Clinical Pediatric Nephrology

Kanwal Kher, H. William Schnaper, Larry A. Greenbaum, Kanwal Kher, H. William Schnaper, Larry A. Greenbaum

• Publisher: CRC Press
• Year: 2016
• ISBN:
  9781498716017
• Edition: 3
• Topic: Medizin
• Subtopic: Nephrologie

The third edition of a bestseller, this book provides insight from a wide array of international contributors in the field of pediatric nephrology. Copiously illustrated with photomicrographs and clinical diagrams, the third edition reflects current advances in the field.

Each chapter contains a set of questions, directed at helping fellows succeed at the American Pediatric Nephrology Board examination. New information for this edition includes changes in treatment options for hyponatremia, and updates on hyperparathyroidism and transplantation. Text boxes highlight important "take home points" throughout the chapters.

Clinical Pediatric Nephrology, Third Edition will be a valuable reference for clinicians in nephrology, pediatrics and urology, and any professional involved in the care of children with renal diseases seeking a reliable contemporary text.

PART I

Inherited renal disorders

41 Tubulopathies

Detlef Bockenhauer

42 Renal tubular acidosis

John W. Foreman

43 Cystic kidney disease

Lisa M. Guay-Woodford

44 Ciliopathies and nephronophthisis

John Sayer, Shreya Raman, and Shalabh Srivastava

45 Alport syndrome and thin basement membrane nephropathy

Michelle N. Rheault and Clifford E. Kashtan

46 Renal disease in syndromic disorders

Patrick Niaudet

41

Tubulopathies

DETLEF BOCKENHAUER

Organization of tubules

Disorders of the proximal tubule

Disorders of thick ascending limb of loop of henle

Disorders of distal convoluted tubule

Disorders of collecting duct

References

Review questions

Answer key

Assuming a glomerular filtration rate of 100 mL/min, the kidneys of an average adult each day filter approximately 150 L of plasma each day, containing approximately 20 mol of sodium (Na⁺), the equivalent of more than a kilogram of table salt. Thus, without tubules, we all would have to drink 150 L a day and eat a kilogram of salt to keep up with urinary losses. The enormity of these numbers demonstrates the importance of proper tubular function. Typically, more than 99% of filtered salt and water are reabsorbed. Yet, the tubules not only need to accomplish the massive bulk transport of water and solutes, they also need to finely regulate the precise amount of reabsorption to balance variable intake and extrarenal losses, to maintain volume and electrolyte homoeostasis.

ORGANIZATION OF TUBULES

The enormous feat of complex tubular functions is accomplished by a whole orchestra of tubular transporters arranged along the entire nephron. Each transporter plays a specific role in coordinating a portion of tubular function. Much has been learned about the individual transport processes through observations of patients in whom one or more of these transport processes is defective, or patients with tubulopathies.

Both from a functional and a histoanatomic perspective, the nephron can be divided into four different segments (Figure 41.1):

1. Proximal tubule (PT)
2. Loop of Henle
3. Distal convoluted and connecting tubule (DCT)
4. Collecting duct (CD)

Disorders of the loop of Henle are mainly restricted to the thick ascending limb (TAL). In general, high-capacity bulk transport occurs in the PT, whereas the fine tuning of reabsorption occurs mostly in the distal end, the CD. Disorders of each segment tend to have a distinctive “fingerprint” of clinical and biochemical abnormalities that informs the diagnosis (Table 41.1).

KEY POINT

The renal tubule can be separated morphologically and functionally into four main segments: PT, loop of Henle, DCT, and CD.

DISORDERS OF THE PROXIMAL TUBULE

PHYSIOLOGY

The PT is not only the site of high-capacity transport, but it is also the exclusive site of reabsorption for several solutes, such as low-molecular-weight (LMW) proteins, amino and organic acids, glucose, and phosphate.¹ Because a sizeable proportion of albumin is also filtered, PT dysfunction is associated with moderately elevated urinary albumin levels, which can lead to confusion with glomerular disorders.² Albumin, like LMW proteins and a host of other solutes, is taken up by the proximal tubular epithelial cells through the promiscuous receptors megalin and cubilin, which are then internalized with the cargo into endosomes (Figure 41.2).³

Figure 41.1 Schematic of a nephron with respect to salt and water (H₂O) reabsorption. Shown is a schematic of a nephron depicting the four main segments for sodium (Na+) reabsorption. The indicated percentages for sodium and water reabsorption are rough estimates and may vary with clinical conditions.

Defects in PT can range from very specific dysfunction, such as isolated renal glucosuria, caused by impaired function of the Na+-glucose cotransporter SGLT2 (SLC5A2),⁴ to a generalized dysfunction of the PT. Clinically, cases of generalized PT dysfunction with glucosuria, acidosis, and hypophosphatemic rickets were first described in the 1930s by De Toni,⁵ Debre et al.,⁶ and Fanconi,⁷ and consequently this constellation of symptoms is referred to as De Toni– Debre-Fanconi syndrome, or just renal Fanconi syndrome. It can be acquired or inherited, either isolated or in the context of systemic disorders, such as mitochondrial cytopathies or nephropathic cystinosis (Table 41.2).⁸

CYSTINOSIS

Cystinosis, albeit a rare disorder with an estimated incidence of approximately less than 1 in 100,000, is the most common inherited cause of renal Fanconi syndrome in children.⁹ The underlying gene, CTNS, encodes a transporter involved in exporting cysteine from lysosomes.¹⁰ Consequently, impaired CTNS function leads to intracellular cystine accumulation.¹¹ However, how exactly this accumulation leads to cellular damage has yet to be clarified, although several hypothesis have been proposed, such as increased apoptosis, impaired energy production, and altered glutathione metabolism.¹²

Clinical features and diagnosis

Although cystinosis is a multiorgan disorder, the renal manifestations initially dominate, potentially because of the high cystine turnover in the PT from amino acid and LMW protein reabsorption. Measurement of urinary excretion of several LMW proteins, such as α₁- and β₂-microglobulins, can be used as markers for LMW proteinuria, but retinol-binding protein has been shown to have the highest sensitivity and specificity¹³ for proximal tubular proteinuria.

Presentation is usually in the first 2 years of life with poly-uria or polydipsia, failure to thrive, and rickets. Biochemical testing reveals the typical features of renal Fanconi syndrome (Table 41.3). However, because cystinosis affects most cells, other renal segments can be affected: glomerular function deteriorates with time, and other tubular features, such as secondary nephrogenic diabetes insipidus, have also been reported.¹⁴

Table 41.1 Selected tubulopath¡es, associated genes, and pertinent clinical and biochemical characteristics*

Figure 41.2 Uptake of low-molecular-weight protein in the proximal tubule. Low-molecular-weight proteins and many other solutes bind to the receptors megalin or cubilin and are subsequently incorporated into endosomes. The proteins are degraded in lysosomes, a process that involves CLCN5. The receptors (megalin and cubilin) are recycled back to the apical membrane. OCRL is involved in regulation of the endosomal trafficking. AMN, amnionless.

Once suspected, the diagnosis is easily established by slit-lamp examination of the eyes, which demonstrates characteristic cystine crystals in virtually all children older than 16 months of age.¹⁵ The absence of crystals before this age does not exclude the diagnosis. The diagnosis can be confirmed by measurement of an increased leukocyte cystine content or genetic testing, or both. Most children with typical clinical features of cystinosis have identifiable biallelic mutations in CTNS.¹⁶

Later in life, other types of organ dysfunction can become apparent, such as hypothyroidism, myopathy with swallowing dysfunction, retinal blindness, diabetes mellitus, male hypogonadism, and pulmonary and central nervous system dysfunction.⁹

Table 41.2 Causes of renal Fanconi syndrome

Treatment and prognosis

Treatment used to be just supportive, by replacing renal fluid and solute losses, enhancing nutrition, and treating the rickets. Patients developed end-stage renal disease (ESRD) i...