Nephrology

SAN DIEGO — Olmesartan reduced the risk of microalbuminuria by 23% in normoalbuminuric patients with type 2 diabetes and at least one additional cardiovascular disease risk factor, results from a large European trial showed.

The angiotensin receptor blocker also yielded unprecedented blood pressure control for this population of patients.

Those are the first key findings from the Randomized Olmesartan and Diabetes Microalbuminuria Prevention (ROADMAP) study, which were unveiled during a press briefing at the annual meeting of the American Society of Nephrology.

“Despite all of our efforts, we still have problems effectively treating diabetic nephropathy,” said the study's steering committee chair, Dr. Hermann G. Haller of the department of nephrology at Hannover (Germany) Medical School. “The problem for prevention is that we have to diagnose and treat it early. Microalbuminuria is the first sign of the pathogenesis of diabetic nephropathy. It is also an important marker of early development of cardiovascular disease and can indicate microvascular disease.”

The primary end point of the study was the occurrence of microalbuminuria based on two or more positive morning spot urine measurements. Secondary end points were cardiovascular events, renal function, and microvascular morbidity.

With support from Daiichi Sankyo, which markets olmesartan, researchers in 19 countries enrolled 4,449 patients, aged 18-75 years, with well-controlled type 2 diabetes. All patients were normoalbuminuric (defined as a level of 25 mg/g or less for men and 35 mg/g or less for women) and had at lease one additional cardiovascular risk factor, such as high triglyceride levels or hypertension. None of the participants had received an ACE inhibitor or an angiotensin receptor blocker within 6 months of participation.

The patients were randomized to receive either 40 mg olmesartan per day or placebo (conventional antihypertensive treatment without blockade of the renin-angiotensin system). The urine albumin- creatinine ratio was determined every 6 months. Patients were followed for an average of 3.2 years.

At their discretion, study investigators could add calcium channel blockers, diuretics, or beta-blockers to the regimen to help patients achieve the target blood pressure goal of 130/80 mm Hg.

The patients' mean age was 58 years, mean duration of diabetes was 6 years, mean hemoglobin A_1c level was 7.6%, and mean body mass index was 31 kg/m

Dr. Haller reported that nearly 80% of patients in the olmesartan group reached the target BP of 130/80 mm Hg at 42 months, compared with about 75% of patients in the placebo group. “The percentage of patients reaching the blood pressure goal was very high,” he said. “ROADMAP will need further analysis to find out what this high percentage of control actually means.”

Over the study period, microalbuminuria occurred in about 8% of the patients in the olmesartan group and 10% of the patients in the placebo group, a statistically significant difference (hazard ratio 0.77). This translated into a risk reduction of 23% for the olmesartan group, compared with the placebo group.

After 1 year, the first incidence of microalbuminuria occurred in about 3% of patients in both groups. For the remainder of the study, fewer patients in the olmesartan group experienced microalbuminuria, compared with patients in the placebo group. “The divergence after 1 year indicates that the specific effects of olmesartan are not due to early hemodynamic changes that would have happened in the first couple of months,” Dr. Haller said in an interview. “We think that olmesartan has a specific, perhaps structural effect on the kidney, either in the glomeruli or in the basal membrane, in the microcirculation.”

Dr. Haller disclosed that he has received honoraria and is a paid consultant for several pharmaceutical companies, including Daiichi Sankyo.

SAN DIEGO — Olmesartan reduced the risk of microalbuminuria by 23% in normoalbuminuric patients with type 2 diabetes and at least one additional cardiovascular disease risk factor, results from a large European trial showed.

The angiotensin receptor blocker also yielded unprecedented blood pressure control for this population of patients.

Those are the first key findings from the Randomized Olmesartan and Diabetes Microalbuminuria Prevention (ROADMAP) study, which were unveiled during a press briefing at the annual meeting of the American Society of Nephrology.

“Despite all of our efforts, we still have problems effectively treating diabetic nephropathy,” said the study's steering committee chair, Dr. Hermann G. Haller of the department of nephrology at Hannover (Germany) Medical School. “The problem for prevention is that we have to diagnose and treat it early. Microalbuminuria is the first sign of the pathogenesis of diabetic nephropathy. It is also an important marker of early development of cardiovascular disease and can indicate microvascular disease.”

The primary end point of the study was the occurrence of microalbuminuria based on two or more positive morning spot urine measurements. Secondary end points were cardiovascular events, renal function, and microvascular morbidity.

With support from Daiichi Sankyo, which markets olmesartan, researchers in 19 countries enrolled 4,449 patients, aged 18-75 years, with well-controlled type 2 diabetes. All patients were normoalbuminuric (defined as a level of 25 mg/g or less for men and 35 mg/g or less for women) and had at lease one additional cardiovascular risk factor, such as high triglyceride levels or hypertension. None of the participants had received an ACE inhibitor or an angiotensin receptor blocker within 6 months of participation.

The patients were randomized to receive either 40 mg olmesartan per day or placebo (conventional antihypertensive treatment without blockade of the renin-angiotensin system). The urine albumin- creatinine ratio was determined every 6 months. Patients were followed for an average of 3.2 years.

At their discretion, study investigators could add calcium channel blockers, diuretics, or beta-blockers to the regimen to help patients achieve the target blood pressure goal of 130/80 mm Hg.

The patients' mean age was 58 years, mean duration of diabetes was 6 years, mean hemoglobin A_1c level was 7.6%, and mean body mass index was 31 kg/m

Dr. Haller reported that nearly 80% of patients in the olmesartan group reached the target BP of 130/80 mm Hg at 42 months, compared with about 75% of patients in the placebo group. “The percentage of patients reaching the blood pressure goal was very high,” he said. “ROADMAP will need further analysis to find out what this high percentage of control actually means.”

Over the study period, microalbuminuria occurred in about 8% of the patients in the olmesartan group and 10% of the patients in the placebo group, a statistically significant difference (hazard ratio 0.77). This translated into a risk reduction of 23% for the olmesartan group, compared with the placebo group.

After 1 year, the first incidence of microalbuminuria occurred in about 3% of patients in both groups. For the remainder of the study, fewer patients in the olmesartan group experienced microalbuminuria, compared with patients in the placebo group. “The divergence after 1 year indicates that the specific effects of olmesartan are not due to early hemodynamic changes that would have happened in the first couple of months,” Dr. Haller said in an interview. “We think that olmesartan has a specific, perhaps structural effect on the kidney, either in the glomeruli or in the basal membrane, in the microcirculation.”

Dr. Haller disclosed that he has received honoraria and is a paid consultant for several pharmaceutical companies, including Daiichi Sankyo.

SAN DIEGO — Olmesartan reduced the risk of microalbuminuria by 23% in normoalbuminuric patients with type 2 diabetes and at least one additional cardiovascular disease risk factor, results from a large European trial showed.

The angiotensin receptor blocker also yielded unprecedented blood pressure control for this population of patients.

Those are the first key findings from the Randomized Olmesartan and Diabetes Microalbuminuria Prevention (ROADMAP) study, which were unveiled during a press briefing at the annual meeting of the American Society of Nephrology.

“Despite all of our efforts, we still have problems effectively treating diabetic nephropathy,” said the study's steering committee chair, Dr. Hermann G. Haller of the department of nephrology at Hannover (Germany) Medical School. “The problem for prevention is that we have to diagnose and treat it early. Microalbuminuria is the first sign of the pathogenesis of diabetic nephropathy. It is also an important marker of early development of cardiovascular disease and can indicate microvascular disease.”

The primary end point of the study was the occurrence of microalbuminuria based on two or more positive morning spot urine measurements. Secondary end points were cardiovascular events, renal function, and microvascular morbidity.

With support from Daiichi Sankyo, which markets olmesartan, researchers in 19 countries enrolled 4,449 patients, aged 18-75 years, with well-controlled type 2 diabetes. All patients were normoalbuminuric (defined as a level of 25 mg/g or less for men and 35 mg/g or less for women) and had at lease one additional cardiovascular risk factor, such as high triglyceride levels or hypertension. None of the participants had received an ACE inhibitor or an angiotensin receptor blocker within 6 months of participation.

The patients were randomized to receive either 40 mg olmesartan per day or placebo (conventional antihypertensive treatment without blockade of the renin-angiotensin system). The urine albumin- creatinine ratio was determined every 6 months. Patients were followed for an average of 3.2 years.

At their discretion, study investigators could add calcium channel blockers, diuretics, or beta-blockers to the regimen to help patients achieve the target blood pressure goal of 130/80 mm Hg.

The patients' mean age was 58 years, mean duration of diabetes was 6 years, mean hemoglobin A_1c level was 7.6%, and mean body mass index was 31 kg/m

Dr. Haller reported that nearly 80% of patients in the olmesartan group reached the target BP of 130/80 mm Hg at 42 months, compared with about 75% of patients in the placebo group. “The percentage of patients reaching the blood pressure goal was very high,” he said. “ROADMAP will need further analysis to find out what this high percentage of control actually means.”

Over the study period, microalbuminuria occurred in about 8% of the patients in the olmesartan group and 10% of the patients in the placebo group, a statistically significant difference (hazard ratio 0.77). This translated into a risk reduction of 23% for the olmesartan group, compared with the placebo group.

After 1 year, the first incidence of microalbuminuria occurred in about 3% of patients in both groups. For the remainder of the study, fewer patients in the olmesartan group experienced microalbuminuria, compared with patients in the placebo group. “The divergence after 1 year indicates that the specific effects of olmesartan are not due to early hemodynamic changes that would have happened in the first couple of months,” Dr. Haller said in an interview. “We think that olmesartan has a specific, perhaps structural effect on the kidney, either in the glomeruli or in the basal membrane, in the microcirculation.”

Dr. Haller disclosed that he has received honoraria and is a paid consultant for several pharmaceutical companies, including Daiichi Sankyo.

Although diabetes is the most common cause of end-stage renal disease (ESRD) worldwide, accounting for 44.2% of ESRD patients in the US Renal Data System in 2005,¹ data are scarce on how diabetes should best be treated in patients in ESRD.

We do know that blood glucose levels need to be well controlled in these patients. Several observational studies and one nonrandomized interventional study^2–10 showed that higher levels of hemoglobin A_1c were associated with higher death rates in patients with diabetes and chronic kidney disease after adjusting for markers of inflammation and malnutrition.

However, ESRD significantly alters glycemic control, the results of hemoglobin A_1c testing, and the excretion of antidiabetic medications. The various and opposing effects of ESRD and dialysis can make blood glucose levels fluctuate widely, placing patients at risk of hypoglycemia—and presenting a challenge for nephrologists and internists.

In this review, we summarize the available evidence and make practical recommendations for managing diabetes in patients on hemodialysis.

GLUCOSE LEVELS MAY FLUCTUATE WIDELY

In ESRD, both uremia and dialysis can complicate glycemic control by affecting the secretion, clearance, and peripheral tissue sensitivity of insulin.

Several factors, including uremic toxins, may increase insulin resistance in ESRD, leading to a blunted ability to suppress hepatic gluconeogenesis and regulate peripheral glucose utilization. In type 2 diabetes without kidney disease, insulin resistance leads to increased insulin secretion. This does not occur in ESRD because of concomitant metabolic acidosis, deficiency of 1,25 dihydroxyvitamin D, and secondary hyperparathyroidism.^11,12 Hemodialysis further alters insulin secretion, clearance, and resistance as the result of periodic improvement in uremia, acidosis, and phosphate handling.

The dextrose concentration in the dialysate can also affect glucose control. In general, dialysates with lower dextrose concentrations are used and may be associated with hypoglycemia. Conversely, dialysates with higher dextrose concentrations are occasionally used in peritoneal dialysis to increase ultrafiltration, but this can lead to hyperglycemia.^10,13

Thus, ESRD and hemodialysis exert opposing forces on insulin secretion, action, and metabolism, often creating unpredictable serum glucose values. For example, one would think that a patient who has insulin resistance would need more supplemental insulin; however, the reduced renal gluconeogenesis and insulin clearance seen in ESRD may result in variable net effects in different patients. In addition, ESRD and hemodialysis alter the pharmacokinetics of diabetic medications. Together, all of these factors contribute to wide fluctuations in glucose levels and increase the risk of hypoglycemic events.

HEMOGLOBIN A_1c MAY BE FALSELY HIGH

Self-monitoring of blood glucose plus serial hemoglobin A_1c measurements are the standard of care in diabetic patients without renal failure.

However, in diabetic patients with ESRD, elevated blood urea nitrogen causes formation of carbamylated hemoglobin, which is indistinguishable from glycosylated hemoglobin by electrical-charge-based assays and can cause the hemoglobin A_1c measurement to be falsely elevated. Other factors such as the shorter red life span of red blood cells, iron deficiency, recent transfusion, and use of erythropoietin-stimulating agents may also cause underestimation of glucose control.¹⁴

Despite these limitations, the hemoglobin A_1c level is considered a reasonable measure of glycemic control in ESRD. Glycated fructosamine and albumin are other measures of glycemic control with some advantages over hemoglobin A_1c in dialysis patients. However, they are not readily available and can be affected by conditions that alter protein metabolism, including ESRD.^15–18

Self-monitoring of blood glucose and continuous glucose monitoring systems provide real-time assessments of glycemic control, but both have limitations. Self-monitoring is subject to errors from poor technique, problems with the meters and strips, and lower sensitivity in measuring low blood glucose levels. Continuous monitoring is expensive and is less reliable at lower glucose concentrations, and thus it needs to be used in conjunction with other measures of glucose control. For these reasons, continuous glucose monitoring is not yet widely used.

The guidelines of the 2005 National Kidney Foundation Kidney Disease Outcomes Quality Initiative did not clearly establish a target hemoglobin A_1c level for patients with diabetes and ESRD, but levels of 6% to 7% appear to be safe. The target fasting plasma glucose level should be lower than 140 mg/dL, and the target postprandial glucose level should be lower than 200 mg/dL.¹⁹

 

 

MOST ORAL DIABETES DRUGS ARE CONTRAINDICATED IN ESRD

Oral antihyperglycemic drugs include the insulin secretagogues (sulfonylureas and meglitinides), biguanides, thiazolidinediones, and alpha-glucosidase inhibitors (Table 1). Most of these drugs are contraindicated in ESRD.

Sulfonylureas

Sulfonylureas reduce blood glucose by stimulating the pancreatic beta cells to increase insulin secretion.

Sulfonylureas have a wide volume of distribution and are highly protein-bound,²⁰ but only the unbound drug exerts a clinical effect. Because of protein binding, dialysis cannot effectively clear elevated levels of sulfonylurea drugs. Furthermore, many ESRD patients take drugs such as salicylates, sulfonamides, vitamin K antagonists, beta-blockers, and fibric acid derivatives, which may displace sulfonylureas from albumin, thus increasing the risk of severe hypoglycemia.

The first-generation sulfonylureas—chlorpropamide (Diabinese), acetohexamide (Dymelor), tolbutamide (Orinase), and tolazamide (Tolinase)—are almost exclusively excreted by the kidney and are therefore contraindicated in ESRD.²¹ Second-generation agents include glipizide (Glucotrol), glimepiride (Amaryl), glyburide (Micronase), and gliclazide (not available in the United States). Although these drugs are metabolized in the liver, their active metabolites are excreted in the urine, and so they should be avoided in ESRD.²²

The only sulfonylurea recommended in ESRD is glipizide, which is also metabolized in the liver but has inactive or weakly active metabolites excreted in the urine. The suggested dose of glipizide is 2.5 to 10 mg/day. In ESRD, sustained-release forms should be avoided because of concerns of hypoglycemia.²³

Meglitinides

The meglitinides repaglinide (Prandin) and nateglinide (Starlix) are insulin secretagogues that stimulate pancreatic beta cells. Like the sulfonylureas, nateglinide is hepatically metabolized, with renal excretion of active metabolites. Repaglinide, in contrast, is almost completely converted to inactive metabolites in the liver, and less than 10% is excreted by the kidneys.^24,25 The meglitinides still pose a risk of hypoglycemia, especially in ESRD, and hence are not recommended for patients on hemodialysis.^24,25

Biguanides

Metformin (Glucophage) is a biguanide that reduces hepatic gluconeogenesis and glucose output. It is excreted essentially unchanged in the urine and is therefore contraindicated in patients with renal disease due to the risks of bioaccumulation and lactic acidosis.²²

Thiazolidinediones

The thiazolidinediones rosiglitazone (Avandia) and pioglitazone (Actos) are highly potent, selective agonists that work by binding to and activating a nuclear transcription factor, specifically, peroxisome proliferator-activated receptor gamma (PPAR-gamma). These drugs do not bioaccumulate in renal failure and so do not need dosing adjustments.²⁶

The main adverse effect of these agents is edema, especially when they are combined with insulin therapy. Because of this effect, a joint statement of the American Diabetes Association and the American Heart Association recommends avoiding thiazolidinediones in patients in New York Heart Association (NYHA) class III or IV heart failure.²⁷ Furthermore, caution is required in patients in compensated heart failure (NYHA class I or II) or in those at risk of heart failure, such as patients with previous myocardial infarction or angina, hypertension, left ventricular hypertrophy, significant aortic or mitral valve disease, age greater than 70 years, or diabetes for more than 10 years.²⁷

In summary, although ESRD and dialysis do not affect the metabolism of thiazolidinediones, these agents are not recommended in ESRD because of the associated risk of fluid accumulation and precipitation of heart failure.

Alpha-glucosidase inhibitors

The alpha-glucosidase inhibitors acarbose (Precose) and miglitol (Glyset) slow carbohydrate absorption from the intestine. The levels of these drugs and their active metabolites are higher in renal failure,²² and since data are scarce on the use of these drugs in ESRD, they are contraindicated in ESRD.

GLP-1 ANALOGUES AND ‘GLIPTINS,’ NEW CLASSES OF DRUGS

Glucagon-like peptide-1 (GLP-1) stimulates glucose-dependent insulin release from pancreatic beta cells and inhibits inappropriate postprandial glucagon release. It also slows gastric emptying and reduces food intake. Dipeptidyl peptidase IV (DPP-IV) is an active ubiquitous enzyme that deactivates a variety of bioactive peptides, including GLP-1.

Exenatide (Byetta) is a naturally occurring GLP-1 analogue that is resistant to degradation by DPP-IV and has a longer half-life. Given subcutaneously, exenatide undergoes minimal systemic metabolism and is excreted in the urine.

No dose adjustment is required if the glomerular filtration rate (GFR) is greater than 30 mL/min, but exenatide is contraindicated in patients undergoing hemodialysis or in patients who have a GFR less than 30 mL/min (Table 1).

Sitagliptin (Januvia) is a DPP-IV inhibitor, or “gliptin,” that can be used as initial pharmacologic therapy for type 2 diabetes, as a second agent in those who do not respond to a single agent such as a sulfonylurea,²⁸ metformin,^29–31 or a thiazolidinedione,³² and as an additional agent when dual therapy with metformin and a sulfonylurea does not provide adequate glycemic control.²⁸ Sitagliptin is not extensively metabolized and is mainly excreted in the urine.

The usual dose of sitagliptin is 100 mg orally once daily, with reduction to 50 mg for patients with a GFR of 30 to 50 mL/min, and 25 mg for patients with a GFR less than 30 mL/min.³³ Sitagliptin may be used at doses of 25 mg daily in ESRD, irrespective of dialysis timing (Table 1).

Other drugs of this class are being developed. Saxagliptin (Onglyza) was recently approved by the US Food and Drug Administration and can be used at a dosage of 2.5 mg daily after dialysis.

Sitagliptin has been associated with gastrointestinal adverse effects. Anaphylaxis, angioedema, and Steven-Johnson syndrome have been reported. The risk of hypoglycemia increases when sitagliptin is used with sulfonylureas.

 

 

ESRD REDUCES INSULIN CLEARANCE

In healthy nondiabetic people, the pancreatic beta cells secrete half of the daily insulin requirement (about 0.5 units/kg/day) at a steady basal rate independent of glucose levels. The other half is secreted in response to prandial glucose stimulation.

Secreted into the portal system, insulin passes through the liver, where about 75% is metabolized, with the remaining 25% metabolized by the kidneys. About 60% of the insulin in the arterial bed is filtered by the glomerulus, and 40% is actively secreted into the nephric tubules.³⁴ Most of the insulin in the tubules is metabolized into amino acids, and only 1% of insulin is secreted intact.

For diabetic patients receiving exogenous insulin, renal metabolism plays a more significant role since there is no first-pass metabolism in the liver. As renal function starts to decline, insulin clearance does not change appreciably, due to compensatory peritubular insulin uptake.³⁵ But once the GFR drops below 20 mL/min, the kidneys clear markedly less insulin, an effect compounded by a decrease in the hepatic metabolism of insulin that occurs in uremia.³⁶ Thus, despite the increase in insulin resistance caused by renal failure, the net effect is a reduced requirement for exogenous insulin in ESRD.³⁷

A variety of insulin preparations are available, including rapid-acting, intermediate-acting, and long-acting forms and premixed combinations, each with its specific onset, peak, and duration of action (Table 2). To our knowledge, no study of neutral protamine Hagedorn (NPH) insulin or other long-acting insulins has been done in patients with ESRD, and very few studies have described the use of insulin analogues in ESRD.

Aisenpreis et al³⁸ showed that the pharmacokinetic profile of insulin lispro (Humalog), which has a short onset of action and a short duration of action, may not only facilitate the correction of hyperglycemia but may also decrease the risk of late hypoglycemic episodes, which is of increased relevance in hemodialysis patients.

On the basis of the available evidence,^39,40 we recommend a long-acting insulin such as insulin glargine (Lantus) or NPH insulin for basal requirements, along with a rapid-acting insulin analogue such as lispro or insulin aspart (NovoLog) before meals two or three times daily.

When the GFR drops to between 10 and 50 mL/min, the total insulin dose should be reduced by 25%; once the filtration rate is below 10 mL/min, as in ESRD, the insulin dose should be decreased by 50% from the previous amount.^41,42

The newer insulins such as glargine and lispro are more favorable than NPH and regular insulin, but they cost more, which can be an obstacle for some patients.

OBSERVATIONS AND RECOMMENDATIONS

After reviewing the available evidence for the use of diabetic therapy in ESRD, we offer the following observations and recommendations:

• Glycemic control and monitoring in ESRD are complex.
• Patients with ESRD are especially susceptible to hypoglycemia, so diabetic drug therapy requires special caution.
• ESRD patients need ongoing diabetes education, with an emphasis on how to recognize and treat hypoglycemia.
• Diabetic pharmacotherapy in ESRD should be individualized. The targets of therapy are a hemoglobin A_1c value between 6% and 7%, a fasting blood glucose level less than 140 mg/dL, and a postprandial glucose level less than 200 mg/dL.
• Of the oral antidiabetic drugs available, glipizide, sitagliptin, and saxagliptin may be used in ESRD. Glipizide, starting with 2.5 mg daily, should be reserved for ESRD patients with a hemoglobin A_1c value less than 8.5%.
• Thiazolidinediones may cause fluid overload and thus should be avoided in ESRD.
• We recommend a long-acting insulin (glargine or NPH) for basal requirements, along with rapid-acting insulin before meals two or three times daily.
• The newer basal insulin (glargine) and rapid-acting insulin analogues (lispro or aspart insulin) are more favorable than NPH and regular insulin, but their higher cost could be an issue.
• Some patients may prefer a premixed insulin combination for convenience of dosing. In that case, NPH plus lispro insulin may be better than NPH plus regular insulin.
• For ESRD patients with type 1 diabetes, insulin therapy should be started at 0.5 IU/kg, which is half the calculated dose in patients without renal failure.
• For ESRD patients with type 2 diabetes, insulin therapy should be started at a total daily dose of 0.25 IU/kg.
• Further adjustments to the regimen should be individualized based on self-monitored blood glucose patterns.
• We recommend consulting an endocrinologist with expertise in managing diabetes in ESRD.

Although diabetes is the most common cause of end-stage renal disease (ESRD) worldwide, accounting for 44.2% of ESRD patients in the US Renal Data System in 2005,¹ data are scarce on how diabetes should best be treated in patients in ESRD.

We do know that blood glucose levels need to be well controlled in these patients. Several observational studies and one nonrandomized interventional study^2–10 showed that higher levels of hemoglobin A_1c were associated with higher death rates in patients with diabetes and chronic kidney disease after adjusting for markers of inflammation and malnutrition.

However, ESRD significantly alters glycemic control, the results of hemoglobin A_1c testing, and the excretion of antidiabetic medications. The various and opposing effects of ESRD and dialysis can make blood glucose levels fluctuate widely, placing patients at risk of hypoglycemia—and presenting a challenge for nephrologists and internists.

In this review, we summarize the available evidence and make practical recommendations for managing diabetes in patients on hemodialysis.

GLUCOSE LEVELS MAY FLUCTUATE WIDELY

In ESRD, both uremia and dialysis can complicate glycemic control by affecting the secretion, clearance, and peripheral tissue sensitivity of insulin.

Several factors, including uremic toxins, may increase insulin resistance in ESRD, leading to a blunted ability to suppress hepatic gluconeogenesis and regulate peripheral glucose utilization. In type 2 diabetes without kidney disease, insulin resistance leads to increased insulin secretion. This does not occur in ESRD because of concomitant metabolic acidosis, deficiency of 1,25 dihydroxyvitamin D, and secondary hyperparathyroidism.^11,12 Hemodialysis further alters insulin secretion, clearance, and resistance as the result of periodic improvement in uremia, acidosis, and phosphate handling.

The dextrose concentration in the dialysate can also affect glucose control. In general, dialysates with lower dextrose concentrations are used and may be associated with hypoglycemia. Conversely, dialysates with higher dextrose concentrations are occasionally used in peritoneal dialysis to increase ultrafiltration, but this can lead to hyperglycemia.^10,13

Thus, ESRD and hemodialysis exert opposing forces on insulin secretion, action, and metabolism, often creating unpredictable serum glucose values. For example, one would think that a patient who has insulin resistance would need more supplemental insulin; however, the reduced renal gluconeogenesis and insulin clearance seen in ESRD may result in variable net effects in different patients. In addition, ESRD and hemodialysis alter the pharmacokinetics of diabetic medications. Together, all of these factors contribute to wide fluctuations in glucose levels and increase the risk of hypoglycemic events.

HEMOGLOBIN A_1c MAY BE FALSELY HIGH

Self-monitoring of blood glucose plus serial hemoglobin A_1c measurements are the standard of care in diabetic patients without renal failure.

However, in diabetic patients with ESRD, elevated blood urea nitrogen causes formation of carbamylated hemoglobin, which is indistinguishable from glycosylated hemoglobin by electrical-charge-based assays and can cause the hemoglobin A_1c measurement to be falsely elevated. Other factors such as the shorter red life span of red blood cells, iron deficiency, recent transfusion, and use of erythropoietin-stimulating agents may also cause underestimation of glucose control.¹⁴

Despite these limitations, the hemoglobin A_1c level is considered a reasonable measure of glycemic control in ESRD. Glycated fructosamine and albumin are other measures of glycemic control with some advantages over hemoglobin A_1c in dialysis patients. However, they are not readily available and can be affected by conditions that alter protein metabolism, including ESRD.^15–18

Self-monitoring of blood glucose and continuous glucose monitoring systems provide real-time assessments of glycemic control, but both have limitations. Self-monitoring is subject to errors from poor technique, problems with the meters and strips, and lower sensitivity in measuring low blood glucose levels. Continuous monitoring is expensive and is less reliable at lower glucose concentrations, and thus it needs to be used in conjunction with other measures of glucose control. For these reasons, continuous glucose monitoring is not yet widely used.

The guidelines of the 2005 National Kidney Foundation Kidney Disease Outcomes Quality Initiative did not clearly establish a target hemoglobin A_1c level for patients with diabetes and ESRD, but levels of 6% to 7% appear to be safe. The target fasting plasma glucose level should be lower than 140 mg/dL, and the target postprandial glucose level should be lower than 200 mg/dL.¹⁹

 

 

MOST ORAL DIABETES DRUGS ARE CONTRAINDICATED IN ESRD

Oral antihyperglycemic drugs include the insulin secretagogues (sulfonylureas and meglitinides), biguanides, thiazolidinediones, and alpha-glucosidase inhibitors (Table 1). Most of these drugs are contraindicated in ESRD.

Sulfonylureas

Sulfonylureas reduce blood glucose by stimulating the pancreatic beta cells to increase insulin secretion.

Sulfonylureas have a wide volume of distribution and are highly protein-bound,²⁰ but only the unbound drug exerts a clinical effect. Because of protein binding, dialysis cannot effectively clear elevated levels of sulfonylurea drugs. Furthermore, many ESRD patients take drugs such as salicylates, sulfonamides, vitamin K antagonists, beta-blockers, and fibric acid derivatives, which may displace sulfonylureas from albumin, thus increasing the risk of severe hypoglycemia.

The first-generation sulfonylureas—chlorpropamide (Diabinese), acetohexamide (Dymelor), tolbutamide (Orinase), and tolazamide (Tolinase)—are almost exclusively excreted by the kidney and are therefore contraindicated in ESRD.²¹ Second-generation agents include glipizide (Glucotrol), glimepiride (Amaryl), glyburide (Micronase), and gliclazide (not available in the United States). Although these drugs are metabolized in the liver, their active metabolites are excreted in the urine, and so they should be avoided in ESRD.²²

The only sulfonylurea recommended in ESRD is glipizide, which is also metabolized in the liver but has inactive or weakly active metabolites excreted in the urine. The suggested dose of glipizide is 2.5 to 10 mg/day. In ESRD, sustained-release forms should be avoided because of concerns of hypoglycemia.²³

Meglitinides

The meglitinides repaglinide (Prandin) and nateglinide (Starlix) are insulin secretagogues that stimulate pancreatic beta cells. Like the sulfonylureas, nateglinide is hepatically metabolized, with renal excretion of active metabolites. Repaglinide, in contrast, is almost completely converted to inactive metabolites in the liver, and less than 10% is excreted by the kidneys.^24,25 The meglitinides still pose a risk of hypoglycemia, especially in ESRD, and hence are not recommended for patients on hemodialysis.^24,25

Biguanides

Metformin (Glucophage) is a biguanide that reduces hepatic gluconeogenesis and glucose output. It is excreted essentially unchanged in the urine and is therefore contraindicated in patients with renal disease due to the risks of bioaccumulation and lactic acidosis.²²

Thiazolidinediones

The thiazolidinediones rosiglitazone (Avandia) and pioglitazone (Actos) are highly potent, selective agonists that work by binding to and activating a nuclear transcription factor, specifically, peroxisome proliferator-activated receptor gamma (PPAR-gamma). These drugs do not bioaccumulate in renal failure and so do not need dosing adjustments.²⁶

The main adverse effect of these agents is edema, especially when they are combined with insulin therapy. Because of this effect, a joint statement of the American Diabetes Association and the American Heart Association recommends avoiding thiazolidinediones in patients in New York Heart Association (NYHA) class III or IV heart failure.²⁷ Furthermore, caution is required in patients in compensated heart failure (NYHA class I or II) or in those at risk of heart failure, such as patients with previous myocardial infarction or angina, hypertension, left ventricular hypertrophy, significant aortic or mitral valve disease, age greater than 70 years, or diabetes for more than 10 years.²⁷

In summary, although ESRD and dialysis do not affect the metabolism of thiazolidinediones, these agents are not recommended in ESRD because of the associated risk of fluid accumulation and precipitation of heart failure.

Alpha-glucosidase inhibitors

The alpha-glucosidase inhibitors acarbose (Precose) and miglitol (Glyset) slow carbohydrate absorption from the intestine. The levels of these drugs and their active metabolites are higher in renal failure,²² and since data are scarce on the use of these drugs in ESRD, they are contraindicated in ESRD.

GLP-1 ANALOGUES AND ‘GLIPTINS,’ NEW CLASSES OF DRUGS

Glucagon-like peptide-1 (GLP-1) stimulates glucose-dependent insulin release from pancreatic beta cells and inhibits inappropriate postprandial glucagon release. It also slows gastric emptying and reduces food intake. Dipeptidyl peptidase IV (DPP-IV) is an active ubiquitous enzyme that deactivates a variety of bioactive peptides, including GLP-1.

Exenatide (Byetta) is a naturally occurring GLP-1 analogue that is resistant to degradation by DPP-IV and has a longer half-life. Given subcutaneously, exenatide undergoes minimal systemic metabolism and is excreted in the urine.

No dose adjustment is required if the glomerular filtration rate (GFR) is greater than 30 mL/min, but exenatide is contraindicated in patients undergoing hemodialysis or in patients who have a GFR less than 30 mL/min (Table 1).

Sitagliptin (Januvia) is a DPP-IV inhibitor, or “gliptin,” that can be used as initial pharmacologic therapy for type 2 diabetes, as a second agent in those who do not respond to a single agent such as a sulfonylurea,²⁸ metformin,^29–31 or a thiazolidinedione,³² and as an additional agent when dual therapy with metformin and a sulfonylurea does not provide adequate glycemic control.²⁸ Sitagliptin is not extensively metabolized and is mainly excreted in the urine.

The usual dose of sitagliptin is 100 mg orally once daily, with reduction to 50 mg for patients with a GFR of 30 to 50 mL/min, and 25 mg for patients with a GFR less than 30 mL/min.³³ Sitagliptin may be used at doses of 25 mg daily in ESRD, irrespective of dialysis timing (Table 1).

Other drugs of this class are being developed. Saxagliptin (Onglyza) was recently approved by the US Food and Drug Administration and can be used at a dosage of 2.5 mg daily after dialysis.

Sitagliptin has been associated with gastrointestinal adverse effects. Anaphylaxis, angioedema, and Steven-Johnson syndrome have been reported. The risk of hypoglycemia increases when sitagliptin is used with sulfonylureas.

 

 

ESRD REDUCES INSULIN CLEARANCE

In healthy nondiabetic people, the pancreatic beta cells secrete half of the daily insulin requirement (about 0.5 units/kg/day) at a steady basal rate independent of glucose levels. The other half is secreted in response to prandial glucose stimulation.

Secreted into the portal system, insulin passes through the liver, where about 75% is metabolized, with the remaining 25% metabolized by the kidneys. About 60% of the insulin in the arterial bed is filtered by the glomerulus, and 40% is actively secreted into the nephric tubules.³⁴ Most of the insulin in the tubules is metabolized into amino acids, and only 1% of insulin is secreted intact.

For diabetic patients receiving exogenous insulin, renal metabolism plays a more significant role since there is no first-pass metabolism in the liver. As renal function starts to decline, insulin clearance does not change appreciably, due to compensatory peritubular insulin uptake.³⁵ But once the GFR drops below 20 mL/min, the kidneys clear markedly less insulin, an effect compounded by a decrease in the hepatic metabolism of insulin that occurs in uremia.³⁶ Thus, despite the increase in insulin resistance caused by renal failure, the net effect is a reduced requirement for exogenous insulin in ESRD.³⁷

A variety of insulin preparations are available, including rapid-acting, intermediate-acting, and long-acting forms and premixed combinations, each with its specific onset, peak, and duration of action (Table 2). To our knowledge, no study of neutral protamine Hagedorn (NPH) insulin or other long-acting insulins has been done in patients with ESRD, and very few studies have described the use of insulin analogues in ESRD.

Aisenpreis et al³⁸ showed that the pharmacokinetic profile of insulin lispro (Humalog), which has a short onset of action and a short duration of action, may not only facilitate the correction of hyperglycemia but may also decrease the risk of late hypoglycemic episodes, which is of increased relevance in hemodialysis patients.

On the basis of the available evidence,^39,40 we recommend a long-acting insulin such as insulin glargine (Lantus) or NPH insulin for basal requirements, along with a rapid-acting insulin analogue such as lispro or insulin aspart (NovoLog) before meals two or three times daily.

When the GFR drops to between 10 and 50 mL/min, the total insulin dose should be reduced by 25%; once the filtration rate is below 10 mL/min, as in ESRD, the insulin dose should be decreased by 50% from the previous amount.^41,42

The newer insulins such as glargine and lispro are more favorable than NPH and regular insulin, but they cost more, which can be an obstacle for some patients.

OBSERVATIONS AND RECOMMENDATIONS

After reviewing the available evidence for the use of diabetic therapy in ESRD, we offer the following observations and recommendations:

• Glycemic control and monitoring in ESRD are complex.
• Patients with ESRD are especially susceptible to hypoglycemia, so diabetic drug therapy requires special caution.
• ESRD patients need ongoing diabetes education, with an emphasis on how to recognize and treat hypoglycemia.
• Diabetic pharmacotherapy in ESRD should be individualized. The targets of therapy are a hemoglobin A_1c value between 6% and 7%, a fasting blood glucose level less than 140 mg/dL, and a postprandial glucose level less than 200 mg/dL.
• Of the oral antidiabetic drugs available, glipizide, sitagliptin, and saxagliptin may be used in ESRD. Glipizide, starting with 2.5 mg daily, should be reserved for ESRD patients with a hemoglobin A_1c value less than 8.5%.
• Thiazolidinediones may cause fluid overload and thus should be avoided in ESRD.
• We recommend a long-acting insulin (glargine or NPH) for basal requirements, along with rapid-acting insulin before meals two or three times daily.
• The newer basal insulin (glargine) and rapid-acting insulin analogues (lispro or aspart insulin) are more favorable than NPH and regular insulin, but their higher cost could be an issue.
• Some patients may prefer a premixed insulin combination for convenience of dosing. In that case, NPH plus lispro insulin may be better than NPH plus regular insulin.
• For ESRD patients with type 1 diabetes, insulin therapy should be started at 0.5 IU/kg, which is half the calculated dose in patients without renal failure.
• For ESRD patients with type 2 diabetes, insulin therapy should be started at a total daily dose of 0.25 IU/kg.
• Further adjustments to the regimen should be individualized based on self-monitored blood glucose patterns.
• We recommend consulting an endocrinologist with expertise in managing diabetes in ESRD.

Although diabetes is the most common cause of end-stage renal disease (ESRD) worldwide, accounting for 44.2% of ESRD patients in the US Renal Data System in 2005,¹ data are scarce on how diabetes should best be treated in patients in ESRD.

We do know that blood glucose levels need to be well controlled in these patients. Several observational studies and one nonrandomized interventional study^2–10 showed that higher levels of hemoglobin A_1c were associated with higher death rates in patients with diabetes and chronic kidney disease after adjusting for markers of inflammation and malnutrition.

However, ESRD significantly alters glycemic control, the results of hemoglobin A_1c testing, and the excretion of antidiabetic medications. The various and opposing effects of ESRD and dialysis can make blood glucose levels fluctuate widely, placing patients at risk of hypoglycemia—and presenting a challenge for nephrologists and internists.

In this review, we summarize the available evidence and make practical recommendations for managing diabetes in patients on hemodialysis.

GLUCOSE LEVELS MAY FLUCTUATE WIDELY

In ESRD, both uremia and dialysis can complicate glycemic control by affecting the secretion, clearance, and peripheral tissue sensitivity of insulin.

Several factors, including uremic toxins, may increase insulin resistance in ESRD, leading to a blunted ability to suppress hepatic gluconeogenesis and regulate peripheral glucose utilization. In type 2 diabetes without kidney disease, insulin resistance leads to increased insulin secretion. This does not occur in ESRD because of concomitant metabolic acidosis, deficiency of 1,25 dihydroxyvitamin D, and secondary hyperparathyroidism.^11,12 Hemodialysis further alters insulin secretion, clearance, and resistance as the result of periodic improvement in uremia, acidosis, and phosphate handling.

The dextrose concentration in the dialysate can also affect glucose control. In general, dialysates with lower dextrose concentrations are used and may be associated with hypoglycemia. Conversely, dialysates with higher dextrose concentrations are occasionally used in peritoneal dialysis to increase ultrafiltration, but this can lead to hyperglycemia.^10,13

Thus, ESRD and hemodialysis exert opposing forces on insulin secretion, action, and metabolism, often creating unpredictable serum glucose values. For example, one would think that a patient who has insulin resistance would need more supplemental insulin; however, the reduced renal gluconeogenesis and insulin clearance seen in ESRD may result in variable net effects in different patients. In addition, ESRD and hemodialysis alter the pharmacokinetics of diabetic medications. Together, all of these factors contribute to wide fluctuations in glucose levels and increase the risk of hypoglycemic events.

HEMOGLOBIN A_1c MAY BE FALSELY HIGH

Self-monitoring of blood glucose plus serial hemoglobin A_1c measurements are the standard of care in diabetic patients without renal failure.

However, in diabetic patients with ESRD, elevated blood urea nitrogen causes formation of carbamylated hemoglobin, which is indistinguishable from glycosylated hemoglobin by electrical-charge-based assays and can cause the hemoglobin A_1c measurement to be falsely elevated. Other factors such as the shorter red life span of red blood cells, iron deficiency, recent transfusion, and use of erythropoietin-stimulating agents may also cause underestimation of glucose control.¹⁴

Despite these limitations, the hemoglobin A_1c level is considered a reasonable measure of glycemic control in ESRD. Glycated fructosamine and albumin are other measures of glycemic control with some advantages over hemoglobin A_1c in dialysis patients. However, they are not readily available and can be affected by conditions that alter protein metabolism, including ESRD.^15–18

Self-monitoring of blood glucose and continuous glucose monitoring systems provide real-time assessments of glycemic control, but both have limitations. Self-monitoring is subject to errors from poor technique, problems with the meters and strips, and lower sensitivity in measuring low blood glucose levels. Continuous monitoring is expensive and is less reliable at lower glucose concentrations, and thus it needs to be used in conjunction with other measures of glucose control. For these reasons, continuous glucose monitoring is not yet widely used.

The guidelines of the 2005 National Kidney Foundation Kidney Disease Outcomes Quality Initiative did not clearly establish a target hemoglobin A_1c level for patients with diabetes and ESRD, but levels of 6% to 7% appear to be safe. The target fasting plasma glucose level should be lower than 140 mg/dL, and the target postprandial glucose level should be lower than 200 mg/dL.¹⁹

 

 

MOST ORAL DIABETES DRUGS ARE CONTRAINDICATED IN ESRD

Oral antihyperglycemic drugs include the insulin secretagogues (sulfonylureas and meglitinides), biguanides, thiazolidinediones, and alpha-glucosidase inhibitors (Table 1). Most of these drugs are contraindicated in ESRD.

Sulfonylureas

Sulfonylureas reduce blood glucose by stimulating the pancreatic beta cells to increase insulin secretion.

Sulfonylureas have a wide volume of distribution and are highly protein-bound,²⁰ but only the unbound drug exerts a clinical effect. Because of protein binding, dialysis cannot effectively clear elevated levels of sulfonylurea drugs. Furthermore, many ESRD patients take drugs such as salicylates, sulfonamides, vitamin K antagonists, beta-blockers, and fibric acid derivatives, which may displace sulfonylureas from albumin, thus increasing the risk of severe hypoglycemia.

The first-generation sulfonylureas—chlorpropamide (Diabinese), acetohexamide (Dymelor), tolbutamide (Orinase), and tolazamide (Tolinase)—are almost exclusively excreted by the kidney and are therefore contraindicated in ESRD.²¹ Second-generation agents include glipizide (Glucotrol), glimepiride (Amaryl), glyburide (Micronase), and gliclazide (not available in the United States). Although these drugs are metabolized in the liver, their active metabolites are excreted in the urine, and so they should be avoided in ESRD.²²

The only sulfonylurea recommended in ESRD is glipizide, which is also metabolized in the liver but has inactive or weakly active metabolites excreted in the urine. The suggested dose of glipizide is 2.5 to 10 mg/day. In ESRD, sustained-release forms should be avoided because of concerns of hypoglycemia.²³

Meglitinides

The meglitinides repaglinide (Prandin) and nateglinide (Starlix) are insulin secretagogues that stimulate pancreatic beta cells. Like the sulfonylureas, nateglinide is hepatically metabolized, with renal excretion of active metabolites. Repaglinide, in contrast, is almost completely converted to inactive metabolites in the liver, and less than 10% is excreted by the kidneys.^24,25 The meglitinides still pose a risk of hypoglycemia, especially in ESRD, and hence are not recommended for patients on hemodialysis.^24,25

Biguanides

Metformin (Glucophage) is a biguanide that reduces hepatic gluconeogenesis and glucose output. It is excreted essentially unchanged in the urine and is therefore contraindicated in patients with renal disease due to the risks of bioaccumulation and lactic acidosis.²²

Thiazolidinediones

The thiazolidinediones rosiglitazone (Avandia) and pioglitazone (Actos) are highly potent, selective agonists that work by binding to and activating a nuclear transcription factor, specifically, peroxisome proliferator-activated receptor gamma (PPAR-gamma). These drugs do not bioaccumulate in renal failure and so do not need dosing adjustments.²⁶

The main adverse effect of these agents is edema, especially when they are combined with insulin therapy. Because of this effect, a joint statement of the American Diabetes Association and the American Heart Association recommends avoiding thiazolidinediones in patients in New York Heart Association (NYHA) class III or IV heart failure.²⁷ Furthermore, caution is required in patients in compensated heart failure (NYHA class I or II) or in those at risk of heart failure, such as patients with previous myocardial infarction or angina, hypertension, left ventricular hypertrophy, significant aortic or mitral valve disease, age greater than 70 years, or diabetes for more than 10 years.²⁷

In summary, although ESRD and dialysis do not affect the metabolism of thiazolidinediones, these agents are not recommended in ESRD because of the associated risk of fluid accumulation and precipitation of heart failure.

Alpha-glucosidase inhibitors

The alpha-glucosidase inhibitors acarbose (Precose) and miglitol (Glyset) slow carbohydrate absorption from the intestine. The levels of these drugs and their active metabolites are higher in renal failure,²² and since data are scarce on the use of these drugs in ESRD, they are contraindicated in ESRD.

GLP-1 ANALOGUES AND ‘GLIPTINS,’ NEW CLASSES OF DRUGS

Glucagon-like peptide-1 (GLP-1) stimulates glucose-dependent insulin release from pancreatic beta cells and inhibits inappropriate postprandial glucagon release. It also slows gastric emptying and reduces food intake. Dipeptidyl peptidase IV (DPP-IV) is an active ubiquitous enzyme that deactivates a variety of bioactive peptides, including GLP-1.

Exenatide (Byetta) is a naturally occurring GLP-1 analogue that is resistant to degradation by DPP-IV and has a longer half-life. Given subcutaneously, exenatide undergoes minimal systemic metabolism and is excreted in the urine.

No dose adjustment is required if the glomerular filtration rate (GFR) is greater than 30 mL/min, but exenatide is contraindicated in patients undergoing hemodialysis or in patients who have a GFR less than 30 mL/min (Table 1).

Sitagliptin (Januvia) is a DPP-IV inhibitor, or “gliptin,” that can be used as initial pharmacologic therapy for type 2 diabetes, as a second agent in those who do not respond to a single agent such as a sulfonylurea,²⁸ metformin,^29–31 or a thiazolidinedione,³² and as an additional agent when dual therapy with metformin and a sulfonylurea does not provide adequate glycemic control.²⁸ Sitagliptin is not extensively metabolized and is mainly excreted in the urine.

The usual dose of sitagliptin is 100 mg orally once daily, with reduction to 50 mg for patients with a GFR of 30 to 50 mL/min, and 25 mg for patients with a GFR less than 30 mL/min.³³ Sitagliptin may be used at doses of 25 mg daily in ESRD, irrespective of dialysis timing (Table 1).

Other drugs of this class are being developed. Saxagliptin (Onglyza) was recently approved by the US Food and Drug Administration and can be used at a dosage of 2.5 mg daily after dialysis.

Sitagliptin has been associated with gastrointestinal adverse effects. Anaphylaxis, angioedema, and Steven-Johnson syndrome have been reported. The risk of hypoglycemia increases when sitagliptin is used with sulfonylureas.

 

 

ESRD REDUCES INSULIN CLEARANCE

In healthy nondiabetic people, the pancreatic beta cells secrete half of the daily insulin requirement (about 0.5 units/kg/day) at a steady basal rate independent of glucose levels. The other half is secreted in response to prandial glucose stimulation.

Secreted into the portal system, insulin passes through the liver, where about 75% is metabolized, with the remaining 25% metabolized by the kidneys. About 60% of the insulin in the arterial bed is filtered by the glomerulus, and 40% is actively secreted into the nephric tubules.³⁴ Most of the insulin in the tubules is metabolized into amino acids, and only 1% of insulin is secreted intact.

For diabetic patients receiving exogenous insulin, renal metabolism plays a more significant role since there is no first-pass metabolism in the liver. As renal function starts to decline, insulin clearance does not change appreciably, due to compensatory peritubular insulin uptake.³⁵ But once the GFR drops below 20 mL/min, the kidneys clear markedly less insulin, an effect compounded by a decrease in the hepatic metabolism of insulin that occurs in uremia.³⁶ Thus, despite the increase in insulin resistance caused by renal failure, the net effect is a reduced requirement for exogenous insulin in ESRD.³⁷

A variety of insulin preparations are available, including rapid-acting, intermediate-acting, and long-acting forms and premixed combinations, each with its specific onset, peak, and duration of action (Table 2). To our knowledge, no study of neutral protamine Hagedorn (NPH) insulin or other long-acting insulins has been done in patients with ESRD, and very few studies have described the use of insulin analogues in ESRD.

Aisenpreis et al³⁸ showed that the pharmacokinetic profile of insulin lispro (Humalog), which has a short onset of action and a short duration of action, may not only facilitate the correction of hyperglycemia but may also decrease the risk of late hypoglycemic episodes, which is of increased relevance in hemodialysis patients.

On the basis of the available evidence,^39,40 we recommend a long-acting insulin such as insulin glargine (Lantus) or NPH insulin for basal requirements, along with a rapid-acting insulin analogue such as lispro or insulin aspart (NovoLog) before meals two or three times daily.

When the GFR drops to between 10 and 50 mL/min, the total insulin dose should be reduced by 25%; once the filtration rate is below 10 mL/min, as in ESRD, the insulin dose should be decreased by 50% from the previous amount.^41,42

The newer insulins such as glargine and lispro are more favorable than NPH and regular insulin, but they cost more, which can be an obstacle for some patients.

OBSERVATIONS AND RECOMMENDATIONS

After reviewing the available evidence for the use of diabetic therapy in ESRD, we offer the following observations and recommendations:

• Glycemic control and monitoring in ESRD are complex.
• Patients with ESRD are especially susceptible to hypoglycemia, so diabetic drug therapy requires special caution.
• ESRD patients need ongoing diabetes education, with an emphasis on how to recognize and treat hypoglycemia.
• Diabetic pharmacotherapy in ESRD should be individualized. The targets of therapy are a hemoglobin A_1c value between 6% and 7%, a fasting blood glucose level less than 140 mg/dL, and a postprandial glucose level less than 200 mg/dL.
• Of the oral antidiabetic drugs available, glipizide, sitagliptin, and saxagliptin may be used in ESRD. Glipizide, starting with 2.5 mg daily, should be reserved for ESRD patients with a hemoglobin A_1c value less than 8.5%.
• Thiazolidinediones may cause fluid overload and thus should be avoided in ESRD.
• We recommend a long-acting insulin (glargine or NPH) for basal requirements, along with rapid-acting insulin before meals two or three times daily.
• The newer basal insulin (glargine) and rapid-acting insulin analogues (lispro or aspart insulin) are more favorable than NPH and regular insulin, but their higher cost could be an issue.
• Some patients may prefer a premixed insulin combination for convenience of dosing. In that case, NPH plus lispro insulin may be better than NPH plus regular insulin.
• For ESRD patients with type 1 diabetes, insulin therapy should be started at 0.5 IU/kg, which is half the calculated dose in patients without renal failure.
• For ESRD patients with type 2 diabetes, insulin therapy should be started at a total daily dose of 0.25 IU/kg.
• Further adjustments to the regimen should be individualized based on self-monitored blood glucose patterns.
• We recommend consulting an endocrinologist with expertise in managing diabetes in ESRD.

Kidney stones are not all the same, and neither are their causes (Table 1), treatment, and prevention. This paper reviews the diagnostic approach and pathophysiologic mechanisms for nephrolithiasis in order to provide a rationale for preventive management.

See related article

COMMON AND ON THE INCREASE

Nephrolithiasis is common, with a lifetime prevalence of 10% in men and 5% in women.^1,2 Studies have shown that the prevalence is increasing in the United States. In the second National Health and Nutrition Examination Survey (1988–1994), the prevalence in adults ages 20 to 74 was greater than in the 1976–1980 survey (5.2% vs 3.2%).³ The increase was observed in whites but not in African Americans or Mexican Americans, was greater in men than in women, and was greater with age in each time period.

In addition, stones often recur, and each stone event can be associated with significant metabolic and intervention-related morbidity.

PRESENTATION: SEVERE COLIC

Most patients present with moderate to severe colic, caused by the stone entering the ureter. Stones in the proximal (upper) ureter cause pain in the flank or anterior upper abdomen. When the stone reaches the distal third of the ureter, pain is noted in the ipsilateral testicle or labia. A stone at the junction of the ureter and the bladder often causes dysuria, urgency, and frequency and may be mistaken for a lower urinary tract infection.

Less often, patients present with silent ureteral obstruction, unexplained persistent urinary infection, or painless hematuria. However, even in patients with symptoms, the absence of hematuria does not exclude urolithiasis. In a study of 397 patients presenting with acute symptomatic urolithiasis, 9% did not have hematuria.⁴

The differential diagnosis in a patient with symptoms suggesting renal colic includes:

• Musculoskeletal pain
• Herpes zoster
• Diverticulitis
• Duodenal ulcer
• Cholecystitis
• Pyelonephritis
• Renal infarct
• Renal hemorrhage
• Gynecologic disorders
• Ureteral obstruction from renal papillary necrosis with sloughed papillae, a blood clot, or a ureteral stricture.

HELICAL CT WITHOUT CONTRAST IS THE PREFERED IMAGING STUDY

The diagnosis can be confirmed by computed tomography (CT), renal ultrasonography, or intravenous pyelography.

Helical CT without contrast is the preferred imaging study in patients with suspected nephrolithiasis. It has several advantages over other imaging studies: it requires no radiocontrast material; it shows the distal ureters; it can detect radiolucent stones (ie, uric acid stones), radio-opaque stones, and stones as small as 1 to 2 mm; and it can detect hydronephrosis and intra-abdominal and renal disorders other than stones that could be causing the patient’s symptoms.

In a study in 100 consecutive patients presenting to an emergency department with flank pain, helical CT had a sensitivity of 98%, a specificity of 100%, a positive predictive value of 100%, and a negative predictive value of 97% for the diagnosis of ureteral stones.⁵ In a study of 1,000 consecutive patients with suspected stones, helical CT identified significant, additional, or alternative reasons for the patient’s symptoms in 10% of cases.⁶

Ultrasonography has the advantage of not using radiation, but it is less sensitive for detecting stones and can image only the kidney and the proximal ureter. A retrospective study in 123 patients found that, compared with helical CT as the gold standard, ultrasonography had a sensitivity of 24% and a specificity of 90%.⁷ Ultrasonography may also miss stones smaller than 3 mm in diameter.

Conventional radiography (kidney-ureter-bladder view) is inadequate for diagnosis as it may miss stones in the kidney or ureter (even small radio-opaque stones) and provides no information about possible obstruction.

Intravenous pyelography has few advantages in renal lithiasis, exposes the patient to the risk of radiocontrast infusion and contrast-mediated acute renal injury, and gives less information than noncontrast CT.

MEDICAL MANAGEMENT OF ACUTE STONE EVENTS

Most stones are smaller than 5 mm and readily pass without interventions such as lithotripsy, ureteroscopy, or percutaneous nephrolithotomy. (For more information on these interventions, see the review by Samplaski and colleagues in this issue of the Cleveland Clinic Journal of Medicine.⁸)

Even if the stone is as large as 1 cm, I would let the patient try to pass it spontaneously if it is in the distal ureter, and I would allow up to 4 weeks for this to happen.

For most patients, pain management is paramount. Randomized controlled trials suggest that parenteral nonsteroidal anti-inflammatory drugs (NSAIDs) are as effective as narcotics for controlling the pain of renal colic.⁹ Diclofenac (Voltaren) has been used in several studies.

To hasten stone passage, some recommend inducing high urine flow with oral intake of at least 2 to 3 L of fluids per 24 hours to ensure a urine output of at least 2 L per day.

Drugs may also help the stone to pass. A recent study in 210 patients with ureteral stones averaging 6 mm in diameter showed that tamsulosin (Flomax) increased the likelihood of spontaneous stone passage.¹⁰ A meta-analysis of 693 patients in nine randomized trials concluded that alpha-blockers and calcium channel blockers increased the likelihood of stone passage compared with no treatment.¹¹ Borghi et al,¹² in a randomized, double-blind study in 86 patients with unilateral ureteral stones, reported a higher rate of stone passage in patients treated with methylprednisolone (Medrol) 16 mg/day plus nifedipine (Procardia) 40 mg/day than in those given methylprednisolone alone.

 

PREVENTING RECURRENT STONES: PRINCIPLES AND SPECIFICS

Urinary stone disease recurs in 30% to 50% of patients within 5 years.^1,13,14

In preventing recurrent stones, some principles apply to all patients and some are specific to the type of stone the patient had.

Stones form when the urine is supersaturated

Nephrolithiasis occurs when the concentration of stone-forming salts such as calcium oxalate, calcium phosphate, or uric acid is high. When the concentration is high enough to allow crystals to form or preformed crystals to grow, the urine is said to be supersaturated.

Several facors are the major determinants of whether the urine is supersaturated by different salts:

• Calcium oxalate—low urine volume and high concentrations of calcium and oxalate
• Calcium phosphate—a high urine calcium concentration and alkaline urine
• Uric acid—acidic urine
• Cystine—a high urinary cystine concentration and acidic urine.

Increasing daily fluid intake

Since the urinary concentration of stone-forming salts is strongly affected by the daily urine volume, it follows that increasing daily fluid intake is important in preventing recurrent stone disease.

In one study,¹⁵ 199 patients with a first calcium stone were randomized to a program of high oral fluid intake or no intervention. Five years later, 12 (12%) of the 99 patients in the high-fluid intake group had had a second stone, compared with 27 (27%) in the untreated group (P = .008). Of interest, the baseline 24-hour urine volumes were significantly lower in patients with stones than in 101 normal controls (P = .001), suggesting that habitual low daily fluid intake is a risk factor for calcium stone disease.¹³

PREVENTING CALCIUM STONES

Most stones are composed of calcium oxalate or calcium phosphate. Calcium stone disease occurs most often in the 3rd to 5th decades of life.

Naturally occurring inhibitors of calcium crystal formation in the urine include citrate, nephrocalcin, uropontin, and magnesium. Of these, only citrate and magnesium levels are routinely measured; low levels of citrate are treated as a cause of calcium stone disease. It follows that the risk of calcium nephrolithiasis is the result of the interplay between the supersaturated state and the level of urinary inhibitors.¹⁶

Hypercalciuria and calcium oxalate stones

Calcium oxalate stones begin as crystals that form on the surface of the renal papillae over collections of suburothelial calcium phosphate particles called Randall plaque.¹⁷ The driving force for calcium oxalate overgrowth on plaque is calcium oxalate supersaturation, which is strongly linked to high urinary calcium excretion. The fraction of papillary surface covered by plaque in patients with idiopathic calcium oxalate stones correlates directly with the urine calcium level and inversely with urine volume and pH.¹⁸

Most patients with calcium oxalate stones have hypercalciuria (defined as 24-hour urinary calcium excretion > 300 mg in men, > 250 mg in women, or > 4 mg/kg in men or women).

Hypercalciuria can be idiopathic

Hypercalciuria can occur in primary hyperparathyroidism, sarcoidosis, vitamin D excess, corticosteroid treatment, renal tubular acidosis, hyperthyroidism, and malignant neoplasms. If none of these conditions is present, elevated urinary calcium excretion is considered idiopathic.

Some patients with idiopathic hypercalciuria have a strong family history of hypercalciuria and, likely, a genetic basis for the disease. This condition has been categorized by the presumed site of the primary abnormality:

Absorptive hypercalciuria. Most patients with idiopathic hypercalciuria absorb too much calcium from the intestine. In many of them, 1,25 dihydroxyvitamin D levels are slightly high and serum phosphorous levels are slightly low; the hypothesis is that they produce more 1,25 dihydroxyvitamin D or are more sensitive to it.¹⁹ However, Breslau et al²⁰ showed that not all patients with idiopathic hypercalciuria have absorptive hypercalciuria mediated by 1,25 dihydroxyvitamin D, which suggests that the intestinal hyperabsorption of calcium has other mechanisms.

Resorptive hypercalciuria occurs if increased bone turnover leads to urinary loss of bone calcium.

Renal leak is due to a primary defect in renal tubular transport that causes loss of calcium into the urine and a secondary increase in intestinal calcium absorption or mobilization from bone.

This categorization is based on measuring fasting and 24-hour urine calcium, urinary calcium responses to a low-calcium diet, and responses to an oral calcium load.²¹ However, these studies are difficult to do and have been shown to have minimal clinical value.

To reduce calcium in the urine, limit sodium, give thiazides

Idiopathic hypercalciuria is worsened by a diet high in sodium^22,23 and animal protein.²⁴ Thiazide diuretics lower urinary calcium excretion and promote mineral retention.²⁵ Therefore, treatment of idiopathic hypercalciuria consists of high fluid intake, dietary sodium restriction, and thiazide diuretics.

 

 

Calcium restriction is not advised

For several reasons, a calcium-restricted diet is not advised for patients with idiopathic hypercalciuria. ²⁶ Dietary calcium restriction can put the patient into negative calcium balance. Further, it is thought that with less calcium to bind to dietary oxalate, more unbound oxalate can be absorbed in the colon and eventually excreted in the urine. This increase in urinary oxalate can be to the point of supersaturation, even though urinary calcium levels remain unchanged.^25,27,28 This, in turn, increases the likelihood of stone formation.

Several studies showed that a higher intake of dietary calcium is actually associated with fewer calcium stone events in both men and women.^25,27,28

Further, a study in 120 Italian patients with hypercalciuric calcium oxalate stones concluded that a diet that is normal in calcium, low in sodium, and low in animal protein was associated with a lower frequency of calcium stones than a low-calcium diet.²⁹ Although both diets were associated with a reduction in urinary calcium concentrations, urinary oxalate excretion rose in those on a low-calcium diet and fell in those on a normal-calcium diet. The reduction in urinary oxalate excretion in patients on a normal-calcium diet was attributed to intestinal binding of dietary oxalate by dietary calcium, thus lessening the amount of free oxalate available for absorption. Although calcium oxalate excretion fell in both groups, it fell more in those on a normal calcium intake. Compared with those on a low-calcium diet, the patients on the normal-calcium, low-sodium, low-protein diet had a 50% lower risk of stones at 5 years.

Hyperparathyroidism

Primary hyperparathyroidism can cause hypercalciuria and nephrolithiasis. In one series,³⁰ 56 (4.9%) of 1,132 consecutive patients with nephrolithiasis had a confirmed diagnosis of hyperparathyroidism. Parathyroidectomy prevented subsequent stone disease in 48 patients.

However, only 17% to 24% of patients with primary hyperparathyroidism have urinary stones composed of calcium oxalate or calcium phosphate.^31,32 In many studies, it was difficult to determine why a minority of these patients develop stones, but two studies shed some light on this.

Parks et al³⁰ found that, compared with nephrolithiasis patients with idiopathic hypercalciuria, those with primary hyperparathyroidism have elevated serum calcium levels (but usually < 11.5 mg/dL), greater degrees of hypercalciuria (352 mg/day vs 252 mg/day, P < .001), and lower serum phosphate levels (2.45 vs 3.10 mg/dL, P < .001).

Odvina et al³³ found, in a study of 131 patients with proven primary hyperparathyroidism, that 78 had nephrolithiasis and 53 did not. Those with stones excreted more calcium (343 mg/day) than those without stones (273 mg/day), had a higher urinary saturation of calcium oxalate and brushite, and excreted twice as much calcium following a 1-g oral calcium load.

These studies suggest that in patients with primary hyperparathyroidism, the risk of forming stones is related to the degree of hypercalciuria, and in particular to the increased intestinal absorption of dietary calcium.

Renal tubular acidosis

Features of distal renal tubular acidosis are systemic metabolic acidosis, alkaline urine, hypokalemia, hypercalciuria, hypocitraturia, and nephrolithiasis. The chronic metabolic acidosis results in loss of bone calcium, contributes to hypercalciuria, and is responsible for the hypocitraturia.³⁴ Stone formation is the result of excessive urinary calcium excretion, the deficiency of the urinary crystal inhibitor citrate, and persistently alkaline urine.

Treatment with sodium bicarbonate or potassium citrate corrects the metabolic acidosis, reduces the loss of calcium from bone, corrects hypokalemia, and increases urinary citrate.

Too much uric acid in the urine

Elevated urinary uric acid excretion (> 800 mg/day in men, > 750 mg/day in women) is associated with formation of calcium oxalate stones³⁵ and, in conjunction with low urine pH, with uric acid stones. An increase in dissolved uric acid salts induces heterogeneous calcium oxalate nucleation.³⁶ In one randomized clinical trial,³⁷ giving allopurinol (Zyloprim) lowered urinary uric acid excretion and was associated with a lower rate of calcium stone disease.

Too much oxalate in the urine

The 95th percentile for urinary oxalate excretion is 45 mg/day in women and 55 mg/day in men.³⁸ Hyperoxaluria increases calcium oxalate supersaturation and contributes to calcium stone formation.

Normally, 90% of dietary oxalate binds to dietary calcium in the small intestine and passes into the stool as calcium oxalate; 10% of dietary oxalate remains free and is absorbed in the colon and subsequently excreted in the urine.

Hyperoxaluria may simply be a result of high dietary oxalate intake. However, increased enteric absorption of dietary oxalate can occur in those on a low-calcium diet (in which less calcium is available to bind to dietary oxalate, as described above) and may partially explain why a low-calcium diet has been associated with increased frequency of calcium stone disease.

Patients with enteric malabsorption of fat (eg, due to inflammatory bowel disease or intestinal bypass surgery for obesity) may also develop hyperoxaluria. This occurs because the excess enteric fat binds dietary calcium and allows free oxalate to be more readily absorbed in the colon.³⁹

Rarely, hyperoxaluria is caused by one of several recessively inherited disorders of oxalate metabolism.⁴⁰

The growing number of people with obesity has resulted in an upsurge in gastric bypass surgery. Although the current procedures do not pose the same metabolic risks as were noted in the 1970s when a different type of bypass was performed, the incidence of kidney stones does appear to be higher after these procedures. A recent analysis of 1,436 patients undergoing Roux-en-Y gastric bypass surgery found that 60 of them developed calcium stones afterward. Of these, 31 who underwent metabolic studies were found to have higher oxalate and lower citrate levels at 12 months of follow-up.⁴¹

Not enough citrate, a stone inhibitor

Hypocitraturia is defined as a daily urine citrate excretion less than 500 mg in women and 434 mg in men.⁴² As already mentioned, citrate plays an important role in inhibiting calcium crystal formation and preventing stone formation.

Urinary citrate excretion is mainly determined by tubular reabsorption, which is increased by acid loads and decreased by alkali loads.⁴³ Low urine citrate levels are often seen in conditions that cause chronic metabolic acidosis, such as inflammatory bowel disease, intestinal malabsorption, and renal tubular acidosis—all of which are associated with increased occurrence of nephrolithiasis. However, in most nephrolithiasis patients with hypocitraturia, the cause is not apparent, and the mechanism of the hypocitraturia cannot be determined.⁴⁴

In recent years, high-protein, low-carbohydrate diets have become popular for weight reduction, but they also have metabolic effects that increase the risk of stones.⁴⁵ The metabolism of a diet high in animal protein produces more hydrogen ions that are buffered by bone, releasing calcium from bone and increasing urinary calcium excretion. These diets also cause intracellular acidosis, resulting in decreased urinary excretion of citrate. As a result of these effects, the stone-forming propensity of the urine is increased.

 

STRUVITE STONES MUST BE REMOVED

Struvite stones are the result of chronic upper urinary infection with urease-producing bacteria (Proteus sp, Haemophilus sp, Klebsiella sp, and Ureaplasma urealyticum).^46,47 The hydrolysis of urea yields ammonium and hydroxyl ions and a persistently alkaline urine, and this scenario promotes the formation of stones composed of magnesium ammonium phosphate, ie, struvite.

Struvite stones, which are often branched (“staghorn” stones), occur more often in women and in patients who have chronic urinary obstruction or a neurologic disorder that impairs normal emptying of the bladder.

Treatment requires eradicating the infection with antibiotics and removing the bacteria-laden stones by one of several interventional techniques. Acetohydroxamic acid inhibits urease and has been used to treat struvite stone disease, but it has frequent and serious adverse effects.⁴⁸

URIC ACID STONES FORM IN VERY ACIDIC URINE

Uric acid stones occur especially in patients with unusually low urine pH and hyperuricosuria. In some patients, this very low urine pH is the result of a defect in renal ammonia secretion, which results in less buffering of secreted hydrogen ions.⁴⁹

The tendency to form uric acid stones is reported to be increasing in obese people with the metabolic syndrome. Some studies have shown that the defect in ammonia production by the kidney may be the result of insulin resistance.⁵⁰

Urate stones are radiolucent but can be seen on ultrasonography and helical CT. On helical CT, they can be distinguished from calcium stones by their lower density.⁵¹

Since uric acid is much more soluble in an alkaline solution, both prevention and treatment should consist of alkalinization of urine to a pH of more than 6.0 with oral sodium bicarbonate or citrate solution and hydration. This treatment may actually dissolve uric acid stones. If hyperuricemia or hyperuricosuria is present, allopurinol can be prescribed.

CYSTINE STONES ALSO FORM IN ACIDIC URINE

Cystine stone disease occurs in people who have inherited an autosomally recessive gastrointestinal and renal tubular transport disorder of four amino acids, ie, cystine, ornithine, arginine, and lysine.⁵² Of these, cystine is the most insoluble in normally acidic urine and thus precipitates into stones. The onset is at a younger age than in calcium stone disease; the stones are radio-opaque.

Cystine solubility is about 243 mg/L in normal urine and rises with pH. Some patients can excrete as much as 1,000 mg per day.

Treatment^53,54 consists of:

• Hydration, to achieve daily urine volumes of 3 to 3.5 L
• Alkalinization of the urine to a pH higher than 6.5 with potassium alkali (potassium citrate) or sodium bicarbonate
• Reduction of protein and sodium intake to reduce cystine excretion.

If these measures fail, D-penicillamine (Depen), tiopronin (Thiola), or captopril (Capoten)^55–57 can be given to convert the cystine to a more soluble disulfide cysteine-drug complex. Captopril has only a modest effect at best and is usually given with another disulfide-complexing drug; it also has the disadvantage of producing hypotension. Adverse effects of D-penicillamine and tiopronin include abdominal pain, loss of taste, fever, proteinuria, and, in rare cases, nephrotic syndrome.

WORKUP AND MANAGEMENT OF NEPHROLITHIASIS

The diagnostic evaluation of a first stone (Table 2) includes a routine chemistry panel (electrolytes, creatinine, calcium), urinalysis, parathyroid hormone measurement, and helical CT without contrast. Stone analysis should always be done whenever stone material is available.

Anyone under age 20 with an initial stone deserves a more extensive evaluation, including screening for renal tubular acidosis, cystinuria, and hyperoxaluria. A more extensive workup is also warranted in patients with a history of chronic diarrhea, sarcoidosis, or a condition associated with renal tubular acidosis (eg, Sjögren syndrome), in patients with a family history of kidney stones, in patients with high-protein weight-loss diets, and in those undergoing gastric bypass surgery for obesity. In these high-risk patients, the evaluation should include 24-hour urine studies to measure calcium, oxalate, citrate, uric acid, creatinine, sodium, and volume.

Other diagnostic clues are often helpful in the decision to do a more comprehensive evaluation.

• Nephrocalcinosis on roentgenography suggests hyperparathyroidism, medullary sponge kidney, or renal tubular acidosis.
• Hypercalcemia that develops after treatment of hypercalciuria with a thiazide diuretic suggests latent hyperparathyroidism.
• A history of recurrent urinary tract infections or of anatomic abnormalities in the urinary tract should lead to an evaluation for struvite stone disease.
• Uric acid stones should be suspected in a patient with metabolic syndrome or a history of gout and are usually accompanied by a urine pH lower than 5.5.
• A urinalysis showing cystine crystals always indicates cystinuria, which should be confirmed by 24-hour urine cystine determination.
• A family history of renal stones is more common in idiopathic hypercalciuria, cystinuria, primary hyperoxaluria, and renal tubular acidosis.

Kidney stones are not all the same, and neither are their causes (Table 1), treatment, and prevention. This paper reviews the diagnostic approach and pathophysiologic mechanisms for nephrolithiasis in order to provide a rationale for preventive management.

See related article

COMMON AND ON THE INCREASE

Nephrolithiasis is common, with a lifetime prevalence of 10% in men and 5% in women.^1,2 Studies have shown that the prevalence is increasing in the United States. In the second National Health and Nutrition Examination Survey (1988–1994), the prevalence in adults ages 20 to 74 was greater than in the 1976–1980 survey (5.2% vs 3.2%).³ The increase was observed in whites but not in African Americans or Mexican Americans, was greater in men than in women, and was greater with age in each time period.

In addition, stones often recur, and each stone event can be associated with significant metabolic and intervention-related morbidity.

PRESENTATION: SEVERE COLIC

Most patients present with moderate to severe colic, caused by the stone entering the ureter. Stones in the proximal (upper) ureter cause pain in the flank or anterior upper abdomen. When the stone reaches the distal third of the ureter, pain is noted in the ipsilateral testicle or labia. A stone at the junction of the ureter and the bladder often causes dysuria, urgency, and frequency and may be mistaken for a lower urinary tract infection.

Less often, patients present with silent ureteral obstruction, unexplained persistent urinary infection, or painless hematuria. However, even in patients with symptoms, the absence of hematuria does not exclude urolithiasis. In a study of 397 patients presenting with acute symptomatic urolithiasis, 9% did not have hematuria.⁴

The differential diagnosis in a patient with symptoms suggesting renal colic includes:

• Musculoskeletal pain
• Herpes zoster
• Diverticulitis
• Duodenal ulcer
• Cholecystitis
• Pyelonephritis
• Renal infarct
• Renal hemorrhage
• Gynecologic disorders
• Ureteral obstruction from renal papillary necrosis with sloughed papillae, a blood clot, or a ureteral stricture.

HELICAL CT WITHOUT CONTRAST IS THE PREFERED IMAGING STUDY

The diagnosis can be confirmed by computed tomography (CT), renal ultrasonography, or intravenous pyelography.

Helical CT without contrast is the preferred imaging study in patients with suspected nephrolithiasis. It has several advantages over other imaging studies: it requires no radiocontrast material; it shows the distal ureters; it can detect radiolucent stones (ie, uric acid stones), radio-opaque stones, and stones as small as 1 to 2 mm; and it can detect hydronephrosis and intra-abdominal and renal disorders other than stones that could be causing the patient’s symptoms.

In a study in 100 consecutive patients presenting to an emergency department with flank pain, helical CT had a sensitivity of 98%, a specificity of 100%, a positive predictive value of 100%, and a negative predictive value of 97% for the diagnosis of ureteral stones.⁵ In a study of 1,000 consecutive patients with suspected stones, helical CT identified significant, additional, or alternative reasons for the patient’s symptoms in 10% of cases.⁶

Ultrasonography has the advantage of not using radiation, but it is less sensitive for detecting stones and can image only the kidney and the proximal ureter. A retrospective study in 123 patients found that, compared with helical CT as the gold standard, ultrasonography had a sensitivity of 24% and a specificity of 90%.⁷ Ultrasonography may also miss stones smaller than 3 mm in diameter.

Conventional radiography (kidney-ureter-bladder view) is inadequate for diagnosis as it may miss stones in the kidney or ureter (even small radio-opaque stones) and provides no information about possible obstruction.

Intravenous pyelography has few advantages in renal lithiasis, exposes the patient to the risk of radiocontrast infusion and contrast-mediated acute renal injury, and gives less information than noncontrast CT.

MEDICAL MANAGEMENT OF ACUTE STONE EVENTS

Most stones are smaller than 5 mm and readily pass without interventions such as lithotripsy, ureteroscopy, or percutaneous nephrolithotomy. (For more information on these interventions, see the review by Samplaski and colleagues in this issue of the Cleveland Clinic Journal of Medicine.⁸)

Even if the stone is as large as 1 cm, I would let the patient try to pass it spontaneously if it is in the distal ureter, and I would allow up to 4 weeks for this to happen.

For most patients, pain management is paramount. Randomized controlled trials suggest that parenteral nonsteroidal anti-inflammatory drugs (NSAIDs) are as effective as narcotics for controlling the pain of renal colic.⁹ Diclofenac (Voltaren) has been used in several studies.

To hasten stone passage, some recommend inducing high urine flow with oral intake of at least 2 to 3 L of fluids per 24 hours to ensure a urine output of at least 2 L per day.

Drugs may also help the stone to pass. A recent study in 210 patients with ureteral stones averaging 6 mm in diameter showed that tamsulosin (Flomax) increased the likelihood of spontaneous stone passage.¹⁰ A meta-analysis of 693 patients in nine randomized trials concluded that alpha-blockers and calcium channel blockers increased the likelihood of stone passage compared with no treatment.¹¹ Borghi et al,¹² in a randomized, double-blind study in 86 patients with unilateral ureteral stones, reported a higher rate of stone passage in patients treated with methylprednisolone (Medrol) 16 mg/day plus nifedipine (Procardia) 40 mg/day than in those given methylprednisolone alone.

 

PREVENTING RECURRENT STONES: PRINCIPLES AND SPECIFICS

Urinary stone disease recurs in 30% to 50% of patients within 5 years.^1,13,14

In preventing recurrent stones, some principles apply to all patients and some are specific to the type of stone the patient had.

Stones form when the urine is supersaturated

Nephrolithiasis occurs when the concentration of stone-forming salts such as calcium oxalate, calcium phosphate, or uric acid is high. When the concentration is high enough to allow crystals to form or preformed crystals to grow, the urine is said to be supersaturated.

Several facors are the major determinants of whether the urine is supersaturated by different salts:

• Calcium oxalate—low urine volume and high concentrations of calcium and oxalate
• Calcium phosphate—a high urine calcium concentration and alkaline urine
• Uric acid—acidic urine
• Cystine—a high urinary cystine concentration and acidic urine.

Increasing daily fluid intake

Since the urinary concentration of stone-forming salts is strongly affected by the daily urine volume, it follows that increasing daily fluid intake is important in preventing recurrent stone disease.

In one study,¹⁵ 199 patients with a first calcium stone were randomized to a program of high oral fluid intake or no intervention. Five years later, 12 (12%) of the 99 patients in the high-fluid intake group had had a second stone, compared with 27 (27%) in the untreated group (P = .008). Of interest, the baseline 24-hour urine volumes were significantly lower in patients with stones than in 101 normal controls (P = .001), suggesting that habitual low daily fluid intake is a risk factor for calcium stone disease.¹³

PREVENTING CALCIUM STONES

Most stones are composed of calcium oxalate or calcium phosphate. Calcium stone disease occurs most often in the 3rd to 5th decades of life.

Naturally occurring inhibitors of calcium crystal formation in the urine include citrate, nephrocalcin, uropontin, and magnesium. Of these, only citrate and magnesium levels are routinely measured; low levels of citrate are treated as a cause of calcium stone disease. It follows that the risk of calcium nephrolithiasis is the result of the interplay between the supersaturated state and the level of urinary inhibitors.¹⁶

Hypercalciuria and calcium oxalate stones

Calcium oxalate stones begin as crystals that form on the surface of the renal papillae over collections of suburothelial calcium phosphate particles called Randall plaque.¹⁷ The driving force for calcium oxalate overgrowth on plaque is calcium oxalate supersaturation, which is strongly linked to high urinary calcium excretion. The fraction of papillary surface covered by plaque in patients with idiopathic calcium oxalate stones correlates directly with the urine calcium level and inversely with urine volume and pH.¹⁸

Most patients with calcium oxalate stones have hypercalciuria (defined as 24-hour urinary calcium excretion > 300 mg in men, > 250 mg in women, or > 4 mg/kg in men or women).

Hypercalciuria can be idiopathic

Hypercalciuria can occur in primary hyperparathyroidism, sarcoidosis, vitamin D excess, corticosteroid treatment, renal tubular acidosis, hyperthyroidism, and malignant neoplasms. If none of these conditions is present, elevated urinary calcium excretion is considered idiopathic.

Some patients with idiopathic hypercalciuria have a strong family history of hypercalciuria and, likely, a genetic basis for the disease. This condition has been categorized by the presumed site of the primary abnormality:

Absorptive hypercalciuria. Most patients with idiopathic hypercalciuria absorb too much calcium from the intestine. In many of them, 1,25 dihydroxyvitamin D levels are slightly high and serum phosphorous levels are slightly low; the hypothesis is that they produce more 1,25 dihydroxyvitamin D or are more sensitive to it.¹⁹ However, Breslau et al²⁰ showed that not all patients with idiopathic hypercalciuria have absorptive hypercalciuria mediated by 1,25 dihydroxyvitamin D, which suggests that the intestinal hyperabsorption of calcium has other mechanisms.

Resorptive hypercalciuria occurs if increased bone turnover leads to urinary loss of bone calcium.

Renal leak is due to a primary defect in renal tubular transport that causes loss of calcium into the urine and a secondary increase in intestinal calcium absorption or mobilization from bone.

This categorization is based on measuring fasting and 24-hour urine calcium, urinary calcium responses to a low-calcium diet, and responses to an oral calcium load.²¹ However, these studies are difficult to do and have been shown to have minimal clinical value.

To reduce calcium in the urine, limit sodium, give thiazides

Idiopathic hypercalciuria is worsened by a diet high in sodium^22,23 and animal protein.²⁴ Thiazide diuretics lower urinary calcium excretion and promote mineral retention.²⁵ Therefore, treatment of idiopathic hypercalciuria consists of high fluid intake, dietary sodium restriction, and thiazide diuretics.

 

 

Calcium restriction is not advised

For several reasons, a calcium-restricted diet is not advised for patients with idiopathic hypercalciuria. ²⁶ Dietary calcium restriction can put the patient into negative calcium balance. Further, it is thought that with less calcium to bind to dietary oxalate, more unbound oxalate can be absorbed in the colon and eventually excreted in the urine. This increase in urinary oxalate can be to the point of supersaturation, even though urinary calcium levels remain unchanged.^25,27,28 This, in turn, increases the likelihood of stone formation.

Several studies showed that a higher intake of dietary calcium is actually associated with fewer calcium stone events in both men and women.^25,27,28

Further, a study in 120 Italian patients with hypercalciuric calcium oxalate stones concluded that a diet that is normal in calcium, low in sodium, and low in animal protein was associated with a lower frequency of calcium stones than a low-calcium diet.²⁹ Although both diets were associated with a reduction in urinary calcium concentrations, urinary oxalate excretion rose in those on a low-calcium diet and fell in those on a normal-calcium diet. The reduction in urinary oxalate excretion in patients on a normal-calcium diet was attributed to intestinal binding of dietary oxalate by dietary calcium, thus lessening the amount of free oxalate available for absorption. Although calcium oxalate excretion fell in both groups, it fell more in those on a normal calcium intake. Compared with those on a low-calcium diet, the patients on the normal-calcium, low-sodium, low-protein diet had a 50% lower risk of stones at 5 years.

Hyperparathyroidism

Primary hyperparathyroidism can cause hypercalciuria and nephrolithiasis. In one series,³⁰ 56 (4.9%) of 1,132 consecutive patients with nephrolithiasis had a confirmed diagnosis of hyperparathyroidism. Parathyroidectomy prevented subsequent stone disease in 48 patients.

However, only 17% to 24% of patients with primary hyperparathyroidism have urinary stones composed of calcium oxalate or calcium phosphate.^31,32 In many studies, it was difficult to determine why a minority of these patients develop stones, but two studies shed some light on this.

Parks et al³⁰ found that, compared with nephrolithiasis patients with idiopathic hypercalciuria, those with primary hyperparathyroidism have elevated serum calcium levels (but usually < 11.5 mg/dL), greater degrees of hypercalciuria (352 mg/day vs 252 mg/day, P < .001), and lower serum phosphate levels (2.45 vs 3.10 mg/dL, P < .001).

Odvina et al³³ found, in a study of 131 patients with proven primary hyperparathyroidism, that 78 had nephrolithiasis and 53 did not. Those with stones excreted more calcium (343 mg/day) than those without stones (273 mg/day), had a higher urinary saturation of calcium oxalate and brushite, and excreted twice as much calcium following a 1-g oral calcium load.

These studies suggest that in patients with primary hyperparathyroidism, the risk of forming stones is related to the degree of hypercalciuria, and in particular to the increased intestinal absorption of dietary calcium.

Renal tubular acidosis

Features of distal renal tubular acidosis are systemic metabolic acidosis, alkaline urine, hypokalemia, hypercalciuria, hypocitraturia, and nephrolithiasis. The chronic metabolic acidosis results in loss of bone calcium, contributes to hypercalciuria, and is responsible for the hypocitraturia.³⁴ Stone formation is the result of excessive urinary calcium excretion, the deficiency of the urinary crystal inhibitor citrate, and persistently alkaline urine.

Treatment with sodium bicarbonate or potassium citrate corrects the metabolic acidosis, reduces the loss of calcium from bone, corrects hypokalemia, and increases urinary citrate.

Too much uric acid in the urine

Elevated urinary uric acid excretion (> 800 mg/day in men, > 750 mg/day in women) is associated with formation of calcium oxalate stones³⁵ and, in conjunction with low urine pH, with uric acid stones. An increase in dissolved uric acid salts induces heterogeneous calcium oxalate nucleation.³⁶ In one randomized clinical trial,³⁷ giving allopurinol (Zyloprim) lowered urinary uric acid excretion and was associated with a lower rate of calcium stone disease.

Too much oxalate in the urine

The 95th percentile for urinary oxalate excretion is 45 mg/day in women and 55 mg/day in men.³⁸ Hyperoxaluria increases calcium oxalate supersaturation and contributes to calcium stone formation.

Normally, 90% of dietary oxalate binds to dietary calcium in the small intestine and passes into the stool as calcium oxalate; 10% of dietary oxalate remains free and is absorbed in the colon and subsequently excreted in the urine.

Hyperoxaluria may simply be a result of high dietary oxalate intake. However, increased enteric absorption of dietary oxalate can occur in those on a low-calcium diet (in which less calcium is available to bind to dietary oxalate, as described above) and may partially explain why a low-calcium diet has been associated with increased frequency of calcium stone disease.

Patients with enteric malabsorption of fat (eg, due to inflammatory bowel disease or intestinal bypass surgery for obesity) may also develop hyperoxaluria. This occurs because the excess enteric fat binds dietary calcium and allows free oxalate to be more readily absorbed in the colon.³⁹

Rarely, hyperoxaluria is caused by one of several recessively inherited disorders of oxalate metabolism.⁴⁰

The growing number of people with obesity has resulted in an upsurge in gastric bypass surgery. Although the current procedures do not pose the same metabolic risks as were noted in the 1970s when a different type of bypass was performed, the incidence of kidney stones does appear to be higher after these procedures. A recent analysis of 1,436 patients undergoing Roux-en-Y gastric bypass surgery found that 60 of them developed calcium stones afterward. Of these, 31 who underwent metabolic studies were found to have higher oxalate and lower citrate levels at 12 months of follow-up.⁴¹

Not enough citrate, a stone inhibitor

Hypocitraturia is defined as a daily urine citrate excretion less than 500 mg in women and 434 mg in men.⁴² As already mentioned, citrate plays an important role in inhibiting calcium crystal formation and preventing stone formation.

Urinary citrate excretion is mainly determined by tubular reabsorption, which is increased by acid loads and decreased by alkali loads.⁴³ Low urine citrate levels are often seen in conditions that cause chronic metabolic acidosis, such as inflammatory bowel disease, intestinal malabsorption, and renal tubular acidosis—all of which are associated with increased occurrence of nephrolithiasis. However, in most nephrolithiasis patients with hypocitraturia, the cause is not apparent, and the mechanism of the hypocitraturia cannot be determined.⁴⁴

In recent years, high-protein, low-carbohydrate diets have become popular for weight reduction, but they also have metabolic effects that increase the risk of stones.⁴⁵ The metabolism of a diet high in animal protein produces more hydrogen ions that are buffered by bone, releasing calcium from bone and increasing urinary calcium excretion. These diets also cause intracellular acidosis, resulting in decreased urinary excretion of citrate. As a result of these effects, the stone-forming propensity of the urine is increased.

 

STRUVITE STONES MUST BE REMOVED

Struvite stones are the result of chronic upper urinary infection with urease-producing bacteria (Proteus sp, Haemophilus sp, Klebsiella sp, and Ureaplasma urealyticum).^46,47 The hydrolysis of urea yields ammonium and hydroxyl ions and a persistently alkaline urine, and this scenario promotes the formation of stones composed of magnesium ammonium phosphate, ie, struvite.

Struvite stones, which are often branched (“staghorn” stones), occur more often in women and in patients who have chronic urinary obstruction or a neurologic disorder that impairs normal emptying of the bladder.

Treatment requires eradicating the infection with antibiotics and removing the bacteria-laden stones by one of several interventional techniques. Acetohydroxamic acid inhibits urease and has been used to treat struvite stone disease, but it has frequent and serious adverse effects.⁴⁸

URIC ACID STONES FORM IN VERY ACIDIC URINE

Uric acid stones occur especially in patients with unusually low urine pH and hyperuricosuria. In some patients, this very low urine pH is the result of a defect in renal ammonia secretion, which results in less buffering of secreted hydrogen ions.⁴⁹

The tendency to form uric acid stones is reported to be increasing in obese people with the metabolic syndrome. Some studies have shown that the defect in ammonia production by the kidney may be the result of insulin resistance.⁵⁰

Urate stones are radiolucent but can be seen on ultrasonography and helical CT. On helical CT, they can be distinguished from calcium stones by their lower density.⁵¹

Since uric acid is much more soluble in an alkaline solution, both prevention and treatment should consist of alkalinization of urine to a pH of more than 6.0 with oral sodium bicarbonate or citrate solution and hydration. This treatment may actually dissolve uric acid stones. If hyperuricemia or hyperuricosuria is present, allopurinol can be prescribed.

CYSTINE STONES ALSO FORM IN ACIDIC URINE

Cystine stone disease occurs in people who have inherited an autosomally recessive gastrointestinal and renal tubular transport disorder of four amino acids, ie, cystine, ornithine, arginine, and lysine.⁵² Of these, cystine is the most insoluble in normally acidic urine and thus precipitates into stones. The onset is at a younger age than in calcium stone disease; the stones are radio-opaque.

Cystine solubility is about 243 mg/L in normal urine and rises with pH. Some patients can excrete as much as 1,000 mg per day.

Treatment^53,54 consists of:

• Hydration, to achieve daily urine volumes of 3 to 3.5 L
• Alkalinization of the urine to a pH higher than 6.5 with potassium alkali (potassium citrate) or sodium bicarbonate
• Reduction of protein and sodium intake to reduce cystine excretion.

If these measures fail, D-penicillamine (Depen), tiopronin (Thiola), or captopril (Capoten)^55–57 can be given to convert the cystine to a more soluble disulfide cysteine-drug complex. Captopril has only a modest effect at best and is usually given with another disulfide-complexing drug; it also has the disadvantage of producing hypotension. Adverse effects of D-penicillamine and tiopronin include abdominal pain, loss of taste, fever, proteinuria, and, in rare cases, nephrotic syndrome.

WORKUP AND MANAGEMENT OF NEPHROLITHIASIS

The diagnostic evaluation of a first stone (Table 2) includes a routine chemistry panel (electrolytes, creatinine, calcium), urinalysis, parathyroid hormone measurement, and helical CT without contrast. Stone analysis should always be done whenever stone material is available.

Anyone under age 20 with an initial stone deserves a more extensive evaluation, including screening for renal tubular acidosis, cystinuria, and hyperoxaluria. A more extensive workup is also warranted in patients with a history of chronic diarrhea, sarcoidosis, or a condition associated with renal tubular acidosis (eg, Sjögren syndrome), in patients with a family history of kidney stones, in patients with high-protein weight-loss diets, and in those undergoing gastric bypass surgery for obesity. In these high-risk patients, the evaluation should include 24-hour urine studies to measure calcium, oxalate, citrate, uric acid, creatinine, sodium, and volume.

Other diagnostic clues are often helpful in the decision to do a more comprehensive evaluation.

• Nephrocalcinosis on roentgenography suggests hyperparathyroidism, medullary sponge kidney, or renal tubular acidosis.
• Hypercalcemia that develops after treatment of hypercalciuria with a thiazide diuretic suggests latent hyperparathyroidism.
• A history of recurrent urinary tract infections or of anatomic abnormalities in the urinary tract should lead to an evaluation for struvite stone disease.
• Uric acid stones should be suspected in a patient with metabolic syndrome or a history of gout and are usually accompanied by a urine pH lower than 5.5.
• A urinalysis showing cystine crystals always indicates cystinuria, which should be confirmed by 24-hour urine cystine determination.
• A family history of renal stones is more common in idiopathic hypercalciuria, cystinuria, primary hyperoxaluria, and renal tubular acidosis.

Kidney stones are not all the same, and neither are their causes (Table 1), treatment, and prevention. This paper reviews the diagnostic approach and pathophysiologic mechanisms for nephrolithiasis in order to provide a rationale for preventive management.

See related article

COMMON AND ON THE INCREASE

Nephrolithiasis is common, with a lifetime prevalence of 10% in men and 5% in women.^1,2 Studies have shown that the prevalence is increasing in the United States. In the second National Health and Nutrition Examination Survey (1988–1994), the prevalence in adults ages 20 to 74 was greater than in the 1976–1980 survey (5.2% vs 3.2%).³ The increase was observed in whites but not in African Americans or Mexican Americans, was greater in men than in women, and was greater with age in each time period.

In addition, stones often recur, and each stone event can be associated with significant metabolic and intervention-related morbidity.

PRESENTATION: SEVERE COLIC

Most patients present with moderate to severe colic, caused by the stone entering the ureter. Stones in the proximal (upper) ureter cause pain in the flank or anterior upper abdomen. When the stone reaches the distal third of the ureter, pain is noted in the ipsilateral testicle or labia. A stone at the junction of the ureter and the bladder often causes dysuria, urgency, and frequency and may be mistaken for a lower urinary tract infection.

Less often, patients present with silent ureteral obstruction, unexplained persistent urinary infection, or painless hematuria. However, even in patients with symptoms, the absence of hematuria does not exclude urolithiasis. In a study of 397 patients presenting with acute symptomatic urolithiasis, 9% did not have hematuria.⁴

The differential diagnosis in a patient with symptoms suggesting renal colic includes:

• Musculoskeletal pain
• Herpes zoster
• Diverticulitis
• Duodenal ulcer
• Cholecystitis
• Pyelonephritis
• Renal infarct
• Renal hemorrhage
• Gynecologic disorders
• Ureteral obstruction from renal papillary necrosis with sloughed papillae, a blood clot, or a ureteral stricture.

HELICAL CT WITHOUT CONTRAST IS THE PREFERED IMAGING STUDY

The diagnosis can be confirmed by computed tomography (CT), renal ultrasonography, or intravenous pyelography.

Helical CT without contrast is the preferred imaging study in patients with suspected nephrolithiasis. It has several advantages over other imaging studies: it requires no radiocontrast material; it shows the distal ureters; it can detect radiolucent stones (ie, uric acid stones), radio-opaque stones, and stones as small as 1 to 2 mm; and it can detect hydronephrosis and intra-abdominal and renal disorders other than stones that could be causing the patient’s symptoms.

In a study in 100 consecutive patients presenting to an emergency department with flank pain, helical CT had a sensitivity of 98%, a specificity of 100%, a positive predictive value of 100%, and a negative predictive value of 97% for the diagnosis of ureteral stones.⁵ In a study of 1,000 consecutive patients with suspected stones, helical CT identified significant, additional, or alternative reasons for the patient’s symptoms in 10% of cases.⁶

Ultrasonography has the advantage of not using radiation, but it is less sensitive for detecting stones and can image only the kidney and the proximal ureter. A retrospective study in 123 patients found that, compared with helical CT as the gold standard, ultrasonography had a sensitivity of 24% and a specificity of 90%.⁷ Ultrasonography may also miss stones smaller than 3 mm in diameter.

Conventional radiography (kidney-ureter-bladder view) is inadequate for diagnosis as it may miss stones in the kidney or ureter (even small radio-opaque stones) and provides no information about possible obstruction.

Intravenous pyelography has few advantages in renal lithiasis, exposes the patient to the risk of radiocontrast infusion and contrast-mediated acute renal injury, and gives less information than noncontrast CT.

MEDICAL MANAGEMENT OF ACUTE STONE EVENTS

Most stones are smaller than 5 mm and readily pass without interventions such as lithotripsy, ureteroscopy, or percutaneous nephrolithotomy. (For more information on these interventions, see the review by Samplaski and colleagues in this issue of the Cleveland Clinic Journal of Medicine.⁸)

Even if the stone is as large as 1 cm, I would let the patient try to pass it spontaneously if it is in the distal ureter, and I would allow up to 4 weeks for this to happen.

For most patients, pain management is paramount. Randomized controlled trials suggest that parenteral nonsteroidal anti-inflammatory drugs (NSAIDs) are as effective as narcotics for controlling the pain of renal colic.⁹ Diclofenac (Voltaren) has been used in several studies.

To hasten stone passage, some recommend inducing high urine flow with oral intake of at least 2 to 3 L of fluids per 24 hours to ensure a urine output of at least 2 L per day.

Drugs may also help the stone to pass. A recent study in 210 patients with ureteral stones averaging 6 mm in diameter showed that tamsulosin (Flomax) increased the likelihood of spontaneous stone passage.¹⁰ A meta-analysis of 693 patients in nine randomized trials concluded that alpha-blockers and calcium channel blockers increased the likelihood of stone passage compared with no treatment.¹¹ Borghi et al,¹² in a randomized, double-blind study in 86 patients with unilateral ureteral stones, reported a higher rate of stone passage in patients treated with methylprednisolone (Medrol) 16 mg/day plus nifedipine (Procardia) 40 mg/day than in those given methylprednisolone alone.

 

PREVENTING RECURRENT STONES: PRINCIPLES AND SPECIFICS

Urinary stone disease recurs in 30% to 50% of patients within 5 years.^1,13,14

In preventing recurrent stones, some principles apply to all patients and some are specific to the type of stone the patient had.

Stones form when the urine is supersaturated

Nephrolithiasis occurs when the concentration of stone-forming salts such as calcium oxalate, calcium phosphate, or uric acid is high. When the concentration is high enough to allow crystals to form or preformed crystals to grow, the urine is said to be supersaturated.

Several facors are the major determinants of whether the urine is supersaturated by different salts:

• Calcium oxalate—low urine volume and high concentrations of calcium and oxalate
• Calcium phosphate—a high urine calcium concentration and alkaline urine
• Uric acid—acidic urine
• Cystine—a high urinary cystine concentration and acidic urine.

Increasing daily fluid intake

Since the urinary concentration of stone-forming salts is strongly affected by the daily urine volume, it follows that increasing daily fluid intake is important in preventing recurrent stone disease.

In one study,¹⁵ 199 patients with a first calcium stone were randomized to a program of high oral fluid intake or no intervention. Five years later, 12 (12%) of the 99 patients in the high-fluid intake group had had a second stone, compared with 27 (27%) in the untreated group (P = .008). Of interest, the baseline 24-hour urine volumes were significantly lower in patients with stones than in 101 normal controls (P = .001), suggesting that habitual low daily fluid intake is a risk factor for calcium stone disease.¹³

PREVENTING CALCIUM STONES

Most stones are composed of calcium oxalate or calcium phosphate. Calcium stone disease occurs most often in the 3rd to 5th decades of life.

Naturally occurring inhibitors of calcium crystal formation in the urine include citrate, nephrocalcin, uropontin, and magnesium. Of these, only citrate and magnesium levels are routinely measured; low levels of citrate are treated as a cause of calcium stone disease. It follows that the risk of calcium nephrolithiasis is the result of the interplay between the supersaturated state and the level of urinary inhibitors.¹⁶

Hypercalciuria and calcium oxalate stones

Calcium oxalate stones begin as crystals that form on the surface of the renal papillae over collections of suburothelial calcium phosphate particles called Randall plaque.¹⁷ The driving force for calcium oxalate overgrowth on plaque is calcium oxalate supersaturation, which is strongly linked to high urinary calcium excretion. The fraction of papillary surface covered by plaque in patients with idiopathic calcium oxalate stones correlates directly with the urine calcium level and inversely with urine volume and pH.¹⁸

Most patients with calcium oxalate stones have hypercalciuria (defined as 24-hour urinary calcium excretion > 300 mg in men, > 250 mg in women, or > 4 mg/kg in men or women).

Hypercalciuria can be idiopathic

Hypercalciuria can occur in primary hyperparathyroidism, sarcoidosis, vitamin D excess, corticosteroid treatment, renal tubular acidosis, hyperthyroidism, and malignant neoplasms. If none of these conditions is present, elevated urinary calcium excretion is considered idiopathic.

Some patients with idiopathic hypercalciuria have a strong family history of hypercalciuria and, likely, a genetic basis for the disease. This condition has been categorized by the presumed site of the primary abnormality:

Absorptive hypercalciuria. Most patients with idiopathic hypercalciuria absorb too much calcium from the intestine. In many of them, 1,25 dihydroxyvitamin D levels are slightly high and serum phosphorous levels are slightly low; the hypothesis is that they produce more 1,25 dihydroxyvitamin D or are more sensitive to it.¹⁹ However, Breslau et al²⁰ showed that not all patients with idiopathic hypercalciuria have absorptive hypercalciuria mediated by 1,25 dihydroxyvitamin D, which suggests that the intestinal hyperabsorption of calcium has other mechanisms.

Resorptive hypercalciuria occurs if increased bone turnover leads to urinary loss of bone calcium.

Renal leak is due to a primary defect in renal tubular transport that causes loss of calcium into the urine and a secondary increase in intestinal calcium absorption or mobilization from bone.

This categorization is based on measuring fasting and 24-hour urine calcium, urinary calcium responses to a low-calcium diet, and responses to an oral calcium load.²¹ However, these studies are difficult to do and have been shown to have minimal clinical value.

To reduce calcium in the urine, limit sodium, give thiazides

Idiopathic hypercalciuria is worsened by a diet high in sodium^22,23 and animal protein.²⁴ Thiazide diuretics lower urinary calcium excretion and promote mineral retention.²⁵ Therefore, treatment of idiopathic hypercalciuria consists of high fluid intake, dietary sodium restriction, and thiazide diuretics.

 

 

Calcium restriction is not advised

For several reasons, a calcium-restricted diet is not advised for patients with idiopathic hypercalciuria. ²⁶ Dietary calcium restriction can put the patient into negative calcium balance. Further, it is thought that with less calcium to bind to dietary oxalate, more unbound oxalate can be absorbed in the colon and eventually excreted in the urine. This increase in urinary oxalate can be to the point of supersaturation, even though urinary calcium levels remain unchanged.^25,27,28 This, in turn, increases the likelihood of stone formation.

Several studies showed that a higher intake of dietary calcium is actually associated with fewer calcium stone events in both men and women.^25,27,28

Further, a study in 120 Italian patients with hypercalciuric calcium oxalate stones concluded that a diet that is normal in calcium, low in sodium, and low in animal protein was associated with a lower frequency of calcium stones than a low-calcium diet.²⁹ Although both diets were associated with a reduction in urinary calcium concentrations, urinary oxalate excretion rose in those on a low-calcium diet and fell in those on a normal-calcium diet. The reduction in urinary oxalate excretion in patients on a normal-calcium diet was attributed to intestinal binding of dietary oxalate by dietary calcium, thus lessening the amount of free oxalate available for absorption. Although calcium oxalate excretion fell in both groups, it fell more in those on a normal calcium intake. Compared with those on a low-calcium diet, the patients on the normal-calcium, low-sodium, low-protein diet had a 50% lower risk of stones at 5 years.

Hyperparathyroidism

Primary hyperparathyroidism can cause hypercalciuria and nephrolithiasis. In one series,³⁰ 56 (4.9%) of 1,132 consecutive patients with nephrolithiasis had a confirmed diagnosis of hyperparathyroidism. Parathyroidectomy prevented subsequent stone disease in 48 patients.

However, only 17% to 24% of patients with primary hyperparathyroidism have urinary stones composed of calcium oxalate or calcium phosphate.^31,32 In many studies, it was difficult to determine why a minority of these patients develop stones, but two studies shed some light on this.

Parks et al³⁰ found that, compared with nephrolithiasis patients with idiopathic hypercalciuria, those with primary hyperparathyroidism have elevated serum calcium levels (but usually < 11.5 mg/dL), greater degrees of hypercalciuria (352 mg/day vs 252 mg/day, P < .001), and lower serum phosphate levels (2.45 vs 3.10 mg/dL, P < .001).

Odvina et al³³ found, in a study of 131 patients with proven primary hyperparathyroidism, that 78 had nephrolithiasis and 53 did not. Those with stones excreted more calcium (343 mg/day) than those without stones (273 mg/day), had a higher urinary saturation of calcium oxalate and brushite, and excreted twice as much calcium following a 1-g oral calcium load.

These studies suggest that in patients with primary hyperparathyroidism, the risk of forming stones is related to the degree of hypercalciuria, and in particular to the increased intestinal absorption of dietary calcium.

Renal tubular acidosis

Features of distal renal tubular acidosis are systemic metabolic acidosis, alkaline urine, hypokalemia, hypercalciuria, hypocitraturia, and nephrolithiasis. The chronic metabolic acidosis results in loss of bone calcium, contributes to hypercalciuria, and is responsible for the hypocitraturia.³⁴ Stone formation is the result of excessive urinary calcium excretion, the deficiency of the urinary crystal inhibitor citrate, and persistently alkaline urine.

Treatment with sodium bicarbonate or potassium citrate corrects the metabolic acidosis, reduces the loss of calcium from bone, corrects hypokalemia, and increases urinary citrate.

Too much uric acid in the urine

Elevated urinary uric acid excretion (> 800 mg/day in men, > 750 mg/day in women) is associated with formation of calcium oxalate stones³⁵ and, in conjunction with low urine pH, with uric acid stones. An increase in dissolved uric acid salts induces heterogeneous calcium oxalate nucleation.³⁶ In one randomized clinical trial,³⁷ giving allopurinol (Zyloprim) lowered urinary uric acid excretion and was associated with a lower rate of calcium stone disease.

Too much oxalate in the urine

The 95th percentile for urinary oxalate excretion is 45 mg/day in women and 55 mg/day in men.³⁸ Hyperoxaluria increases calcium oxalate supersaturation and contributes to calcium stone formation.

Normally, 90% of dietary oxalate binds to dietary calcium in the small intestine and passes into the stool as calcium oxalate; 10% of dietary oxalate remains free and is absorbed in the colon and subsequently excreted in the urine.

Hyperoxaluria may simply be a result of high dietary oxalate intake. However, increased enteric absorption of dietary oxalate can occur in those on a low-calcium diet (in which less calcium is available to bind to dietary oxalate, as described above) and may partially explain why a low-calcium diet has been associated with increased frequency of calcium stone disease.

Patients with enteric malabsorption of fat (eg, due to inflammatory bowel disease or intestinal bypass surgery for obesity) may also develop hyperoxaluria. This occurs because the excess enteric fat binds dietary calcium and allows free oxalate to be more readily absorbed in the colon.³⁹

Rarely, hyperoxaluria is caused by one of several recessively inherited disorders of oxalate metabolism.⁴⁰

The growing number of people with obesity has resulted in an upsurge in gastric bypass surgery. Although the current procedures do not pose the same metabolic risks as were noted in the 1970s when a different type of bypass was performed, the incidence of kidney stones does appear to be higher after these procedures. A recent analysis of 1,436 patients undergoing Roux-en-Y gastric bypass surgery found that 60 of them developed calcium stones afterward. Of these, 31 who underwent metabolic studies were found to have higher oxalate and lower citrate levels at 12 months of follow-up.⁴¹

Not enough citrate, a stone inhibitor

Hypocitraturia is defined as a daily urine citrate excretion less than 500 mg in women and 434 mg in men.⁴² As already mentioned, citrate plays an important role in inhibiting calcium crystal formation and preventing stone formation.

Urinary citrate excretion is mainly determined by tubular reabsorption, which is increased by acid loads and decreased by alkali loads.⁴³ Low urine citrate levels are often seen in conditions that cause chronic metabolic acidosis, such as inflammatory bowel disease, intestinal malabsorption, and renal tubular acidosis—all of which are associated with increased occurrence of nephrolithiasis. However, in most nephrolithiasis patients with hypocitraturia, the cause is not apparent, and the mechanism of the hypocitraturia cannot be determined.⁴⁴

In recent years, high-protein, low-carbohydrate diets have become popular for weight reduction, but they also have metabolic effects that increase the risk of stones.⁴⁵ The metabolism of a diet high in animal protein produces more hydrogen ions that are buffered by bone, releasing calcium from bone and increasing urinary calcium excretion. These diets also cause intracellular acidosis, resulting in decreased urinary excretion of citrate. As a result of these effects, the stone-forming propensity of the urine is increased.

 

STRUVITE STONES MUST BE REMOVED

Struvite stones are the result of chronic upper urinary infection with urease-producing bacteria (Proteus sp, Haemophilus sp, Klebsiella sp, and Ureaplasma urealyticum).^46,47 The hydrolysis of urea yields ammonium and hydroxyl ions and a persistently alkaline urine, and this scenario promotes the formation of stones composed of magnesium ammonium phosphate, ie, struvite.

Struvite stones, which are often branched (“staghorn” stones), occur more often in women and in patients who have chronic urinary obstruction or a neurologic disorder that impairs normal emptying of the bladder.

Treatment requires eradicating the infection with antibiotics and removing the bacteria-laden stones by one of several interventional techniques. Acetohydroxamic acid inhibits urease and has been used to treat struvite stone disease, but it has frequent and serious adverse effects.⁴⁸

URIC ACID STONES FORM IN VERY ACIDIC URINE

Uric acid stones occur especially in patients with unusually low urine pH and hyperuricosuria. In some patients, this very low urine pH is the result of a defect in renal ammonia secretion, which results in less buffering of secreted hydrogen ions.⁴⁹

The tendency to form uric acid stones is reported to be increasing in obese people with the metabolic syndrome. Some studies have shown that the defect in ammonia production by the kidney may be the result of insulin resistance.⁵⁰

Urate stones are radiolucent but can be seen on ultrasonography and helical CT. On helical CT, they can be distinguished from calcium stones by their lower density.⁵¹

Since uric acid is much more soluble in an alkaline solution, both prevention and treatment should consist of alkalinization of urine to a pH of more than 6.0 with oral sodium bicarbonate or citrate solution and hydration. This treatment may actually dissolve uric acid stones. If hyperuricemia or hyperuricosuria is present, allopurinol can be prescribed.

CYSTINE STONES ALSO FORM IN ACIDIC URINE

Cystine stone disease occurs in people who have inherited an autosomally recessive gastrointestinal and renal tubular transport disorder of four amino acids, ie, cystine, ornithine, arginine, and lysine.⁵² Of these, cystine is the most insoluble in normally acidic urine and thus precipitates into stones. The onset is at a younger age than in calcium stone disease; the stones are radio-opaque.

Cystine solubility is about 243 mg/L in normal urine and rises with pH. Some patients can excrete as much as 1,000 mg per day.

Treatment^53,54 consists of:

• Hydration, to achieve daily urine volumes of 3 to 3.5 L
• Alkalinization of the urine to a pH higher than 6.5 with potassium alkali (potassium citrate) or sodium bicarbonate
• Reduction of protein and sodium intake to reduce cystine excretion.

If these measures fail, D-penicillamine (Depen), tiopronin (Thiola), or captopril (Capoten)^55–57 can be given to convert the cystine to a more soluble disulfide cysteine-drug complex. Captopril has only a modest effect at best and is usually given with another disulfide-complexing drug; it also has the disadvantage of producing hypotension. Adverse effects of D-penicillamine and tiopronin include abdominal pain, loss of taste, fever, proteinuria, and, in rare cases, nephrotic syndrome.

WORKUP AND MANAGEMENT OF NEPHROLITHIASIS

The diagnostic evaluation of a first stone (Table 2) includes a routine chemistry panel (electrolytes, creatinine, calcium), urinalysis, parathyroid hormone measurement, and helical CT without contrast. Stone analysis should always be done whenever stone material is available.

Anyone under age 20 with an initial stone deserves a more extensive evaluation, including screening for renal tubular acidosis, cystinuria, and hyperoxaluria. A more extensive workup is also warranted in patients with a history of chronic diarrhea, sarcoidosis, or a condition associated with renal tubular acidosis (eg, Sjögren syndrome), in patients with a family history of kidney stones, in patients with high-protein weight-loss diets, and in those undergoing gastric bypass surgery for obesity. In these high-risk patients, the evaluation should include 24-hour urine studies to measure calcium, oxalate, citrate, uric acid, creatinine, sodium, and volume.

Other diagnostic clues are often helpful in the decision to do a more comprehensive evaluation.

• Nephrocalcinosis on roentgenography suggests hyperparathyroidism, medullary sponge kidney, or renal tubular acidosis.
• Hypercalcemia that develops after treatment of hypercalciuria with a thiazide diuretic suggests latent hyperparathyroidism.
• A history of recurrent urinary tract infections or of anatomic abnormalities in the urinary tract should lead to an evaluation for struvite stone disease.
• Uric acid stones should be suspected in a patient with metabolic syndrome or a history of gout and are usually accompanied by a urine pH lower than 5.5.
• A urinalysis showing cystine crystals always indicates cystinuria, which should be confirmed by 24-hour urine cystine determination.
• A family history of renal stones is more common in idiopathic hypercalciuria, cystinuria, primary hyperoxaluria, and renal tubular acidosis.

Very few patients undergo surgery for stones in the kidney or ureters anymore, now that less-invasive interventions are available, such as extracorporeal shock-wave lithotripsy, ureteroscopic stone removal, and percutaneous nephrolithotomy. Each of these options has advantages and disadvantages, depending on the characteristics of the stone or stones, such as size, number, location, and composition, as well as patient factors such as renal anatomy, body habitus, and comorbidities.

See related article

This article reviews the current interventional management of upper tract urolithiasis.

NOT ALL STONES NEED INTERVENTION

From 10% to 15% of people in the United States develop a stone at some point in their life,^1,2 and this number is increasing.³ Not all of them need intervention (Table 1).

In a patient who has symptoms of urinary obstruction or sepsis, the decision to intervene is obvious. Stones that obstruct the flow of urine often cause symptoms due to distension of the ureter, the renal pelvis, or the renal capsule in a relatively predictable and characteristic pattern of pain originating in the flank and often radiating to the groin, testicle, or labia. And untreated struvite (“staghorn”) stones, a result of infection, can lead to life-threatening sepsis.

However, in patients with asymptomatic stones, the decision may not be clear-cut. Approximately 32% of patients with asymptomatic renal calculi go on to develop symptoms in the next 2.5 years, increasing to 49% at 5 years.³ Of the patients who develop symptoms, half will require a procedure to remove the stone, while half will pass the offending stone spontaneously.³

If even a small amount of stone is left in the kidney after surgery or other intervention, a large stone can form again, and ultimately, the function of that renal unit can decline. For this reason, most renal calculi should be treated or at least followed for signs of progression with serial imaging studies.

Today, although some patients are followed with kidney-ureter-bladder radiographic studies, most undergo computed tomography, which has the advantages of clearly delineating the stone location and size, the presence of small ureteral stones, and the presence and magnitude of hydronephrosis.

If the patient has no refractory symptoms related to obstruction and no signs of infection or of parenchymal damage, then observation with close follow-up is reasonable. However, infection with urinary tract obstruction, urosepsis, intractable pain or vomiting, acute kidney injury, obstruction in a solitary or transplanted kidney, or bilateral obstructing stones are all indications for urgent intervention.

Additionally, some patients who have asymptomatic stones should undergo evaluation and treatment because of their occupation. Examples are airline pilots and soldiers, in whom an episode of intractable renal colic could prove dangerous.

Stones in women

Women who are pregnant or of childbearing age and have an asymptomatic renal stone are not at any higher risk of stone growth and so should be treated the same as any other patient—except that ultrasonography should be used for imaging to minimize radiation exposure. Urine should be sent for culture. From 50% to 80% of these patients will pass their stones spontaneously with hydration and analgesia.⁴

If intervention is required, percutaneous nephrostomy and placement of ureteral stents can be done to expose the patient to the least possible amount of anesthesia or radiation.⁵

Ureteroscopic stone extraction in pregnant patients has also been shown not to cause pregnancy-related complications, and it entails minimal fluoroscopic exposure.⁶

Although lithotripsy has been used inadvertently in pregnant patients, its routine use in pregnant patients remains contraindicated.⁷

MEDICAL EXPULSIVE THERAPY

Conservative management, consisting of oral or intravenous hydration and analgesia, can be tried in patients with renal calculi whose condition is otherwise stable. Typically, intravenous hydration is given at a maintenance rate.⁸ Analgesia can be provided with both nonsteroidal anti-inflammatory drugs (NSAIDs) and narcotics, although NSAIDs, in particular ketorolac (Toradol), provide the best pain control.⁹

Calcium channel blockers and alphablockers inhibit ureteral spasms and promote the spontaneous passage of ureteral calculi.¹⁰ Compared with hydration alone, nifedipine (Procardia) has been shown to lead to an absolute increase of 9% in stone passage rates, and alpha-blockers have produced an absolute increase of 29%.¹¹ These drugs can be given in conjunction with corticosteroids to reduce ureteral edema, which may contribute to stone retention in the ureter.¹²

As of this date, medical expulsive therapy is well established only for stones in the lower (distal) ureter. The applicability of this treatment for stones in the proximal ureter and kidney is still being investigated. In patients who have stones smaller than 1 cm in diameter and whose symptoms are under control, observation with medical expulsive therapy may well be appropriate. However, after 4 weeks, intervention is indicated, as the risk of complications and renal deterioration increase.

STONE SURGERY HAS BECOME RARE

Before the advent of lithotripsy and ureteroscopy (see below), most patients with symptomatic upper tract calculi underwent open surgical lithotomy. Many variations of pyelolithotomy and nephrolithotomy were performed, even bench surgery with autotransplantation (ie, removing the kidney, removing the stone, and then reimplanting the kidney). However, lithotripsy and ureteroscopic extraction have dramatically reduced the role of open stone surgery: it is currently done in only 0.3% to 0.7% of cases.^13,14

Laparoscopic surgery for renal calculi is also rarely done. Although almost every type of stone procedure has been done laparoscopically,^15–19 this approach is indicated only in situations in which lithotripsy or ureteroscopic treatment is expected to fail.

 

LESS-INVASIVE OPTIONS

Lithotripsy for small renal stones

Lithotripsy breaks up urinary calculi. In this noninvasive outpatient procedure, a generator creates a shock wave that is propagated toward a fixed focus centered on the stone (Figure 1).

Soon after it became available, lithotripsy became immensely popular because of its ability to break up stones without surgery. Ureteroscopic treatment has assumed a bigger role in recent years because it is more versatile, but lithotripsy remains the most common treatment for urolithiasis.

Advantages, uses. Lithotripsy is generally indicated for renal stones smaller than 2 cm,²⁰ especially those not located in the calyx in the lower pole. It is most effective for stones in the renal pelvis (76% of patients become stone-free), and least effective for stones in the lower pole (59% stone-free).²¹ For this reason, for stones in the lower pole, only those smaller than 1 cm in diameter are treated with lithotripsy.

In the past, lithotripsy was also favored in patients who had stones in the proximal ureter, an area that was technically difficult to access with a ureteroscope. Recent advances in ureteroscope design have all but eliminated this difficulty.

Disadvantages. Lithotripsy can damage nearly any structure in the trajectory of the shock wave, causing bleeding, inflammation, or perforation. It can also cause disturbances in cardiac electrical signal transmission, leading to cardiac arrhythmias during treatment. Long-term concerns include a possible link between lithotripsy and the development of diabetes and hypertension.²² Lithotripsy is contraindicated in pregnancy and coagulopathic states and is less effective in morbidly obese patients.

Lithotripsy is more likely to fail if the skinto-stone distance is more than 10 mm, if the lower pole forms an acute angle with the ureter, or if the body mass index is greater than 30 kg/m² (ie, if the patient is obese).²³

Percutaneous nephrolithotomy for large or staghorn stones

Percutaneous nephrolithotomy is highly effective for renal calculi but is associated with more complications than lithotripsy or ureteroscopy. It involves inserting a needle through the skin into the renal collecting system and then dilating the tract to approximately 1 cm. Instruments are then inserted through this tract to break up and remove stones. In contrast to laparoscopy, no insufflation is used; the percutaneous tract provides direct access to the kidney for stone removal.

Advantages, uses. Outcomes of percutaneous nephrolithotomy are uniformly favorable across a wide spectrum of stone sizes, compositions, and locations.

Percutaneous nephrolithotomy is indicated in patients who have renal or ureteral stones larger than 2 cm or lower-pole stones larger than 1 cm (Figure 1).^24,25

Staghorn stones, commonly associated with infection, lead to renal destruction with significant risk of morbidity and even death if left untreated.²⁶ Because they must be completely removed, which is often difficult or impossible to do with ureteroscopy or lithotripsy, percutaneous nephrolithotomy is the first-line treatment.²⁴

Disadvantages. Percutaneous nephrolithotomy is invasive and carries the associated risks of any major surgical procedure, including sepsis, perirenal hematoma or bleeding, and inadvertent injury to adjacent organs, including the pleurae, lungs, bowel, or spleen.

Ureteroscopy has improved

With improvements in design, stone treatment with flexible and semirigid ureteroscopy have become major options for urinary calculi, even those as far up as the kidney (Figure 1).

Advantages, uses. Ureteroscopy offers a low risk of complications (similar to that of lithotripsy), and stone-free rates approach those of percutaneous nephrolithotomy for small to moderate-sized renal stones.^27,28 Outcomes are best for stones smaller than 1 cm, with residual fragments being seen with larger stones.

New flexible ureteroscopes that deflect up to 270° allow stones in the lower pole to be treated successfully.²⁹ In conjunction with laser lithotripsy, ureteroscopy can be used to successfully treat hard stones (density > 1,000 Hounsfield units), stones in obese patients, and stones refractory to lithotripsy.

Rates of complications and second procedures are low, and, compared with lithotripsy, ureteroscopy takes less time to clear the stone.³⁰ Ureteroscopy can also be used to treat stones in kidneys with complex anatomy, in which poor clearance of fragments may be a problem.²⁸ It may also be used in coagulopathic, pregnant, or morbidly obese patients, in whom lithotripsy or percutaneous nephrolithotomy is less effective or contraindicated.

Disadvantages. Of note, ureteroscopy is a surgical skill, and better outcomes are obtained by surgeons with more experience.³¹

Complications of ureteroscopy include ureteral stricture, perforation, thermal injury, avulsion, intussusception, infection, or steinstrasse (obstruction with fragments of stones). In addition, after ureteroscopy, a temporary ureteral stent is often placed: the stent may cause discomfort and requires a minor adjunctive procedure for removal.

 

FACTORS THAT AFFECT THE CHOICE OF TREATMENT

Size and location of the stone

The most important predictors of spontaneous passage of ureteral stones are size and location. In general, small stones are more likely to pass spontaneously than large ones, and distal stones are more likely to pass than stones more proximal in the urinary tract.

Stones are typically classified as either ureteral (proximal, middle, or distal) or renal (pelvic or calyceal), depending on their location.

In the ureter. Most ureteral stones smaller than 5 mm in diameter pass spontaneously within 4 weeks of the onset of symptoms.^25,32 In patients who have stones smaller than 1 cm, whose pain is controlled, and who show no evidence of sepsis or renal insufficiency, a period of observation is a reasonable option.¹¹ Medications such as tamsulosin (Flomax) and nifedipine have been shown to reduce the need for analgesia and to reduce the time to stone passage.^33,34

Lithotripsy and ureteroscopy are the two primary interventions for ureteral calculi.

Regardless of size, stones in the ureter can usually be removed by ureteroscopy. This may involve laser or pneumatic lithotripsy within the ureter or simple ureteroscopic basket retrieval of the intact stone. In situ lithotripsy is an option for proximal ureteral calculi and may be favored by patients who wish to avoid placement of a ureteral stent at the time of intervention. Percutaneous nephrolithotomy is reserved for large (> 2-cm) or impacted proximal ureteral stones, or for cases in which ureteroscopy has failed.³⁵

For stones in the proximal ureter, no difference has been shown in stone passage rates between lithotripsy and ureteroscopy. For proximal stones smaller than 1 cm, lithotripsy has a higher stone-free rate, and for stones larger than 1 cm, ureteroscopy has been shown to have superior stone-free rates.¹¹

For mid-ureteral and distal ureteral stones of all sizes, ureteroscopy has been shown to have superior stone-free rates, although the difference is statistically significant only for distal stones.¹¹

In the kidney. Large renal stones (> 2 cm) or staghorn calculi within the renal collecting system are best treated with percutaneous nephrolithotomy, whereas renal stones smaller than 1 cm can usually be treated ureteroscopically or with lithotripsy.

Stones within the renal collecting system measuring between 1 and 2 cm in diameter can be treated with ureteroscopy, lithotripsy, percutaneous nephrolithotomy, or a combination, depending on the location and composition of the stone and the wishes of patient.

Stone composition

Cystine stones and calcium oxalate stones are hard, with a density greater than 1,000 Hounsfield units. Lithotripsy has a high failure rate with these types of stones.³⁶

Uric acid stones are softer and do not show up well on x-ray imaging. While it is technically feasible to perform lithotripsy under ultrasonographic guidance, most practitioners prefer to use fluoroscopy to locate the stone. For this reason, patients with radiolucent stones (ie, uric acid stones) are also not good candidates for lithotripsy.

Struvite (staghorn) stones are by definition infected, with bacteria residing within the stone itself. Thus, it is imperative to remove all stone fragments during treatment to prevent sepsis and stone reformation. Over time, an untreated staghorn calculus will lead to failure of the renal unit.

Although lithotripsy, ureteroscopy, and percutaneous nephrolithotomy can all be used to treat staghorn calculi, percutaneous nephrolithotomy has the best stone-free rate (78%), and lithotripsy has the lowest (54%).²⁴ Therefore, percutaneous nephrolithotomy is recommended as the first treatment for these stones, and if combination therapy is used, then percutaneous nephrolithotomy should be done last to ensure that the stone is completely removed.²⁴ If lithotomy is to be used, drainage of the renal unit must be done in advance with either percutaneous nephrostomy or a ureteral stent, to ensure that all infected stone fragments will be flushed out.²⁴

PREVENTING RECURRENCES

Metabolic abnormalities that increase the risk of urolithiasis can be identified and treated in up to 95% of patients who form recurrent stones.³⁷ Most of these patients require simple dietary modifications, and just 15% require pharmacotherapy. (For more on this topic, see the review by Dr. Phillip Hall in this issue of the Journal.³⁸) As urolithiasis is common and often recurrent, the appropriate interventive management, combined with dietary prophylaxis, should minimize patient morbidity and preserve renal function.

Very few patients undergo surgery for stones in the kidney or ureters anymore, now that less-invasive interventions are available, such as extracorporeal shock-wave lithotripsy, ureteroscopic stone removal, and percutaneous nephrolithotomy. Each of these options has advantages and disadvantages, depending on the characteristics of the stone or stones, such as size, number, location, and composition, as well as patient factors such as renal anatomy, body habitus, and comorbidities.

See related article

This article reviews the current interventional management of upper tract urolithiasis.

NOT ALL STONES NEED INTERVENTION

From 10% to 15% of people in the United States develop a stone at some point in their life,^1,2 and this number is increasing.³ Not all of them need intervention (Table 1).

In a patient who has symptoms of urinary obstruction or sepsis, the decision to intervene is obvious. Stones that obstruct the flow of urine often cause symptoms due to distension of the ureter, the renal pelvis, or the renal capsule in a relatively predictable and characteristic pattern of pain originating in the flank and often radiating to the groin, testicle, or labia. And untreated struvite (“staghorn”) stones, a result of infection, can lead to life-threatening sepsis.

However, in patients with asymptomatic stones, the decision may not be clear-cut. Approximately 32% of patients with asymptomatic renal calculi go on to develop symptoms in the next 2.5 years, increasing to 49% at 5 years.³ Of the patients who develop symptoms, half will require a procedure to remove the stone, while half will pass the offending stone spontaneously.³

If even a small amount of stone is left in the kidney after surgery or other intervention, a large stone can form again, and ultimately, the function of that renal unit can decline. For this reason, most renal calculi should be treated or at least followed for signs of progression with serial imaging studies.

Today, although some patients are followed with kidney-ureter-bladder radiographic studies, most undergo computed tomography, which has the advantages of clearly delineating the stone location and size, the presence of small ureteral stones, and the presence and magnitude of hydronephrosis.

If the patient has no refractory symptoms related to obstruction and no signs of infection or of parenchymal damage, then observation with close follow-up is reasonable. However, infection with urinary tract obstruction, urosepsis, intractable pain or vomiting, acute kidney injury, obstruction in a solitary or transplanted kidney, or bilateral obstructing stones are all indications for urgent intervention.

Additionally, some patients who have asymptomatic stones should undergo evaluation and treatment because of their occupation. Examples are airline pilots and soldiers, in whom an episode of intractable renal colic could prove dangerous.

Stones in women

Women who are pregnant or of childbearing age and have an asymptomatic renal stone are not at any higher risk of stone growth and so should be treated the same as any other patient—except that ultrasonography should be used for imaging to minimize radiation exposure. Urine should be sent for culture. From 50% to 80% of these patients will pass their stones spontaneously with hydration and analgesia.⁴

If intervention is required, percutaneous nephrostomy and placement of ureteral stents can be done to expose the patient to the least possible amount of anesthesia or radiation.⁵

Ureteroscopic stone extraction in pregnant patients has also been shown not to cause pregnancy-related complications, and it entails minimal fluoroscopic exposure.⁶

Although lithotripsy has been used inadvertently in pregnant patients, its routine use in pregnant patients remains contraindicated.⁷

MEDICAL EXPULSIVE THERAPY

Conservative management, consisting of oral or intravenous hydration and analgesia, can be tried in patients with renal calculi whose condition is otherwise stable. Typically, intravenous hydration is given at a maintenance rate.⁸ Analgesia can be provided with both nonsteroidal anti-inflammatory drugs (NSAIDs) and narcotics, although NSAIDs, in particular ketorolac (Toradol), provide the best pain control.⁹

Calcium channel blockers and alphablockers inhibit ureteral spasms and promote the spontaneous passage of ureteral calculi.¹⁰ Compared with hydration alone, nifedipine (Procardia) has been shown to lead to an absolute increase of 9% in stone passage rates, and alpha-blockers have produced an absolute increase of 29%.¹¹ These drugs can be given in conjunction with corticosteroids to reduce ureteral edema, which may contribute to stone retention in the ureter.¹²

As of this date, medical expulsive therapy is well established only for stones in the lower (distal) ureter. The applicability of this treatment for stones in the proximal ureter and kidney is still being investigated. In patients who have stones smaller than 1 cm in diameter and whose symptoms are under control, observation with medical expulsive therapy may well be appropriate. However, after 4 weeks, intervention is indicated, as the risk of complications and renal deterioration increase.

STONE SURGERY HAS BECOME RARE

Before the advent of lithotripsy and ureteroscopy (see below), most patients with symptomatic upper tract calculi underwent open surgical lithotomy. Many variations of pyelolithotomy and nephrolithotomy were performed, even bench surgery with autotransplantation (ie, removing the kidney, removing the stone, and then reimplanting the kidney). However, lithotripsy and ureteroscopic extraction have dramatically reduced the role of open stone surgery: it is currently done in only 0.3% to 0.7% of cases.^13,14

Laparoscopic surgery for renal calculi is also rarely done. Although almost every type of stone procedure has been done laparoscopically,^15–19 this approach is indicated only in situations in which lithotripsy or ureteroscopic treatment is expected to fail.

 

LESS-INVASIVE OPTIONS

Lithotripsy for small renal stones

Lithotripsy breaks up urinary calculi. In this noninvasive outpatient procedure, a generator creates a shock wave that is propagated toward a fixed focus centered on the stone (Figure 1).

Soon after it became available, lithotripsy became immensely popular because of its ability to break up stones without surgery. Ureteroscopic treatment has assumed a bigger role in recent years because it is more versatile, but lithotripsy remains the most common treatment for urolithiasis.

Advantages, uses. Lithotripsy is generally indicated for renal stones smaller than 2 cm,²⁰ especially those not located in the calyx in the lower pole. It is most effective for stones in the renal pelvis (76% of patients become stone-free), and least effective for stones in the lower pole (59% stone-free).²¹ For this reason, for stones in the lower pole, only those smaller than 1 cm in diameter are treated with lithotripsy.

In the past, lithotripsy was also favored in patients who had stones in the proximal ureter, an area that was technically difficult to access with a ureteroscope. Recent advances in ureteroscope design have all but eliminated this difficulty.

Disadvantages. Lithotripsy can damage nearly any structure in the trajectory of the shock wave, causing bleeding, inflammation, or perforation. It can also cause disturbances in cardiac electrical signal transmission, leading to cardiac arrhythmias during treatment. Long-term concerns include a possible link between lithotripsy and the development of diabetes and hypertension.²² Lithotripsy is contraindicated in pregnancy and coagulopathic states and is less effective in morbidly obese patients.

Lithotripsy is more likely to fail if the skinto-stone distance is more than 10 mm, if the lower pole forms an acute angle with the ureter, or if the body mass index is greater than 30 kg/m² (ie, if the patient is obese).²³

Percutaneous nephrolithotomy for large or staghorn stones

Percutaneous nephrolithotomy is highly effective for renal calculi but is associated with more complications than lithotripsy or ureteroscopy. It involves inserting a needle through the skin into the renal collecting system and then dilating the tract to approximately 1 cm. Instruments are then inserted through this tract to break up and remove stones. In contrast to laparoscopy, no insufflation is used; the percutaneous tract provides direct access to the kidney for stone removal.

Advantages, uses. Outcomes of percutaneous nephrolithotomy are uniformly favorable across a wide spectrum of stone sizes, compositions, and locations.

Percutaneous nephrolithotomy is indicated in patients who have renal or ureteral stones larger than 2 cm or lower-pole stones larger than 1 cm (Figure 1).^24,25

Staghorn stones, commonly associated with infection, lead to renal destruction with significant risk of morbidity and even death if left untreated.²⁶ Because they must be completely removed, which is often difficult or impossible to do with ureteroscopy or lithotripsy, percutaneous nephrolithotomy is the first-line treatment.²⁴

Disadvantages. Percutaneous nephrolithotomy is invasive and carries the associated risks of any major surgical procedure, including sepsis, perirenal hematoma or bleeding, and inadvertent injury to adjacent organs, including the pleurae, lungs, bowel, or spleen.

Ureteroscopy has improved

With improvements in design, stone treatment with flexible and semirigid ureteroscopy have become major options for urinary calculi, even those as far up as the kidney (Figure 1).

Advantages, uses. Ureteroscopy offers a low risk of complications (similar to that of lithotripsy), and stone-free rates approach those of percutaneous nephrolithotomy for small to moderate-sized renal stones.^27,28 Outcomes are best for stones smaller than 1 cm, with residual fragments being seen with larger stones.

New flexible ureteroscopes that deflect up to 270° allow stones in the lower pole to be treated successfully.²⁹ In conjunction with laser lithotripsy, ureteroscopy can be used to successfully treat hard stones (density > 1,000 Hounsfield units), stones in obese patients, and stones refractory to lithotripsy.

Rates of complications and second procedures are low, and, compared with lithotripsy, ureteroscopy takes less time to clear the stone.³⁰ Ureteroscopy can also be used to treat stones in kidneys with complex anatomy, in which poor clearance of fragments may be a problem.²⁸ It may also be used in coagulopathic, pregnant, or morbidly obese patients, in whom lithotripsy or percutaneous nephrolithotomy is less effective or contraindicated.

Disadvantages. Of note, ureteroscopy is a surgical skill, and better outcomes are obtained by surgeons with more experience.³¹

Complications of ureteroscopy include ureteral stricture, perforation, thermal injury, avulsion, intussusception, infection, or steinstrasse (obstruction with fragments of stones). In addition, after ureteroscopy, a temporary ureteral stent is often placed: the stent may cause discomfort and requires a minor adjunctive procedure for removal.

 

FACTORS THAT AFFECT THE CHOICE OF TREATMENT

Size and location of the stone

The most important predictors of spontaneous passage of ureteral stones are size and location. In general, small stones are more likely to pass spontaneously than large ones, and distal stones are more likely to pass than stones more proximal in the urinary tract.

Stones are typically classified as either ureteral (proximal, middle, or distal) or renal (pelvic or calyceal), depending on their location.

In the ureter. Most ureteral stones smaller than 5 mm in diameter pass spontaneously within 4 weeks of the onset of symptoms.^25,32 In patients who have stones smaller than 1 cm, whose pain is controlled, and who show no evidence of sepsis or renal insufficiency, a period of observation is a reasonable option.¹¹ Medications such as tamsulosin (Flomax) and nifedipine have been shown to reduce the need for analgesia and to reduce the time to stone passage.^33,34

Lithotripsy and ureteroscopy are the two primary interventions for ureteral calculi.

Regardless of size, stones in the ureter can usually be removed by ureteroscopy. This may involve laser or pneumatic lithotripsy within the ureter or simple ureteroscopic basket retrieval of the intact stone. In situ lithotripsy is an option for proximal ureteral calculi and may be favored by patients who wish to avoid placement of a ureteral stent at the time of intervention. Percutaneous nephrolithotomy is reserved for large (> 2-cm) or impacted proximal ureteral stones, or for cases in which ureteroscopy has failed.³⁵

For stones in the proximal ureter, no difference has been shown in stone passage rates between lithotripsy and ureteroscopy. For proximal stones smaller than 1 cm, lithotripsy has a higher stone-free rate, and for stones larger than 1 cm, ureteroscopy has been shown to have superior stone-free rates.¹¹

For mid-ureteral and distal ureteral stones of all sizes, ureteroscopy has been shown to have superior stone-free rates, although the difference is statistically significant only for distal stones.¹¹

In the kidney. Large renal stones (> 2 cm) or staghorn calculi within the renal collecting system are best treated with percutaneous nephrolithotomy, whereas renal stones smaller than 1 cm can usually be treated ureteroscopically or with lithotripsy.

Stones within the renal collecting system measuring between 1 and 2 cm in diameter can be treated with ureteroscopy, lithotripsy, percutaneous nephrolithotomy, or a combination, depending on the location and composition of the stone and the wishes of patient.

Stone composition

Cystine stones and calcium oxalate stones are hard, with a density greater than 1,000 Hounsfield units. Lithotripsy has a high failure rate with these types of stones.³⁶

Uric acid stones are softer and do not show up well on x-ray imaging. While it is technically feasible to perform lithotripsy under ultrasonographic guidance, most practitioners prefer to use fluoroscopy to locate the stone. For this reason, patients with radiolucent stones (ie, uric acid stones) are also not good candidates for lithotripsy.

Struvite (staghorn) stones are by definition infected, with bacteria residing within the stone itself. Thus, it is imperative to remove all stone fragments during treatment to prevent sepsis and stone reformation. Over time, an untreated staghorn calculus will lead to failure of the renal unit.

Although lithotripsy, ureteroscopy, and percutaneous nephrolithotomy can all be used to treat staghorn calculi, percutaneous nephrolithotomy has the best stone-free rate (78%), and lithotripsy has the lowest (54%).²⁴ Therefore, percutaneous nephrolithotomy is recommended as the first treatment for these stones, and if combination therapy is used, then percutaneous nephrolithotomy should be done last to ensure that the stone is completely removed.²⁴ If lithotomy is to be used, drainage of the renal unit must be done in advance with either percutaneous nephrostomy or a ureteral stent, to ensure that all infected stone fragments will be flushed out.²⁴

PREVENTING RECURRENCES

Metabolic abnormalities that increase the risk of urolithiasis can be identified and treated in up to 95% of patients who form recurrent stones.³⁷ Most of these patients require simple dietary modifications, and just 15% require pharmacotherapy. (For more on this topic, see the review by Dr. Phillip Hall in this issue of the Journal.³⁸) As urolithiasis is common and often recurrent, the appropriate interventive management, combined with dietary prophylaxis, should minimize patient morbidity and preserve renal function.

Very few patients undergo surgery for stones in the kidney or ureters anymore, now that less-invasive interventions are available, such as extracorporeal shock-wave lithotripsy, ureteroscopic stone removal, and percutaneous nephrolithotomy. Each of these options has advantages and disadvantages, depending on the characteristics of the stone or stones, such as size, number, location, and composition, as well as patient factors such as renal anatomy, body habitus, and comorbidities.

See related article

This article reviews the current interventional management of upper tract urolithiasis.

NOT ALL STONES NEED INTERVENTION

From 10% to 15% of people in the United States develop a stone at some point in their life,^1,2 and this number is increasing.³ Not all of them need intervention (Table 1).

In a patient who has symptoms of urinary obstruction or sepsis, the decision to intervene is obvious. Stones that obstruct the flow of urine often cause symptoms due to distension of the ureter, the renal pelvis, or the renal capsule in a relatively predictable and characteristic pattern of pain originating in the flank and often radiating to the groin, testicle, or labia. And untreated struvite (“staghorn”) stones, a result of infection, can lead to life-threatening sepsis.

However, in patients with asymptomatic stones, the decision may not be clear-cut. Approximately 32% of patients with asymptomatic renal calculi go on to develop symptoms in the next 2.5 years, increasing to 49% at 5 years.³ Of the patients who develop symptoms, half will require a procedure to remove the stone, while half will pass the offending stone spontaneously.³

If even a small amount of stone is left in the kidney after surgery or other intervention, a large stone can form again, and ultimately, the function of that renal unit can decline. For this reason, most renal calculi should be treated or at least followed for signs of progression with serial imaging studies.

Today, although some patients are followed with kidney-ureter-bladder radiographic studies, most undergo computed tomography, which has the advantages of clearly delineating the stone location and size, the presence of small ureteral stones, and the presence and magnitude of hydronephrosis.

If the patient has no refractory symptoms related to obstruction and no signs of infection or of parenchymal damage, then observation with close follow-up is reasonable. However, infection with urinary tract obstruction, urosepsis, intractable pain or vomiting, acute kidney injury, obstruction in a solitary or transplanted kidney, or bilateral obstructing stones are all indications for urgent intervention.

Additionally, some patients who have asymptomatic stones should undergo evaluation and treatment because of their occupation. Examples are airline pilots and soldiers, in whom an episode of intractable renal colic could prove dangerous.

Stones in women

Women who are pregnant or of childbearing age and have an asymptomatic renal stone are not at any higher risk of stone growth and so should be treated the same as any other patient—except that ultrasonography should be used for imaging to minimize radiation exposure. Urine should be sent for culture. From 50% to 80% of these patients will pass their stones spontaneously with hydration and analgesia.⁴

If intervention is required, percutaneous nephrostomy and placement of ureteral stents can be done to expose the patient to the least possible amount of anesthesia or radiation.⁵

Ureteroscopic stone extraction in pregnant patients has also been shown not to cause pregnancy-related complications, and it entails minimal fluoroscopic exposure.⁶

Although lithotripsy has been used inadvertently in pregnant patients, its routine use in pregnant patients remains contraindicated.⁷

MEDICAL EXPULSIVE THERAPY

Conservative management, consisting of oral or intravenous hydration and analgesia, can be tried in patients with renal calculi whose condition is otherwise stable. Typically, intravenous hydration is given at a maintenance rate.⁸ Analgesia can be provided with both nonsteroidal anti-inflammatory drugs (NSAIDs) and narcotics, although NSAIDs, in particular ketorolac (Toradol), provide the best pain control.⁹

Calcium channel blockers and alphablockers inhibit ureteral spasms and promote the spontaneous passage of ureteral calculi.¹⁰ Compared with hydration alone, nifedipine (Procardia) has been shown to lead to an absolute increase of 9% in stone passage rates, and alpha-blockers have produced an absolute increase of 29%.¹¹ These drugs can be given in conjunction with corticosteroids to reduce ureteral edema, which may contribute to stone retention in the ureter.¹²

As of this date, medical expulsive therapy is well established only for stones in the lower (distal) ureter. The applicability of this treatment for stones in the proximal ureter and kidney is still being investigated. In patients who have stones smaller than 1 cm in diameter and whose symptoms are under control, observation with medical expulsive therapy may well be appropriate. However, after 4 weeks, intervention is indicated, as the risk of complications and renal deterioration increase.

STONE SURGERY HAS BECOME RARE

Before the advent of lithotripsy and ureteroscopy (see below), most patients with symptomatic upper tract calculi underwent open surgical lithotomy. Many variations of pyelolithotomy and nephrolithotomy were performed, even bench surgery with autotransplantation (ie, removing the kidney, removing the stone, and then reimplanting the kidney). However, lithotripsy and ureteroscopic extraction have dramatically reduced the role of open stone surgery: it is currently done in only 0.3% to 0.7% of cases.^13,14

Laparoscopic surgery for renal calculi is also rarely done. Although almost every type of stone procedure has been done laparoscopically,^15–19 this approach is indicated only in situations in which lithotripsy or ureteroscopic treatment is expected to fail.

 

LESS-INVASIVE OPTIONS

Lithotripsy for small renal stones

Lithotripsy breaks up urinary calculi. In this noninvasive outpatient procedure, a generator creates a shock wave that is propagated toward a fixed focus centered on the stone (Figure 1).

Soon after it became available, lithotripsy became immensely popular because of its ability to break up stones without surgery. Ureteroscopic treatment has assumed a bigger role in recent years because it is more versatile, but lithotripsy remains the most common treatment for urolithiasis.

Advantages, uses. Lithotripsy is generally indicated for renal stones smaller than 2 cm,²⁰ especially those not located in the calyx in the lower pole. It is most effective for stones in the renal pelvis (76% of patients become stone-free), and least effective for stones in the lower pole (59% stone-free).²¹ For this reason, for stones in the lower pole, only those smaller than 1 cm in diameter are treated with lithotripsy.

In the past, lithotripsy was also favored in patients who had stones in the proximal ureter, an area that was technically difficult to access with a ureteroscope. Recent advances in ureteroscope design have all but eliminated this difficulty.

Disadvantages. Lithotripsy can damage nearly any structure in the trajectory of the shock wave, causing bleeding, inflammation, or perforation. It can also cause disturbances in cardiac electrical signal transmission, leading to cardiac arrhythmias during treatment. Long-term concerns include a possible link between lithotripsy and the development of diabetes and hypertension.²² Lithotripsy is contraindicated in pregnancy and coagulopathic states and is less effective in morbidly obese patients.

Lithotripsy is more likely to fail if the skinto-stone distance is more than 10 mm, if the lower pole forms an acute angle with the ureter, or if the body mass index is greater than 30 kg/m² (ie, if the patient is obese).²³

Percutaneous nephrolithotomy for large or staghorn stones

Percutaneous nephrolithotomy is highly effective for renal calculi but is associated with more complications than lithotripsy or ureteroscopy. It involves inserting a needle through the skin into the renal collecting system and then dilating the tract to approximately 1 cm. Instruments are then inserted through this tract to break up and remove stones. In contrast to laparoscopy, no insufflation is used; the percutaneous tract provides direct access to the kidney for stone removal.

Advantages, uses. Outcomes of percutaneous nephrolithotomy are uniformly favorable across a wide spectrum of stone sizes, compositions, and locations.

Percutaneous nephrolithotomy is indicated in patients who have renal or ureteral stones larger than 2 cm or lower-pole stones larger than 1 cm (Figure 1).^24,25

Staghorn stones, commonly associated with infection, lead to renal destruction with significant risk of morbidity and even death if left untreated.²⁶ Because they must be completely removed, which is often difficult or impossible to do with ureteroscopy or lithotripsy, percutaneous nephrolithotomy is the first-line treatment.²⁴

Disadvantages. Percutaneous nephrolithotomy is invasive and carries the associated risks of any major surgical procedure, including sepsis, perirenal hematoma or bleeding, and inadvertent injury to adjacent organs, including the pleurae, lungs, bowel, or spleen.

Ureteroscopy has improved

With improvements in design, stone treatment with flexible and semirigid ureteroscopy have become major options for urinary calculi, even those as far up as the kidney (Figure 1).

Advantages, uses. Ureteroscopy offers a low risk of complications (similar to that of lithotripsy), and stone-free rates approach those of percutaneous nephrolithotomy for small to moderate-sized renal stones.^27,28 Outcomes are best for stones smaller than 1 cm, with residual fragments being seen with larger stones.

New flexible ureteroscopes that deflect up to 270° allow stones in the lower pole to be treated successfully.²⁹ In conjunction with laser lithotripsy, ureteroscopy can be used to successfully treat hard stones (density > 1,000 Hounsfield units), stones in obese patients, and stones refractory to lithotripsy.

Rates of complications and second procedures are low, and, compared with lithotripsy, ureteroscopy takes less time to clear the stone.³⁰ Ureteroscopy can also be used to treat stones in kidneys with complex anatomy, in which poor clearance of fragments may be a problem.²⁸ It may also be used in coagulopathic, pregnant, or morbidly obese patients, in whom lithotripsy or percutaneous nephrolithotomy is less effective or contraindicated.

Disadvantages. Of note, ureteroscopy is a surgical skill, and better outcomes are obtained by surgeons with more experience.³¹

Complications of ureteroscopy include ureteral stricture, perforation, thermal injury, avulsion, intussusception, infection, or steinstrasse (obstruction with fragments of stones). In addition, after ureteroscopy, a temporary ureteral stent is often placed: the stent may cause discomfort and requires a minor adjunctive procedure for removal.

 

FACTORS THAT AFFECT THE CHOICE OF TREATMENT

Size and location of the stone

The most important predictors of spontaneous passage of ureteral stones are size and location. In general, small stones are more likely to pass spontaneously than large ones, and distal stones are more likely to pass than stones more proximal in the urinary tract.

Stones are typically classified as either ureteral (proximal, middle, or distal) or renal (pelvic or calyceal), depending on their location.

In the ureter. Most ureteral stones smaller than 5 mm in diameter pass spontaneously within 4 weeks of the onset of symptoms.^25,32 In patients who have stones smaller than 1 cm, whose pain is controlled, and who show no evidence of sepsis or renal insufficiency, a period of observation is a reasonable option.¹¹ Medications such as tamsulosin (Flomax) and nifedipine have been shown to reduce the need for analgesia and to reduce the time to stone passage.^33,34

Lithotripsy and ureteroscopy are the two primary interventions for ureteral calculi.

Regardless of size, stones in the ureter can usually be removed by ureteroscopy. This may involve laser or pneumatic lithotripsy within the ureter or simple ureteroscopic basket retrieval of the intact stone. In situ lithotripsy is an option for proximal ureteral calculi and may be favored by patients who wish to avoid placement of a ureteral stent at the time of intervention. Percutaneous nephrolithotomy is reserved for large (> 2-cm) or impacted proximal ureteral stones, or for cases in which ureteroscopy has failed.³⁵

For stones in the proximal ureter, no difference has been shown in stone passage rates between lithotripsy and ureteroscopy. For proximal stones smaller than 1 cm, lithotripsy has a higher stone-free rate, and for stones larger than 1 cm, ureteroscopy has been shown to have superior stone-free rates.¹¹

For mid-ureteral and distal ureteral stones of all sizes, ureteroscopy has been shown to have superior stone-free rates, although the difference is statistically significant only for distal stones.¹¹

In the kidney. Large renal stones (> 2 cm) or staghorn calculi within the renal collecting system are best treated with percutaneous nephrolithotomy, whereas renal stones smaller than 1 cm can usually be treated ureteroscopically or with lithotripsy.

Stones within the renal collecting system measuring between 1 and 2 cm in diameter can be treated with ureteroscopy, lithotripsy, percutaneous nephrolithotomy, or a combination, depending on the location and composition of the stone and the wishes of patient.

Stone composition

Cystine stones and calcium oxalate stones are hard, with a density greater than 1,000 Hounsfield units. Lithotripsy has a high failure rate with these types of stones.³⁶

Uric acid stones are softer and do not show up well on x-ray imaging. While it is technically feasible to perform lithotripsy under ultrasonographic guidance, most practitioners prefer to use fluoroscopy to locate the stone. For this reason, patients with radiolucent stones (ie, uric acid stones) are also not good candidates for lithotripsy.

Struvite (staghorn) stones are by definition infected, with bacteria residing within the stone itself. Thus, it is imperative to remove all stone fragments during treatment to prevent sepsis and stone reformation. Over time, an untreated staghorn calculus will lead to failure of the renal unit.

Although lithotripsy, ureteroscopy, and percutaneous nephrolithotomy can all be used to treat staghorn calculi, percutaneous nephrolithotomy has the best stone-free rate (78%), and lithotripsy has the lowest (54%).²⁴ Therefore, percutaneous nephrolithotomy is recommended as the first treatment for these stones, and if combination therapy is used, then percutaneous nephrolithotomy should be done last to ensure that the stone is completely removed.²⁴ If lithotomy is to be used, drainage of the renal unit must be done in advance with either percutaneous nephrostomy or a ureteral stent, to ensure that all infected stone fragments will be flushed out.²⁴

PREVENTING RECURRENCES

Metabolic abnormalities that increase the risk of urolithiasis can be identified and treated in up to 95% of patients who form recurrent stones.³⁷ Most of these patients require simple dietary modifications, and just 15% require pharmacotherapy. (For more on this topic, see the review by Dr. Phillip Hall in this issue of the Journal.³⁸) As urolithiasis is common and often recurrent, the appropriate interventive management, combined with dietary prophylaxis, should minimize patient morbidity and preserve renal function.

A 39-year-old woman presented 1 month ago with left flank pain, chills, and spiking fever over the past day. She reported having an episode of acute pyelonephritis with similar manifestations 6 months previously.

Blood tests showed a leukocyte count of 12.2 × 10⁹/L (normal range 7.05–14.99 × 10⁹/L) with predominant neutrophils, C-reactive protein 6.3 mg/dL (0.0–1.0 mg/dL), blood urea nitrogen 16 mg/dL (10–25 mg/dL), and serum creatinine 1.1 mg/dL (0.70–1.40 mg/dL). Radiographic study of the kidneys, ureters, and bladder showed multiple radiopaque densities in the calyces of both kidneys (Figure 1). Computed tomography of the abdomen without contrast revealed multiple punctuated calcifications aligned concentrically in the medulla of both kidneys (Figure 2). Blood and urine cultures were positive for Escherichia coli that was sensitive to ceftriaxone (Rocephin). This antibiotic was started, and her acute pyelonephritis and bacteremia resolved.

Now, at a follow-up visit 1 month later, intravenous urography clearly shows unique linear and striated opacities and cupping of renal papillae, key features of medullary sponge kidney (Figure 3). Because medullary sponge kidney is strongly associated with kidney stones, potassium citrate is given to prevent medullary calculi formation.

KEY FEATURES

Medullary sponge kidney causes extensive cystic dilation of medullary collecting tubules.¹ It is usually an incidental finding in patients undergoing intravenous urography as part of the evaluation for infection, hematuria, or kidney stones.

The classic urographic appearance is linear striations with small brushes or “bouquets of flowers,” which represent the collection of contrast material in small papillary cysts.

Medullary sponge kidney has long been considered a congenital disorder, but the genetic defect has not yet been identified, and the pathogenesis is not yet known. It has only rarely been reported in children.²

It is usually asymptomatic, but complications may occur, including nephrocalcinosis or lithiasis, urinary tract infection, renal tubular acidosis, and impaired urine concentrating ability.

RISK OF LITHIASIS

Gambaro et al³ estimated that medullary sponge kidney is found in up to 20% of patients with urolithiasis, and that more than 70% of patients with medullary sponge kidney develop stones.

Cystic dilation of medullary collecting tubules (an anatomic abnormality) inevitably causes urinary stasis. This, combined with hypercalciuria and reduced excretion of urinary citrate and magnesium (metabolic abnormalities), contributes to lithiasis.⁴ Lithiasis in medullary sponge kidney is a well-known cause of urinary tract infection, and it tends to facilitate infective stone formation after episodes of urinary tract infection.⁵

The unique anatomic derangement of medullary sponge kidney contributes to the recurrence of pyelonephritis, in addition to the conventional risk factors—frequent sexual intercourse, avoidance of voiding because it is inconvenient, incomplete bladder emptying, ureteropelvic junction obstruction, ectopic ureter, and impaired immunity.⁶

DIAGNOSIS AND TREATMENT

Intravenous urography is the gold standard for the diagnosis of medullary sponge kidney; computed tomography and ultrasonography are generally limited in their ability to clearly show the tubular ectasia.⁷

Treatment includes antibiotics for acute pyelonephritis and thiazide diuretics and potassium citrate to prevent stone formation and renal tubular acidosis. Due to its silent course, medullary sponge kidney should be considered not only as a cause of nephrocalcinosis and nephrolithiasis, but also as a distinct entity complicating recurrent pyelonephritis.