Pneumonia from Nephrologist's Perspective

1. Dr Sanjay Maitra
MD,DM(PGI,CHD)
Clinical Fellowship,Univ.of Toronto(CANADA)
Senior Consultant Nephrologist
Apollo Health City, Hyderabad
PNEUMONIA- A
NEPHROLOGIST’S PERSPECTIVE

2. Situations where pneumonia is probable in
Nephrology practice
 Nephrotic Syndrome
 Chronic Kidney Disease
 ESRD and Dialysis patients
 Renal Transplant Patients
 As part of Sepsis ,AKI and Multi-organ
Dysfunction

3. Nephrotic Syndrome
Syndrome characterised by
 Nephrotic Range Proteinuria, Hypoalbuminaemia,
oedema and hyperlipidemia
 Classified as Primary and Secondary
 Very common in children, many have a benign
course
 Infections are a very common complication in these
patients

4. Increased infection rates in Nephrotics
Observational Study done to study the incidence of Major Infections
in Nephrotic Syndrome
Total of 86 children upto the age of 13 yrs were included
Period of Study November 2010 to July 2012
Major infections occurred in 36.6% of patients; nearly 1/3 of them had
pneumonia

5. Increased infection rates in Nephrotics
 Most common infections are bacterial sepsis ,
pneumonia , cellulitis and peritonitis
 Most common organisms are Streptococcus
Pneumoniae, Haemophilus Influenzae, Escherichia
Coli and other gm. negative organisms
 The proposed mechanism for infections in NS are
 Urinary Immunoglobulin losses
 Urinary losses of Properdin Factor B that opsonizes certain
bacteria

6. CKD, ESRD and Dialysis Patients

7. Heterogeneous group of disorders characterized by alterations in
kidney structure and function, which manifest in various ways
depending upon the underlying cause or causes and the severity
of disease
What is CKD- Current understanding

8. CKD- a continuum
Stages of CKD –KDIGO 2012

9. Complications increase as CKD progresses
Stage V
Kidney
Failure
ESRD
Stage IV
Severe 
Kidney
Function
Stage III
Moderate 
Kidney
Function
Stage II
Mild 
Kidney
Function
Stage I
CKD Risk
Factors/Damage
with preserved
GFR
130 120 110 100 90 80 70 60 50 40 30 20 15 10 0
Kidney Function - Glomerular Filtration Rate (ml/min/1.73m2 )
MI, CHF, CV Death

10. CARDIOVASCULAR AND INFECTIONS ARE THE MAIN CAUSES OF
DEATH IN ESRD PTS

11. Age-specific ESRD incidence rates
GK Modi, V Jha. The incidence of end-stage renal disease in India: A population-based study. Kidney International (2006) 70,
2131–2133

12. Cross sectional study involving 52,273 patients
Mean age 50.1±14.6 yrs
M:F ratio 70:30
Diabetic nephropathy –commonest cause of CKD (31%)
CKD of unknown aetiology (16%)
CGN (14%)
Hypertensive nephrosclerosis (13%)

13. Different infection rates in CKD
Sakina B. Naqvi et al. Infectious Complications in Chronic Kidney Disease. Advances in Chronic Kidney
Disease, Vol 13, No 3 (July), 2006: pp 199-204

14. Pulmonary Infectious Mortality of Dialysis
Patients Compared with the General Population
Sarnak & Jaber: Chest120:1883-1887, 200
Dialysis population
General population
10 fold

15. Pneumococcal pneumonia infection is associated with ESRD
Shih-Ting Huang et al. Pneumococcal pneumonia infection is associated with end-stage renal disease in adult hospitalized
patients. Kidney International advance online publication, 2 April 2014; doi:10.1038/ki.2014.79

16. Guo H et al. Nephrol. Dial. Transplant. 2008;23:680-686
Cumulative survival probabilities following pneumonia in dialysis patients
Cumulative survival
probabilities were 0.51 at 1
years
Half of dialysis pts who had
pneumonia died within 1 yr
of the pneumonia

17. Sepsis-Related Mortality of Dialysis
Patients Compared with the General
Population
Sarnak & Jaber: Kidney Int 58:1758–1764, 2000
100 Fold

18. Overview of immunological responses
in CKD- Response to vaccines
T BAPC
Adaptive ImmunityInnate Immunity

19. http://library.thinkquest.org/03oct/01254/images/immune_map.jpg
Recognised by APCs, Complement (C3b), Acute phase
proteins (eg CRP). Inflammatory response initiated by
cytokines (Il-1, IL-6, TNF)
Sentry
Function
Initial response –
acute inflammation
Adaptive
response
initiated by
APCs
Innate
response
Defects in the immune system are collectively termed “immunodeficiency
disorders”. They may involve the innate, adaptive systems or external/
physiological barriers. They may be primary or secondary disorders. There are
also situations where the immune response may be impaired, but not classically
immunodeficient.
Th0
Th2
Th1

20. T cell activation model
www.nejm.org december 23, 2004

21. B cell activation and differentiation
Copied from Ron L and Benhur Lee,
http://www.pia.org.uk/publications/general_publications/igg
_subclass_deficiency.htm#whatare
IgG1. This is the most
abundant subclass:
recognises protein antigens -
important in fighting viral
infections.
IgG2. This is the second
highest subclass in
concentration. It neutralises
infections caused by bacteria
with polysaccharide capsules.
IgG3. This is present in
smaller quantities, and has a
similar function to IgG1.
IgG4. Normal concentrations
of this subclass can be very
low - functional role not
known.
process Ag with MHC II
B cell Dendritic cells

22. Activation of Ab response to vaccines
Antibody
Secreting
Plasma Cell
Peptide-specific
T Cell
Dendritic Cell
Activated
T Cell
Naïve B Cell
Vaccine Antigens
+/- Adjuvant
Memory
B Cell
2º Immunization
differentiation
Ag presentation
Primary Ab response
Clonal expansion
Maturation of naïve, “immature” B cell
of infant to a polysaccharide-responsive
B cell, conjugate priming

23. Summary of immune disturbances in ESRD
patients
Clin J Am Soc Nephrol 3: 1526–1533, 2008

24. Adapted from: http://www.kidney.org/professionals/kls/pdf/cme/mono_immuno_infect.pdf
Sequence of Infections after Organ
Transplantation

25. Characteristics of transplant patients with Invasive
Pneumococcal Disease
Study Period 1995-2004
Looked into the Incidence ,Clinical significance ,serotypes , and microbial
resistance patterns of Invasive Pneumococcal disease in Transplant
patients as well as the general population
In transplants there were 146 infections per 1lakh persons/year
In general population it was 11.5infections per 1lakh persons/year
Serotypes 23F and 22F were the most common
85% had a sertype covered in the PPV23 vaccine
Risk of Invasive Pneumococcal disease in Kidney Transplants is
2800/1,00,000 pt. yrs

26. Prevention of Pneumonia in CKD/ESRD

27. New era of Pneumococcal Prevention
Andrew J. Pollard et al. Maintaining protection against invasive bacteria with protein–polysaccharide conjugate vaccines
PPV
response
PCV
response

31. PCV & PPV have divergent effect on B cells
Adapted from: Clutterbuck et al. JID 2012:205:1408-16.

32. OPA GMT Ratio (1 Month After Dose)
12.0
6A
0 1 2.0 3.0 4.0 5.0 8.0
1
3
4
5
6B
7F
9V
14
18C
19A
19F
23F
*
Primary Objective Results
• Noninferiority criteria met
for all serotypes
• Statistically-higher response
(>4-fold rise) for serotype 6A
– 88.5% for PCV13
– 49.3% for PPSV23
Secondary Objective Results
• Statistically-higher response
for 8 of 12 serotypes in common
• Statistically-higher response
(95% LCI >2) for serotype 6A
*Serotype 6A is not contained in PPSV23. GMT, geometric mean titer; OPA, opsonophagocytosis assay.
0.5
PCV13 vs PPSV23 in Adults

33. Country Year Title Recommendations
KDIGO: Kidney Disease
Improving Global Outcomes
(managed by the NKF, U.S.)1
Global 2013 Clinical Practice Guideline
for the Evaluation and
Management of CKD
All adults with eGFR <30 & those at high risk of
PD (e.g., nephrotic syndrome, diabetes, or those
receiving immunosuppression) receive
vaccination with POLYVALENT PNEUMOCOCCAL
VACCINE
The National Kidney
Foundation - Kidney Disease
Outcomes Quality Initiative
(KDOQI)2
USA 2014 KDOQI US Commentary
on the 2012 KDIGO
Guidelines for CKD
• Same as KDIGO
• Also, “NEWER VACCINES recommended for
the general population should also be
administered to patients with CKD”
Advisory Committee on
Immunization Practices (US
CDC)3
USA 2014 Recommended Adult
Immunization Schedule—
United States
Adults aged ≥19 yrs with immunocompromising
conditions (including CRF and NS)
1 PCV13 + PPSV23 + PPSV23
Infectious Diseases Society
of America4
USA 2013 2013 IDSA Clinical Practice
Guideline for Vaccination of
the Immunocompromised
Host
Same as (ACIP) US CDC
Indian Society of
Nephrology6
India 2005 Vaccine recommendations
for Patients of CKD
1 dose of PPV23 to all dialysis patients ≥2 years
of age (Revaccination 3 years if <10 years old or
5 years for other dialysis patients
ISN for Govt. of India 7 India 2013 Standard Treatment
Guidelines Haemodialysis
All patients over 5 years old should receive
23vPPV
Guidelines for Pneumococcal Vaccinations in CKD

34. Country Year Title Recommendations
European Renal Best
Practice (ERBP)1
Europe 2013 ERBP position statement
on KIDGO 2013
No mention of any vaccine
Spanish Society of
Nephrology 2
Spain 2014 Spanish Society of
Nephrology document
on KDIGO guidelines for
CKD
Vaccinate against pneumococcal infection in
patients with a GFR <30 & in high risk cases
such as patients with NS, diabetes or those
who receive immunosuppressive treatment
Canadian Society of
Nephrology 3
Canada 2010 Commentary on the
2009 KDIGO Clinical
Practice Guideline
for the Care of KTR
KTR: Pneumococcal Vaccination recommended
Caring for Australians with
Renal Impairment (CARI)4
Australia 2012 KHA-CARI guideline:
KHA-CARI adaptation of
the KDIGO Guideline for
the Care of KTR
Vacciate all kidney transplant recipients
according to recommended schedules for the
general population.
Australian Government
Department of Health and
Ageing5
Australia 2013 The Australian
Immunisation handbook
CRF or relapsing or persistent NS : single dose
of PCV13. For those with a newly diagnosed
condition, the dose of 13vPCV should be
followed by 23vPPV doses.
Guidelines for Pneumococcal Vaccinations in CKD

35. Therapeutic interventions under consideration
to alter the immune dysfunction in CKD
1.High dose hemodialysis therapy may improve aspects
that are directly related to uraemic intoxication
2.Improvement of dialyser biocompatibility has shown to
influence the proinflammatory activation
3.New membranes can provide active reduction on
inflammatory factors e.g by coating of surfaces with anti-
inflammatory agents such as Vit E
4.IL-10 supplementation in pts who cannot upregulate this
factor

36. Effect of interventions in infection
outcomes
Michael Allon et al. J Am Soc Nephrol 14: 1863–1870, 2003

37. Pneumonia etiology in patients with CKD
Diego Viasus et al. Nephrol Dial Transplant (2011) 26: 2899–2906

38. Objectives
1. Cumulative pneumonia-free survival over time
2. Microbiological source of pneumonia
3. Association with cardiovascular (CV) events
4. Association with mortality
Haifeng Guo et al. Nephrol Dial Transplant (2008) 23: 680–

39. Methods
 Linked 3 databases from US Centers for Medicare and Medicaid Services
(CMS)
 Outcomes: Pneumonia and CV events identified by ICD-9 codes; identify
deaths
 Kaplan-Meier analysis (cumulative survival probabilities)
 Cox proportional hazards model (associations)
 Poisson model (relative risk adjusted for many factors)
1996 2001
Identify pts initiating maintenance dialysis therapy
-f/u start at 90 days after dialysis start
-identify pneumonia
-from pneumonia event, measure survival
-from pneumonia event, identify CV event
Follow-up
2003
end of f/u
Haifeng Guo et al. Nephrol Dial Transplant (2008) 23: 680–

40. Results
 N=289,210 dialysis patients in study; mean age =64
years
 21% of inception dialysis cohort developed pneumonia
within 1 yr
 Overall incidence rate = 27.9/100 patient-years
 Hospitalization with pneumonia as 1° diagnosis = 6.1/100 pt-
yrs
 Hospitalization with pneumonia as 2° diagnosis = 5.7/100 pt-
yrs
 Outpatient pneumonia incidence rates = 16.2/100 pt-yrs
• 84% had no pathogen identified
Haifeng Guo et al. Nephrol Dial Transplant (2008) 23: 680–

41. Pneumococcal vaccination & clinical
outcomes in
HD patients
D T Gilbertson et al. Nephrol Dial Transplant (2011) 26: 2934–2939
[1,18,533 patients >18 years age who initiated HD 90 days before enrollment]

42. ANTIBIOTIC CHOICE IS ACCORDING TO
LOCAL SENSITIVITY PATTERNS

44. Composition: (Prevenar 13) Pneumococcal 13 - valent conjugate vaccine (Diphtheria CRM197 Protein) is a sterile
solution of saccharides of the capsular antigens of Streptococcus pneumoniae serotypes 1, 3, 4, 5, 6A, 6B, 7F,
9V, 14, 18C, 19A, 19F and 23F individually conjugated to diphtheria CRM197 protein.
Indications: In infants and children from 2 months to 5 years of age, Prevenar 13 is indicated for active
immunization for the prevention of disease caused by Streptococcus pneumoniae serotypes 1, 3, 4, 5, 6A, 6B,
7F, 9V, 14, 18C, 19A, 19F and 23F (including sepsis, meningitis, bacteraemia, pneumonia and acute otitis
media); In adults of 50 years and older age group, Prevenar 13 is indicated for active immunization for the
prevention of pneumonia and invasive disease caused by Streptococcus pneumoniae serotypes 1, 3, 4, 5, 6A, 6B,
7F, 9V, 14, 18C, 19A, 19F and 23F.
Contraindications: Hypersensitivity to any component of the vaccine, or to diphtheria toxoid
Adverse reactions: In pediatric population: decreased appetite, irritability, drowsiness/increased sleep, restless
sleep/decreased sleep, fever, any injection-site erythema, induration/swelling or pain/tenderness. In adult
population: The safety of Prevenar 13 was assessed in 6 clinical studies, which included 6,198 adults (5,667
received Prevenar 13) ranging in age from 50 through 95 years. Pain, redness, swelling and limitation of arm
movement were observed locally; generalized muscle and joint pains, fatigue, headache, rash, chills, vomiting,
decreased appetite, fever have been observed. Across the 6 studies, serious adverse events within 1 month of
vaccination were reported after an initial study dose in 0.2%-1.4% of 5055 persons vaccinated with Prevenar 13
and in 0.4%-1.7% of 1124 persons vaccinated after an initial study dose of PPSV23. From 1 month to 6 months
after an initial study dose, serious adverse events were reported in 1.2%-5.8% of persons Vaccinated during the
studies with Prevenar 13 and in 2.4%-5.5% of persons vaccinated with PPSV23. One case of erythema multiforme
occurred 34 days after receipt of a second dose of Prevenar 13. Concomitant administration with TIV may lead
to an increase in some non-serious systemic adverse reactions.
SUMMARY OF PRESCRIBING INFORMATION FOR PREVENAR 13

45. Warnings and Precautions: Prevenar 13 will only protect against pneumococcal serotypes included in
the vaccine, and may not protect all individuals receiving the vaccine. Safety and
immunogenicity data on Prevenar 13 are not available for immunocompromised individuals (e.g.,
ndividuals with splenic dysfunction, HIV infection, malignancy, nephrotic syndrome) and
vaccination should be considered on an individual basis. Premature infants may suffer from apnea
after primary immunization series. Very premature infants (born ≤ 30 weeks of gestation)
may require monitoring for at least 48 hours after vaccination. Different injectable vaccines should
always be given at different injection sites. The safety and immunogenicity for other routes
(e.g. subcutaneous) have not been evaluated.
Dosage: For infants, the immunization series of Prevenar 13 consists of three doses of 0.5ml each at
approximately 2-month intervals, followed by a fourth dose of 0.5 ml at 12-15 months of age.
The customary age for the first dose is 2 months of age, but it can be given as young as 6 weeks of
age. The recommended dosing interval is 4 to 8 weeks. The fourth dose should be administered
at least 2 months after the third dose. For adults 50 years of age and older, Prevenar13 is to be
administered as a single dose, including for those previously vaccinated with a pneumococcal
polysaccharide vaccine. The need for re-vaccination with a subsequent dose of Prevenar13 has not
been established.
Administration: 0.5 mL/dose intramuscularly. Prevenar 13 is available as a pre-filled syringe. The
preferred sites are the anterolateral aspect of the thigh in infants or the deltoid muscle of the
upper arm in older children and adults.
Storage: Prevenar 13 should not be frozen. Store in a refrigerated place, away from the freezer
compartment, at 2o C to 8 o C (36 o F to 46 o F). Discard if the vaccine has been frozen. Parenteral
products should be inspected visually for particulate matter or discoloration prior to use.
SUMMARY OF PRESCRIBING INFORMATION FOR PREVENAR 13

46. Balancing Risk Information
Prevenar 13 does not provide 100% protection against vaccine serotypes nor protect against nonvaccine serotypes. The
approval of Prevenar 13 was based upon functional antibody responses in adults 50 years and older. An efficacy study in
adults is ongoing. Prevenar 13 has not been shown to reduce morbidity or mortality due to invasive or non-invasive
pneumococcal disease in adults. The most commonly reported solicited local and systemic adverse reactions (≥20%) in
clinical trials with Prevenar 13 were redness, swelling, tenderness, hardness, and pain at the injection site, limitation of
arm movement, decreased appetite, headache, diarrhea, chills, fatigue, rash, and worsening of or new joint or muscle
pain. Hypersensitivity (e.g., anaphylaxis) to any component of Prevenar 13 or any diphtheria toxoid–containing vaccine is a
contraindication to the use of Prevenar 13. Limited safety and immunogenicity data on Prevenar 13 are available for
patients with certain specific immunocompromizing conditions, but are not available for other immunocompromised
patient groups; vaccination should be considered on an individual basis. Immunocompromised individuals or individuals with
impaired immune responsiveness due to the use of immunosuppressive therapy may have a reduced antibody response to
Prevenar 13. Studies were not powered to identify differences in immune responses between healthy adults and
immunocompetent adults with stable, comorbid conditions. An antibody threshold that correlates with protection against
invasive or noninvasive pneumococcal disease in adults has not been determined. The clinical significance of differences in
functional antibody titers between serotypes, age groups, and between Prevenar 13 and pneumococcal polysaccharide
vaccine is unknown. Antibody responses to Prevenar 13 when administered concomitantly with TIV were diminished
compared with when Prevenar 13 was administered alone. The clinical significance of this is unknown. Memory B cell
production has not been studied with Prevenar 13 in adults. Since serotypes other than those contained in the vaccine may
contribute to the burden of pneumococcal disease/invasive pneumococcal disease, protection against all pneumococcal
disease/invasive pneumococcal disease should not be expected. The frequency of pneumococcal serotypes and serogroups
can vary from country to country, which could influence the effectiveness of vaccination in any given country Antimicrobial
resistance rates vary by region and from country to country.