(1)
Department of Emergency Medicine, Erasmus Medical Center, Rotterdam, The Netherlands
Kidney and Urinary Embryology
It’s a good idea to refresh your memory on the basics of kidney development, because it makes remembering and understanding malformations of the kidney much easier. You don’t need the details about embryological development, though, for your boards.
There are three phases of embryological kidney development:
1.
The pronephros – a very rudimentary kidney develops that is similar to that of primitive fish. It never functions in human embryos.
2.
The mesonephros – the same type of kidney found in (modern) fish and amphibians. It functions briefly in the human embryo prior to development of the next type of kidney.
3.
The metanephros – this kidney starts developing at about 5 weeks of gestational age and begins to make urine at about 12 weeks. It will develop into the adult human kidney.
Origin of the Kidneys
Kidneys develop from two embryological structures.
1.
The metanephric diverticulum (aka ureteric bud) – this structure forms the ureter, renal pelvis, calyces, & collecting tubules. It penetrates the adjacent tissue (the metanephric mesoderm), to induce formation of the metanephric cap.
2.
The metanephric mesoderm – forms the nephrons.
A uriniferous tubule is defined as a nephron from the metanephric mesoderm and a collecting tubule from the metanephric diverticulum.
The end of each collecting tubule induces formation of metanephric vesicles, and then tubules of the nephron, in adjacent tissue. The glomeruli invaginate into these tubules.
Kidney Function
During fetal life, the purpose of the kidney is to simply produce urine . Metabolic processing that would normally be done by the kidney is done entirely by the placenta during fetal development.
The production of urine supplies the fetus with much of the amniotic fluid. It is essential that the fetus swallow amniotic fluid to keep the amount of fluid in balance, and to foster proper development of the organs, especially the gastrointestinal system.
Oligohydramnios (very little water) – less amniotic fluid than normal. Results from bilateral renal agenesis or dysfunctional kidney, or from genitourinary obstruction (such as a posterior urethral valve in male infants).
Polyhydramnios (much water) – more amniotic fluid than normal. Results from any type of GI obstruction that prevents the fetus from swallowing amniotic fluid (including anencephaly), or from absorbing it into the fetal gut. Because the fluid is not swallowed and reabsorbed by the GI tract, the total amount of fluid increases. Overproduction of urine can also lead to polyhydramnios. This sometimes occurs with diabetic mothers, due to fetal hyperglycemia & the resulting polyuria. Bartter syndrome, in which urine is overproduced due to altered function in the (renal) loop of Henle.
Kidney Migration & Blood Supply
Kidneys start in the pelvis, very close together, and then move up and out into the abdomen. They also rotate during this process – the hilum starts out pointing directly ventral (down), but rotates clockwise to point medially when they end up in the retroperitoneal space.
At about 9 weeks, the kidneys “run into” the adrenal glands and the glands attach to the top of the kidneys.
The blood supply is initially from the common iliacs. As the kidneys migrate upward into the abdomen, new vessels grow from the aorta and the old vessels disappear. 25 % of adult kidneys have 2–4 renal arteries (extra arteries) that enter the kidney directly – if present these arteries are “end arteries” not collateral circulation. If these arteries are cut or ligated, renal ischemia will result.
Kidney Malformations
Renal agenesis – unilateral occurs 1 per 1,000 live births, bilateral occurs 0.3 per 1,000 live births (more rare, fortunately). Occurs when the metanephric diverticulum doesn’t develop, deteriorates, or doesn’t invaginate into the metanephric mesoderm. In the end, no nephrons are formed.
Ectopic kidneys – usually in the pelvis – hilar orientation may also be abnormal because the kidney has not rotated during migration.
There is an association between pelvic kidneys and fused kidneys. When the kidneys are in the pelvis they are very close together. If they complete their development there, they sometimes fuse producing one large kidney. (This kidney is usually disc shaped.) Occasionally, a fused kidney migrates to normal position.
Horseshoe kidneys – Horseshoe kidney occurs when one pole of the two kidneys fuses – usually the inferior pole. These kidneys are often found low in the abdomen as they get “caught” under the inferior mesenteric artery (IMA) during the attempted migration process (because they are solid in the middle instead of separated). Horseshoe kidneys are usually asymptomatic but are sometimes prone to obstruction/infection.
Duplication of upper urinary tract – Duplication of the ureters and renal pelvices can occur due to various divisions of the metanephric diverticulum during development. A truly duplicated whole kidney is rare and probably only occurs if two metanephric diverticula develop.
Ectopic ureteral orifice – Rare – usually the ureteric orifice is lower than expected and not within the bladder. In females, if the ureter inserts directly into the vagina, parents complain that their daughters’ diapers and underwear are continuously wet (incontinence).
Congenital bilateral polycystic kidney – multiple cysts form in the kidney during development which can result in severe renal insufficiency. The cysts are thought to result from abnormal development of the collecting tubules.
LOWER URINARY TRACT DEVELOPMENT
The urorectal septum invaginates into the cloaca forming the rectum and urethra (initially the urogenital sinus).
The urethra has three parts:
1) Vesical – continuous with the allantois. Becomes the urachus, then median umbilical ligament in the adult.
2)
Pelvic .
3)
Phallic – urogenital membrane covers this portion externally.
The urethral epithelium comes from urogenital sinus endoderm. (The urogenital sinus is the embryological tissue common to both sexes that eventually differentiates into external genitalia and associated structures.) The rest of the urethral tissue comes from “splanchnic mesenchyme,” a type of mesoderm adjacent to the epithelium.
The transitional epithelium of the bladder is derived from endoderm from the urogenital sinus – the rest of the bladder develops from the mesoderm.
Note: The bladder is an abdominal organ (whether full or empty) until puberty. After puberty it is ordinarily within the pelvic brim.
Urethral Malformations
Urachal fistula or sinus – This occurs when the urachus remains patent, or when one end or the other is not completely closed forming a blind-ended pouch (sinus). Patients may complain of urine, or simply fluid, leaking from the umbilicus.
Urachal cysts – This occurs when a portion of the midpart of the urachus does not completely close. A small pouch is then formed. Approximately 1/3 of adults have urachal cysts. They are asymptomatic unless they become infected.
Bladder exstrophy – This occurs when the inferior abdominal wall fails to close revealing the anterior portion of the bladder wall and the ureteric orifice area. The anterior bladder wall usually ruptures during birth. Babies are placed on prophylactic antibiotics until surgical repair is performed. It is important to note that bladder exstrophy may be associated with epispadias or lower spinal cord defects.
Epispadias – The urethra does not develop to its full, usual length, and the urethral meatus opens on dorsal or lateral surface of the penis, in its mild form. In the more severe form, it is combined with bladder exstrophy. The basic mechanism for bladder exstrophy & epispadias is thought to be the same (failure of fusion).
Hypospadias – The urethral meatus opens on ventral surface of the penis. The cause is multifactorial involving endocrine, genetic, and environmental factors, and not well understood. The incidence is increased in small-for-gestational-age infants, and infants for whom assisted reproductive technology (especially intracytoplasmic sperm injection – ICSI) was utilized.
Posterior urethral valve (PUV) – In male embryological development, the caudal (tail) end of the Wolffian duct should fuse into the posterior urethral area, forming a collection of folds (plicae colliculi). If the duct does not fuse, but instead forms separate tissue that stretches across the urethral area, a posterior urethral valve is formed. The obstruction it causes in GU outflow both during development often leads to both bladder & kidney abnormalities (as well as secondary effects on lung development).
ADRENAL DEVELOPMENT
Medulla – develops from neural crest cells
Cortex – develops from mesoderm – very large relative to kidney size in fetus and infants – the cortical zones begin to develop late in fetal life and are not completely developed until after birth.
Congenital adrenal hyperplasia – This condition occurs when certain cortical enzymes are deficient, so that some steroid hormones cannot be produced. ACTH is therefore oversecreted (from the pituitary), hyperstimulating the gland and causing hyperplasia.
Hypoplastic adrenals – Occurs in anencephalic infants due to lack of ACTH production and adrenal gland stimulation. The pituitary gland is absent or poorly developed in these infants, so there is no source for ACTH production.
Multicystic vs. Polycystic Kidney Disease
Most physicians are much more familiar with polycystic kidney disease than we are with multicystic kidneys. Multicystic kidneys are an especially important topic, though, for neonatology & pediatric nephrology. This document provides a quick summary comparison of the two disorders.
Polycystic kidney disease
Polycystic kidney disease is an inherited disorder. There are two modes of inheritance, autosomal dominant and autosomal recessive.
Both kidneys are affected in either type of polycystic kidney disease.
The natural history of polycystic kidney disease is that the kidney architecture and function begin relatively normal. As time goes by, the number of cysts increases until kidney function is compromised. In the recessive disorder, this occurs early in childhood, but in the dominant disorder it doesn’t occur until well into adulthood.
Multicystic kidney disease
Multicystic kidney disease is a congenital disorder (present at birth) but it is not inherited. It results from mechanical problems in the urological system that occur during embryological/fetal development. Most commonly, there is no ureter on the affected side. Multicystic kidneys often have dysplastic tissue (tissue that wouldn’t normally occur in the kidney), and always have abnormal architecture. Kidneys that have both cysts and dysplastic tissue are designated to have “multicystic dysplastic kidney disease.”
Multicystic kidney disease is usually unilateral.
Multicystic kidney disease is the most common cause of an abdominal mass in a newborn, overall (both genders combined).
The natural history of multicystic kidney disease is that the affected kidney is nonfunctional from birth. No normal parenchymal tissue can be identified in multicystic kidneys – the entire kidney is replaced by non-communicating large cysts.
The contralateral kidney should be evaluated for normal urological function in children with a multicystic kidney. This is because up to 30 % will have reflux on the unaffected side. Untreated reflux could compromise kidney function in the sole functioning kidney if reflux-related complications develop over time.
The treatment of multicystic kidneys is a matter of some controversy. Children with multicystic kidneys are at increased risk for development of renin-mediated hypertension, as well as renal malignancies arising from the scattered stromal cells in the cystic kidney. Some physicians surgically remove the multicystic kidney (nephrectomy ), but most currently advocate close monitoring with yearly renal ultrasounds, because the dysplastic kidney typically regresses fully by adolescence.
Amyloidosis: The Essentials
While amyloid disorders do not occur often in pediatrics, they do occur. They are most commonly seen in dialysis patients (usually after about 10 years of dialysis), patients with chronic inflammatory conditions including both rheumatologic disorders & chronic infectious diseases, and rarely in association with certain malignancies. They are uncommon enough to be interesting targets for board examinations & ward discussion of “zebra” disorders.
It is important to understand that amyloid is an amorphous, eosinophilic, proteinaceous substance that can develop from a variety of other molecules in the body. These include immunoglobulin, calcitonin, serum protein, and insulin or glucagon. This material is deposited in a variety of tissues, usually extracellularly, and can cause a number of different problems. Amyloidosis refers to the whole group of disorders caused by deposits of proteinaceous, eosinophilic, extracellular material. The tissue the amyloid is ultimately deposited in depends on its molecule of origin.
Amyloidosis that is not linked to another disease or inflammatory state is termed “ primary amyloidosis .” Most of these disorders are late onset & seen in the adult population. Primary amyloidosis mainly affects the heart, tongue, and muscle.
“ Secondary amyloidosis ” refers to the same problem when it results from a certain serum protein that is present in patients with autoimmune and chronic inflammatory conditions (such as rheumatoid conditions and long-term infections like TB & leprosy). This form is mainly deposited in tissues of the reticuloendothelial system – liver, spleen, lymph nodes, & kidney. Amyloid deposition is also seen in islet cells with type II DM, long-term renal dialysis, and cancers such as medullary thyroid carcinomas.
A newer classification based on the specific molecule in a particular patient’s amyloid is now in use. For dialysis patients, this type is β2M-globulin amyloidosis. For most other pediatric patients, the type is “AA.” In nations with well-resourced healthcare systems, the frequency of AA due to chronic infectious diseases, as well as disorders such as juvenile idiopathic arthritis (formerly juvenile rheumatoid arthritis), has decreased due to better recognition & management of those disorders. The most common etiologies for AA amyloidosis in the pediatric populations of those countries now are thought to be autoimmune disorders, and in particular, familial Mediterranean fever.
While less of an issue during the pediatric period, Down’s syndrome patients invariably develop amyloid deposition in later life in the central nervous system, producing an early-onset type of Alzheimer’s dementia.
The structure of amyloid is always a β-pleated sheet. Buzzwords in the diagnosis of amyloidosis are Congo red dye (a dye that it absorbs) and apple green birefringence (its appearance under polarized light microscopy).
Word associations that you may find useful:
AMYLOID — β-PLEATED SHEETS — CONGO RED DYE — APPLE GREEN BIREFRINGENCE
AMYLOID — PRIMARY — IG — HEART, MUSCLE, TONGUE — PLASMA CELL DISEASES
AMYLOID — SECONDARY — AA TYPE — CHRONIC INFLAMMATION — SERUM PROTEIN — LIVER, KIDNEY, SPLEEN
AMYLOID – SECONDARY – RENAL DIALYSIS – LONG TERM — β2M-GLOBULIN TYPE
AMYLOID β-PROTEIN – ALZHEIMER’S DISEASE — CHROMOSOME 21
Fluids and Electrolytes: Critical Care and Boards Topics
Sodium
Sodium is the main thing (or at least the main electrolyte) that determines extracellular fluid volume (ECFV). It is also the main extracellular cation (potassium is the main intracellular cation).
Regulating sodium is an important way to regulate ECFV – what we normally think of as the patient’s “volume status.”
Total body sodium – How is it regulated?
1.
Kidney juxtaglomerular cells notice if renal perfusion decreases – they release renin → angiotensin → angiotensin I → angiotensin II
Angiotensin II tells the kidney to retain more sodium than usual, and causes release of aldosterone —
Released by the adrenal cortex, aldosterone also increases the amount of sodium the kidney retains (rather than excreting the sodium into the urine, Na is absorbed in the collecting duct).
2.
Volume sensors in the atria and great veins notice if volume is unusually high – if it is, they cause release of atrial natriuretic factor (ANF) from the heart. ANF increases sodium excretion (dumps sodium out of the body – like aldosterone, ANF also acts on the collecting duct, but this time it prevents absorption of sodium).
(This makes sense because “atrial” refers to the atrium, which is monitoring the volume status, while “natri” refers to sodium, and “uretic” refers to urinary excretion, like in the word “diuretic.”)
3.
Low-volume sensors in the carotid sinus and aorta activate the sympathetic nervous system – producing more renin release, and sodium retention by the kidney.
Total body water – How is it regulated (by the kidney, that is)?
1.
Adequate GFR (glomerular filtration rate) must be available
2.
Adequate delivery of fluid to the glomerulous must happen
3.
Kidney must be working properly (able to concentrate or dilute – a healthy kidney is able to concentrate or dilute urine until the GFR reaches 20 % of normal)
4.
ADH system must work (turns on and off correctly)
5.
Kidney is responding properly to ADH
In addition to the total body water , other contributors to ECFV are as follows:
Thirst/tonicity – Hypertonicity is the main trigger for thirst and ADH release. (Hypertonicity is defined as the ability of the solutes in a solution to generate an osmotic driving force for water movement.)
ADH status:
The most important factor in determining whether concentrated or dilute urine is produced is ADH (antidiuretic hormone – made by the pituitary).
Lack of ADH (centrally) is central diabetes insipidus (DI).
Kidney unresponsiveness to ADH is nephrogenic DI.
Drugs or conditions with ADH-like effects, or that increase ADH → SIADH syndrome.
Potassium
Remember that potassium is the main intracellular cation (only 3.5–5.0 mEq/L outside cells, but 130–140 mEq/L inside cells).
How are appropriate potassium levels maintained?
Basic mechanisms:
Regular body cells maintain their potassium gradient with a Na-K ATPase pump.
Dietary potassium is handled by the kidney and the gut –
Kidney – 90 % of dietary K is excreted in urine
Gut – 10 % of dietary K is excreted in stool
The kidney can dump up to 10 mEq/kg/24 h, if necessary. Needless to say, hyperkalemia rarely develops when kidney function is normal. The kidney maintains its ability to dump potassium until it is down to only 20 % of its regular function!
Kidney cells (of the collecting duct) are set up to allow secretion of one K ion into the urine, with resorption of one Na ion. This means that the more K is dumped in the urine, the greater the sodium retention will be.
Clinically, if less sodium is sitting in the collecting duct, as often happens in the newborn period due to low sodium content in formula or breast milk, then less K will be secreted, increasing serum K levels.
Other modifying factors:
Gut – much more potassium (than the usual 10 % of dietary potassium) can be dumped via the gut if the serum is hyperkalemic, and also with diarrhea
Insulin – drives K inside cells
Acidosis – drives K out of cells, and decreases renal excretion of K (generally) (because the collecting duct secretes H ions instead of K ions in an effort to decrease the acidosis)
Alkalosis – drives K inside cells, and increases renal excretion of K (generally)
β-2 receptor stimulation – drives K inside cells (remember that albuterol can be used to temporarily decrease the plasma K level, because it is a beta-2 agonist)
Increased serum osmolality – brings K out of cells (remember that increased osmolality means increased solutes compared to the fluid volume – the solutes that determine osmolality are sodium (main determinant), glucose, and urea)
Why?
1.
As cells dehydrate, the K concentration inside the cell gets higher, pushing some of the K to leave the cell.
2.
Solvent drag – As water exits the cell due to the high osmolality outside it, some of the solutes are literally just drug out of the cell with the water.
Aldosterone – lowers potassium because it increases potassium loss in the urine (aldosterone release is stimulated by hyperkalemia, as well as the renin-angiotensin system)
How? It upregulates the number of Na/K exchangers in the collecting tubule. It also increases Na channel activity. Together, this increases Na absorption from the tubular lumen – K secretion goes up so that one positive ion goes out for each positive ion taken in (electroneutrality).
High sodium load – The more sodium is presented to the collecting tubule, the more potassium is excreted (because more sodium/potassium exchange is possible, and encouraged, by the presence of so much sodium!).
Poorly resorbed anions – These anions, including excess bicarb, carry sodium and water (the water comes along due to osmosis) into the collecting tubule. For example, sodium can be transported across as sodium bicarb. Higher flow in the collecting duct due to the increased water volume further stimulates K secretion through a mechanism known as “flow-dependent K secretion.”
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