This document summarizes renal disorders that can occur in pregnancy. It discusses the normal physiologic changes in pregnancy that affect the kidneys as well as specific disorders like preeclampsia, hypertension, AKI, lupus nephritis, diabetic nephropathy, and nephrotic syndrome. It provides diagnostic criteria and recommendations for management and treatment for many of these conditions to help support healthy pregnancies and outcomes.
Dr Abdullah Ansari
MBBS, MD Medicine
Aligarh Muslim University
Physiological changes during pregnancy
Systemic changes
Renal changes
Renal function
Tubular function
Plasma osmolality
Anatomical changes
AKI during pregnancy
Pre-renal causes
Renal causes
Post-renal causes
Investigations
Management
Dr Abdullah Ansari
MBBS, MD Medicine
Aligarh Muslim University
Physiological changes during pregnancy
Systemic changes
Renal changes
Renal function
Tubular function
Plasma osmolality
Anatomical changes
AKI during pregnancy
Pre-renal causes
Renal causes
Post-renal causes
Investigations
Management
Renal disorders in pregnancy can range from asymptomatic bacteriuria to end-stage renal disease requiring dialysis, all being influenced by the physiologic changes of pregnancy. Women who have mild to moderate renal disease or a renal transplant are now challenging obstetricians and nephrologists with pregnancy.
Hormonal changes during pregnancy allow for increased blood flow to the kidneys and altered autoregulation such that glomerular filtration rate (GFR) increases significantly through reductions in net glomerular oncotic pressure and increased renal size.
Renal disorders in pregnancy can range from asymptomatic bacteriuria to end-stage renal disease requiring dialysis, all being influenced by the physiologic changes of pregnancy. Women who have mild to moderate renal disease or a renal transplant are now challenging obstetricians and nephrologists with pregnancy.
Hormonal changes during pregnancy allow for increased blood flow to the kidneys and altered autoregulation such that glomerular filtration rate (GFR) increases significantly through reductions in net glomerular oncotic pressure and increased renal size.
HYPERTENSION IN PREGNANCY SOGON FINAL ONE.pptAdeniyiAkiseku
Hypertensive disorders are the most common medical complication of pregnancy
It complicates up to 10% of pregnancies
It is a leading cause of maternal and perinatal morbidity and mortality worldwide
Rates are rising because of the older, more obese obstetric population with medical issues
Operation “Blue Star” is the only event in the history of Independent India where the state went into war with its own people. Even after about 40 years it is not clear if it was culmination of states anger over people of the region, a political game of power or start of dictatorial chapter in the democratic setup.
The people of Punjab felt alienated from main stream due to denial of their just demands during a long democratic struggle since independence. As it happen all over the word, it led to militant struggle with great loss of lives of military, police and civilian personnel. Killing of Indira Gandhi and massacre of innocent Sikhs in Delhi and other India cities was also associated with this movement.
Model Attribute Check Company Auto PropertyCeline George
In Odoo, the multi-company feature allows you to manage multiple companies within a single Odoo database instance. Each company can have its own configurations while still sharing common resources such as products, customers, and suppliers.
Read| The latest issue of The Challenger is here! We are thrilled to announce that our school paper has qualified for the NATIONAL SCHOOLS PRESS CONFERENCE (NSPC) 2024. Thank you for your unwavering support and trust. Dive into the stories that made us stand out!
Embracing GenAI - A Strategic ImperativePeter Windle
Artificial Intelligence (AI) technologies such as Generative AI, Image Generators and Large Language Models have had a dramatic impact on teaching, learning and assessment over the past 18 months. The most immediate threat AI posed was to Academic Integrity with Higher Education Institutes (HEIs) focusing their efforts on combating the use of GenAI in assessment. Guidelines were developed for staff and students, policies put in place too. Innovative educators have forged paths in the use of Generative AI for teaching, learning and assessments leading to pockets of transformation springing up across HEIs, often with little or no top-down guidance, support or direction.
This Gasta posits a strategic approach to integrating AI into HEIs to prepare staff, students and the curriculum for an evolving world and workplace. We will highlight the advantages of working with these technologies beyond the realm of teaching, learning and assessment by considering prompt engineering skills, industry impact, curriculum changes, and the need for staff upskilling. In contrast, not engaging strategically with Generative AI poses risks, including falling behind peers, missed opportunities and failing to ensure our graduates remain employable. The rapid evolution of AI technologies necessitates a proactive and strategic approach if we are to remain relevant.
Acetabularia Information For Class 9 .docxvaibhavrinwa19
Acetabularia acetabulum is a single-celled green alga that in its vegetative state is morphologically differentiated into a basal rhizoid and an axially elongated stalk, which bears whorls of branching hairs. The single diploid nucleus resides in the rhizoid.
Welcome to TechSoup New Member Orientation and Q&A (May 2024).pdfTechSoup
In this webinar you will learn how your organization can access TechSoup's wide variety of product discount and donation programs. From hardware to software, we'll give you a tour of the tools available to help your nonprofit with productivity, collaboration, financial management, donor tracking, security, and more.
The Roman Empire A Historical Colossus.pdfkaushalkr1407
The Roman Empire, a vast and enduring power, stands as one of history's most remarkable civilizations, leaving an indelible imprint on the world. It emerged from the Roman Republic, transitioning into an imperial powerhouse under the leadership of Augustus Caesar in 27 BCE. This transformation marked the beginning of an era defined by unprecedented territorial expansion, architectural marvels, and profound cultural influence.
The empire's roots lie in the city of Rome, founded, according to legend, by Romulus in 753 BCE. Over centuries, Rome evolved from a small settlement to a formidable republic, characterized by a complex political system with elected officials and checks on power. However, internal strife, class conflicts, and military ambitions paved the way for the end of the Republic. Julius Caesar’s dictatorship and subsequent assassination in 44 BCE created a power vacuum, leading to a civil war. Octavian, later Augustus, emerged victorious, heralding the Roman Empire’s birth.
Under Augustus, the empire experienced the Pax Romana, a 200-year period of relative peace and stability. Augustus reformed the military, established efficient administrative systems, and initiated grand construction projects. The empire's borders expanded, encompassing territories from Britain to Egypt and from Spain to the Euphrates. Roman legions, renowned for their discipline and engineering prowess, secured and maintained these vast territories, building roads, fortifications, and cities that facilitated control and integration.
The Roman Empire’s society was hierarchical, with a rigid class system. At the top were the patricians, wealthy elites who held significant political power. Below them were the plebeians, free citizens with limited political influence, and the vast numbers of slaves who formed the backbone of the economy. The family unit was central, governed by the paterfamilias, the male head who held absolute authority.
Culturally, the Romans were eclectic, absorbing and adapting elements from the civilizations they encountered, particularly the Greeks. Roman art, literature, and philosophy reflected this synthesis, creating a rich cultural tapestry. Latin, the Roman language, became the lingua franca of the Western world, influencing numerous modern languages.
Roman architecture and engineering achievements were monumental. They perfected the arch, vault, and dome, constructing enduring structures like the Colosseum, Pantheon, and aqueducts. These engineering marvels not only showcased Roman ingenuity but also served practical purposes, from public entertainment to water supply.
Palestine last event orientationfvgnh .pptxRaedMohamed3
An EFL lesson about the current events in Palestine. It is intended to be for intermediate students who wish to increase their listening skills through a short lesson in power point.
1. Renal Disorders in Pregnancy
AJKD 2018
PRESENTER –DR SCIENTHIA SANJEEVANI
MODERATOR DR SAHIL BAGAI
2. Physiologic Changes in Pregnancy
BP decrease in systemic blood pressure (BP), usually reaching a nadir by 20 weeks’
gestation.
Glomerular filtration rate (GFR) increases by >50%, resulting in a physiologic
reduction in serum creatinine (Scr) level in the setting of hyperfiltration. Normal
Scr level in pregnancy is in the 0.4- to 0.6-mg/Dl range.
Physiological hydronephrosis The combination of smooth muscle relaxation due
to progesterone and mechanical compression by the enlarging uterus can cause
physiologic hydronephrosis and retention of urine in the collecting system
during pregnancy
3. PROTEINURIA
Urine PCR increases during the course of normal pregnancy, from 60 to 90 mg/d to
180 to 250 mg/d, as measured by a 24-hour urine collection.
Threshold for elevated proteinuria in pregnancy has been set at a higher level of
protein excretion of 300 mg/d
Increase in tubular proteinuria, reflected as an increase in urinary retinol binding
protein, as opposed to an increase in albuminuria (glomerular source).
UPCR > 0.3 g/g in favor in the diagnosis of preeclampsia
Isolated proteinuria- increased UPCR in the absence of hypertension or kidney
present in 15% of pregnancies.
4. IMMUNITIY
shift from TH1 to TH2 --important for tolerance to fetal antigens, trophoblast
invasion, and placental formation.
Regulatory T cells, which promote immune tolerance, is increased in normal
pregnancy, further contributing to establishing fetal tolerance.
In autoimmune diseases, such as SLE lead to increased risk for pregnancy
complications, such as preeclampsia, and poor fetal and maternal outcomes.
5. Physiologic Changes in Pregnancy
Increased
Blood volume
Cardiac output
Levels of nitric oxide and relaxin
Relative resistance to vasoconstrictors
GFR by 50%
Urine protein excretion
TH2 phenotype
Circulation of Tregs
Decreased
Systemic vascular resistance
Systemic blood pressure
Serum creatinine
6. Hypertension in Pregnancy
6% to 8% of pregnancies
chronic hypertension, gestational hypertension, preeclampsia, eclampsia.
Chronic hypertension Patients who have a known history of hypertension before
pregnancy or those who are found to have BPs ≥ 140/90 mm Hg before 20 weeks
of gestation. They have an increased risk for superimposed preeclampsia, which
can occur in up to 35% of their pregnancies
Gestational hypertension occurs during the second half of pregnancy in patients
with no history of pre-existing hypertension, and has an incidence of 6% to 7%.
7. Preeclampsia
Diagnostic Criteria
SBP ≥ 140 mm Hg or DBP ≥ 90 mm Hg (aMeasured on 2 occasions, at least 4 hours apart, after 20
weeks of pregnancy in a previously normotensive patient) AND
Proteinuria ≥ 300 mg/d, or UPCR ≥ 0.3 g/g OR
If no proteinuria is present, new onset of any of the followingb:
Platelets < 100 ×103/Μl
Scr > 1.1 mg/dL or doubling of Scr concentration in the absence of other kidney disease
Liver transaminases 2× upper limits of normal
Pulmonary edema
Cerebral or visual symptoms (new-onset and persistent headaches, blurred vision, flashing lights)
8. PATHOGENESIS
imbalance between proangiogenic VEGF and PIGF and antiangiogenic (soluble fms-like tyrosine kinase 1
[sFlt-1] and soluble endoglin , favoring the latter.
Angiogenic abnormalities -severe and early (<34 weeks of gestation) forms of preeclampsia, but not for
disease (≥34 weeks of gestation).
sFlt-1:PIGF ratio- screening tests to predict preeclampsia, currently not recommended for clinical practice.
The only available screening approach -serial BP measurements during pregnancy.
AT RISK PATIENTS
patients with history of preeclampsia and preterm delivery at less than 34 weeks
those with history of preeclampsia in 2 or more pregnancies
TO PREVENT PREECLAMPSIA
low-dose aspirin during the late first trimester in patients with moderate or high risk for preeclampsia,
10. Hypertension Management
Control of Hypertension in Pregnancy [CHIP] Trial
analyzed 987 pregnant women with pre-existing or gestational hypertension who
were randomly assigned to less tight BP control (target diastolic BP, 100 mm
Hg) versus tight BP control (targetdiastolic BP, 85 mm Hg) during pregnancy.
No significant differences were found other than a higher frequency of severe
maternal hypertension in the less tight control arm (40.6% vs 27.5%, respectively)
11. American College of Obstetricians and Gynecologists recommends
gestational hypertension or preeclampsia with persistent BP ≥ 160/110 mm Hg.
Delivery is recommended for these women at 37 weeks or later if no severe
features of preeclampsia are observed.
women with pre-existing hypertension if systolic BP is ≥160 mm Hg and/or
diastolic BP is ≥105 mm Hg, without evidence of end-organ damage.
The National Institute for Health and Care Excellence (NICE) recommends
initiation of treatment in pregnant women with systolic BPs ≥ 150 mm Hg
diastolic BPs ≥ 100 mm Hg
12. AKI
CAUSES
PRERENAL AKI
Hemorrhage
pulmonary embolism
Heart failure
Sepsis
Hyperemesis gravidarum leading to hypovolemia
RENAL
Acute tubular necrosis
acute fatty liver of pregnancy
amniotic fluid embolism
severe preeclampsia
HELLP
hypertensive disorders of pregnancy
Acute cortical necrosis
Severe hypotension
Hypercoaugulable state
13. Kidney biopsy
Kidney biopsy should be considered in women at less than 32 weeks of gestation,
when delivery is not a viable alternative and treatment may result in prolongation of a
desired pregnancy
Most common reason for biopsy- to differentiate between pre eclampsia and
glomerulonephritis
COMPLICATION
significantly higher later in pregnancy -peak at 25 weeks of gestation
major bleeding requiring transfusion
embolization
severe obstetric complications- early preterm delivery, rarely fetal death
14. Renal cortical necrosis
Coagulative necrosis of glomeruli and tubules surrounded by dense neutrophilic infiltrate
Thrombus occluding the vascular lumen
16. Lupus nephritis
Patients with SLE should have quiescent disease for at least 6 months before attempting to
conceive.
Extrarenal lupus flares are more common during the second and third trimesters, whereas kidney
disease activity seems to be more common during the postpartum period.
Evidence suggests that severe maternal flares occur in 3% to 5% of pregnancies
Renal flare not an absolute contraindication to maintaining a pregnancy.
Immunologic activity at conception (as measured by low C3 levels and anti-DNA antibodies)-best
predictor of renal flares.
Low C4 levels and high anti-C1q antibody levels -associated with early flares (encountered during
the first or second trimesters of pregnancy).
High body mass index associated with increased risk for late flares, defined as flares encountered
during the third trimester or postpartum period
17. PROGNOSIS
PROMISSE STUDY
Predictors of Pregnancy Outcome: Biomarkers in Antiphospholipid Antibody Syndrome and Systemic
Lupus Erythematosus
385 pregnant patients with SLE
evaluated adverse pregnancy outcomes and pregnancy-related flare rates.
ADVERSE PEGNANCY OUTCOME 19%
FETAL DEATH 4%
NEONATAL DEATH 1%
PRETERM DELIVERY 9%
SMALL FOR GESTATIONAL AGE 10%
18. Independent predictors of adverse pregnancy outcomes included
presence of a lupus anticoagulant
physician global assessment of disease activity score > 1
antihypertensive use
Platelet count < 100 × 103/μL.
19. Predictor of fetal outcomes
MISCARRIAGES Amount of steroid taken in year before conception
stillbirth No of SLE flares 1 yr before conception
Pre term births APLA and anti dsDNA levels
Complete congenital heart block • 1-2 % after exposure to to SSA/Ro and/or SSB/ La
antibodies.
• Incidence increases to 20% if there is a maternal history
of previous delivery of an infant with neonatal lupus.
20. Antiphospholipid antibody syndrome
Antiphospholipid antibodies may be present in up to 25% of SLE pregnancies
screening is recommended
mainstay of APS management – anticoagulation using either unfractionated heparin or
lowmolecular- weight heparin during pregnancy.
INDICATION
-all patients with SLE who have antiphospholipid antibodies and a history of thrombotic
event(s)
-for those lacking a history of thrombotic event(s), but who meet obstetric criteria for APS,
such as 3 or more pregnancy losses, or a late pregnancy loss.
22. ATYPICAL HUS
microangiopathic hemolytic anemia, thrombocytopenia, and decreased kidney function as a result of
uncontrolled alternate pathway complement activation.
Presents most commonly in post partum period
D/D
TTP- most commonly in the third trimester
Severe pre-eclampsia with HELPP
TREATMENT
When suspected, plasma exchange should be started while awaiting ADAMTS13 (von Willebrand
factor protease) activity results (<10% is associated with TTP). I
If ADAMTS13 activity is normal and aHUS is suspected,eculizumab
PROGNOSIS - before the use of eculizumab was poor and associated with high morbidity and
mortality rates.
23. mutations in the genes encoding for complement regulatory proteins may
enhance the risk for preeclampsia in other disease entities, such as SLE and/or
antiphospholipid antibodies
overlap in disease processes leads to difficulty in diagnosis
24. Immunoglobulin A Nephropathy
pregnancy does not affect long term kidney function
Systemic review and meta analysis (Liu Y et al) –
high risk for pregnancy complications, including pregnancy loss, preterm delivery,
low birth weight, preeclampsia/ eclampsia
women with hypertension, baseline estimated GFR < 60 mL/min/1.73 m2, or
proteinuria with protein excretion > 1 g/d had significantly higher risk for kidney
disease progression
25. MANAGEMENT
Mild, stable, or slowly progressive IgA nephropathy do not receive immunosuppressive
treatment.
In most cases, ACE inhibitor treatment should be discontinued before pregnancy and
immunosuppressive agents should be reviewed and switched to pregnancy-safe
ideally before conception or at the first sign of pregnancy o minimize risk to the fetus.
Steroids can be used in pregnancy if immunosuppression is needed for more active disease.
26. DIABETIC NEPHROPATHY
present in 6% of pregnant women with type 1 DM.
Type 2 DM and associated nephropathy less common among women of child-bearing age.
risk for pregnancy complications in young women with type 1 DM is related to the degree of pre
pregnancy decrease in kidney function
Progression to ESRD highest in women with Scr levels > 1.4 mg/dL.
In the absence of RAAS blockade and under the physiologic conditions of pregnancy, urinary albumin
excretion may increase substantially during the course of pregnancy in women with diabetic
nephropathy
27. MANAGEMENT
Prepregnancy counseling is critical
Tighter glycemic control for at least 6 months before conceiving associated with improved outcomes
ADA recommends targeting HbA1c goal of <6.5% while watching carefully for hypoglycemia.
Insulin is the mainstay of therapy
OHA- metformin and glyburide may be continued in some women with pregestational type 2 DM and
glycemic control.
A baseline ophthalmic examination before pregnancy is needed in all women with DM.
Women with moderate to severe retinopathy at the time of conception may need more careful monitoring
even intervention in pregnancy.
women with high HbA1c at the beginning of pregnancy who has rapid improvement in glycemic control in
pregnancy is associated with worsening of retinopathy
ACE inhibitors /ARB contraindicated in pregnancy
3 to 6 months of therapy before conceiving may have renal protective effects.
ASPIRIN- as preeclampsia prophylaxis given the theoretical benefit and overall low risk for harm.
28. PROGNOSIS
Women with type 1 DM are at increased risk for preeclampsia irrespective of the
baseline proteinuria
miscarriage, congenital malformations, preterm delivery, macrosomia, and
perinatal mortality
Patients with diabetic retinopathy may have worsening in the setting of
pregnancy.
29. Nephrotic Syndrome in Pregnancy
If presentation is before 20 weeks’ gestation, kidney biopsy can be safely
performed to determine whether immunosuppression is needed.
Close differential – preeclampsia, particularly after 20 weeks of gestation.
women with a pre-existing diagnosis should be in clinical remission before
conceiving
30. FSGS
Primary FSGS
diffuse foot-process effacement (>80%)
acute or subacute onset of nephrotic syndrome
Secondary FSGS
moderate foot-process effacement. Primary FSGS will present
presents with non–nephrotic-range proteinuria and decreased kidney function.
Glucocorticoids and/or calcineurin inhibitors can be safely used for primary FSGS
in pregnancy
31. MINIMAL CHANGE DISEASE
Rare in pregnancy
Management
antihypertensive therapy and glucocorticoids.
Diuretics to be used with caution – theoretical concern of causing intravascular
volume depletion leading to systemic vasoconstriction and placental
hypoperfusion
Restricted fluid intake and low-salt diet
Patients with relapsing disease desiring to become pregnant can be safely treated
with AZA or calcineurin inhibitors.
32. Membranous nephropathy
in women of child-bearing age is rarely primary and most often secondary to other
causes
Underlying diseases, such as SLE
drug exposure (in particular, NSAIDS or biologic agents)
Infection -hepatitis B or hepatitis C virus infection, syphilis
Malignancy
MANAGEMENT
ACE inhibitors, lipid-lowering therapy, warfarin, and cyclophosphamide are
contraindicated.
Prednisone and calcineurin inhibitors can be used
33. PROGNOSIS
In the setting of massive proteinuria and hypoalbuminemia (albumin < 2
women may be at risk for thrombosis
35. PROGNOSIS
Classic study by Jones and Hayslett of 67 women (with 82 pregnancies) with Scr levels
≥ 1.4 mg/dL in pregnancy
51% of women had no change in GFR
31% had a decline in kidney function that persisted 6 months postpartum
Women with antepartum Scr levels > 2.0 mg/dL were at particularly high risk for
kidney function
Women with milder CKD (Scr < 1.4 mg/dL) may expect to have good maternal and
fetal outcomes,
women with advanced disease (Scr, 1.4-2.9 mg/dL) are at high risk for pregnancy
complications.
Women with Scr values ≥ 3.0 mg/ dL may permanently lose kidney function with
pregnancy.
The underlying disease, such as DM or lupus nephritis, may impose additional
specific risks
36. ESRD in Pregnancy
Fertility is significantly diminished in woman requiring dialysis therapy, may be
due to erratic and/or absent menstrual cycles
Diagnosis of pregnancy is also delayed
significant elevations of hCG with appropriate doubling of values every 48 to 72
hours are indicative of true pregnancy.
Ultrasonography - confirmatory test.
37. MANAGEMENT
Can have positive maternal and fetal outcomes with intensive dialysis therapy to
maintain a near-normal serum urea nitrogen level
ideal goal- 36 hours per week
Viable goal- more than 20 hours per week, with a serum urea nitrogen target < 50
mg/dL
Fetal outcomes better with high efficiency dialysis treatment
-prevalence of SGA babies higher n mothers receiving peritoneal dialysis compared
with those receiving hemodialysis (66% vs 31%, respectively).
38. Kidney Transplant Recipients and Pregnancy
Pregnancy is a sensitizing event leading to formation of anti-HLA antibodies
KDIGO guidelines state that women should wait for 1 year posttransplantation
before pursuing pregnancy, provided kidney function is stable.
recent study suggested that waiting 2 years may be prudent
39. MANAGEMENT
immunosuppressive regimen needs to bemodified
Usuallya combination of AZA, tacrolimus/cyclosporine, and prednisone.
Tacrolimus doses often need to be increased substantially in pregnancy
recent pharmacologic studies have shown that whole-blood measurements of
tacrolimus do not accurately reflect free tacrolimus levels in the setting of
pregnancy- women may experience toxicity with seemingly therapeutic levels.
40. PROGNOSIS
fertility is improved after transplantation
risks for pregnancy complications, such as preterm delivery and preeclampsia,
much lower.
41. Kidney donors and pregnancy
Careful monitoring in pregnancy
increased risk for preeclampsia
Garg et al (2015) suggested that kidney donors had 2.4 times increased odds of
having preeclampsia or gestational hypertension (11% vs 5%), but did not have
increased risk for preterm delivery or low birth weight
42. Medications in Pregnancy
ANTIHYPERTENSIVES
SAFE- methyldopa, labetalol, or nifedipine.
UNSAFE- ACE inhibitors and ARB
ANTICOAGULANTS
severe nephrotic syndrome, APS, or other thrombophilic conditions.
Warfarin is contraindicated due to teratogenicity
LMWH or unfractionated heparin administered as a subcutaneous injection can safely
be given.
Novel oral anticoagulants are known to cross the placenta and available data about
maternal and fetal outcomes are insufficient
43. IMMUNOSUPPRESANTS IN GOMERULONEPHRITEDES
Glucocorticoids remain the mainstay of immunosuppressive therapy .
-Prednisone is considered safe during pregnancy due to placental metabolism, with <10% of the
maternal dose found in the fetal circulation.
Calcineurin inhibitors (ie, cyclosporine and tacrolimus) induce hypertension and gestational
diabetes AND are teratogenic
Cyclophosphamide and mycophenolate mofetil are teratogenic
AZA is the drug of choice for pregnant patients previously using mycophenolate mofetil who
require continuation of immunosuppressive therapy.
- AZA treatment ideally should be started 3 months before conception.
calcineurin inhibitors and AZA have been associated with SGA infants and preterm deliveries.
Rituximab may be used during pregnancy as part of a chemotherapy regimen for treatment of
incident or recurrent malignancies or severe non malignant hematologic diseases.
- considered safe to administer during the first trimester
- neonatal B-cell depletion has been seen in those who have been exposed in utero during the
third trimester of pregnancy.
Editor's Notes
Hydroxychloroquine therapy should be continued throughout pregnancy to maintain quiescence of lupus nephritis and decrease the risk for systemic flares.