DIFFERENTIAL DIAGNOSIS OF HEREDITARY DISEASES OF THE URINARY SYSTEM IN CHILDREN.
Hereditary nephropathy – kidney disease, whose development is associated with a mutation (monogenic hereditary) or multiple (QTL inherited) genes, as well as kidney disease, developed against the background of hereditary predisposition.
Actuality
1. The prevalence of this disease. Among children with congenital kidney diseases and hereditary diseases range is from 14 to 20%.
2. As a result of combined malformations of the kidneys and urinary system raise complex malformation with problems of diagnosis.
3. Poor prognosis due to the development of chronic renal failure and death. 43% of children with hereditary nephropathies have ChRF, 9,5% – adverse nephrotic syndrome. Disablement in children is not only medical but also social problem.
4. Difficulties in treatment. Some hereditary nephropathy requires long-term care throughout their lives, sometimes surgery and serious methods of therapy (artificial kidney, kidney transplantation). And the prognosis is much worse in the bilateral lesions of the kidneys.
5. Many of these diseases and ignorance of doctors of all types of congenital and hereditary diseases of urinary system lead to the late diagnosis at the stage of chronic renal failure, which affects the prognosis.
Etiology
Etiological factors that lead to the appearance of congenital and hereditary nephropathies can be divided into 3 groups:
1. Mutation of the gene expression which does not depend on external factors.
2. Mutation of the gene for penetrance of which must influence of environmental factors.
3. External influences: microbes, viruses, toxins, cooling, radiation, poisoning, implementation of which occurs in individuals with a genetic predisposition.
Classification of congenital and hereditary diseases of the kidneys.
nephropathy with chromosomal diseases (Edwards, Down syndrome, Patau, etc.).
nephropathy associated with gene mutations (monogenic and polygenic).
multifactorial nephropathy: expression of the mutant gene only under certain adverse environmental impacts.
Monogenic the type of transmission:
autosomal dominant type.
autosomal recessive type.
type, X-linked.
Pathological Anatomy
The morphological changes that occur in the kidneys are very diverse with different forms of congenital and hereditary diseases. In the parenchyma of the kidneys often detect dysplasia with thinning of the cortical layer (hypoplasia and various defects of the tubules, urinary system), sclerosis, cystic transformation of kidneys. Wheephropathies are associated with metabolic disorders, identification of nephrocalcinosis, proliferative, infiltrative changes in the interstitium, tubular epithelium dystrophy, fibrosis, crystals of salt in kidney tissue must be done.
Clinical classification of congenital and hereditary nephropathies.
І. In the anatomical structure of the anomalies of the kidneys and urinary organs:
Ø Malformations of the kidney (agenesis, aplasia, extra kidney, dystopia, nephroptosis, S-like, horseshoe kidneys, etc.)
Ø Malformation of the urethers (change the number, size, etc.)
Ø Anomalies of the urinary bladder, urethra
Ø Anomalies of the renal blood vessels
II. Violation of the differentiation of renal tissue (histological anomalies):
Ø With cysts (polycystic kidney, etc.).
Ø No cysts (segmental or atrophic dysplasia, etc.).
III.Congenital nephritis:
Ø Without deafness.
Ø With deafness (Alport syndrome).
IV. Tubulopathy:
Primary:
Ø with polyuria (renal diabetes insipidus, etc.)
Ø the deformation of the bones (phosphate diabetes, de Toni-Debre–Fanconi)
Ø with renal and bone (renal tubular acidosis)
Ø with nephrolithiasis (cystinuria, oksaluriya, etc.)
Secondary – a hereditary pathology of metabolism (Galactosemia, cystinosis, etc.).
V. Dysmetabolic nephropathy (oxalate-calcium crystalluria).
VI. Amiloidosis of kidney (hereditary, with periodic disease).
VII. Embrional renal tumors (Wilms‘ tumor),
Different variants of the doubling of the kidneys:
A doubling of the right kidney with a doubling of the ureters which individually fall into the bladder
A doubling of the right kidney with a doubling of the ureters, which connect near the bladder
A doubling of bilateral kidneys and ureters, which are separately flow into the bladder
A doubling of bilateral kidneys and ureters, which connect near the kidney calyx
A doubling of bilateral kidneys with a doubling of the ureters (right – falls apart in the bladder, the left – are interconnected near the bladder).
Variants of kidneys dystopia:
1 – gas
2 – iliac
3 – lumbar
4 – breast
5 – normal location of kidneys
Nephroptosis and dystopia of kidney.
L-and S- like kidney.
Schematic representation of the kidney with an asymmetrical seam forms: – S-like kidney, – L- like kidney; – I- like kidney, 1 – abdominal aorta, 2 – inferior vena cava, 3 – ureter; 4 – kidney.
Here is a “horseshoe” kidney. This is a congenital anomaly that may occur in association with other anomalies or syndromes with specific genetic defects such as trisomy 18. However, it can also occur as an isolated anomaly and an incidental finding. The uncommon potential problem here is that the ureters take an abnormal course across the “bridge” of renal tissue and this could lead to partial obstruction with hydronephrosis.
Multicystic kidney
Polycystic kidneys
This is the kidney of the patient, who died of renal failure. This is a congenital anomaly with intra-nephron obstruction.
This is a cut section of that kidney, again showing cysts extending throughout the entire renal mass – polycystic kidneys.
Hypoplasia of one kidney
Occasionally, congenital hypoplasia of one kidney is found in an symptomatic patient, either during pyelography or at autopsy. Here the right kidney (in the lower part of the picture) is represented by a small amount of pelvis and a very small amount of renal parenchyma. The left kidney (top) is hypertrophied.
Echo sings of kidney hypoplasia
Excretory urogram (15 th minute).
Hypoplasia of right kidney – it is small size, the calyx are clothed together, there is shortened pelvix.
Megaureter
Megaureter is an innate uretherectasia, accompanied by violation of its discharge. Urethers are the two tubular organs located between the renal pelvis and the bladder and their main function is to free transport urine from the kidney to the bladder.
Developmental abnormalities of the ureter encompass a wide range of disorders. Ureteral anomalies are a common cause of morbidity in children and frequently require surgical intervention.
History of the Procedure
Interestingly, Leonardo da Vinci and Galen were the first to begin to recognize the importance of the ureterovesical junction (UVJ) and to identify vesicoureteral reflux (VUR). Semblinow’s 1883 animal experiments renewed enthusiasm for the study of reflux and began the modern era of research to clarify the anatomy, function, and pathophysiology of UVJ anomalies.
Megaureter
A megaureter is a wide ureter, greater than 7mm in diameter.
Megaureters may be classified into 4 categories:
Obstructed
Refluxing
Obstructed and refluxing
Nonobstructed/nonrefluxing.
Etiology
There are several reasons of the formation of megaureter. The main reason is increased pressure inside the ureter with a loss of urine outflow. Sometimes the pressure is normalized, and the expansion of the ureter remains. It also may be congenital deficiency of the muscle of ureter. In this case the normal muscular of the ureter is replaced by inelastic scar tissue. Ureter is so weak that it is unable to effectively push the urine in the bladder. Another cause of megaureter is the narrowing of the ureter at the site of its connection with the bladder. Bladder ureteral reflux (urine from the bladder into the ureter and kidney) may also be the cause of megaureter.
Bilateral megaureter is more often a consequence of breach outflow of urine from the urethra, due to the presence of congenital valve in the urethra or the persistent spasm of urethral sphincter encountered ieurological disorders. This is called secondary megaureter.
Clinic
Megaureter is usually diagnosed with ultrasound of the fetus. After birth, in the absence of pathology of the bladder and urethra megaureter is usually not manifest itself clinically. In the future, if the diagnosis was not put in utero, the disease can manifest itself unexpected attack of pyelonephritis. The older children sometimes complain of pains in the abdomen or lumbar region. There are admixture of blood in the urine, palpable abdominal tumor formation, incontinence, and formation of stones in the urinary tract.
Diagnosis
Many infants and children with megaureter have no symptoms. With increasing frequency this condition is detected on prenatal ultrasound. However in other cases, a child may be referred to a pediatric urologist or pediatric surgeon after experiencing at least one of the following symptoms during infancy or early childhood:
· abdominal mass that can be seen or felt
· acute pain in the back or abdomen
· febrile urinary tract infection
· blood in the urine (hematuria)
· urinary incontinence
· urolithiasis (stone formation within the urinary tract).
Other studies are usually needed to confirm the diagnosis and to determine the cause. These tests may include:
ü Intravenous pyelogram (IVP), which allows doctors to visualize the anatomy of the ureter and assess how well the kidneys collect and drain urine. The IVP also allows doctors to estimate ureteral diameter. In general, megaureter is a ureter with a diameter of greater than seven to ten millimeters.
ü Voiding cystouretrogram (VCUG) a specialized x-ray that is used if the doctor suspects that vesicoureteral reflux (backward flow of urine from the bladder to the ureter and/or kidney) is causing the problem. Vesicoureteral reflux is responsible for the ureteral dilation in a significant proportion of patients with megaureter.
ü A renal (kidney) scan (MAG 3 with lasix) is used if the doctor suspects that an obstruction at the ureterovesical junction is causing the problem. This scan provides very sensitive quantitative information regarding kidney function and drainage characteristics. Along with the IVP, it is particularly helpful in identifying and assessing the degree of blockage in this kind of obstruction.
Evaluation for both vesicoureteral reflux and obstruction allows doctors to place your child’s megaureter or dilated upper urinary tract into one of the four following categories:
§ refluxing megaureter: vesicoureteral reflux alone is responsible for the dilation
§ obstructed megaureter: a significant degree of blockage alone is present at the ureterovesical junction (UVJ)
§ refluxing and obstructed megaureter: both vesicoureteral reflux and blockage at the UVJ are present
§ nonrefluxing and nonobstructed megaureter: dilation of the upper urinary tract is present but no evidence of reflux or clinically significant obstruction is documented during evaluation.
Mild obstructed megaureter, showing fullness of the pelvic ureter, normal proximal ureter, and calyces
Two-month-old boy with bilateral megaureters.
A- DTPA renal scan bilateral hydronephrosis and megaureters; left ureter incompletely filled. B- left retrograde pyelogram immediately prior to surgical correction. Note the sharp cut-off at the distal ureter. C- Following transvesical mobilization of the megaureters. The longitudinal channel vessels are preserved and seen through the periureteral adventitia. D- Postoperative pyelogram following bilateral ureteral plication of the lower half of each megaureter and cross-trigonal ureteroneocystostomy. E- Follow-up radionuclide renal scan.
Electron microscopic findings in primary obstructive megaureter.
A- Operative specimen. B- Muscle cell atrophy, absent nexus, and excessive collagen and ground substance in the intercellular space from dilated ureter. C- Abnormal collagen fibers between muscle cells reduced from x 4000. D- Abnormality reduced from x 17,000 from narrow ureter.
Therapy
The choice of treatment or monitoring regime depends on the severity of pathology, the child’s age, the presence of pyelonephritis, the degree of renal dysfunction.
The disease can be solved independently with moderate obstruction, mild expansion of the ureter or reflux of low intensity. If there are changed functions of the bladder, urinary tract infection a positive effect requires the selection and conduct of drug therapy.
Evaluation of changes (dynamics) takes place during follow-up surveys (1 per 2-6 months) and the results of tests. Surgical treatment is necessary in children with more severe forms of megaureter with negative impact on kidney function. Indications for surgical treatment is usually occur in intrauterine diagnosis of megaureter after the observation period. (1 to 6 months after birth).
Common clinical signs of congenital and
hereditary nephropathies:
· The genetic anamnesis: presence of similar diseases in the family, clearly manifested in the pedigree.
· Long-term latent course, which often is with isolated urinary syndrome.
· Multiple external and somatic stigma disembriogenesis (minor anomalies
· Early decrease in renal function, usually by a tubular type.
· Formation of renal insufficiency.
Hereditary nephritis
It is a group of inherited conditions characterized initially by hematuria and slowly progressing to renal insufficiency. The most common form is the Alport syndrome (hereditary nephritis with hearing loss) which is caused by mutations in genes for TYPE IV collagen and defective glomerular basement membrane.
Alport syndrome
Alport syndrome is an inherited disorder that damages tiny blood vessels in the kidneys.
Causes
Alport syndrome is an inherited form of kidney inflammation (nephritis). It is caused by a mutation in a gene for a protein in connective tissue, called collagen.
The disorder is uncommon, and most often affects males. Women can transmit the
gene for the disorder to their children, even if they have no symptoms.
Risk factors include:
Ø End-stage kidney disease in male relatives
Ø Family history of Alport syndrome
Ø Glomerulonephritis
Ø Hearing loss before age 30
Defects in type IV collagen, a collagenous protein involved in the formation of basement membranes, have been implicated in hereditary Alport’s syndrome and acquired Goodpasture’s syndrome. Mutations in genes corresponding to the building blocks of type IV collagen cause Alport’s syndrome, whereas autoantibodies against structures that are usually hidden in the recesses of collagen IV cause Goodpasture’s syndrome.
A very highly enlarged view of the filter in the glomerulus. These electron microscope images are magnified x100,000, and show glomerular basement membrane (GBM) in a normal glomerulus (LEFT) and in Alport syndrome (RIGHT). The diagrams below illustrate the thickening and ‘falling apart’ of Alport GBM.
The normal GBM (left) and the GBM in Alport syndrome (right)
Alport syndrome (AS) is a genetic disease in which a collagen mutation affects the kidneys, the ears, and the eyes. The syndrome was named for Dr. Alport who in 1927 described a British family in which many members developed renal disease as well as deafness. He noted that affected men in the family died as a result of their kidney problems, whereas females were less affected and lived until old age.
It is now known that most cases of AS are caused by a mutation in the collagen gene COL4A5. This gene encodes for the alpha-5 chain of collagen type IV and is located on the X chromosome. Because women have two X chromosomes (XX), affected women usually have one normal copy and one abnormal copy of the gene. Men only have one copy of the X chromosome (XY). If they inherit the COL4A5 mutation, this abnormal copy of the gene is the only copy they have and the effects are more severe.
Type IV collagen is found in basement membranes (BM), which are selective barriers between cells. In the kidney, the glomerular BM filters waste products into the urine while keeping useful molecules within the blood stream. In AS, the abnormal collagen disrupts this filter, leading to the loss of proteins and red blood cells into the urine. Blood in the urine (hematuria) is a sign common to all types of AS. In the ear, abnormal collagen in the cochlea results in a progressive deafness in which the ability to hear high tones is lost first. Abnormal collagen can also affect the lens of the eye.
Currently, renal failure due to AS is treated by dialysis or, for some, renal transplantation. However, gene therapy may one day be able to provide a cure for AS by replacing the faulty COL4A5 gene.
Clinics
The disorder damages the tiny blood vessels in the kidneys, called glomeruli, that filter wastes.
At first, there are no symptoms. However, progressive destruction of the glomeruli leads to blood in the urine and may decrease the effectiveness of the kidney’s filtering system. There is a progressive loss of kidney function and a build-up of fluids and waste products in the body.
In girls, the disorder is usually mild, with minimal or no symptoms. In men, the symptoms are more severe and get worse faster.
Fragment of glomerular capillary wall of proband families S. Diagnosis: Alport syndrome. The basal membrane is expanded, the substance is enlightened, thick plate is weak. Electron. x16000
Symptoms include:
§ Abnormal urine color
§ Ankle, feet, and leg swelling
§ Blood in the urine
§ Decrease or loss of vision, more common in males
§ Loss of hearing, more common in males
§ Swelling around the eyes
§ Swelling, overall
The perifoveal dot and fleck retinopathy in a patient with X linked Alport syndrome (NH).
The condition can progress to end-stage renal disease (ESRD) at an early age (between adolescence and age 40).
Note: There may be no symptoms in some cases. Symptoms of chronic kidney failure or heart failure may be present or may develop.
Possible approach to confirming a suspected diagnosis of Alport syndrome.
Exams and Tests
o Changes to the eye, including the fundus (posterior inner part of eye), lens, cataracts, or lens protrusion (lenticonus)
o Elevated blood pressure
o Tiny amounts of blood in the urine (microscopic hematuria)
The following tests may be done:
Ø Urinalysis shows blood, protein, and other abnormalities.
Ø BUN and creatinine are elevated.
Ø Red blood cell count, hematocrit may decrease.
Ø Audiometry may show nerve deafness.
Ø Renal biopsy shows chronic glomerulonephritis with changes typical of Alport syndrome.
Treatment
The goals of treatment include monitoring and controlling progression of the disease and treating the symptoms. Most important is to strictly control blood pressure.
Treatment of chronic kidney failure may become necessary. This can include dietary modifications, fluid restriction, and other treatments. Ultimately, chronic kidney failure progresses to end-stage kidney disease, requiring dialysis or transplantation.
Surgical repair of cataracts (cataract extraction), or repair of the anterior lenticonus in the eye may be needed.
Loss of hearing is likely to be permanent. Counseling and education to increase coping skills can be helpful. Learning new skills such as lip reading or sign language may be of some benefit. Hearing aids are helpful. Young men with Alport syndrome should use hearing protection in noisy environments.
Genetic counseling may be recommended because of the inherited pattern of the disorder.
Outlook (Prognosis)
Women usually have a normal life span with no signs of the disease except for blood in the urine. Rarely, women will have high blood pressure, swelling, and nerve deafness as a complication of pregnancy.
In men, deafness, visual difficulties, and kidney failure are likely by age 50.
Possible Complications
Ø Chronic renal failure
Ø Decrease or loss of vision
Ø End-stage renal disease
Ø Permanent deafness
Syndrome nail-patella
Syndrome nail-patella (hereditary onihoosteodisplasia) is heritage disease with autosomal-dominant type and is closely linked to blood group gene which is localized on chromosome IX (9q34).
Clinics:
1) hypoplasia, absence of the convexity or thickness of nail plates (especially the big toe, pointing fingers)
2) the absence or hypoplasia of the patella in combination with other bone anomalies – hypoplasia of the proximal radial head, iliac bone with patologic of their projections , deformity of the foot (” horse toes”)
3) flexion contracture of the joints (especially elbows)
4) Ophthalmic pathology (glaucoma, strabizm, ptosis, etc.)
5) Pathology of the kidney (proteinuria, microhematuria, development of CRF). Glomerular basement membrane is thickened, tubules areatrophic, with mesangial sclerosis.
There is no specific treatment.
Hereditary tubulopathies
A group of hereditary tubulopathies whose clinical picture in the early stages of the disease simulates rickets, but are not associated with a deficit entering the body of vitamin D; their leading syndrome are skeletal abnormalities (renal osteopathy).
TP-group of diseases in violation of membrane transport of various disorders of the renal tubules. There are distinguished primary TP at which transport of various substances disruptes predominantly in the membranes of renal tubules, and secondary TP when there is destruction of nephron or part of a general defect of metabolism, or glomerular disease, and other parts of the kidney that has spread to the tubules.
Pathogenesis
Pathogenic mechanisms of formation of primary (hereditary) tubulopathies are associated with the following factors:
• genetical determined disorders the structure of membrane protein carriers
• enzimopathic hereditary enzyme deficiency caused by ensuring the activity of
membrane transport
• changes in sensitivity of receptors tubular epithelial cells to the action of hormones
• change in the overall structure cells membrane in dysplasia, in which the hereditary
factors are the origin of a role for.
Secondary tubulopathies result from damage to transport systems of renal tubules in both hereditary and acquired diseases at the exchange in relation to metabolic disturbances outside the nephron. They are also being developed for inflammatory diseases of the kidneys, which may lead to significant differential diagnostic difficulties.
There are vitamin-D-resistant rickets, vitamin-D-dependent rickets, a disease de Toni – Debreu – Fanconi and renal tubular acidosis.
Vitamin-D-resistant rickets
X-linked hypophosphatemia (hypophosphatemic rickets, vitamin D-resistant rickets) is an X-linked dominant form of rickets (or osteomalacia) that differs from most cases of rickets in that ingestion of Vitamin D is relatively ineffective. It can cause bone deformity including short stature and genu varum (bow leggedness). This is the most frequently encountered form of rickets and consists of a genetic fault in the handling of phosphate in the proximal tubule.
It is associated with the gene PHEX on chromosome Xp22.1, which encodes a product that inactivates hormone-like substances (phosphatonins) that promote phosphate excretion and impair bone mineralization.
Patholophysiology
· decreased reabsorpion of phosphate by the renal tubule (causing hypophosphatemia) (otherwise the renal function is normal, ie BUN and Cr are normal)
· decreased absorption of calcium and phosphorous from the GI tract
· genetics:
Þ hypophosphatemic Vitamin D-resistant rickets is one of the few disorders inherited as a sex-linked dominant trait
Þ as in other sex-linked dominant disease, the degree of expressivity varies
Clinics
– Classic picture is short stature, bowing of lower limbs (esp at knees causing genu varum) & rachitic changes in the long bones;
– Ht at initial dx is usually <10 % & always< 25th
– Coxa vara is also common in untreated patients;
– In some affected patients, the disorder is manifested only by a low serum phosphorus;
– In others there is also widening of epiphyseal plates and bowing of the legs;
Diagnostic criteria of phosphate diabetes
• The appearance of clinical signs in the 1-2 years of life
• Deformations of the skeleton, more pronounced in the lower extremities (O-strain), growth retardation
• Muscle hypotonia, muscle soreness
• Late eruption of teeth, enamel defects
• Hypophosphataemia (less than 1.3 mmol / l), increased activity of alkaline phosphatase, hyperphosphaturia (more than 2.3 mmol / l) with normal content of calcium in the blood
• Radiographic bone changes, especially the lower extremities.
Lab Data:
– Serum phosphorus is low, serum Ca is usually normal (or low normal), and serum alk phos is elevated when turnover of bone is increased
– Patients with hypophosphatemic ricket have low concentrations of inorganic phosphorous, secondary to abnormal reabsorption of phosphate;
– Serum BUN and Cr are normal (which distinguishes this from renal osteodystrophy)
A teenage male with Vitamin D-resistant rickets. Note deformities of legs (bow legs) and compromised height.
A girl with Vitamin D-resistant rickets. Note deformities of legs (bow legs) and compromised height.
Radiographs:
Treatment
– Administration of high doses of vitamin D (by itself) will have no beneficial effect
– Instead, it is more appropriate to manage these patients with neutral phosphate orally and 1.25-dihydroxyvitamin D
– If oral phosphate supplements are given alone, secondary hyperparathyroidism may result
– Organic phosphate should be given every 4 hours along w/ supportive vit D therapy
Surgical considerations
– It is important to avoid “recumbency hypercalcemia” which is common in postoperative patients who are non with bearing and who are taking Ca supp and
vitamin D
– Untreated hypercalcemia in these patients leads to renal stones, mental changes, etc.
Complications
Hypercalcemia and secondary extraskeletal calcification may occur w/ overly aggressive therapy.
Idiopathic De Toni-Debre-Fanconi syndrome
It is a rare inherited disorder characterized by defective reabsorption of various substances such as phosphate, potassium, amino acids and glucose which manifests as a wide range of abnormalities and problems.
The main symptoms of De Toni-Debre–Fanconi syndrome (Hereditary primary Fanconi disease) are:
Ø Failure to thrive
Ø Vomiting
Ø Unexplained fever
Ø Excessive urination
Ø Dehydration
The list of signs and symptoms mentioned in various sources for hereditary primary Fanconi disease includes the 18 symptoms listed below:
Ø Failure to thrive
Ø Vomiting
Ø Unexplained fever
Ø Excessive urination
Ø Dehydration
Ø Rickets
Ø Osteomalacia
Ø Swan-neck kidney deformity
Ø Kidney lesions
Ø Pyelonephritis
Ø Kidney fibrosis
Ø Kidney vacuolization
Ø Liver cirrhosis
Ø Chronic acidosis
Ø Hypokalemia
Ø Excess sugar in the urine
Ø Excess phosphates in urine
Ø Excess amino acids in urine
Diagnostic criteria of the disease de Toni-Debre–Fanconi:
Beginning clinical manifestations at the end of І and II years of life with glucosuria
Changes in the skeleton, malnutrition, underdevelopment
Reduced resistance
Manifestations of hypokalemia: muscular hypotonia, hyporeflexia, lower AT
Signs of metabolic acidosis: weakness, irritability, pale skin
Changes in urine: Glycosuria, hyperaminoaciduria, hyperphosphaturia, increased excretion of bicarbonate, and after 2 years – hypoizostenuria, ketosis
Boy 12 years with the disease de Toni – Debre – Fanconi: sharp physical retardation and bone deformities, mainly the lower extremities.
Systemic osteoporosis
Electron micrograph of Patients with osteoporosis
normal bone tissue.
Treatment
· The treatment of a child with Fanconi syndrome mainly consists of the replacement of substances lost in the urine. Prominent among these substances are fluids and electrolytes.
· Dehydration due to polyuria must be prevented by allowing free access to water; treat dehydration with either oral or parenteral solutions.
· Metabolic acidosis due to the loss of bicarbonate is corrected by the administration of alkali, usually 3-10 mg/kg/d of sodium bicarbonate in divided doses.
· Addition of a diuretic, such as 1-3 mg/kg/d of hydrochlorothiazide, may be necessary to avoid volume expansion, which magnifies the excretion of bicarbonate by lowering the renal threshold. Unfortunately, the diuretic increases potassium wasting and thus the need to augment potassium supplementation in the form of potassium bicarbonate, citrate, or acetate.
· Correction of metabolic acidosis is beneficial but is not sufficient for the treatment of bone disease. Phosphate and vitamin D supplementation are also necessary.
· Normalization of serum phosphate levels may be achieved by administering 1-3 g/d of supplemental phosphate. Administration should start at the lower level and be slowly increased over several weeks to minimize GI symptoms.
· Vitamin D, administered as 1.25-dihydroxyvitamin D3 or 1a-hydroxyvitamin D3, is preferred because liver and/or renal hydroxylation may be impaired in patients with Fanconi syndrome.
· The losses of glucose, amino acids, and uric acid are not usually symptomatic and do not require replacement. Recently, carnitine supplementation has been tried in an attempt to increase muscle strength; however, results have been mixed.
The list of complications that have been mentioned in various sources for Hereditary primary Fanconi disease includes:
Death due to renal insufficiency and uremia
Renal tubular acidosis (RTA)
Renal tubular acidosis (RTA) is a medical condition that involves the
accumulation of acid in the body due to a failure of the kidneys to appropriately acidify the urine.
When blood is filtered by the kidney, the filtrate passes through the tubules of the nephron, allowing for exchange of salts, acid equivalents, and other solutes before it drains into the bladder as urine. The metabolic acidosis that results from RTA may be caused either by failure to recover sufficient (alkaline) bicarbonate ions from the filtrate in the early portion of the nephron (proximal tubule) or by insufficient secretion of (acid) hydrogen ions into the latter portions of the nephron (distal tubule). Although a metabolic acidosis also occurs in those with renal insufficiency, the term RTA is reserved for individuals with poor urinary acidification in otherwise well-functioning kidneys. Several different types of RTA exist, which all have different syndromes and different causes.
The word acidosis refers to the tendency for RTA to lower the blood’s pH. When the blood pH is below normal (7.35), this is called acidemia. The metabolic acidosis caused by RTA is a normal anion gap acidosis.
Type 1: Classical Distal RTA
Type 1 is also called classical distal RTA. “Distal,” which means distant, refers to the point in the urine-forming tube of the kidney where the defect occurs—relatively distant from the point where fluid from the blood enters the tiny tube, or tubule, that collects fluid and wastes to form urine.
This disorder may be inherited as a primary disorder or may be one symptom of a disease that affects many parts of the body. Researchers have discovered abnormal genes responsible for the inherited forms of the disease. More often, however, classical distal RTA occurs as a result of systemic diseases—diseases that affect many organ systems—like the autoimmune disorders and lupus, which also attack the distal tubule.
Other diseases and conditions associated with classical distal RTA include sickle cell anemia, hyperparathyroidism, hyperthyroidism, chronic active hepatitis, primary biliary cirrhosis, a hereditary form of deafness, analgesic nephropathy, rejection of a transplanted kidney, renal medullary cystic disease, obstructive uropathy, and chronic urinary tract infections. Many of these conditions cause abnormal calcium deposits to build up in the kidney and impair distal tubule function.
A major consequence of classical distal RTA is a low blood potassium level. The level drops if the kidneys excrete too much potassium into urine instead of returning it to the blood supply. Because potassium helps regulate nerve and muscle health and heart rate, low levels can cause extreme weakness, irregular heartbeat, paralysis, and even death.
Untreated classical distal RTA causes growth retardation in children and progressive kidney and bone disease in adults. Restoring normal growth and preventing kidney stones are the major goals of therapy.
Significant bilateral nephrocalcinosis
(calcification of the kidneys) on a frontal X-ray (radiopacities (white) in the right upper and left upper quadrant of the image), as seen in distal renal tubular acidosis.
Patients suffering from distal renal
tubular acidosis (RTA) often form stones of calcium phosphate because alkaline calcium phosphate salts are insoluble.
If acidosis is corrected with sodium bicarbonate or sodium citrate, then low blood-potassium, salt depletion, and calcium leakage into urine will be corrected. This alkali therapy also helps decrease the development of kidney stones and stabilizes kidney function so kidney failure does not progress. Infants may need potassium supplements, but older children and adults rarely do because alkali therapy prevents the kidney from excreting potassium into the urine.
To diagnose RTA, doctors check the acid-base balance in blood and urine samples. If the blood is more acidic than it should be and the urine less acidic than it should be, RTA may be the reason, but additional information is needed to rule out other causes. If RTA is the reason, additional information about the sodium, potassium, and chloride levels in the urine and the potassium level in the blood will help identify the type of RTA a person has. In all cases, the first goal of therapy is to neutralize acid in the blood, but different treatments may be needed to address the different underlying causes of acidosis.
Type 2: Proximal RTA
Type 2 is also called proximal RTA. The word “proximal”, which means near, indicates that the defect is closer to the point where fluid and wastes from the blood enter the tubule.
This form of RTA occurs most frequently in children as part of a disorder called Fanconi’s syndrome. The features of Fanconi’s syndrome include the abnormal excretion of glucose, amino acids, citrate, and phosphate into the urine, as well as vitamin D deficiency and low blood-potassium.
Proximal RTA can also result from inherited disorders that disrupt the body’s normal breakdown and use of nutrients. Examples include the rare disease cystinosis, in which cystine crystals are deposited in bones and other tissues; hereditary fructose intolerance; and Wilson disease.
The clinical features of proximal renal tubular acidosis are:
· Polyuria, polydipsia and dehydration
· Hypophosphatemic rickets (in children) and osteomalacia (in adults)
· Growth failure
· Acidosis
· Hypokalemia
· Hyperchloremia
Other features of the generalized proximal tubular dysfunction of the Fanconi syndrome are:
· Hypophosphatemia/phosphaturia
· Glycosuria
· Proteinuria/aminoaciduria
· Hyperuricosuria
When possible, identifying and correcting the underlying causes are important steps in treating the acquired forms of proximal RTA. The diagnosis is based on the chemical analysis of blood and urine samples. Children with this disorder would likely receive large doses of an oral alkali, such as sodium bicarbonate or potassium citrate, to treat acidosis and prevent bone disorders, kidney stones, and growth failure. Correcting acidosis and low potassium levels restores normal growth patterns, allowing bone to mature while preventing further renal disease.
Renal tubular acidosis
Plain radiograph of the kidneys in a patient with a long history of renal tubular acidosis. This image shows bilateral pyramidal calcification that is consistent with nephrocalcinosis. Bottom: Sonograms of the kidneys in the same patient as above show a hyperechoic medulla associated with echogenic foci, some of which are casting shadows.
Axial computed tomography scans obtained from a patient with a long history of renal tubular acidosis
Type 3
Type 3 is rarely used as a classification because it is now thought to be a combination of type 1 and type 2. Vitamin D supplements may also be needed to help prevent bone problems.
Type 4: Hyperkalemic RTA
Type 4 is also called hyperkalemic RTA and is caused by a generalized transport abnormality of the distal tubule. The transport of electrolytes such as sodium, chloride, and potassium that normally occurs in the distal tubule is impaired.
This form is distinguished from classical distal RTA and proximal RTA because it results in high levels of potassium in the blood instead of low levels.
Either low potassium—hypokalemia—or high potassium—hyperkalemia—can be a problem because potassium is important in regulating heart rate.
Type 4 RTA occurs when blood levels of the hormone aldosterone are low or when the kidneys do not respond to it. Aldosterone directs the kidneys to regulate the levels of sodium, potassium, and chloride in the blood. Type 4 RTA also occurs when the tubule transport of electrolytes such as sodium, chloride, and potassium is impaired due to an inherited disorder or the use of certain drugs.
Drugs that may cause type 4 RTA include
· diuretics used to treat congestive heart failure such as spironolactone or eplerenone
· blood pressure drugs called angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs)
· the antibiotic trimethoprim
· the antibiotic pentamidine, which is used to treat pneumonia
· an agent called heparin that keeps blood from clotting
· a class of painkillers called nonsteroidal anti-inflammatory drugs (NSAIDs)
· some immunosuppressive drugs used to prevent rejection
Type 4 RTA may also result from diseases that alter kidney structure and function such as diabetic nephropathy, HIV/AIDS, Addison’s disease, sickle cell disease, urinary tract obstruction, lupus, amyloidosis, removal or destruction of both adrenal glands, and kidney transplant rejection.
For patients who produce aldosterone but cannot use it, researchers have identified the genetic basis for their body’s resistance to the hormone. To treat type 4 RTA successfully, patients may require alkaline agents to correct acidosis and medication to lower the potassium in their blood.
If treated early, most patients with any type of RTA will not develop permanent kidney failure. Therefore, the goal is early recognition and adequate therapy, which will need to be maintained and monitored throughout the person’s lifetime.
Referens:
A – Basic:
1. Pediatrics. Textbook. / O. V. Tiazhka, T. V. Pochinok, A. N. Antoshkina et al. / edited by O. Tiazhka – Vinnytsia : Nova Knyha Publishers, 2011 – 584 pp. : il.
2. ISBN 978-966-382-355-3Nelson Textbook of Pediatrics, 19th Edition Kliegman, Behrman. Published by Jenson & Stanton, 2011, 2608. ISBN: 978-080-892-420-3.
3. Illustrated Textbook of Paediatrics, 4th Edition. Published by Lissauer & Clayden, 2012, 552 p. ISBN: 978-072-343-566-2.
4. Denial Bernstein. Pediatrics for medical Students. – Second edition, 2012. – 650 p.
2. http://www.merckmanuals.com/professional/index.html
