malarial nephropathy

7/27/2019 Malarial Nephropathy

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Malaria

Didi Candradikusuma

Tropical and Infectious DiseasesDepartment of Internal Medicine Dr. Saiful Anwar General Hospital

Brawijaya University School of Medicine

Malang


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IntroductionMalaria is parasite disease of great epidemiologic

importance in the tropics

Each year: 300 500 million clinical case

40% population in tropic area are at risk

10.000 50.000 visiting people from tropical

countries will contract malaria

Malarial infection is caused by genus Plasmodium

and Anopheles mosquitoes are definite hosts of

malarial parasites Principal vector


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IntroductionThe relevance of malaria to modern nephrology

has emerged over the past few decades

because of:

It has been one of the leading causes of ARFin SEA, Vietnam, Indian Peninsula, Africa

Its responsible for a significant proportion of

chronic glomerular disease

Its becoming an increasingly recognizedcomplications of renal transplantations


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Malarial Infection

Malaria is an Italian word composed of mala and

aria, means bad air for describe a fever which

was wrongly attributed to exposure to poisonous

air rising from marshes

Described in the Hippocratic Collection (460 to

377 BC)

Susruta (5th century AD) suggested its relation to

mosquitoes

Charles Laveran, discovered Plasmodium as the

true causative agent (1880)

Mapping the malaria genome


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Malarial is caused by Protozoon, Plasmodium, of whichfour species are pathogenic to man :

Plasmodium falciparum falciparum malaria

Plasmodium malariae quartan malaria

Plasmodium vivax vivax malaria

Plasmodium ovale

In Indonesia, the most species that infected

human are P. falciparum and P. vivax

P. malariae Lampung, NTT, PapuaP. ovale NTT and Papua

Malarial Infection


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Malaria Distribution

Area of Malaria


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Life-Cycle of Malaria


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Life-Cycle of Malaria


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Pathogenicity

Several species affect humans different

patterns of the disease because of genetic

interspecies differences:

- rate of multiplication- expression of different antigenic and ligand

proteins

- influences of host factors, etc

divergence of the ability of different strains to

invade human red cells of different ages


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Pathogenicity

Parasitized erythrocytes initiate the three

principal pathogenetic feature in

Plasmodium infection:

Hemodynamic Derangement

Immune Perturbation(gangguan)

Metabolic Disturbance


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Plasmodium species which

infect humans

Plasmodium vivax (tertian)

Plasmodium ovale (tertian)

Plasmodium falciparum (tertian)

Plasmodium malariae (quartian)


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Exo-erythrocytic(hepatic) cycle

Sporozoites

Mosquito SalivaryGland

Malaria LifeCycleLife Cycle

Gametocytes

Oocyst

ErythrocyticCycle

Zygote

Schizogony

Sporogony

Hypnozoites(for P. vivaxand P. ovale)


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Malaria Transmission Cycle

Parasite undergoes

sexual reproduction in

the mosquito

Some merozoites

differentiate into male or

female gametocyctes

Erythrocy t ic Cycle:

Merozoites infect red

blood cel ls to form

sch izonts

Dormant l iver s tages

(hypn ozoites) of P.

viv ax and P. ovale

Exo-erythroc yt ic (hepat ic) Cycle:

Sporozoites infect l iver cel ls and

develop into sch izonts, whic h release

merozoites into the blood

MOSQUITO HUMAN

Sporozoires in jected

in to human host dur ing

b lood m eal

Parasites

mature in

mosquito

midgut and

migrate to

salivary

glands


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Components of the Malaria Life

Cycle

Mosquito Vector

Human Host

Sporogonic cycle

Infective Period

Mosquito bites

gametocytemic

person

Mosquito bites

uninfectedperson

Prepatent Period

Incubation Period

Clinical Illness

Parasites visible

Recovery

Symptom onset


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Exo-erythrocytic (tissue)

phase

Blood is infected with sporozoites about30 minutes after the mosquito bite

The sporozoites are eaten by

macrophages or enter the liver cellswhere they multiply

pre-erythrocytic schizogeny

P. vivax and P. ovale sporozoites formparasites in the liver called hypnozoites

E h i ( i )


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phase

P. malariae orP. falciparum sporozoitesdo not form hypnozites, develop directly

into pre-erythrocytic schizonts in the

liver Pre-erythrocytic schizogeny takes 6-16

days post infection

Schizonts rupture, releasing merozoiteswhich invade red blood cells (RBC) in

liver


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Relapsing malaria

P. vivax and P. ovale hypnozoitesremain dormant for months

They develop and undergoe pre-

erythrocytic sporogeny

The schizonts rupture, releasing

merozoites and produce clinical relapse

E th ti (ti )


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phase

P. vivax and P. ovale hypnozoitesremain dormant for months

They develop and undergoe pre-

erythrocytic sporogeny

The schizonts rupture, releasing

merozoites and producing clinical

relapse


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Erythrocytic phase

Pre-patent period interval between date ofinfection and detection of parasites inperipheral blood

Incubation period time between infection

and first appearance of clinical symptoms Merozoites from liver invade peripheral (RBC)

and develop causing changes in the RBC

There is variability in all 3 of these featuresdepending on species of malaria

E th ti h


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Erythrocytic phase

stages of parasite in RBC

Trophozoites are early stages with ring formthe youngest

Tropohozoite nucleus and cytoplasm divide

forming a schizont Segmentation of schizonts nucleus and

cytoplasm forms merozoites

Schizogeny complete when schizont

ruptures, releasing merozoites into bloodstream, causing fever

These are asexual forms

E th ti h


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Erythrocytic phase

stages of parasite in RBC

Merozoites invade other RBCs and

schizongeny is repeated

Parasite density increases until hostsimmune response slows it down

Merozoites may develop into

gametocytes, the sexual forms of theparasite

S hi i i di i d


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Schizogenic periodicity and

fever patterns

Schizogenic periodicity is length of asexualerythrocytic phase 48 hours in P.f., P.v., and P.o. (tertian)

72 hours in P.m. (quartian) Initially may not see characteristic fever

pattern if schizogeny not synchronous

With synchrony, periods of fever or febrile

paroxsyms assume a more definite 3(tertian)- or 4 (quartian)- day pattern


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Clinical presentation

Early symptoms Headache

Malaise

Fatigue Nausea

Muscular pains

Slight diarrhea

Slight fever, usually not intermittent Could mistake for influenza or gastrointestinal

infection


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Acute febrile illness, may have periodic febrileparoxysms every 48 72 hours with

Afebrile asymptomatic intervals

Tendency to recrudesce or relapse overmonths to years

Anemia, thrombocytopenia, jaundice,hepatosplenomegaly, respiratory distress

syndrome, renal dysfunction, hypoglycemia,mental status changes, tropical splenomegalysyndrome


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Early symptoms Headache

Malaise

Fatigue Nausea

Muscular pains

Slight diarrhea

Slight fever, usually not intermittent Could mistake for influenza or gastrointestinal

infection


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Signs Anemia

Thrombocytopenia

Jaundice Hepatosplenomegaly

respiratory distress syndrome

renal dysfunction

Hypoglycemia Mental status changes

Tropical splenomegaly syndrome


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Types of Infections

Recrudescence exacerbation of persistent undetectable

parasitemia, due to survival of erythrocytic forms,no exo-erythrocytic cycle (P.f., P.m.)

Relapse

reactivation of hypnozoites forms of parasite inliver, separate from previous infection with samespecies (P.v. and P.o.)

Recurrence or reinfection

exo-erythrocytic forms infect erythrocytes,separate from previous infection (all species)

Can not always differentiate recrudescencefrom reinfection

C


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Clinical presentation Varies in severity and course

Parasite factors

Species and strain of parasite

Geographic origin of parasite

Size of inoculum of parasite

Host factors Age

Immune status

General health condition and nutritional status

Chemoprophylaxis or chemotherapy use

Mode of transmission Mosquito

Bloodborne, no hepatic phase (transplacental,needlestick, transfusion, organ

donation/transplant)

M l i l P


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Malarial Paroxysm

Can get prodrome 2-3 days before Malaise, fever,fatigue, muscle pains, nausea,

anorexia

Can mistake for influenza or gastrointestinal

infection Slight fever may worsen just prior to paroxysm

Paroxysm Cold stage - rigors

Hot stage Max temp can reach 40-41o C,splenomegaly easily palpable

Sweating stage

Lasts 8-12 hours, start between midnight andmidday

M l i l P


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Malarial Paroxysm

Periodicity

Days 1 and 3 for P.v., P.o., (and P.f.) -

tertian

Usually persistent fever or daily paroxyms

for P.f.

Days 1 and 4 for P.m. - quartian


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Presentation of P.v.

Lack classical paroxysm followed by

asymptomatic period

Headache,dizziness, muscle pain, malaise,

anorexia, nausea, vague abdominal pain,vomiting

Fever constant or remittent

Postural hypotension, jaundice, tender

hepatosplenomegaly


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Common features ofP.vivax

infections Incubation period in non-immunes 12-17 days

but can be 8-9 months or longer

Some strains from temperate zones showlonger incubation periods, 250-637 days

First presentation of imported cases 1 monthover 1 year post return from endemic area

Typical prodromal and acute symptoms

Can be severe However, acute mortality is very low


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Common features of

P.vivax infections Most people of West African descent are

resistant to P.v.

Lack Duffy blood group antigens needed for

RBC invasion Mild severe anemia, thrombocytopenia,

mild jaundice, tender hepatosplenomegaly

Splenic rupture carries high mortality More common with P.v. than with P.f.


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Common features of

P.vivaxinfections Relapses

60% untreated or inadequately treated will

relapse

Time from primary infection to relapse variesby strain

Treat blood stages as well as give terminal

prophylaxis for hypnozoites


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Common features of

P. ovale infections Clinical picture similar to P.v. but

Spontaneous recovery more common

Fewer relapses

Anemia and splenic enlargement less severe Lower risk of splenic rupture

Parasite often latent and easily suppressed bymore virulent species ofPlasmodia

Mixed infection with P.o. usually in thoseexposed in tropical Africa


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Common features of

P. malariae infections Clinical picture similar to P.v. but

prodrome may be more severe

Incubation period long 18- 40 days

Anemia less pronounced than P.v. Gross splenomegaly but risk of rupture

less common than in P.v.

No relapse no hepatic phase orpersisting hepatic cycle


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Common features of

P. malariae infections Undetectable parasitemia may persist with

symptomatic recrudescences Frequent during first year

Then longer intervals up to 52 years

Asymptomatic carriers may be detected at timeof blood donation or in cases of congenitaltransmission

Parasitemia rarely > 1%, all asexual stages canbe present

Can cause nephrotic syndrome, prognosis ispoor

Features of P falciparum


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Features ofP.falciparum

cases

Lack classical paroxysm followed by asymptomaticperiod

Headache,dizziness, muscle pain, malaise, anorexia,nausea, vague abdominal pain, vomiting

Fever constant or remittent

Postural hypotension, jaundice, tenderhepatosplenomegaly

Can progress to severe malaria rapidly in non-immunepatients

Cerebral malaria can occur with P.f.

Parasites can sequester in tissues, not detected on

peripheral smear

S h t i ti f i f ti ith


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Some characteristics of infection with

four species of human Plasmodia

P.v. P.o. P.m. P.f.

Pre-

erythroctic

stage (days)

6-8 9 14-16 5.5-7

Pre-patent

period (days)

11-13 10-14 15-16 9-10

Incubation

period (days)

15 (12-17)

or up to 6-12 months

17 (16-18)

or longer

28 (18-40)

or longer

12 (9-14)

Erythrocytic

cycle (hours)

48 (about) 50 72 48



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P.v. P.o. P.m. P.f.

Paraitemia

perl

Average

Maximum

20,000

50,000

9,000

30,000

6,000

20,000

20,000-50,000

2,000,000

Primary

attack*

Mild-

severe

Mild Mild Severe in

non-

immunes

Febrile

paroxysms

(hours)

8-12 8-12 8-10 16-36 or

longer



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P.v. P.o. P.m. P.f.

Invasion

requirements

Duffy ve

blood

group

? ? ?

Relapses ++ ++ - -

Recrude-

scences

+ + - -



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P.v. P.o. P.m. P.f.

Period of

recurrence **

Variable Variable Very long short

Duration ofuntreated

infection

(years)

1.5-5 Probablysame as

P.v.

3-50 1-2

*The severity of infection and the degree of parasitemia are greatly influenced by the immune response. Chemo

May suppress an initial attack for weeks or months.

** Patterns of infection and of relapses vary greatly in different strains.

Bruce-Chwatt Essential Malariology, 3rd rev ed. 1993

Congenital malaria


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Congenital malaria

Transplacental infection

Can be all 4 species Commonly P.v. and P.f. in endemic areas

P.m. infections in nonendemic areas due to longpersistence of species

Neonate can be diagnosed with parasitemiawithin 7 days of birth or longer if no other riskfactors for malaria (mosquito exposure, bloodtransfusion)

Fever, irritability, feeding problems, anemia,hepatosplenomegaly, and jaundice

Be mindful of this problem even if mother hasnot been in malarious area for years before

delivery

Immunity


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Immunity

Influenced by

GeneticsAge

Health condition

Pregnancy status

Intensity of transmission in region

Length of exposure

Maintenance of exposure


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Immunity

Innate Red cell polymorphisms associated with some

protection

Hemoglobin S sickle cell trait or disease

Hemoglobin C and hemoglobin E Thalessemia and

Glucose 6 phosphate dehydrogenase deficiency(G6PD)

Red cell membrane changes Absence of certain Duffy coat antigens improvesresistance to P.v.


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Immunity

Acquired Transferred from mother to child

3-6 months protection

Then children have increased susceptibility

Increased susceptibility during early childhood Hyper- and holoendemic areas

By age 5 attacks usually < frequent and severe

Can have > parasite densities with fewer symptoms

Meso- or hypoendemic areas Less transmission and repeated attacks

May acquire partial immunity and be at higher risk forsymptomatic disease as adults


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Immunity

Acquired No complete immunity

Can be parasitemic without clinical disease

Need long period of exposure for induction

May need continued exposure for maintenance Immunity can be unstable

Can wane as one spends time outside endemicarea

Can change with movement to area with differentendemicity

Decreases during pregnancy, risk improves withincreasing gravidity


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Clinical Features


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Clinical Features

Based on severity of the complications,

malaria

- Uncomplicated Malaria

- Severe Malaria

Anemia and neutrophil leucocytosisprominent laboratory finding

Dx is confirmed by direct visualization of the

parasite in Giemsa-stain peripheral blood

smearAcridine-orange staining enhanced the Dx

accuracy

Cli i l F


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Clinical Features

DNA probe not yet widely applicable

Serology limited Dx value, especially in

endemic areas

Disease may become chronic if sporozoon

manages to establish a persistent extra-

erythrocytic reservoir cycle in the liver

M


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Management

Antimalarial agents

Supportive and symptomatictreatment

Treatment for complications

Treatment Modalities

M


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Management

Chloroquine is the gold standard treatment of

malaria

Initially doses 10mg base/kgBW per os,

followed by 5mg/kgBW after 6 8 h and on thefollowing days 2 and 3

For i.v: 10mg/kgBW as an infusion drip over 4 h,

followed by 5mg/kgBW over 2 h at 12-h interval

for a total dose of 25 mg/kgBW

But, many P. falciparum strains are chloroquine-

resistant

Antimalarial


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Management

Day Antimalarial Dose

1Artesunat

Amodiaquine

Primaquine

200 mg800 mg

30 45 mg

2

Artesunat

Amodiaquine

200 mg

800 mg

3

Artesunat

Amodiaquine

200 mg

800 mg

Uncomplicated malaria

First Line

(Depkes RI, 2005)


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Management

Day Antimalarial Dose

1Quinine

Tetracycline/Doxycyclin

Primaquine

3 x 2 tab4 x 1 cap

30 45 mg

2 - 7

Quinine

Tetracycline/Doxycyclin

3 x 2 tab

4 x 1 cap

Uncomplicated malaria

Second Line

(Depkes RI, 2005)


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Management

Artesunat

Initial dose 2.4 mg/kgBW i.v. for 2 minutes

followed 1.2 mg/kgBW i.v. / 12 hand 1.2 mg/kgBW i.v. / d, d2 d7

Arthemeter

Initial dose 160 mg i.m. d1

followed 80 mg i.m. d2 d5

Severe malariaFirst Line

(Depkes RI, 2005)

Management


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Management

Quinine is the most widely used in the tx of chloroquine-resistant falciparum malaria

In severe malaria, should be administered as a loadingdose by rate-controlled infusion instead by bolus i.v

The normal loading dose: 20mg/kg over 4 hor initial dose 7mg/kg over 30 minutes (inf. Pump)followed immediately by 10mg/kg over 4 h

The maintenance dose: 10mg/kg for 7 d should be

infused at a rate-not > 6mg/kg/h every 8 / 12 hReduction dose is not necessary when serum creatininare 3 mg/dL or lower

Severe malariaSecond Line

(Depkes RI, 2005)

Management


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Management

In more severe renal failure, the quinine

dose should be reduced by 1/3 on the 3rddIn areas of multidrug resistance, addictionof 7-day Doxycycline 3mg/kg/d orTetracyclin 4mg/kg 4 x/d to Quinine

decrease of recrudescenceAnother chemotherapeutic: Mefloquine,Benflumetol, and Proguanil

Primaquine for P. vivax and P. ovale toeradicate hypnozoites and subsequentrelapses

Management


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Management

A-B-C

Anti Pyretics

Anti ConvulsantsNutrition

etc

Supportive and Symptomatic Treatment

Management


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Management

For ARF detection, serum creatinin should be

measured daily in severe malaria patients

ClinicallyOliguric manifestation (urine output

< 400 mL/d) would receive a fluid challengeof up to 20 mL/kg of 0.9% saline infused over 60

mnts

Examination for fluid overload after every 200

mL of fluid replacementIf fluid replacement is not successful

Furosemide should be i.v. administered

Treatment for Complications

Management


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Management

Dose of Furosemide:initially 40 mg increasing to 100, 200, and

400mg at half-hour intervals

Several studies could not elicit clearly that

dopamine, administered i.v. at the low dose 2.5

to 5g/kg/min, improves renal function or

outcome in ARF patients

Combination of dopamine and furosemide

attenuate further deterioration of renal function

and shorten the clinical course of ARF when

serum creatinine < 5 mg/dL

Anuric condition or s.c. > 5 mg/dL ineffective

Treatment for Complications..

Management


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Management

If Fluid replacement with or without the aboveprocedure is ineffective further fluid should be

restricted and kept CVP between 8 12 cm H2O

Monitored for need of dialysis

Dialysis has improved the survival when institutedearly in the course

Indications for dialysis include:

Clinical indications uraemic symptoms,

symptomatic volume overload, pericardial rubLaboratory indications severe metabolic acidosis

(HCO3 < 15 mEq/l), hyperkalemia (> 6.5 mEq/l),

rapid increase s.c. greater than 2.5 3.0 mg/dL/d


Management


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Management

Peritoneal Dialysis less effective than hemodialysisbecause hypercatabolic states, impaired peritonealmicrocirculation, vasoconstriction reduce thecapability of solute transport

Efficacy P.D return to normal when parasitemiadeclines

If hemodialysis is selected, the procedure should beperformed frequently and initiated early in the courseof illness

Haemofiltrations also effectiveThere were no significant changes in plasmaantimalarial during hemodialysis


Management


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Management

Exchange Blood Transfusion helpful in patientswith heavy parasitemia and those with severe

jaundice

Apheresis successfully support anuric patients

with cerebral and pulmonary complicationsProstacyclin useful in patients with severe

intravascular hemolysis

Patients with ARDS empiric antibiotic coverage

There is no place for corticosteroid


Prognosis


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Prognosis

Overall mortality among this with ARF 45 %,without ARF 10 %

Anuric patients and delayed rate of renal function

recovery worse mortality

50 75 % without dialysis rapid dieDialysis patients mortality rate 25 %

Nephropathy in Quartan Malaria


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Nephropathy in Quartan Malaria

P. malariae infection is common in tropical Africa,parts of Indian subcontinent, Myanmar, Sri lanka,

Malaysia, Indonesia

P. malariae tends to invade older erythrocytes

infection rate < 1 %There are 2-distinct forms of P. malariae associated

glomerulonephritis:

- Acute Transient Nephritis

- Chronic Malarial Nephropathy

Acute Transient Nephritis


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Acute Transient Nephritis

During 2nd or 3rd week after infectionResolves completely over a duration of a few

weeks

Mild proteinuria, but may occasionally be

severe, maybe precipitated by muscularexertion this disorder does not impair renal

function

Pathologic studies: predominant depositions of

IgM, complement, and malarial antigen


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malarial nephropathy

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