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I. General Background: Principles of Mammalian Genetics. Approaches to Identification of Disease Genes. Clinical Applications of Genetics. II. Primary Genetic Diseases of Nephron Function: Logic of the Kidney. Primary Genetic Diseases of the Glomerulus: Alport's and Thin Basement Membrane Disease. Congenital Nephrotic Syndrome. Focal Segmental Glomerulosclerosis. Primary Genetic Diseases of the Proximal Renal Tubules. Diseases of Renal Glucose Handling. Diseases of Renal Amino Acid Handling. Primary Renal Uricosuria. Fanconi Syndrome. Proximal Renal Tubular Acidosis . Dent's Disease. Primary Genetic Diseases of the Thick Ascending Limb of Henle: Salt and Potassium Handling (Bartter's Syndrome). Renal Mg2+ Wasting Due to Paracellin-1 Mutation. Ca2+-Sensor Receptor-related Diseases. Primary Genetic Diseases of the Distal Convoluted Tubule and Collecting Duct: Gitelman's Syndrome. Syndrome of Hypertension Plus Hyperkalemia. Liddle's Syndrome. The Syndrome of Apparent Mineralocorticoid Excess. Pseudohypaldosteronism Type I and Hypertension Exacerbated in Pregnancy. Distal Renal Tubular Acidosis. Nephrogenic Diabetes Insipidus: Vasopressin Receptor Defect. Nephrogenic Diabetes Insipidus: Aquaporin-2 Defect. III. Genetic Abnormalities of Renal Development and Morphogenesis: Overview of Renal Development. Polycystic Kidney Disease. Juvenile Nephronopthisis. Medullary Cystic Disease. Renal Dysgenesis. IV. Inherited Neoplastic Diseases Affecting the Kidney. The Genetic Basis of Cancer of the Kidney. Wilm's Tumor. Tuberous Sclerosis. V. Systemic Diseases with Renal Involvement: Monogenic Disorders. Nail-Patella Syndrome. The Systemic Anti-Inflammatory Diseases. Renal Defects Due to Mitochondrial Mutations. Primary Hyperoxaluria. Lowe's Syndrome. Fabry's Disease. Hereditary Fructose Intolerance. The Branchio-Oto-Renal Syndrome. Primary Metabolic and Renal Gout. Hereditary Cystinosis. Hepatorenal Tyrosinemia. Renal Disease in Type I Glycogen Storage Disease. Wilson's Disease. Renal Hypophosphatemia Due to Intrinsic Renal Defects. VI. Systemic Hereditary Diseases with Renal Involvement: Multifactorial Diseases: Systemic Lupus Erythematosis. IGA Nephropathy. Type I and II Diabetes Mellitus. Susceptibility to Diabetic Nephropathy. HIV-Associated Nephropathy. Hypertension.

Publisher Summary This chapter provides a short description on the anatomic and functional design of the mammalian kidney and cites examples of regulation of sodium and potassium to describe the complexity of its system. The kidney, to fulfill its homeostatic role, interfaces directly with the intravascular compartment where it modifies the composition and quantity of body fluid via its excretory and endocrine functions. Each human kidney is endowed with approximately 106 nephrons. The bisected surface of the kidney consists of the lighter-colored outer cortex and the darker-appearing inner medulla. The medulla is further divided radially into outer and inner regions with the outer medulla subdivided into outer and inner stripes. There is a drastic morphologic change from the visceral epithelium to the proximal tubule at the exact junction where filtration function ceases and resorptive and secretory functions commence. The proximal tubule can be subdivided anatomically in two ways. The initial convoluted portion (pars convolute) is entirely in the cortex, and the subsequent straight portion (pars recta) is in the cortex and the outer stripe of the outer medulla. The distal convoluted tubule (DCT) starts shortly after the macula densa. The distal convoluted tubule is heterogeneous and can be divided into an early (DCT1) and late portion (DCT2) with functionally but not so much morphologically distinct characteristics. The kidney is responsible for the bulk of potassium excretion but a modest fraction of ingested potassium may be excreted by secretion in the colon. The capacity of the latter to secrete potassium may increase when renal excretory mechanisms fail, but it is insufficient to maintain adequate external balance.

Proximal renal tubular acidosis (pRTA) is a disease of defective proximal tubule function resulting in metabolic acidosis. This chapter will review the transport processes for acid-base equivalents in the proximal tubule, the clinical features of pRTA, and the specific molecular defects that can give rise to pRTA. Two mechanisms contribute to bicarbonate exit across the basolateral membrane of proximal tubule cells, namely Na + -HCO 3 ¯ cotransport and Cl ¯ -HCO 3 ¯ exchange. Na + -HCO 3 ¯ cotransport is the predominant mechanism through most of the length of the proximal tubule (S1 and S2), whereas Cl ¯ -CO 3 ¯ is important in the S3 segment. A Na + :HCO 3 ¯ stoichiometry of 1:3 is required for the transporter to mediate net HCO 3 efflux across the basolateral membrane of proximal tubule cells. Therefore, a regulatory change in stoichiometry from 1:3 to 1:2 would be expected to change the net direction of transport from outward to inward across the basolateral membrane and thereby impede net bicarbonate reabsorption. The pRTA is defined as a hyperchloremic metabolic acidosis due to a defect in bicarbonate transport capacity in the nephron segment. In a patient with pRTA there is a greatly reduced threshold of plasma bicarbonate at which bicarbonate appears in the urine, and the maximal rate of reabsorption of bicarbonate is markedly depressed. The principal cause of isolated pRTA is a defect in basolateral base exit that would be predicted to lead to relative alkalinization of intracellular pH in proximal tubule cells. Such intracellular alkalinization would tend to mitigate the effects of systemic acidosis and thereby maintain citrate excretion at a higher level than observed in distal RTA (dRTA).

Publisher Summary Most diuretics are highly protein bound in the plasma and thus are poorly filtered at the glomerulus. Because most diuretics work from the luminal fluid, their action depends critically on tubule secretion. In general, secretion of diuretics occurs predominantly in the proximal tubule. This chapter discusses the process through which kidney transports electrolytes and water, and the way these processes are regulated. The chapter forms the basis for an understanding of the multiplicity of diuretic effects, many potentially therapeutic, while some responsible for unwanted side effects. The chapter also deals with the mechanisms of renal sodium ion, chlorine ion, hydrogen ion, and potassium ion transport. The transport of ammonium ion, calcium ion, magnesium ion, and phosphate are also discussed. In conclusion, a discussion of water transport, urinary concentration and dilution, and transport of diuretics is provided.

Publisher Summary This chapter describes a compartmental model developed to examine sodium fluxes in isolated perfused proximal tubule segments of the rabbit. A four-step experimental protocol that can be applied to the compartmental analysis and provides a means for testing the applicability of the model to the proximal tubular epithelium is also described. There are several distinct advantages to the choice of the isolated perfused tubule as an experimental technique—for example, the technique can be applied to investigate other tubular segments including those not available to surface micropuncture. Also, as an in vitro preparation, the experimenter has excellent control over the luminal and bath compartments. In addition, the epithelium is isolated as a single cell layer and, therefore, closely approximates a three-compartment system. In presenting the model and experimental procedure in general terms it is expected that the concepts and methodology may have application to other transported species not only in the proximal tubule but also in other nephron segments.

Publisher Summary The fundamental mechanisms of urinary acidification are bicarbonate reabsorption and formation of titratable acidity, and it is generally conceded that hydrogen ion secretion by the tubular epithelium participates in both processes. However, it has repeatedly been proposed that an additional transport mechanism could exist for the bicarbonate anion in its ionic form. This chapter provides evidence that the buffer systems exist with widely varying permeance of their acid components, varying from practically impermeant components to systems with very permeant components that appear to maintain transepithelial concentration equilibrium (glycodiazine) and that this property determines the magnitude of the H + ion flux taken up by them in the tubular lumen. The H + ion source could be related to the process of recirculation of the diffusible acid, as proposed for carbonic acid. The acid formed in the lumen by H + ion secretion would diffuse into tubular cell and there could either dissociate, yielding an H + ion to the proton pump, or neutralize OH - ions formed by the water-splitting process of a redox pump.