KIDNEY STONES ---RECENT ADVANCES IN PATHOGENESIS AND PRACTICAL MANAGEMENT DR SANAJY GUPTA MD DM DNB Kidney stones are common

ailment , and affects approximately one in twenty perosons , although a significant proportion will remain asymptomatic. It is three times more common in males compared with females The difference between the sexes is gradually being eroded. This is thought to be due to lifestyle-associated factors, such as obesity and a Western diet. The peak age for developing stones is between 30 and 50 and recurrence is common

Risk factors
Several risk factors are recognised to increase the potential of a susceptible individual to develop stones. These include:

Anatomical anomalies in the kidneys and/or urinary tract, eg horseshoe kidney, ureteral stricture. Family history of renal stones. Hypertension. Gout. Hyperparathyroidism. Immobilisation. Relative dehydration. Metabolic disorders which increase excretion of solutes, eg chronic metabolic acidosis, hypercalciuria, hyperuricosuria. Deficiency of citrate in the urine. Cystinuria (an autosomal-recessive aminoaciduria). Drugs, eg diuretics such as triamterene and calcium/vitamin D supplements. More common occurrence in hot climates. Increased risk of stones in higher socio-economic groups. Being associated with the recent spate of melamine-contaminated infant milk formula.

A low fluid intake, with a subsequent low volume of urine production, produces high concentrations of stone-forming solutes in the urine. This is an important, if not the most important, environmental factor in kidney stone formation. The exact nature of the tubular damage or dysfunction that leads to stone formation has not been characterized. Most research on the etiology and prevention of urinary tract stone disease has been directed toward the role of elevated urinary levels of calcium, oxalate, and uric acid in stone formation, as well as reduced urinary citrate levels
Hypercalciuria is the most common metabolic abnormality. Some cases of hypercalciuria are related to increased intestinal absorption of calcium (associated with excess dietary calcium and/or overactive calcium absorption mechanisms), some are related to excess resorption of calcium from bone (ie, hyperparathyroidism), and some are related to an inability of the renal tubules to properly reclaim calcium in the glomerular filtrate (renal-leak hypercalciuria). Magnesium and especially citrate are important inhibitors of stone formation in the urinary tract. Decreased levels of these in the urine predispose to stone formation. The following are the 4 main

chemical types of renal calculi, which together are associated with more than 20 underlying etiologies:

Calcium stones, especially calcium oxalate make upto 80% of total renal calculi Struvite (magnesium ammonium phosphate) stones associated with infecion with urea splitting bacteria Uric acid stones associated with gout and metabolic syndrome Cystine stones- uncommon

Although kidney stone nephrolithiasis is perceived as an acute illness, there has been growing evidence that nephrolithiasis is a systemic disorder that may lead to end-stage renal disease ,it is also associated with an increased risk of hypertension, coronary artery disease, the metabolic syndrome , and diabetes mellitus. Numerous epidemiologic studies have shown that obesity, weight gain, and T2DM are associated with an increased risk of nephrolithiasis especially uric acid lithiasis . Over the past 10 years, major progress has been made in the pathogenesis of uric acid and calcium stones. These advances have led to our further understanding of a pathogenetic link between uric acid nephrolithiasis and the metabolic syndrome, the role of Oxalobacter formigenes in calcium oxalate stone formation, oxalate transport in Slc26a6-null mice, the potential pathogenetic role of Randall's plaque as a precursor for calcium oxalate nephrolithiasis, and the role of renal tubular crystal retention. With these advances, we may target the development of novel drugs including (1) insulin sensitizers; (2) probiotic therapy with O. formigenes, recombinant enzymes, or engineered bacteria; (3) treatments that involve the upregulation of intestinal luminal oxalate secretion by increasing anion transporter activity (Slc26a6), luminally active nonabsorbed agents, or oxalate binders; and (4) drugs that prevent the formation of Randall's plaque and/or renal tubular crystal adhesions. Stone analysis, together with serum and 24-hour urine metabolic evaluation, can identify an etiology in more than 95% of patients. Specific therapy can result in a remission rate of more than 80% and can decrease the individual recurrence rate by 90%. Therefore, physicians should stress the importance of urologic follow-up, especially in patients with recurrent stones, solitary kidneys, or previous kidney or stone surgery and in all children.

Etiologic Mechanisms of Uric Acid Stone Formation

Three major factors for the development of uric acid (UA) stones are low urine volume, acidic urine pH, and hyperuricosuria In humans and higher primates, UA is an end product of purine metabolism. Owing to their lack of the hepatic enzyme, uricase, which converts UA to soluble allantoin, their serum and urinary levels of UA are considerably higher than in other mammals.In humans with a urinary UA excretion of 600 mg/day, this should generally exceed the limit of solubility and susceptibility to precipitation. Moreover, urine pH is another important factor in UA solubility. UA is a weak organic acid with an ionization constant (pKa) of 5.5, Therefore, at a urine pH less than 5.5, the urinary environment becomes supersaturated with sparingly soluble, undissociated UA that precipitates to form UA stones

Potential Role of Renal Lipotoxicity

Under standard metabolic conditions, when caloric intake and caloric utilization are well balanced, triglycerides accumulate in adipocytes. A disequilibrium in this tight balance leads to the accumulation of fat to non-adipocyte tissues This process of fat redistribution, termed lipotoxicity, typically affects tissues such as cardiac myocardial cells, pancreatic -cells, skeletal muscle cells, and parenchymal liver cells.

one may propose a three-hit mechanism for the development of low urinary pH and the propensity for UA stone formation. The first mechanism is related to excessive dietary acid intake and/or increased endogenous acid production. However, this alone may not be sufficient in lowering urinary pH. Therefore, the second mechanism is associated with defective NH 4 + excretion. Together, these two defects lower urinary pH adequately enough to convert urate salt into undissociated UA. This is necessary but not sufficient for the formation of UA stones. Finally, the possible absence of inhibitors or presence of promoters of UA precipitation is operative in triggering UA stone formation

Calcium Oxalate Nephrolithiasis

Although it affects both genders, calcium oxalate nephrolithiasis generally tends to occur in more men than women. In the calcium oxalate stone former, urinary oxalate and urinary calcium are equally conducive in raising urinary calcium oxalate supersaturation. Hyperoxaluria is encountered in 8-50% of kidney stone formers. The main etiologic causes of hyperoxaluria can be classified into three groups: (1) increased oxalate production as a result of an inborn error in metabolism of the oxalate synthetic pathway, (2) increased substrate provision from dietary oxalate-rich foods or other oxalate precursors, and (3) increased intestinal oxalate absorption With the study of Oxalobacter formigenes (OF) and the role of putative anion transporter Slc26a6 as potential tools in the treatment of primary hyperoxaluria, our knowledge of the pathophysiologic mechanisms of oxalate metabolism has advanced significantly over the past decade

Randall's Plaque in the Pathogenesis of Calcium Oxalate Stones

Several mechanisms have been proposed for the formation of calcium stones. First, it has been suggested that the increased supersaturation of stone-forming salts are responsible for the process of homogenous nucleation in the lumen of the nephron. This process, followed by crystal growth, ultimately results in an obstruction in the distal nephron. Dr Alexander Randall was the first to argue that intraluminal plugging is an infrequent occurrence in kidney stone formers. Conversely, he suggested that interstitial calcium phosphate deposits are initial niduses that anchor urinary crystals beneath the normal uroepithelial cells of the renal papilla. The erosion of the overlying uroepithelium exposes these deposits, referred to as plaques, to the supersaturated urine that then propagate calcium oxalate stones. He found these lesions to be interstitial as opposed to intraluminal, and without any inflammatory reactions.

The Role of Renal Tubular Crystal Retention

Although the crystallization process is necessary, it alone is not sufficient for the formation of kidney stones. Three decades ago, it was initially proposed that the accumulation of crystals in the renal calices are involved in the pathogenesis of nephrolithiasis. It was further hypothesized that tubular nephrocalcinosis is preceded by renal stone formation. This scheme does not refute Randall's theory that interstitial nephrocalcinosis and plaque formation are precursors for the development of kidney stones. However, it has become increasingly recognized that both mechanisms may be significant in the formation of kidney stones

Presentation

Many stones are asymptomatic and discovered during investigations for other conditions. The classical features of renal colic (or ureteric colic) are sudden severe pain. It is usually caused by stones in the kidney, renal pelvis or ureter, causing dilatation, stretching and spasm of the ureter. o Pain starts in the loin about the level of the costovertebral angle (but sometimes lower) and moves to the groin, with tenderness of the loin or renal angle, sometimes with haematuria.

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If the stone is high and distends the renal capsule then pain will be in the flank but as it moves down pain will move anteriorly and down towards the groin. A stone that is moving is often more painful than a stone that is static. The pain radiates down to the testis, scrotum, labia or anterior thigh. Whereas the pain of biliary or intestinal colic is intermittent, the pain of renal colic is more constant but there are often periods of relief or just a dull ache before it returns. The pain may change as the stone moves. The patient is often able to point to the place of maximal pain and this has a good correlation with the current site of the stone.

Other symptoms which may be present include: Rigors and fever Dysuria Haematuria Urinary retention Nausea and vomiting Examination: o The patient with colic of any sort writhes around in agony. This is in contrast to the patient with peritoneal irritation who lies still. o The patient is apyrexial in uncomplicated renal colic (pyrexia suggests infection and the body temperature is usually very high with pyelonephritis). o Examination of the abdomen will usually reveal tenderness over the affected loin. Bowel sounds may be reduced. This is common with any severe pain. o There may be severe pain in the testis but the testis should not be tender. o Blood pressure may be low. o Full and thorough abdominal examination is essential to check for other possible diagnoses, eg acute appendicitis, ectopic pregnancy, aortic aneurysm.
o o o o o

Differential diagnosis[5]
This depends upon the position of the pain and the presence or absence of pyrexia and includes:

Biliary colic. Dissection of an aortic aneurysm: beware the patient who presents with features of renal colic for the first time over the age of 60. This may be dissection of aortic aneurysm leading to ruptured aortic aneurysm. Pyelonephritis: very high temperature. Pain is unlikely to radiate to the groin. Acute pancreatitis. Acute appendicitis. Perforated peptic ulcer. Epididymo-orchitis or torsion of testis: very tender testis. Sinister causes of back pain: usually tender over vertebrae.

Investigations

Basic analysis should include: o Stick testing of urine for red cells (suggestive of urolithiasis), white cells and nitrites (both suggestive of infection) and pH (pH above 7 suggests urea-splitting organisms such as Proteus spp. whilst a pH below 5 suggests uric acid stones).

Mid-stream specimen of urine for microscopy (pyuria suggests infection), culture and sensitivities. o Blood for FBC, CRP, renal function, electrolytes, calcium, phosphate and urate, creatinine. o Prothrombin time and international normalised ratio if intervention is planned. Non-enhanced CT scanning or MR urography, is now the imaging modality of choice and has replaced Intravenous pyelogram (IVP). Ultrasound scanning may be helpful to initially locate the stone and in detecting evidence of obstruction. Plain X-rays of the kidney, ureter and bladder (KUB) are useful in watching the passage of radio-opaque stones (around 75% of stones are of calcium and so will be radioopaque). The European Association of Urology's guidelines on urolithiasis recommend stone analysis for: o All first-time stone formers. o All patients with recurrent stones who are on pharmacological preventing therapy. o Patients who have had early recurrence after complete stone clearance. o Late recurrence after a long stone-free period (stone composition may change).
o

Encourage the patient to try to catch the stone for analysis. This may mean urinating through a tea strainer, filter paper such as a coffee filter or a gauze.

Management
Initial management can either be done as an inpatient or on an urgent outpatient basis, usually depending on how easily the pain can be controlled.

Indications for hospital admission: o Fever. o Solitary kidney. o Known non-functioning kidney. o Inadequate pain relief or persistent pain. o Inability to take adequate fluids due to nausea and vomiting. o Anuria. o Pregnancy. o Poor social support. o Inability to arrange urgent outpatient department follow-up. o People over the age of 60 years should be admitted if there are concerns on clinical condition or diagnostic certainty (a leaking aortic aneurysm may present with identical symptoms).

Initial management of acute presentation

Non-steroidal anti-inflammatory drugs (NSAIDs),and antispasmodics usually in the form of diclofenac IM or PR, should be offered first-line for the relief of the severe pain of renal colic. NSAIDs are more effective than opioids for this indication and have less tendency to cause nausea. Provide anti-emetics and rehydration therapy if needed. The majority of stones will pass spontaneously but may take 1-3 weeks; patients who have not passed a stone or who have continuing symptoms should have the progress of the stone monitored at a minimum of weekly intervals to assess the progression of the stone.

Conservative management may be continued for up to three weeks unless the patient is unable to manage the pain, or if he or she develops signs of infection or obstruction. Medical expulsive therapy may be used to facilitate the passage of the stone. It is useful in cases where there is no obvious reason for immediate surgical removal. Calciumchannel blockers (eg nifedipine) or alpha-blockers (eg tamsulosin) are given. A corticosteroid such as prednisolone is occasionally added when an alpha-blocker is used but should not be given as monotherapy, caution should be excercised if there is concurrent UTI

Surgical

Approximately 1 in 5 stones will not pass spontaneously and will require some form of intervention. If the ureter is blocked or could potentially become blocked, eg when a larger stone will fragment following other forms of therapy, a DJ stent is usually inserted using a cystoscope. It is a thin hollow tube with both ends coiled (pigtail). It is also used as a temporary holding measure, as it prevents the ureter from contracting and thus reduces pain, buying time until a more definitive measure can be undertaken. Procedures to remove stones include: o Extracorporeal shock wave lithotripsy (ESWL) - shock waves are directed over the stone to break it apart. The stone particles will then pass spontaneously. o Percutaneous nephrolithotomy (PCNL) - used for large stones (>2 cm), staghorn calculi and also cystine stones. Stones are removed at the time of the procedure using a nephroscope. o Ureteroscopy - this involves the use of laser to break up the stone and has an excellent success rate in experienced hands. o Open surgery - rarely necessary and usually reserved for complicated cases or for those in whom all of the above have failed, eg multiple stones.

Complications

Complete blockage of the urinary flow from a kidney decreases glomerular filtration rate (GFR) and, if it persists for more than 48 hours, may cause irreversible renal damage. If ureteric stones cause symptoms after four weeks, there is a 20% risk of complications, including deterioration of renal function, sepsis and ureteric stricture. Infection can be life-threatening. Persisting obstruction predisposes to pyelonephritis.

Prognosis

Most symptomatic renal stones are small (less than 5 mm in diameter) and pass spontaneously. Stones less than 5 mm in diameter pass spontaneously in up to 80% of people. Stones between 5 mm and 10 mm in diameter pass spontaneously in about 50% of people. Stones larger than 1 cm in diameter usually require intervention (urgent intervention is required if complete obstruction or infection is present). Two-thirds of stones that pass spontaneously will do so within four weeks of onset of symptoms. A stone that has not passed within 1-2 months is unlikely to pass spontaneously. The following features predispose to recurrent stone formation: o First attack before 25 years of age. o Single functioning kidney. o A disease that predisposes to stone formation.

Abnormalities of the renal tract.

Prevention
Recurrence of renal stones is common and therefore patients who have had a renal stone should be advised to adapt several lifestyle measures which will help to prevent or delay recurrence:

Increase fluid intake to maintain urine output at 2-3 litres per day. Reduce salt intake. Reduce the amount of meat and animal protein eaten. Reduce oxalate intake (foods rich in oxalate include chocolate, rhubarb, nuts) and uraterich foods (eg offal and certain fish). Drink regular cranberry juice: increases citrate excretion and reduces oxalate and phosphate excretion. Maintain calcium intake at normal levels (lowering intake increases excretion of calcium oxalate). Depending on the composition of the stone, medication to prevent further stone formation is sometimes given, eg thiazide diuretics (for calcium stones), allopurinol (for uric acid stones) and calcium citrate (for oxalate stones).