NEPHROLITHIASIS

Edward Nord MD

INTRODUCTION

The formation of a stone within the urinary tract represents a potential complication of many different diseases. In general, renal stones are composed of calcium salts, uric acid, cystine or struvite (MgNH₄PO₃) depending upon the major etiologic entity. Each type of stone has its own group of causes so that management of each entity is specific. However, all four types of renal stones share a common pathogenesis that is based essentially upon excessive supersaturation of the urine with a poorly soluble material. Renal stones grow upon the surfaces of the papillae, become detached and accompany the urine as it travels the collecting system. Since many of these stones are too large to negotiate the narrow conduits of the collecting system, they obstruct the flow of urine and often cause severe pain. Some stones are formed in the bladder, rather than in the kidney, but will not be considered here.

CLASSIFICATION OF RENAL STONES

There are five major categories of renal stones. Their relative propensities are detailed in Table I which represents reports on 1870 stones from four different series.

Calcium stones are clearly the most commonly occuring form of nephrolithiasis. Calcium oxalate stones are more common than calcium phosphate, but mixed calcium oxalate - calcium phosphate are the most common variety. Struvite stones, usually seen in the setting of urinary tract infections, is the second most common type of renal stone. Uric acid stones, cystine stones and oxalate stones represent a relatively minor proportion of total stones formed, but are important in that they need to be recognized and it is potentially feasible to prevent their formation.

Before discussing at farther length the important features of each subset of stones, theories pertaining to crystal formation, common to all types ofnephrolithiasis will be examined.

PATHOGENESIS OF RENAL STONES

Under steady-state conditions, the normal urine contains minimal quantities of cystals, which represents a delicate balance of a number of forces working in opposing directions' ( see Fig I)

The kidney on the one hand plays an important role in water conservation. At the same time, minerals with low solubility need to be excreted. Furthermore, urine contains

substances known to inhibit crystal formation, e.g.: citrate, and in the instance of calcium stones, substances that bind calcium. It is therefore not difficult to perceive how a pertubation in one or more of these aspects would enhance crystal formation. One simple example would be increased water conservation at the same time as larger quantities of minerals of low solubility are filtered at the level of the glomerulus. In addition, external factors, particularly diet, climate and physical activity will importantly influence the nature of the glomerulat filtrate. In summary, stone formation should be viewed as an imbalance in the factors that are operational under steady-state homeostasis. The physico- chemical factors involved in nephrolithiasis will now be allowed.

PHYSICO-CHEMICAL FACTORS INVOLVED IN STONE FORMATION Multiple theories east pertaining to the exact nature of crystal precipitation, growth and aggregation. While each theory has its proponents, it has been elusive to prove any particular one, since the sensitivity of the available assays to measure products ofsupersaturation are inadequate. A simplistic overview of the problem is illustrated in Fig. 2.

Critical to the formation of a crystal is the saturation state of that solution. This depends not only on solute concentration, but also on pH, ionic strength and the existence of soluble compexes. The lower portion of Fig. 2 depicts a condition where the solution is undersaturated with regard to specific solute. Under this condition crystals can neither form nor grow.

In fact any crystals already present will dissolve. With increasing concentration the saturation product, K_SP is reached when the solution is fully saturated with a specific solute. If the concentration of the solute is further increased, formation product K_FP is reached. The zone between K_SP and K_FP is termed the metastable zone. In this zone crystals of the specific solute will not form spontaneously, but they will grow and aggregate on previously formed crystals. Alternately, they will aggregate on nuclei of different substances which is termed heterogenous nucleation. An example of heterogenous nucleation would be the deposition of calcium phosphate on a calcium oxalate crystal. Deposition of calcium phosphate on a previously formed calcium phosphate crystal represents growth. As indicated above, crystal formation per se ie the initial central nidus, does not occur under metastable conditions.

Only once the concentration of the solute exceeds K_FP does the solution become unstable and spontaneous crystal nucleation occurs, (homogeneous nucleation). Under supersaturated conditions both homogenous and heterogenous nucleation occurs (Fig. 3). As a result crystal growth proceeds. Small crystals evolve into large crystals. Alternately, many small crystals aggregate to form crystal aggregates.

Given this general background each of the five groups of renal stones i.e. calcium salts, uric acid, cystine oxalate and struvite, will now be overviewed in greater detail.

PATHOPHYSIOLOGY OF CALCIUM STONES

Calcium stone formation is by far and away the most common type of nephtolithiasis encountered in clinical practice and accounts for about 71% of all stones analysed. Hypercalciuria is a frequent, but not universal finding. Of these individuals, a systemic or primary cause for the hypercalciuria can occasionally be documented. However, in the majority of cases of hypercalciuria (70-75%) no etiologic factor can be delineated, hence the term idiopathic hypercalciuria. Table II below lists the more common entities associated with hypercalciuna, but is by no means an exhaustive list.

A brief discussion pertaining to the pathophysiology of these entities follow. Emphasis will be placed on the idiopathic variety. Hypercalciuria is defined as >250 mg ofCa⁺⁺ per 24 hrs. in the urine of females, and >300 mg/24 hrs. for males.

I. I. Primary hyperparathyroidism.

Primary hyperparathyroidism is a hypercalcenuc condition in which parathyroid hormone (PTH) production and release are increased. An adenoma of one gland is the commonest pathological entity. Since this disease is surgically curable, emphasis should always be placed on delineating its existence.

The elevated PTH level affects both calcium and phosphate homeostasis. Hypercalcemia is due to increased delivery of calcium into the blood from intestine and bone and to increased renal calcium reabsopting resulting from stimulation by PTH in the distal nephron (Fig. 4A). Despite increased renal reabsorption of calcium, net calcium filtered is increased and hence hypercalcuria ensues. The high PTH level causes phosphaturia by decreasing renal tubule phosphate reabsorption (Fig. 4B). High serum PTH and low serum phosphate levels stimulate 1,25-(OH)* vitamin D which in turn stimulates intestinal calcium and phosphate reabsorption (Fig. 40 In summary, hypercalcemia is mediated via multiple mechanism, and the resultant increased filtration of calcium is a major factor in the pathogenesis of nephrolithiasis in this entity.

I. 2. Immobilization

Immobilization, particularly in adolescence with active bone growth may be complicated by severe hypercalcemla and hypercalciuria. The mechanism whereby immobilization results in skeletal calcium mobilization remains to be elucidated.

patients 1-25(OH)₂D₃ levels have been found to be elevated and much controversy exists regarding this observation. From the simplistic point of view this problem will not be examined in farther detail. Table 3 summarizes the more common observations.

In patients with absorptive hypercalciuria serum calcium falls during a low Ca²⁺ diet as would be seen in normal subjects. Concomitantly PTH levels and 1-25(OH)₂D₃ levels match those of control subjects on a similar diet. In summary, when patients with absorptive hypercalciuria are placed on a low Ca²⁺ diet serum {Ca²⁺}, PTH and 1-25(OH)₂D₃ levels revert to control values, thereby identifying the primary lesion as enhanced absorption of calcium by the intestine.

A second group of patients with idiopathic hypercalciuria fall into the category ofresorptive hypercalciuria. The primary entity, here is abnormal production of 1-25(OH)₂D₃ and subsequent effects on calcium homeostasis are all secondary. Bone mineral loss is a common feature of this entity hence the term "resorptive". Alternately, this entity has been termed 1-25(OH)₂D₃ - induced hypercalciuria.

Figure 6 depicts the sequence of events ø resorptive hypercalciuria. A primary increase in 1-25(OH)₂D₃ production results in increased Ca⁺⁺ reabsorption from the intestine. The resultant raised Ca²⁺ level will suppress PTH secretion. The elevated 1-25(OH)₂D₃ will also result in resorption of bone if dietary intake of calcium is suboptional. Note, therefore, that the divalent ion profile in absorptive and resortive hypercalciuria are indistinguishable (Table 3), on a calcium replete diet.

A low calcium diet readily distinguishes them since serum PTH level remains low,

1-25(OH)₂D₃ remains high, or at least higher than would be appropriate for the previously low value of PTH, and serum Ca²⁺ would not drop to levels seen normal controls.

A third group of patients with idiopathic hypercalciuria have "renal leak" hypercalciuria.

In this entity the primary event is an increased loss of calcium into the urine. The resultant decrease in serum Ca⁺⁺ provokes an increased secretion ofPTH, which distinguishes this entity from the two other forms of ideopathic hypercalciuria (Table 3). Note,

however, that the elevation in PTH level may be extremely modest and often difficult to detect. High PTH and low {Ca²⁺} would increase 1,25-(OH)₂D₃ production with subsequent increase in intestinal absorption of 'Ca²⁺. These events are depicted in Fig. 7. Note that the primary event in this cascade of events is an enhanced renal leak of calcium, with all subsequent pertubations being secondary.

Patients with a primary renal leak, when placed on low calcium diet continue to leak large amounts of calcium in the urine, which distinguishes them from the hyperabsorptive variety. Furthermore, on a low calcium diet, serum calcium levels fall even lower and PTH and 1,25-(OH)₂D₃ levels remain elevated.

It is evident, therefore, that the primary etiologic factor in the three idiopathic hypercalciurias is different i.e. primary increase in Ca⁺⁺ absortion by the intestine vs. primary increase in renal 1,25-(OH)₂D₃ vs. primary renal leak. In most cases the three entities can be separated as follows: a low calcium diet or provoking a calcium load. Much controversy exists regarding the optimal modality of therapy. For example, in the resorptive hypercalciuria where a primary increase in 1,25-(OH)₂D₃ occurs, decreasing dietary calcium would decrease intestinal absorption of calcium. However, 1,25-(OH)₂D₃ would continue reabsorbing calcium from the bone, in an attempt to keep up with the urinary calcium leak. Thiazide diuretics, which cause (a) volume contraction and (b) inhibition of calcium secretion into the distal tubule lumen is the commonest modality of therapy, although not always ideal. Hypercalciuria is decreased by decreasing the filtered load of calcium and Hunting calcium secretion.

II 2. Hyperuricosuria

Hyperuricosuria will be dealt with in a subsequent paragraph. However, the point to be made is that if uric acid crystals are present in the urine they may form a nidus for heterologous nucleation. It is not uncommon to find calcium oxalate stones in the setting of hyperuricosuria. Alternately, in patients with calcium oxalate stones, elevated levels of uric acid in the urine is not an uncommon event.

2. Renal tubular acidosis

For practical purposes, in the adult population renal tubular acidosis Is usually of the distal variety and commonly is associated with systemic diseases e.g. dysproteinenuas, SLE etc. In this entity the distal tubule is unable to lower urine pH below n 5.5, due to a defect in the luminal proton pumping mechanism. Calcium reabsorption is also impaired. Thus a combination of high ph. decreased calcium reabsorption and low urinary citrate (thought to inhibit calcium stone formation) results in supersaturation of urine with respect to calcium phosphate. Calcium phosphate stones are formed. Nephrocalcinosis i.e. deposition of calcium-containing particles within the renal parenchyma is common and may lead to decreased renal function.

PATHOPHYSIOLOGY OF URIC ACID STONES

Uric acid is derived from purines and nucleoproteins synthesised within the body and from dietary purines. (See Tig. 8). These stones form because the urine becomes supersaturated with uric acid. Frequently urinary pH is very low and at these low pH values (5.4 or below) undissociated uric acid is very insoluble.

As with calcium stones, ideopathic nephrolithiasis is the most common entity associated with uric acid stones. These patients do not have gout, nor any recognizable disorder of purine metabolism.

Typically serum uric acid is normal as is urinary uric acid excretion, although in some patients uric acid excretion is increased. Urinary pH is typically low, although the mechanism for this is poorly understood.

Approximately 25% of patients with gout have renal calculi. Although some patients with gout have hyperuricosuria, more commonly this is not the case. It is important to differentiate gout from idiopathic hyperuricemla, a common entity where serum uric acid level is modestly elevated but no crystal precipitation occurs in joints. Both idiopathic hyperuricemia and gout are easily treatable with xanthine oxidase inhibitors, notably allopurinol. Idiopathic hyperuricemia does not mandate therapy.

A pronounced increase in uric acid production, enhanced uricosuria, uric acid lithiasis and acute renal insufficiency are well described entities in myeloproliferative disorders where there is rapid tissue turnover. During chemotherapy and radiation therapy the incidence of this entity peaks. Judicious hydration, urine alkalinization and xanthine oxidase inhibitor therapy can obviate these problems in most instances.

PATHOPHYSIOLOCY OF CYSTINE STONES

Cystinuria is an inherited disorder of amino-acid transport expressed in the mucosa of the renal tubule and small intestine. Its pattern of inheritence is autosomal recessive. Cystine is produced endogenously from the metabolism of dietary methionine. Cystine, together with other anuno acids is filtered at the level of the glomerulus and the bulk is reabsorbed at the level of the proximal tubule. Secretion pathways for cystine from the periceHular capillaries into the cell and ultimately into the urine also exist. The different cystine transport pathways at the level of the renal proximal tubule are illustrated in Fig. 9.

A common pathway exists for cystine, lysine, arginine and ornithine and all four amino acids are therefore not absorbed.

However, cystine is least soluble of these amino acids and it alone is pathogenic. The cystine secretory pathway at the blood surface of the cell does not absorbed to be affected in cystinuria and therefore enhances the flux of cystine into the tubular lumen. The relatively insoluble cystine precipitates, particularly if the urine is acid and the stones thus formed may reach large proportions. Theoretically the quantity of cystine in

the urine can be reduced by a decrease in the methlonine intake (of little practical value), an increase in absorption of cystine or decreased in secretion or both (not currently possible) or by conversion of cystine to a soluble product. For this purpose D-pelucillamine is used which forms a disulphide reaction and the cystine- pemcillamine product is far more soluble in water than cystine alone. Increased fluid intake and maintaining an alkaline pH are added modalities.

PATHOPHYSIOLOGY OF OXALATE STONES.

Oxalic acid is an end product of ascorbic acid and glyoxalic acid metabolism in man. Modest to large amounts of these compounds are present in foods such as spinach, nuts, cocoa and tea. The calcium salt ofoxalate is extremely insoluble in aqueous solution. Increases in oxalate concentration have a greater influence on calcium oxalate solubility than do equimolat concentrations of calcium.

Primary hyperoxaluria is a rare inborn error of metabolism with malignant crystal and stone deposition resulting in end stage renal failure. Far more common and important are the acquired hyperoxulurias, invariably associated with various gastrointestinal disorders including, but not limited to jejunoileal bypass, Crohn's disease, enteric resection and chronic biliary and pancreatic diseases. (See table 5). In all of these entities oxalate hyperabsoprtion occurs. Absorption ofoxalate by the colon is thought to be passive and there are several reasons for the increased oxalate absorption. Èãë, the permeability of the colon to oxalate may be altered by the action ofluminal bile salts and fatty acids on the colonic mucosa. Second, with fat malabsorption, calcium in the bowel lumen is bound by fatty acids instead of precipitating with oxalate, which is left free for absorption. A third cause for hyperoxaluria in this setting is large intravenous doses of ascorbic acid, during implementation of total parenteral nutrition. As noted earlier, ascorbic acid is metabolised to oxalic acid under normal conditions and this pathway is enhanced with excess substrate.

As indicated earlier, hyperoaxaluria frequently accompanies hypercalcuria especially of the absorptive variety. The utility of calcium restriction in the diet is limited since it does not influence oxalaturia.

PATHOPHYSIOLOGY OF STRUVITE STONES

Struvite stones (magnesium ammonium phosphate) always occur in the setting of infection with bacterial organisms that produce urease and metabolize urea resulting in alkalinization of urine by the reaction discussed below. Proteus species are most commonly associated with struvite although some species of staphylococcus, klebsiella, pseudomonas, ureaplasma and even anaerobes produce urease. The chemical reactions leading to struvite stone formation are detailed in Fig. 10.

First urease degrades urea to ammonia and CO₂. The CO₂ hydrates to H₂CO₃ than dissociates to CO₃^2- which precipitates with calcium as CaCO₃. The ammonia hydrolyzes to NH₄⁺ (ammonium) which raises pH to 8 or 9. The ammonium precipitates PO₄^3- and Mg²⁺ to form the triple salt MgNH₄PO₄, or struvite. It is impossible to form struvite in urine that is not infected, because NH₄⁺ concentration is very low under normal circumstances. Accordingly, eradication of the infection is the key to the therapy of this entity.