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Clinical Implications of Renal Physiology

Surjit Tarafdar

Summary

• Besides maintaining a stable acid base, electrolyte, and fluid status of the body, kidneys also have an important endocrine role in producing and secreting 1,25‐dihydroxycholecalciferol (calcitriol), renin, and erythropoietin
• More than 98% of water in the filtered urine is reabsorbed in the tubules; 90–95% of water is reabsorbed as it follows sodium (Na+), which is avidly reabsorbed by the Na+‐deficient epithelial cells, except in the collecting duct (CD), where 5–10% of water is reabsorbed (independent of Na+) under the direct influence of vasopressin or anti‐diuretic hormone (ADH)
• The tubular epithelial cells constantly lose three Na+ and gain two potassium (K+) ions from the basolateral membrane (due to the Na+‐K+‐ATPase), which keeps these cells deficient in Na+
• The countercurrent mechanism, which is dependent on the impermeability of the thick ascending limb (TAL) to water, leads to the creation of an increasing osmotic gradient from the cortex to the deeper medulla, which in turn enables ADH to reabsorb water in the CD
• Aldosterone helps in Na+ reabsorption in the CD and also leads (directly) to K+ and (indirectly) to hydrogen (H+) secretion into urine
• All diuretics act by inhibiting tubular reabsorption of Na+
• Formation of urine begins in the glomerular capillaries where the filtrate has to cross the three filtration layers: endothelium, glomerular basement membrane (GBM) and the foot processes of the podocytes; all these three layers are negatively charged and hence repel anionic proteins like albumin
• Nephrotic syndrome, which is marked by abnormally increased filtration of plasma proteins in the urine, may be due to widening of the pores in the three filtration layers, but is almost always associated with loss of negative charges in these layers
• Nephritis, which is due to glomerular inflammation, is characterized by haematuria with red blood cell (RBC) casts and dysmorphic RBCs, some degree of oliguria, hypertension, and reduction in glomerular filtration rate
• Goodpasture’s disease, which is characterized by antibodies against subtype of type IV collagen, can lead to nephritis and haemoptysis, as this particular collagen is found predominantly in the GBM and alveolar membranes of the lungs
• Familial hypocalciuric hypercalcaemia, which manifests with hypercalcaemia, characteristically low urinary calcium and normal to high serum parathyroid hormone (PTH) level, is due to mutation in the calcium‐sensing receptor (found in the kidney and parathyroid gland) leading to abnormally increased renal reabsorption of calcium and inappropriate secretion of PTH
• Distal renal tubular acidosis (type 1 RTA) is due to an inability of the distal tubules to excrete H+, whilst proximal renal tubular acidosis (type 2 RTA) is due to an inability of the proximal tubules to reabsorb bicarbonate (HCO3−)
• Metabolic acidosis leads to hyperkalaemia and vice versa

The kidneys are paired retroperitoneal structures that are normally located between the transverse processes of the T12–L3 vertebrae, with the left kidney typically somewhat more superior in position than the right. Each kidney has an outer cortex and an inner medulla which protrudes into the pelvis. The pelvis is practically the funnel‐shaped dilated upper end of the ureter.

The kidney maintains a stable acid base, electrolyte, and fluid status inside the body by selective elimination or retention of water, electrolytes, and other solutes (Table 1.1). It does so by three mechanisms:

1. Filtration of blood in the glomerulus to form an ultrafiltrate (water with low molecular weight solutes) which then enters the tubule.
2. Selective reabsorption of water, electrolytes, and solutes from the tubules into the interstitium and peritubular capillaries.
3. Selective secretion from the peritubular capillaries across the tubular epithelium into the tubular fluid.

Besides these mechanisms, the kidneys also play an active endocrine role by the production and secretion of:

• 1,25‐dihydroxycholecalciferol: cholecalciferol is derived from 7‐dehydrocholesterol in the skin on exposure to the ultraviolet rays in sunlight. Cholecalciferol then undergoes two subsequent hydroxylations by 25‐hydroxylase in the liver and 1‐hydroxylase in the proximal tubules of the kidney to yield 1,25‐dihydroxycholecalciferol (calcitriol). Calcitriol is the active form of vitamin D, without which calcium cannot be absorbed from the intestine.

  Table 1.1 Urine to plasma ratios of some physiologically important body substances

  Substance

  Urine to plasma ratio

  Glucose

  0

  Sodium

  0.6

  Urea

  60

  Creatinine

  150

• Renin: discussed later under juxtaglomerular apparatus.
• Erythropoietin (EPO): specialized interstitial cells in the inner cortex and outer medulla of the kidney produce and secrete EPO, which stimulates red blood cell (RBC) production in the bone marrow.

The kidney consists of nephrons with the supporting interstitium, collecting ducts (CDs), and the renal microvasculature. The nephron consists of a glomerulus and a twisted tubule which drains into the CD. The tubule consists of a proximal and a distal tubule connected by Henle's loop [1]. Each kidney has approximately one million nephrons and we cannot develop new nephrons after birth.

Cortex

This is the outer layer of the kidney and all the glomeruli are located here (Figure 1.1). The tubules of the superficial and midcortical nephrons are situated entirely within the cortex. The juxtamedullary nephrons (in the deeper regions of the cortex and nearer the medulla) have longer tubules and their loop of Henle goes down into the medulla and helps in the countercurrent mechanism, as discussed later.

Medulla

The renal medulla contains the loops of Henle of the juxtamedullary nephrons, vasa recta (peritubular capillaries surrounding the long loops of the juxtamedullary nephrons), and the CDs. The medulla consists of 7–10 conical subdivisions called pyramids, whose broad base faces the cortex, and the apical papilla points into the minor calyx. After traversing through the pyramid, the CDs open at the papilla and drain the urine into the minor calyx. Two or three minor calyces converge to form a major calyx, through which urine continues into the renal pelvis, which is the funnel‐shaped dilated proximal end of the ureter. There are usually two or three major calyces in each kidney.

Figure 1.1 The renal cortex, medulla (with the pyramids), and minor and major calyces with their relation to the ureter and renal vasculature.

Renal Vasculature

The kidneys receive 1.2–1.3 l of blood per minute (about 25% of the cardiac output), making them highly vascular organs. After originating from the aorta, the renal artery enters the renal sinus and divides into the interlobar arteries, which extend towards the cortex in the spaces between the medullary pyramids. At the junction between the cortex and medulla, the interlobar arteries divide and pass over into the arcuate arteries. The arcuate arteries give rise to the interlobular arteries, which rise radially through the cortex. It is interesting to note that none of these arteries penetrates the medulla.

Afferent arterioles arise from the interlobular arteries and supply the glomerular tufts. The glomerular tufts are drained by the efferent arterioles, which then form the peritubular plexus and are of two types: cortical and juxtamedullary. The shorter cortical efferent arterioles arise from the superficial and midcortical nephrons and supply the cortex. The longer juxtamedullary efferent arterioles, which arise from the deeper nephrons, represent the sole blood supply to the medulla and are termed vasa recta. Whilst the descending vasa recta supply blood to the medulla, the ascending vasa recta drain it.

Glomerulus and Filtration across it

The glomerulus is the invagination of a tuft of capillaries into the dilated proximal end of the nephron called the Bowman's capsule (Figure 1.2). Supplied by the afferent and drained by the efferent arteriole, the glomerular capillary bunch is attached to the mesangium on the inner side and covered by the glomerular basement membrane (GBM) on the outer side. In a way, the GBM forms the skeleton of the glomeruli, with the podocytes (visceral epithelial cells with long foot processes) on the outer side and the capillaries and mesangium on the inner side. Thus, blood within the glomerular capillary is separated from the urinary space by endothelium, GBM, and podocyte.

Formation of urine begins with the filtration of blood from the glomerular capillaries. For this to happen blood...