Saturday, July 20, 2013

Autosomal dominant polycystic kidney disease

Kidney and Ureter

Anatomy

The kidneys are reddish brown and lie behind the peritoneum high up on the posterior abdominal wall on either side of the vertebral column.
They are largely under cover of the costal margin. 
The right kidney lies slightly lower than the left kidney because of the large size of the right lobe of the liver. 
On the medial concave border of each kidney is a vertical slit that is bounded by thick lips of renal substance and is called the hilum. 
The hilum extends into a large cavity called the renal sinus. The hilum transmits, from the front backward, the renal vein, two branches of the renal artery, the ureter, and the third branch of the renal artery (VAUA). 
Lymph vessels and sympathetic fibers also pass through the hilum.

Coverings
  • The kidneys have the following coverings:
  • Fibrous capsule: This surrounds the kidney and is closely applied to its outer surface.
  • Perirenal fat: This covers the fibrous capsule.
  • Renal fascia: This is a condensation of connective tissue that lies outside the perirenal fat and encloses the kidneys and suprarenal glands; it is continuous laterally with the fascia transversalis.
  • Pararenal fat: This lies external to the renal fascia and is often in large quantity. It forms part of the retroperitoneal fat.
  • The perirenal fat, renal fascia, and pararenal fat support the kidneys and hold them in position on the posterior abdominal wall.


Renal Structure 
  • Each kidney has a dark brown outer cortex and a light brown inner medulla. 
  • The medulla is composed of about a dozen renal pyramids, each having its base oriented toward the cortex and its apex, the renal papilla, projecting medially. 
  • The cortex extends into the medulla between adjacent pyramids as the renal columns. Extending from the bases of the renal pyramids into the cortex are striations known as medullary rays.
  • The renal sinus, which is the space within the hilum, contains the upper expanded end of the ureter, the renal pelvis. This divides into two or three major calyces, each of which divides into two or three minor calyces. Each minor calyx is indented by the apex of the renal pyramid, the renal papilla.


          Anterior and posterior relation of kidneys
          Right Kidney

          Anteriorly: The suprarenal gland, the liver, the second part of the duodenum, and the right colic flexure 
          Posteriorly: The diaphragm; the costodiaphragmatic recess of the pleura; the 12th rib; and the psoas, quadratus lumborum, and transversus abdominis muscles. The subcostal (T12), iliohypogastric, and ilioinguinal nerves (L1) run downward and laterally.

          Left Kidney

          Anteriorly: The suprarenal gland, the spleen, the stomach, the pancreas, the left colic flexure, and coils of jejunum 
          Posteriorly: The diaphragm; the costodiaphragmatic recess of the pleura; the 11th (the left kidney is higher) and 12th ribs; and the psoas, quadratus lumborum, and transversus abdominis muscles. The subcostal (T12), iliohypogastric, and ilioinguinal nerves (L1) run downward and laterally.

          Blood Supply

          Arteries
          • The renal artery arises from the aorta at the level of the second lumbar vertebra. 
          • Each renal artery usually divides into five segmental arteries that enter the hilum of the kidney. They are distributed to different segments or areas of the kidney. 
          • Lobar arteries arise from each segmental artery, one for each renal pyramid. Before entering the renal substance, each lobar artery gives off two or three interlobar arteries. The interlobar arteries run toward the cortex on each side of the renal pyramid. 
          • At the junction of the cortex and the medulla, the interlobar arteries give off the arcuate arteries, which arch over the bases of the pyramids. The arcuate arteries give off several interlobular arteries that ascend in the cortex. The afferent glomerular arterioles arise as branches of the interlobular arteries.


          Blood Supply

          Veins
          • The renal vein emerges from the hilum in front of the renal artery and drains into the inferior vena cava.


          Lymph Drainage
          • Lymph drains to the lateral aortic lymph nodes around the origin of the renal artery.

          Nerve Supply
          • The nerve supply is the renal sympathetic plexus. The afferent fibers that travel through the renal plexus enter the spinal cord in the 10th, 11th, and 12th thoracic nerves.


          Ureter

          Location and Description
          • The two ureters are muscular tubes that extend from the kidneys to the posterior surface of the urinary bladder. 
          • The urine is propelled along the ureter by peristaltic contractions of the muscle coat, assisted by the filtration pressure of the glomeruli.
          • Each ureter measures about 10 in. (25 cm) long and resembles the esophagus (also 10 in. long) in having three constrictions along its course: 
          • where the renal pelvis joins the ureter, 
          • where it is kinked as it crosses the pelvic brim, and 
          • where it pierces the bladder wall 


          • The renal pelvis is the funnel-shaped expanded upper end of the ureter. 
          • It lies within the hilum of the kidney and receives the major calyces. 
          • The ureter emerges from the hilum of the kidney and runs vertically downward behind the parietal peritoneum (adherent to it) on the psoas muscle, which separates it from the tips of the transverse processes of the lumbar vertebrae. 
          • It enters the pelvis by crossing the bifurcation of the common iliac artery in front of the sacroiliac joint. The ureter then runs down the lateral wall of the pelvis to the region of the ischial spine and turns forward to enter the lateral angle of the bladder. 


          Relations

          Right Ureter

          Anteriorly: The duodenum, the terminal part of the ileum, the right colic and ileocolic vessels, the right testicular or ovarian vessels, and the root of the mesentery of the small intestine
          Posteriorly: The right psoas muscle, which separates it from the lumbar transverse processes, and the bifurcation of the right common iliac artery 

          Left ureter

          Anteriorly: The sigmoid colon and sigmoid mesocolon, the left colic vessels, and the left testicular or ovarian vessels 
          Posteriorly: The left psoas muscle, which separates it from the lumbar transverse processes, and the bifurcation of the left common iliac artery 
          The inferior mesenteric vein lies along the medial side of the left ureter 

          Blood Supply

          Arteries
          • The arterial supply to the ureter are: 
          • upper end, the renal artery; 
          • middle portion, the testicular or ovarian artery; and 
          • in the pelvis, the superior vesical artery.
          Veins
          • Venous blood drains into veins that correspond to the arteries.

          Lymph Drainage
          • The lymph drains to the lateral aortic nodes and the iliac nodes.
          • Nerve Supply
          • The nerve supply is the renal, testicular (or ovarian), and hypogastric plexuses (in the pelvis). Afferent fibers travel with the sympathetic nerves and enter the spinal cord in the first and second lumbar segments.

          Congenital Abnormalities of the Kidney

          Renal agenesis
          • Renal ectopia
          • Pelvic kidney
          • Horseshoe kidney
          • Crossed dystopia
          • Infantile polycystic disease
          • Unilateral multicystic  dysplastic kidney
          Aberrant renal vessels
          • Multiple renal arteries and veins
          Duplication
          • Duplex kidney
          • Duplex renal pelvis
          • Duplex kidney and ureter
          Others
          • Congenital hydronephrosis
          • Retrocaval ureter
          • Congenital megaureter

          Renal agenesis

          • Bilateral agenesis
          • Ultrasound: oligohydramnios
          • Potter facies:flattened nose, low-set ears, and recessed chin
          • Talipes equinovarus
          • Pulmonary hypoplasia
          • Incompatible with life
          •  Unilateral agenesis
          • The remaining kidney undergoes compensatory hypertrophy
          • Patients often have adequate renal function
          • May develop progressive glomerular sclerosis

          Horseshoe Kidney
          • When the caudal ends of both kidneys fuse as they develop, the result is horseshoe kidney. 
          • Both kidneys commence to ascend from the pelvis, but the interconnecting bridge becomes trapped behind the inferior mesenteric artery so that the kidneys come to rest in the low lumbar region. 
          • Both ureters are kinked as they pass inferiorly over the bridge of renal tissue, producing urinary stasis, which may result in infection and stone formation. Surgical division of the bridge corrects the condition


          Horseshoe Kidney
          Clinical features
          • Presents as a fixed, nonmobile, firm mass in the midline at the level of lower lumbar region.
          • There may be urinary stasis with consequent infection and nephrolithiasis

          Investigations
          • It is diagnosed radiologically.
          • Urogram shows the lower pole calyces on both sides being directed towards the midline.

          Treatment
          • Whatever the complication occurs, it is treated accordingly.
          • Separation of isthmus is not indicated, unless to approach aorta for aortic diseases.


          Autosomal recessive polycystic kidney disease

          Also known as childhood polycystic kidney disease

          Clinical features

          Rare autosomal recessive disease
          Presents in infancy with progressive and often fatal renal failure
          c. Gross
          Bilaterally enlarged kidneys
          Multiple small cysts in the cortex and medulla
          The cysts are oriented in a radial fashion with their long axis at right angles to the capsule
          May also have multiple hepatic cysts and congenital hepatic fibrosis

          Autosomal recessive polycystic kidney disease

          Autosomal dominant polycystic kidney disease

          Also known as adult polycystic kidney disease

          Genetics
          • Autosomal dominant inheritance
          • Mutation of PKDl gene on chromosome 16
          • The PKDl gene produces a transmembrane protein called polycystin 1

          Other mutations involvePKD2 and PKD3 genes

          Clinical features
          • Asymptomatic with normal renal function until middle age
          • Presents with renal insufficiency,hematuria, and hypertension
          • Abdominal masses and flank pain
          • Most patients develop end-stage renal failure by their seventh decade
          • Diagnosis: ultrasound and CT scans


          Gross
          Massive bilateral kidney enlargement with large bulging cysts
          Cysts are filled with serous, turbid, or hemorrhagic fluid
          Micro: functioning nephrons are present between the cysts

          Extrarenal manifestations
          Liver cysts
          Berry aneurysms of the circle of Willis
          Mitral valve prolapse
          Colonic diverticula

          Friday, July 12, 2013

          Common Drugs (toxicity/poisoning) & Their Antidotes (DOC)

          DRUGS OF CHOICE

          1. Acetaminophen /Paracetamol poisoning :- acetyl cysteine
          2. acute bronchial- asthma :- salbutamol
          3. acute gout :- NSAIDS
          4. acute hyperkalemia:- calcium gluconate
          5. severe DIGITALIS toxicity:-DIGIBIND
          6. acute migraine :- sumatriptan
          7. cheese reaction :- phentolamine
          8. atropine poisoning :- physostigmine
          9. cyanide poisoning :- amyl nitrite
          10. benzodiazepine poisoning:- flumazenil
          11. cholera :- tetracycline
          12. KALA-AZAR :- lipozomal amphotericin- B
          13. iron poisoning :- desferrioxamine
          14. MRSA :- vancomycin
          15. VRSA :- LINEZOLID
          16. warfarin overdose :- vitamin-K
          17. OCD :- fluoxetine
          18. alcohol poisoning :- fomepizole
          19. epilepsy in pregnancy :- phenobarbitone
          20. anaphylactic shock :- adrenaline

          Acute Myeloid Leukemia

          Failure of cell maturation
          Common age group. is 15 to 45 yrs.

          Etiology

          Heredity
              trisomy 21  (Down syndrome),  Inherited diseases with defective DNA repair, e.g., Fanconi anemia, Bloom syndrome, ataxia telangiectasia

          Radiation - ionizing

          Chemical and other occupational exposures
          •    Exposure to benzene, 
          •    Smoking and exposure to petroleum products, paint, herbicides, and pesticides, 

          Drugs
          •     Alkylating agents
          •     Chloramphenicol, phenylbutazone, and, less commonly, chloroquine


          French-American-British (FAB) Classification

          M0: Minimally differentiated leukemia,5%
          M1:Myeloblastic leukemia without     maturation,20%
          M2: Myeloblastic leukemia with maturation,30%
          M3: Hypergranular promyelocytic ,10%
          M4: Myelomonocytic leukemia, 20%
          M4Eo: Variant: Increase in abnormal marrow eosinophils
          M5: Monocytic leukemia,10%
          M6: Erythroleukemia (DiGuglielmo's disease), 4%
          M7: Megakaryoblastic leukemia,1%

          Clinical Presentation

          Symptoms

          Consequence of anemia, leukocytosis, leukopenia or leukocyte dysfunction, or thrombocytopenia. 3 months symptoms
          fatigue or weakness, anorexia, weight loss, fever, Signs of abnormal hemostasis (bleeding, easy bruising) 
          bone pain, lymphadenopathy, nonspecific cough, headache, or diaphoresis 

          a mass lesion located in the soft tissues, breast, uterus, ovary, cranial or spinal dura, gastrointestinal tract, lung, mediastinum, prostate, bone, or other organs. 
          The mass lesion represents a tumor of leukemic cells and is called a granulocytic sarcoma, or chloroma. 

          Physical Findings

          Fever, splenomegaly, hepatomegaly, lymphadenopathy, sternal tenderness, evidence of infection and hemorrhage  
          GI bleeding, intrapulmonary hemorrhage, or intracranial hemorrhage  
          Retinal hemorrhages, Infiltration of gingivae, skin, soft tissues, or the meninges with leukemic blasts at diagnosis is characteristic of the monocytic subtypes and those with 11q23 chromosomal abnormalities.  

          Hematologic Findings

          Severe  anemia : normocytic  normochromic
          Decreased erythropoiesis often results in a reduced reticulocyte count,accelerated destruction of RBC. 
          Active blood loss also contributes to the anemia.

          Leukocytosis between 10,000 to 500,000 per cmm.
          Leukemic cells in the blood 

          Hyperuricemia
          renal precipitation of uric acid and the nephropathy 
          renal tubular dysfunction

          Bone marrow findings

          blasts are >20%
          cytoplasm often contains primary (nonspecific) granules, and the nucleus shows fine, lacy chromatin with one or more nucleoli characteristic of immature cells.
          Abnormal rod-shaped granules called Auer rods


          Prognostic Factors

          Advancing age is associated with a poorer prognosis,
          Patients with t(15;17) have a very good prognosis (approximately 85% cured),

           with t(8;21) and inv(16) a good prognosis (approximately 50% cured

          Treatment

          Remission induction
              Standard therapy includes a 7-day continuous infusion of cytarabine and a 3-day course of daunorubicin or idarubicin with or without 3 days of etoposide.


          Supportive Care

          G-CSF and granulocyte-macrophage colony-stimulating factor (GM-CSF)
          Platelet transfusions to maintain a platelet count >20,000/L
          RBC transfusions to maintain hemoglobin level >8 g/dL
          Prophylactic antibiotics for infection contrl
           Oral nystatin or clotrimazole  to prevent localized candidiasis, acyclovir prophylaxis
          Allopurinol – to prevent from tumor lysis syndrome
          Consolidation
          Patients who achieve complete remission undergo postremission consolidation therapy, including sequential courses of high-dose cytarabine, stem cell transplant (SCT),
          Maintenance
          prednisolone, vincristine, methotrexate and mercaptopurine

          Patients with APL usually receive tretinoin together with anthracycline chemotherapy for remission induction and then consolidation chemotherapy (daunorubicin) followed by maintenance tretinoin, with or without chemotherapy.

          Treatment of relapse
          Once relapse has occurred, AML is generally curable only by SCT.

          Wednesday, July 10, 2013

          CHRONIC MYELOID LEUKEMIA


          A clonal expansion of a hematopoietic stem cell possessing a reciprocal translocation between chromosomes 9 and 22. 

          This translocation results in the head-to-tail fusion of the breakpoint cluster region (BCR) gene on chromosome 22 with the ABL gene located on chromosome 9. 

          Age gp. – 30 to 60 years


          Etiology
          • No evidence of cytotoxic drugs or a viral etiology. 
          • Cigarette smoking accelerated the progression to blast crisis 
          • Atomic bomb survivors had an increased incidence;  only large doses of radiation can induce CML.
          Three phases
          • Chronic phase
          • Accelerated  phase
          • Blast crisis phase

          Clinical Presentation


          Signs and Symptoms
           
          Fatigue, malaise, and weight loss or  splenic enlargement and symptoms, such as early satiety and left               upper quadrant pain or mass.
           
          Granulocyte or platelet dysfunction, such as infections, thrombosis, or bleeding.
           
          Severe leukocytosis or thrombosis such as vasoocclusive disease, cerebrovascular accidents, myocardial infarction, venous thrombosis, priapism, visual disturbances, and pulmonary insufficiency.

          Unexplained fever, significant weight loss, increasing dose requirement of the drugs controlling the disease, bone and joint pain, bleeding, thrombosis, and infections suggest transformation into accelerated or blastic phases.


          Physical Findings

          Minimal to moderate splenomegaly; mild hepatomegaly
          Lymphadenopathy and myeloid sarcomas are unusual except late in the course of the disease; poor prognosis


          Hematologic Findings in chronic phase

          Elevated white blood cell counts (WBCs), with increases in both immature and mature granulocytes, are present at diagnosis; 16,000 to 200,00/cmm
          Usually less than 5% circulating blasts
          Platelet counts elevated or decreased, a mild degree of normocytic normochromic anemia .

          Leukocyte alkaline phosphatase is low in CML cells.
          Histamine production secondary to basophila is increased in later stages, causing pruritus, diarrhea, and flushing.

          Bone marrow cellularity is increased, with an increased myeloid to erythroid ratio. The marrow blast percentage is generally normal to less than 5%

          Marrow or blood basophilia, eosinophilia, and monocytosis

          Disease acceleration: the development of increasing degrees of anemia or blood or marrow blasts between 10 and 20%, blood or marrow basophils 20%, or platelet count less than 100,000/L.
          Blast crisis: Acute leukemia, with blood or marrow blasts 20%.

          Chromosomal Findings

          The cytogenetic hallmark of CML, is the t(9;22)

           Recognized by the presence of a shortened chromosome 22 (22q-), designated as the Philadelphia chromosome, that arises from the reciprocal t(9;22). Some patients may have complex translocations (designated as variant translocations) involving three, four, or five chromosomes (usually including chromosomes 9 and 22).

          Treatment

          The goal is complete hematologic, and cytogenetic remission, cure
          Complete hematologic remission, WBC less than 10,000/mL, normal blood morphology, hemoglobin and platelet counts, and disappearance of splenomegaly.
          Complete cytogenetic remission, no bone marrow metaphases with t(9;22).

          Rapid lowering of WBCs, reduction of symptoms,   and reversal of symptomatic splenomegaly.
          Imatinib mesylate tyrosine kinase inhibitorinduces apoptosis in cells expressing Bcr/Abl.

          Hydroxyurea induces rapid disease control
          Busulphan, an alkylating agent  acts on early progenitor
          Interferon – if all other options have failed; mechanism is unknown

          Autologous SCT

          Intensive leukapheresis may control the blood counts in chronic-phase CML
           leukostasis-related complications such as pulmonary failure or cerebrovascular accidents,
          Splenectomy for symptomatic relief of painful splenomegaly unresponsive to imatinib or chemotherapy, or for significant anemia or thrombocytopenia associated with hypersplenism. Splenic radiation

          Treatment of Blast Crisis
           Only 52% of patients treated with imatinib achieved hematologic remission (21% complete hematologic remission), and the median overall survival was 6.6 months.
           allogeneic SCT with chemotherapy

          Allogeneic SCT

          The Patient
          The Donor
          Sex mismatch has an adverse effect on transplantation, with worse outcome associated with a female donor and male recipient. This has been attributed to GVHD against the male histocompatibility Y antigen.

          Post-transplantation Treatment

          BCR/ABL transcript levels have served as early predictors for hematologic relapse following transplantation.
          Imatinib can control CML that has recurred after allogeneic SCT.

          Tuesday, July 9, 2013

          Acute lymphoblastic leukemia (ALL)

          Clonal proliferation and accumulation of blast cells from lymphoid series in blood, bone marrow and other organs

          Disorder  originates in single B or T lymphocyte progenitor 

          B cell type – 80%     T cell type – 20%
          Common age group – 5 to 15 yrs
          Etiology  - unknown 

          Acute leukemias - clinical features

          1. Bleeding
          2. Fever/infection
          3. Fatiguability and pallor
          4. Hepatomegaly
          5. Splenomegaly
          6. Lymphadenopathy
          7. CNS involvement
          8. Testicular involvement in males


          Acute leukemias - laboratory findings 

          1. Blood examination - anemia, - thrombocytopenia, - variable leukocyte count, usually increased from 10,000 to 500,000/cmm - blood morphology: presence of blast cells 

          2. Bone marrow morphology - presence of blast cells (>20%) - suppression of normal hematopoiesis
          3. Cytochemical stains
          4. Immunophenotyping
          5. Cytogenetics

          Immune phenotyping
          Cytogenetics
          Morphologic subtypes of acute lymphoblastic leukemias  (FAB classification)

          Subtype           Morphology       Occurrence (%)
          L1   Small round blasts              75
          clumped chromatin
          L2 Pleomorphic larger blasts     20
          clefted nuclei, fine chromatin
          L3 Large blasts, nucleoli,       5

          vacuolated cytoplasm

          Chromosomal/molecular abnormalities with prognostic significance in ALL

          Better prognosis
          - normal karyotype
          - hyperdiploidy
          Poor prognosis
          - t (8; 14)
          - t (4; 11)
          Very poor prognosis
          - t (9; 22); BCR/ABL (+)


           Treatment strategy in ALL

          Remission induction therapy in ALL

          1. Antineoplastic treatment
          a.Drugs: L-asparaginase, Daunorubicin, Prednisolone, Vincristine
              b/Treatment duration: 4-8 weeks
          c/ No of courses: 1- 2
          2. CNS prophylaxis – Methotrexate (intrathecal)
          3. Supportive care

          4. Treatment of complications

          Consolidation

          Drugs – Etoposide, cytarabine, and Daunorubicn, Methotrexate(I.v.)
          +/-

          Stem Cell transplantation

          Maintenance of remission


          • Prednisolone, Vincristine, Mercaptopurine and Methotrexate (oral)
          • May need to be continued for 2-3 years



          Treatment results in ALL 

          Adults
          Complete remission  (CR) 80-85%
          Leukemia-free survival (LFS)            30-40%

          Children
          Complete remission (CR) 95-99%
          Leukemia-free survival (LFS)            70-80%

          Sunday, July 7, 2013

          Cleft lip and cleft palate

          Development

          Face develops from 3 processes – frontonasal, maxillary and mandibular

          Intermaxillary segment is formed when medial growth of maxillary prominences cause fusion of medial nasal prominences in midline. In adult this segment forms philtrum, 4 incisors and primary palate.
          Secondary palate forms from the outgrowth of maxillary prominences called palatine shelves
          Primary and secondary palate fuse at the incisive foramen to form the definitive adult palate

          Types 
          • Cleft lip alone 15%
          • Cleft lip and palate 45%
          • Cleft palate only 40%
          • Sometimes cleft can not be seen externally - submucous

          Etiology
          • Genetic
          • Environmental – maternal epilepsy and drugs like steroids, diazepam and phenytoin
          • Syndromic- most common Pierre Robin sequence ( isolated cleft palate , glossoptosis or posteriorly placed tongue and retrognathia). Other syndromes Treacher Collins, down etc

          Complications 
          • Swallowing 
          • Sucking
          • Defective speech
          • Recurrent URTI and its sequelae
          • Cosmetic problem

          Primary management

          Antenatal diagnosis of cleft lip (not isolated cleft palate) possible at 18 weeks of gestation by USG.
          Referred to cleft surgeon if appropriate for counseling to allay fear

          Photographs of before and after surgery are invaluable
          Most babies born with cleft lip and palate feed and thrive well but some may require assistance
          Major respiratory obstruction is uncommon and occurs exclusively in children with Pierre robin sequence

          Definitive management

          Cleft lip repair is commonly performed between 3-6 months of age whereas cleft palate is frequently performed between 6- 18 months of age.
          Millard’s criteria (rule of 10) – cleft lip is repaired when child is 10 weeks old, child gains weight of 10 pounds and its Hb reaches 10g/dl. Millard’s cleft lip repair.
          Cleft palate surgery when child is 10 months old weighs 10 kg and HB is 10g/dl. Wardill-kilner push back operation

          Secondary management

          Following surgery regular review regarding hearing, speech, dental development and facial growth should be done

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