urine, progressively worsening edema, and hypertension.

Edema occurs in 75% of cases and is secondary to retention of sodium and water. It usually resolves within 5-10 days. However in uncontrolled cases it can develop anasarca and pulmonary edema.

Hematuria occurs in up to 50% of cases – the urine has a dark colored appearance. Gross hematuria usually disappears within 3 weeks, although may recur following physical activity. Microscopic hematuria may persist for up to 6 months; however, in some patients can persist up to 1 year.

Hypertension occurs in up to 90% of cases and can be of variable degree. Blood pressure usually normalizes within 3 weeks, although can remain elevated up to 6-8 weeks. Severe hypertensive crisis can be associated with PRES (Posterior reversible encephalopathy syndrome).

Decreased GFR – depending on the degree of inflammation, varying degrees of GFR can occur with a rise in serum creatinine; however, patients with PSGN will rarely require dialysis.

Recently it has been described that acute PSGN is the most common renal cause of Posterior Reversible Encephalopathy Syndrome (PRES) which is a clinical syndrome characterized by headache, confusion, seizures, etc. and is associated with bilateral gray and white matter abnormalities in the posterior regions of the cerebral hemispheres and cerebellum.

B. History Part 2: Prevalence:

PSGN occurs most often in males with a male-to-female ratio of 1.5 to 2:1; the reasons for this gender difference are unknown. There is no racial predilection; however PSGN clusters in areas of overcrowding. Although PSGN can present at any given age, the most commonly affected group are pre-school and school-aged pediatric patients (age 5-12 years) with a peak at age 5-6 years).

Epidemic outbreaks of acute PSGN occur in areas of poverty, overcrowded, with suboptimal hygiene conditions;15% of patient s with pharyngitis and one quarter of patients with skin infections will develop PSGN. Seasonal and geographic variation have been well described too: PSGN preceded by acute tonsillopharyngitis occurs most commonly during winter and spring in temperate areas; PSGN preceded by cellulitis/erysipelas occurs most commonly during summer and autumn in tropical and subtropical areas.

The prognosis is excellent with complete recovery in 95% of children and adolescents.

C. History Part 3: Competing diagnoses that can mimic Post-Streptococcal Glomerulonephritis.

PSGN is a very straightforward diagnosis in the patient with nephritis with history of infection with GAS with a clinical improvement within 2-4 weeks. In the patient with progression of the disease beyond 2 weeks, persistent hematuria or hypertension beyond 6 weeks, and inadequate documentation of a preceding GAS infection, the differential diagnosis may require a renal biopsy to distinguish PSGN from:

Membranoproliferative glomerulonephritis (MPGN)

IgA nephropathy

Anti-GBM (glomerular basement membrane) antibody disease

Lupus nephritis

Henoch-Schönlein purpura nephritis

Hemolytic Uremic Syndrome

Other infectious etiologies [Endocarditis (S. aureus, Strep. viridans), Visceral abscess (S. aureus, E. coli, Pseudomonas, Proteus mirabilis), Shunt nephritis (S. aureus, Staph. albus, Strep. viridans), Pneumonia (Strep. pneumoniae, Mycoplasma), Typhoid fever (Salmonella typhi); Viruses (Epstein Barr, Parvovirus B19, Varicella, Cytomegalovirus, Coxsackie, Rubella, Mumps, Hepatitis B), Parasites (Schistosoma mansoni, Plasmodium falciparum, Toxoplasma gondii, Filaria].

D. Physical Examination Findings.

Edema – can vary from dependent to generalized anasarca with pulmonary edema.Hypertension – can vary from indolent-asymptomatic to hypertensive emergency and associated with posterior reversible encephalopathy syndrome (PRES).Gross hematuria – urine looks dark, from tea-colored to cola colored.

E. What diagnostic tests should be performed?

Kidney biopsy – In patients with prominent nephritic syndrome associated with progressive rise in serum creatinine as well as in patients with persistently low C3 levels beyond 8 weeks, a kidney biopsy should be considered to rule out membranoproliferative glomerulonephritis (MPGN).

1. What laboratory studies (if any) should be ordered to help establish the diagnosis? How should the results be interpreted?

Urinalysis (UA) with microscopic analysis of a freshly voided specimen should be the first test to be ordered in any patient with discolored urine. The microscopic analysis will look for dysmorphic erythrocytes, red blood cell casts and pyuria. In addition to hematuria, it will show proteinuria of various degrees.

Complement – characteristically, patients with PSGN will have decreased levels of C3 and CH50 (total complement activity) with normal C4 levels (which indicates activation of the alternative pathway of complement). The C3 and CH50 return to normal within 4 to 8 weeks after presentation. Persistently elevated levels should prompt for an alternative diagnosis.

Chemistry – documentation of renal function (BUN/creatinine) is important as the degree of GFR impairment correlates with the extent of glomerular injury. Most patients will have normal to slightly elevated BUN/creatinine.

Serology – A recent GAS infection can be determined by elevated titers of antibodies to extracellular streptococcal products. The streptozyme test, which measures five different streptococcal antibodies, is positive in more than 95% of patients with PSGN due to tonsillopharyngitis and about 80% of those with cellulitis/erysipelas. The streptozyme test includes the following antibodies: anti-streptolysin (ASO), anti-hyaluronidase (AHase), anti-streptokinase (ASKase), anti-nicotinamide-adenine dinucleotidase (anti-NAD), anti-DNAse B antibodies. The ASO, anti-DNAse B, anti-NAD, and AHase titers are elevated in patients with tonsillopharyngitis.

An ASO titer of 250 U or higher is highly suggestive of recent streptococcal infections. It is important to acknowledge that measuring ASO alone may provide a false negative result as ASO titers rise may be blunted in patients who have received antibiotics.

In comparison, after a cellulitis/erysipelas only the anti-DNAse B and AHase are elevated.

Culture – this can be used instead of serology in patients with previously documented GAS infections.

2. What imaging studies (if any) should be ordered to help establish the diagnosis? How should the results be interpreted?

No imaging is required in patients with PSGN. However, an ultrasound may be considered in order to document a normal anatomy as the clinical implication of acute nephritis is different in patients with a single kidney.

A chest roentgenogram may be useful in patients with fluid overload and dyspnea to assess the presence and extension of pulmonary edema.

A brain MRI may be required in patients with encephalopathy to rule out PRES.

F. Over-utilized or “wasted” diagnostic tests associated with this diagnosis.

ANA, ANCA antibodies, anti-GBM (glomerular basement membrane) antibodies, ESR, CRP.

III. Default Management.

The treatment for PSGN is supportive and focused on treating the clinical manifestations of the disease, especially the complications associated with volume overload, such as hypertension and pulmonary edema. Non-specific treatment includes sodium and water restriction as well as loop diuretics.

A. Immediate management.

The most important immediate management requirements occur as result of complications of severe hypertension and require an expedited blood pressure reduction.

Loop diuretics (intravenous furosemide at an initial dose of 1 mg/kg in adults or 2 mg/kg in children) generally permit a diuretic response with decrease of both blood pressure and edema.

Patients with hypertensive emergencies and malignant hypertension, including PRES, should be treated with labetalol (0.5-2 mg/kg/h IV), nicardipine (5 -15 mg/hour) or nitroprusside (0.5-2 mcg/kg/min IV); in addition, patients with significant fluid overload, IV furosemide at the doses previously described, should be administered.

In patients with severe hypertension without encephalopathy use of vasodilator drugs such as IV hydralazine or labetalol can be used before starting an oral agent.

Mild-to-moderate hypertension does not warrant emergency management. The use of common oral antihypertensive is sufficient; in patients with proteinuria, the use of ACEI is indicated (in our institution, we start lisinopril 10 mg/day and uptitrate according to blood pressure response). In addition, furosemide (1-3 mg/kg/d oral [PO], administered 1-2 times daily) ensures the control of fluid excess and enhances the control of hypertension.

Patients with evidence of persistent GAS infection should be given a course of antibiotic therapy mostly to prevent contamination of patient contacts with nephritogenic strains.

Although it occurs rarely (< 5%), some patients may require dialysis during the acute episode, especially in cases of rapid development of fluid overload uncontrolled with diuretics.

B. Physical Examination Tips to Guide Management.

The most important clinical signs are the blood pressure and clinical signs of volume overload.

In patients with elevation of blood pressure, an ophthalmoscopic evaluation of the retinal vessels is important to ensure no development of hypertensive eye disease; cardiac auscultation is paramount to detect S4 heart sound associated with hypertension or an S3 gallop associated with congestive heart failure due to volume overload. In children, attention to the liver span is important as this can be a sensitive marker of volume overload.

The degree of edema should be monitored on a daily basis, including the periorbital area, as well as lower and upper extremities.

C. Laboratory Tests to Monitor Response To, and Adjustments in, Management.

The C3 concentration returns to normal by 6-8 weeks after onset in more than 95% of patients. Failure to improve should prompt to consider alternative diagnoses such as MPGN.

Urinary abnormalities resolve at a slower pace. Proteinuria may disappear within the first 2-3 months or may decrease slowly over 6 months. Intermittent or postural proteinuria has been noted in a few patients for as long as 1-2 years after onset.

D. Long-term management.

Patients should have good blood pressure control, daily weight monitoring to avoid fluid retention, monitoring of resolution of hematuria.

Depending on the level of azotemia, patients may require weekly laboratory evaluation (BUN, creatinine) to assess resolution of azotemia.

After 6 to 8 weeks, monitoring of C3 concentrations should be pursued to ensure normalization.

Serial follow every 3 months during the first year is recommended to ensure resolution of proteinuria, microhematuria as well as good blood pressure control.

E. Common Pitfalls and Side-Effects of Management.

The mainstay of treatment is adequate blood pressure control as well as control of edema. There should be blood pressure parameters to avoid overzealous blood pressure control; when starting an oral anti-hypertensive (such as an ACEI), it should be slowly uptitrated according to blood pressure response. It is important to remember that when starting ACEI creatinine should be monitored and avoid further dose increases if creatinine rises by 30% of baseline.

When using furosemide, close attention should be kept to serum electrolytes and renal function. These patients may be volume overloaded due to third spacing with intravascular volume depletion and overzealous diuretic use can lead to prerenal renal failure and electrolyte disturbances.

Medication dosages:- Labetalol (0.5-2 mg/kg/h IV) for SBP > 210 or DBP > 130- Nicardipine (5 -15 mg/hour IV) for SBP > 210 or DBP > 130- Nitroprusside (0.5-2 mcg/kg/min IV) for SBP > 210 or DBP > 130- Furosemide 1 mg/kg IV qday to BID (to maintain weight and edema control)- Hydralazine 10 mg IV q6h PRN for SBP > 180 or DBP > 110- Lisinopril 10 mg/day PO – uptitrated to 20 mg/d to keep SBP < 140 and DBP < 90- Amlodipine 10 mg/day PO to keep SBP < 140 and DBP < 90- Nifedipine (long-acting) 30 mg/day – uptitrated to 120 mg/day to keep SBP < 140 and DBP < 90.

IV. Management with Co-Morbidities.

Given that PSGN can cause uncontrolled hypertension and fluid overload, in addition to proteinuria, its impact is most significant in patients with underlying risk for fluid overload and labile hemodynamic status (renal insufficiency, heart failure, chronic liver disease, etc.).

A. Renal Insufficiency.

In the setting of preexistent chronic renal disease, a significant deterioration of their underlying nephropathy can ensue with subsequent decrease in GFR, worsening proteinuria, etc. These patients may require higher dose of loop diuretics, however at the expense of decreased GFR.

The mainstay of the treatment is to avoid fluid overload and uncontrolled hypertension. Close monitoring of BUN and creatinine is essential as these patients may eventually require renal replacement therapy if worsening GFR, fluid overload and uncontrolled hypertension ensues despite medical management. A consultation with Nephrology may be desirable.

B. Liver Insufficiency.

In patients with cirrhosis, close monitoring of fluid status is essential as underlying hypoalbuminemia can worsen with subsequent development of anasarca. Aggressive diuretic use in patients with cirrhosis can lead to development of hepatorenal syndrome. In addition, the secondary contraction alkalosis can subsequently predispose to development of hepatic encephalopathy; therefore, these patients should be monitored closely with daily weight, ensure euvolemia, adequate diuresis, maintain blood pressure within normal limits. These patients may require the combined support of Nephrology and Gastroenterology consultation.

C. Systolic and Diastolic Heart Failure.

In patients with heart failure, the main issue is avoiding severe third spacing and fluid overload. These patients can become severely fluid overloaded with intravascular volume depletion, which can subsequently cause further renal damage by means of developing cardiorenal syndrome given the decreased cardiac output. In addition, the severe hypertension can trigger development of flash pulmonary edema.

The mainstay of management is maintaining euvolemia with daily weight monitoring, have a low sodium (< 2g Na per day) diet, and most importantly ensure an adequate blood pressure control.

D. Coronary Artery Disease or Peripheral Vascular Disease.

As above.

E. Diabetes or other Endocrine issues.

Patients with severe diabetic nephropathy with underlying nephrotic syndrome can have worsening of the proteinuria with more prominent development of edema. Early initiation of ACE inhibitors in these patients may ensure good blood pressure control as well as control of proteinuria.

F. Malignancy.

No change in standard management.

G. Immunosuppression (HIV, chronic steroids, etc).

No change in standard management.

H. Primary Lung Disease (COPD, Asthma, ILD).

No change in standard management. However, in patients with severe lung disease with cor pulmonale, careful monitoring of volume status is paramount to avoid the development of volume overload with subsequent acute heart failure.

I. Gastrointestinal or Nutrition Issues.

Ensure continuation of diet support and protein intake. In patients with underlying disorders of the intestinal wall (celiac disease, Whipple’s disease, protein losing enteropathy, eosinophilic enteritis, etc.) the malnutrition related hypoalbuminemia can worsen due to renal losses of albumin.

In addition, some of these patients may have initial refractoriness to oral diuretics due to poor GI absorption. Use of intravenous furosemide in these patients is paramount especially in the first few days of treatment – furosemide 1 mg/kg/dose in one to two daily doses ensures adequate diuretic delivery to the kidney and enhance diuresis.

Adequate nutritional support is mainstay; may consider a Gastroenterology consult in patients with severe underlying malnutrition and enteropathy.

J. Hematologic or Coagulation Issues.

No change in standard management. Patients who develop nephrotic syndrome may have transient hypercoagulability which is important to consider in patients with primary hypercoagulable disorders. Appropriate VTE prophylaxis and monitoring for clinical signs of thrombosis is paramount.

K. Dementia or Psychiatric Illness/Treatment.

No change in standard management. Only consideration is the development of acute encephalopathy in the setting of hypertensive emergency (PRES). This requires rapid and stringent control blood pressure control.

V. Transitions of Care.

A. Sign-out considerations While Hospitalized.

The most important issue is to monitor patient’s blood pressure closely. Parameters for blood pressure control should be standing – use of IV labetalol, nicardipine or nitroprusside of SBP > 220 or DBP > 130; – use of IV hydralazine if SBP > 180 or DBP > 110.

In patients with hypertension and worsening edema, blood pressure can be further controlled with intravenous furosemide.

Avoid using steroids in these patients as it not only is ineffective, but can worsen fluid retention and edema.

B. Anticipated Length of Stay.

It varies from patient to patient, but on average these patients require 3 days, in order to control the blood pressure, be able to adjust the diuretic dose, and educate on further care.

C. When is the Patient Ready for Discharge?

Consider discharge when patient’s blood pressure is well controlled; patient understands rationale of treatment with diuretics to keep weight stable, as well as of dipstick monitoring for microhematuria and proteinuria.

D. Arranging for Clinic Follow-up.

1. When should clinic follow up be arranged and with whom.

Patient should follow up with Nephrology within 2 weeks of discharge.

2. What tests should be conducted prior to discharge to enable best clinic first visit.

Urinalysis (UA) with microscopic analysis of a freshly voided specimen. Complement C3, C4, CH50. Chemistry – (BUN/creatinine, electrolytes). Serum albumin. Streptozyme test (if unavailable, only ASO titers).

3. What tests should be ordered as an outpatient prior to, or on the day of, the clinic visit.

A repeat chemistry (BUN, creatinine, sodium potassium chloride, bicarbonate), serum albumin as well as a urinalysis should be obtained prior to the visit.

E. Placement Considerations.

None.

F. Prognosis and Patient Counseling.

PSGN has very good prognosis, ending in complete clinical and histologic resolution and healing in the vast majority of patients (95%), especially children, adolescents and young adults.

Adequate blood pressure control should be paramount; generally blood pressure normalizes after 3 weeks, and can be elevated up to 6-8 weeks in some patients.

Edema resolves within the first 2 weeks, on average within the first 10 days.

Patients should avoid exertion, especially in the first 2 weeks, to minimize worsening of macroscopic hematuria.

Patients should be aware that they will be followed up by Nephrology and will have surveillance urine (protein) and blood studies (C3, albumin, BUN/creatinine) ordered sporadically (every 4 to 6 weeks) according to their progress. Proteinuria usually resolves within the first 6 months, generally within the first 3 months. Microscopic hematuria as well usually resolves within the first 6 months, although it can persist in some patients for up to a year without having any clinically significant meaning.

Patients should be aware that the likelihood of recurrence is rare (< 5%) after 3 months.

VI. Patient Safety and Quality Measures.

A. Core Indicator Standards and Documentation.

None

B. Appropriate Prophylaxis and Other Measures to Prevent Readmission.

Adequate blood pressure control and daily weight is paramount.

Patient should follow up with Nephrology to adjust the antihypertensive medications to ensure adequate blood pressure control.

Patient should weight themselves daily and judiciously use diuretics to avoid fluid overload. Recommendation to weigh daily and use an additional dose of furosemide (e.g., 1 mg/kg) if gaining more than 2 lb per day.

Maintain a low sodium diet (< 2 grams per day).

VII. What’s the evidence?

Eison, TM, Ault, BH, Jones, DP, Chesney, RW, Wyatt, RJ. “Post-streptococcal acute glomerulonephritis in children: clinical features and pathogenesis”. Pediatr Nephrol. vol. 26. 2011. pp. 165-180.

Rodriguez-Iturbe, B, Musser, JM. “The Current State of Poststreptococcal Glomerulonephritis”. J Am Soc Nephrol. vol. 19. 2008. pp. 1855-1864.

Nadasdy, T, Hebert, LA. “Infection-related glomerulonephritis: understanding mechanisms”. Semin Nephrol. vol. 31. 2011. pp. 369-75.

Zafanello, M, Cataldi, L, Franchini, M, Fanos, V. “Evidence-based treatment limitations prevent any therapeutic recommendation for acute poststreptococcal glomerulonephritis in children”. Med Sci Monit. vol. 16. 2010. pp. RA79-84.

Demuynck, M, Lerut, E, Kuypers, D, Evenepoel, P, Claes, K, Naesens, M, Meijers, B, Vanrenterghem, Y, Bammens, B. “Post-streptococcal glomerulonephritis: not an extinct disease”. Acta Clin Belg. vol. 68. 2013. pp. 215-7.

Nasr, SH, Radhakrishnan, J, D’Agati, VD. “Bacterial infection-related glomerulonephritis in adults”. Kidney Int. vol. 83. 2013. pp. 792-803.

Hoy, WE, White, AV, Dowling, A, Sharma, SK, Bloomfield, H, Tipiloura, BT, Swanson, CE, Mathews, JD, McCredie, DA. “Post-streptococcal glomerulonephritis is a strong risk factor for chronic kidney disease in later life”. Kidney Int. vol. 81. 2012. pp. 1026-32.

Brodsky, SV, Nadasdy, T. “Infection-related glomerulonephritis”. Contrib Nephrol. vol. 169. 2011. pp. 153-60.

Endo, A, Fuchigami, T, Hasegawa, M, Hashimoto, K, Fujita, Y, Inamo, Y, Mugishima, H. “Posterior reversible encephalopathy syndrome in childhood: report of four cases and review of the literature”. Pediatr Emerg Care. vol. 28. 2012. pp. 153-7.

Martin, WJ, Steer, AC, Smeesters, PR, Keeble, J, Inouye, M, Carapetis, J, Wicks, IP. “Post-infectious group A streptococcal autoimmune syndromes and the heart”. Autoimmun Rev. vol. 14. 2015. pp. 710-25.

Parks, T, Smeesters, PR, Curtis, N, Steer, AC. “ASO titer or not? When to use streptococcal serology: a guide for clinicians”. Eur J Clin Microbiol Infect Dis. vol. 34. 2015. pp. 845-9.

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