Hereditary Glomerular
Diseases
Hereditary Nephritis
(Alport’s syndrome)
Clinical Features
A genetic disease characterized by the onset of hematuria in early childhood and later progression to renal failure, predominantely in males, accompanied by the development of sensorineural (high frequency) hearing loss. A typical male patient presents with the onset of persistent gross or microscopic hematuria, sometimes exacerbated by upper respiratory illness, before the age of six. After years of recurrent or persistent hematuria, renal insufficiency is noted to occur, usually in the third or forth decade of life, occasionally before the age of twenty. Nephrotic syndrome may occurs in 30 – 40% of patients. Hearing loss is variable, ranging from complete deafness to (more frequently) a high-frequency loss detected by audiometric exam. Associated abnormalities may include megalocornea, lenticlonus, spherophakia, myopia, retinitis pigmentosa, and macrothrombocytopenia. In females, the disorder is usually mild, with only microscopic hematuria, and does not typically progress to renal failure.
In one series, 74% of patients were less than six years of age at presentation. 31% of patients on presentation had macroscopic hematuria, 15% had microscopic hematuria, and 50% presented with microscopic hematuria and proteinuria. Only 1% were deaf at presentation. All patients had at least one relative with renal disease. 37% of males and 12% of females progressed to endstage renal disease. 64% of patients developed hearing impairment. 30% of patients had ocular abnormalities.
Genetics
Genetic heterogeneity (autosomal dominant, autosomal recessive, and X-linked dominant patterns observed).
Pathology
Light microscopy – findings variable, nonspecific, and include focal and segmental glomerulosclerosis, mesangial proliferation, interstitial nephritis.
Immunofluorescent studies – usually negative; there is an absence of a reaction to antibodies directed against glomerular basement membrane.
Electron microscopy – thickening, thinning, splitting, multilaminated appearance of lamina densa of the glomerular basement membrane.
Pathogenesis
Unknown; given the lack of reactivity with anti-glomerular basement membrane antibodies and the observed ultrastructural basement membrane abnormalities, probable defect in basement membrane synthesis or urnover.
Treatment/prognosis
Conservative treatment for renal insufficiency. Patients are go candidates for dialysis and transplantation.
HEREDITARY
RENAL DISEASE – PROXIMAL NEPHRON
Introduction
Renal tubular disorders are a group of conditions in which the renal tubular reabsorption of an ion or organic solute is inappropriately reduced, resulting in excess amounts of these substances in the urine. These disorders may affect a single substance (such as glucose or phosphate), a group of substances (such as neutral amino acids), or an entire array of ions and compounds normally absorbed by a nephron segment (as in Fanconi syndrome). If portions of the glomerular ultrafiltrate are not normally reabsorbed, clinical disorders may result based on two major mechanisms: 1) the substance not reabsorbed is lost in the urine, and therefore not available for its role in physiologic processes (as in osteomalacia in excessive excretion of phosphates in hypophosphatemic rickets), or 2) the substance not reabsorbed is injurious to the kidney (as in stones/crystals found in cystinuria).
Fanconi Sydrome
A dysfunction of the proximal tubule which gives rise to excessive urinary losses of amino acids, glucose, phosphate, bicarbonate, electrolytes, and other solutes. These losses lead to the clinical problems observed in this syndrome, e.g. acidosis, dehydration, rickets, and growth failure.
Pathophysiology
The sequence of events underlying the Fanconi syndrome are incompletely understood. Many mechanisms exist that could lead to diminished net solute reabsorption (see figure 1).
Clinical Features
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Hyperaminoaciduria |
Rickets |
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Glucosuria |
Growth retardation |
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Hypophosphatemia |
Polyuria |
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Hypokalemia |
Dehydration |
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Hypouricemia |
Proteinuria |
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Acidosis |
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Causes
Causes of Fanconi syndrome are listed in the table 3. In children, the most common cause is an inborn error of metabolism (cystnosis). Cystinosis will be discussed in detail.
Cystinosis
Cystinosis is the most frequent cause of renal Fanconi syndrome in children. First describe in 1903, it was then readily confused with cystinuria, a disorder with defective tubular reabsorption of cystine, arginine, lysine, and ornithine. (WARNING! DO NOT CONFUSE WITH CYSTINURIA). The basic defect in cystinosis is not a tubular transport defect, but instead is due to the accumulation of cystine within lysozomes secondary to defective lysozomal membrane transport. This accumulation of cystine eventually damages the cells (especially the cells of the proximal tubule), leading to defects in reabsorpiton.
Incidence
A relatively infrequent disorder, occurring in 1 out of 100,000 – 200,000 live births. This underestimates frequency, since some children die at an early age of dehydration or electrolyte imbalance undiagnosed. Some areas of France have an incidence of 1 in 26,000.
Genetics
An incidence of 1 in 160, 000 corresponds to a carrier frequency for this autosomal recessive disorder of one in 200. The chromosomal location of the gene for cystinosis is unknown.
Clinical features
Children with cystinosis appear normal at birth. The initial manifestations are complications related to Fanconi syndrome, namely dehydration, failure to thrive, and electrolyte imbalance, which arise between 6 and 18 months of age. Fanconi syndrome in cystinosis apparently results from destruction of renal tubular cells by cystine accumulation, which can be present as early as 6 months of age. Early symptoms include gluosuria and polyuria (which may mislead physicians to diagnose juvenile onset diabetes mellitus), proteinuria (tubular), and urinary excesses of amino acids, calcium, phosphates, magnesium, sodium, bicarbonate, potassium, and carnitine. Hypoatremia and hypokalemia, along with acidosis, can be profound, and accompanied by vomiting and diarrhea which may mislead physician to diagnosis acute infectious gastroenteritis with dehydration. Phosphaturia leads to hypophosphatemic rickets with metaphyseal widening, frontal bossing, and genu valgum. Many patients have pale skin and pale blond hair. The eyes are extensively involved this disorder. Corneas are normal at birth, but by one year of age cystine crystals are visible in the anterior cornea, and later in conjunctivea. The retina exhibits a patchy depigmentation. Photophobia is very frequent. Children fail to thrive and exhibit a persistent failure to grow which is multifactorial, including nutritional deficiencies, renal insufficiency, acidosis, hypothyroidism, and cystine accumulation in endocrine organs and bone. Hepatomegaly and spenomegly occurs in one third of patients; hypothyroidism occurs in most and is due to destruction of the thyroid gland by cystine accumulation.
Pathogenesis
Normally, ingested protein enters the lysozome, where acid hydolases degrade it to its component amino acids, including cysteine. This amino acid is readily oxidized to cystine (the disulfide of cysteine) within the lysozome, and cystine then readily enters into the cytoplasm (by carries mediated transport across the lysomomal membrane) and is reduced (by glutathione) back to cysteine. Cytoplasmic cysteine can then become incorporated into protein or degraded to inorganic sulfate for excretion. Cysteine in readily soluble; cystine is relatively insoluble in concentrations above 2 mM. Above that concentration, cystine crystallizes. In cystinosis, the saturable stereospecific lysomzomal membrane transport carrier for cystine was found to be defective. Heterozygotes, while not storing cystine, have decreased rates of transport of cystine out of lysozomes (figure 2).
Pathology/Renal prognosis
The most serious medical threat to the survival of the child with cystinoisis is progressive renal failure. Early in the disease, clinically manifestations are related to defects in proximal tubular function. Glomerular involvement is minimal early in the disease, but progresses to scarring and fibrosis. At some point in the course of renal destruction, the filtration defect balances the tubular dysfunction, and the symptoms of Fanconi’s syndrome appears to regress. However, the tubular cells destruction is irreversible and the glomerular damage progresses to uremia.
Diagnosis
No newborn screening process available. Recognition of corneal crystals on slit lamp examination by an opthamologist is possible in nearly all patients after one year of age. If clinical symptoms are present, elevated cystine levels in cultured fibroblasts or lymphocytes. Pre-natal diagnosis using chronic villi sampling can be done.
Treatment
1. Replacement of ions/compounds lost in urine (table 3a)
2. Thyroid replacement
3. Dialysis/transplantation
4. Use of cystine-depleting agent, cysteamine. This agent binds with lysozomal cystine and then exits the lysozome, bypassing the cystine carrier. Early use of this agent may delay onset of renal failure, and delay cystine induced damage to other organs (eyes, thyroid). (See figure 2a).
Aminoacidurias
Specific amino acid transport systems for at least five groups or classes of amino acids have been described: basic – cystine, ornithine lysine, arginine; acidic – aspartic acid, glutamic acid; neutral imino group – glycine, proline, hydroxyproline; neutral group Hartnup – alaine, serine, threonine, valine, leucine, isoleucine, phenylalanine, glutamine, histidine, asparagine, citruline; beta amino group – taurine, beta-alanine.
Aminoaciduria occurs when an excess amount of amino acid is excreted in the urine. This process may involve a single amino acid, a group of amino acids transported by a similar process, or all amino acids (generalized).
Hereditary aminoacidurias are listed in table 4. Prototype to be discussed is cystinuria (DON’T CONFUSE WITH CYSTINOSIS).
Cystinuria
Cystinuria results from a defect in the transport mechanism of the basic amino acids shared by cystine, ornithine, lysine, and arginine (acronym “cola”). Defective tubular reabsorption of cystine produces excessive urinary excretion and crystalluria; lithiasis is due to limited solubility of cystine in urine.
Clinical findings
Renal clearance and excretion of cystine, ornithine, lysine, and arginine markedly increased. Formation of radio-opaque cystine calculi in renal pelvis, ureter, or bladder occur, usually when cystine content of urine exceeds 250 mg/liter. This results in hematuria, dysuria, urinary tract infection, and renal/ureteral colic. Renal failure may occur if urinary tract is chronically/obstructed and/or infected. There is some suggestion that incidence of mental retardation and psychiatric disturbance may be higher in cystinurics. Some patients have short stature.
Genetics
Autosomal recessive with genetic heterogeneity. Three different mutant alleles (types I, II, III) have been described. Prevalence is about one in 10,000 live births. Heterozygotes have normal aminoaciduria but may have impaired intestinal absorption of cystine and dibasic amino acids.
Diagnosis
Individuals with renal calculi should have calculi analyzed (if passed). Patients with calculi (unknown composition) should have timed urine collection for cystine determination.
Treatment
Various treatment modalities are shown in table 4a.
Renal Glucosuria
Renal glucosuria is an inborn error of transport that is inherited as an autosomal recessive trait. The hallmark clinical finding is abnormally large amounts of glucose in the urine of patients with normal blood glucose concentrations. In this disorder, glucose is the only abnormal urinary finding, thus distinguishing of this disease from more generalized proximal tubular defects.
Glucose is freely filtered at the glomerulus, with filtrate concentration equal to plasma concentration. The proximal tubule reabsorbs the great majority of filtered glucose. If filtered glucose rises, then at some point the glucose concentration exceeds the capacity of the proximal tubule to reabsorb glucose , and more glucose appears in the urine. This is termed the maximal tubular reabsorption capacity for glucose, or TmG. (see figure 3, top panel). The hatched area in the top figure is the so-called normal “splay”. Splay occurs when the filtered load of glucose increases, but the increase in tubular reabsorption of glucose, although still increasing, doesn’t quite keep up with the increase in filtered load and some glucose begins to appear in the urine. Splay may be due to nephron heterogeneity, where some individual nephrons have high capacity to reabsorb glucose, while other nephrons have lower capacity. Splay may also be the result of normal Michaelis-Menton kinetics describing glucose transport by a single saturable system.
Two types of renal glucosuria have been described, with different mechanisms of glucosuria proposed. In “type A”, the TmG for glucose is lower, so that glucose spills into the urine at normal or only slightly elevated serum glucose levels. In “type B” glucosuria, the Tm for glucose is normal, but an increased splay is noted in the glucose titration curve (see figure, lower panel). Type A may be due to a decrease in the number of glucose transporting units, and in type B, the number of transport units is normal, but the affinity of glucose for the transporter is reduced.
Genetics
Most modern studies suggest an autosomal recessive inheritance; heterozygotes may have an abnormality in glucose handling as well (see figure, lower panel). Incidence is unknown.
Diagnostic criteria
1. glucosuria (typically 5-100 grams glucose/day) without hyperglycemia
2. glucosuria present in all urine samples, including specimens obtained after an overnight fast.
3. urine should be tested for glucose with glucose oxidase methods; other sugars (fructosuria, galactosuria, etc.) will then be excluded.
4. oral glucose tolerance test is normal.
Hereditary
Renal Disease – Distal Tubule
Nephrogenic
Diabetes Insipidus
Normal water metabolism and osmoregulation is discussed in other sections of this course. Fluid entering the distal tubule is normally hypotonic to plasma (and certainly hypotonic to the medullary interstitium) during both diuresis and anti-diuresis. The osmolality of the final urine is determined by ADH acting on the distal nephron segments. ADH regulates the permeability of the distal tubule and collecting duct to water. When water loaded (water diuresis), resistance to water reabsorption is high (impermeable to water) and tubular fluid is progressively diluted by reabsorption of NaCl until a lower limiting value of about 40 mOsm/kg is reached. In water deprived (antidiuretic) states, ADH causes the tubule to become more medullary interstitium, and urine becomes concentrated.
In nephrogenic diabetes insipidus, the kidneys do not respond adequately to endogenous or exogenous ADH, and, despite increasing plasma osmolity, the urine continues to be diluted. As the plasma becomes hypertonic, ADH is maximally secreted, with levels similar to normal. However, the kidneys fail to respond to the ADH and don’t reabsorb more water. (Compare this to central diabetes insipidus, where urinary dilution occurs because of the lack of production of ADH).
Genetics
Many different processes can lead to nephrogenic diabetes insipidus (see table 5). The hereditary form occurs largely in males, and is thought to be linked with variable penetrance.
Clinical findings
Manifestations occur shorly after birth, typically with polyuria and polydipsia. Because of the young age at presentation, the poluria may not be recognized, and dehydration may ensue. Symptoms such as irritability, poor feeding, and poor weight gain may develop. Fever develops in some infants, secondary to dehydration. Physical exam shows signs of dehydration, dry skin and mucous membranes, loss of skin turgor, sunken eyeballs, and severe lethargy. Despite dehydration, the infant still voids frequently, and the urine has a low specific gravity. After oral (or intravenous) hydration, remarkable improvement in behavior and appearance occurs.
Complications
Encephalopthy may develop, secondary to repeated damage from dehydration and hypernatremia. Often, there is psychomotor retardation, and learning deficits.
Diagnosis
To confirm polyuria and to distinguish between ADH-resistant (inherited) versus ADH-sensitive (central) DI, a modified water deprivation test can be alone under strict supervision. Children are given breakfast, after which all access to fluid/water is removed. The child must be under constant observation, and the test may take 6-7 hours (child over 3 years). Children with normal concentrating ability will soon become oliguric and have concentrated urine. All urine is checked for volume and osmolality.
After 7 hours, blood is checked for Na and osmolality , and compared to urine. The test is terminated if progressive dehydration develops or weight loss of 3% body weight occurs. If polyuria is present, exogenous ADH, administered as DDAVP, is given. If polyuria is not decreased, a tubular insensitivity to ADH exists. Infants under 2 years of age should not be water deprived for more than 4 hours, and should be weighed every hour to prevent severe dehydration and hypertonicity (see table 5a).
Treatment
1. large volume feeding
2. reduced protein and Na intake (to decrease obligatory water excretion).
3. use of thiazide diuretic (to cause volume contraction and increased proximal tubular fluid reabsorption.
4. use of prostaglandin synthetase inhibitor (indomethacin), which inhibit water may decrease filtration rate slightly.
Hereditary
Renal Cystic Disease
Polycystic Kidney Disease
(PKD)
Autosomal dominant (ADPKD) – occurs in about 1/1250 live births, and found in every 500-800 autopsies. There is 100% penetrance of this autosomal dominant trait, and 50% of offspring will carry the gene, located on the short arm of chromosome 16. Renal size and function are usually normal early in life, with abdominal pain, kidney enlargement, and renal failure appearing in the forth and fifth decade. Hepatic cysts are found in 505 of patients, and Berry aneuryms of the circle of Willis, (as well as the thoracic and abdominal aorta) occur in 10-40%. Cysts occur along the entire length of the nephron, with Bowman’s space, loop of Henle, and the collecting tubule the most frequently involved. Cysts usually communicate with the glomerulus and tubule.
Autosomal recessive (ARPKD) – occurs in approximately 1/10,000 live births and affects females twice as frequently as males. Most commonly, the condition manifests within the first days of life with bilateral flank masses and a protuberant abdomen. Various groups have been described. The perinatal group presents at birth with massively enlarged kidney and cysts affecting over 90% of tubules. Kidneys are so large that lungs may be small, hypoplastic. Death quickly ensues. In the neonatal group, 60% of renal failure occurs within the first year or two. In the infantile group, hepatomegly predominates, presenting between 3 and 6 months of age. 25% of renal tubules are affected; in the liver, distorted intrahepatic biliary ducts and periportal fibrosis is present. In the juvenile group, cases typically present between 3 and 10 years of life, and liver disease predominates, with severe portal hypertension. Less than 10 % of tubules show cystic dilation.
The portion of the tubule involved is the distal and collecting tubule.
Juvenile nephronophthis/medullary cystic disease complex (MCD) – an important cause of renal failure in children. There are two distinct genetic and age related forms. The first is an autosomal recessive disorder and in children is frequently associated with a variety of other organ involvement (opthalmologic, CNS, hepatic, skeletal). This disease presents in children with polyuria, polydypsia, anemia, and growth failure. Salt wasting and hypokalemia are sometimes noted. These symptoms occur around 7-12 years of age, and renal failure quickly ensues. Cysts occur in the medullary collecting ducts and distal convoluted tubule. The second form is an autosomal dominant form, with average age of clinical onset at age 28. There are no other associated organ abnormalities.