Loin pain-hematuria syndrome

INTRODUCTION — The loin pain-hematuria syndrome (LPHS) was first described in 1967 in a report of three young women (20 to 28 years of age) who had recurrent episodes of severe unilateral or bilateral loin (flank) pain that were accompanied by gross or microscopic hematuria [1]. The major causes of flank pain and hematuria, such as nephrolithiasis and blood clot, were not present. Renal arteriography suggested focally impaired cortical perfusion, while kidney biopsy showed interstitial fibrosis and arterial sclerosis.

Since the original report, several hundred cases of LPHS have been reported in the medical literature [2].

This topic will review the epidemiology, pathogenesis, clinical features, diagnosis, and treatment of LPHS. The general evaluation of hematuria in adults and in children is presented elsewhere:

●(See "Etiology and evaluation of hematuria in adults".)

●(See "Evaluation of gross hematuria in children".)

●(See "Evaluation of microscopic hematuria in children".)

EPIDEMIOLOGY — The epidemiology of LPHS is not well understood. Approximately one-half of our more than 200 LPHS patients reside in Central Ohio, which has a population of 2.2 million. If our patients represent one-half of those with LPHS in this region, the prevalence of LPHS is approximately 0.011 percent. This qualifies LPHS as a rare disease (prevalence less than 0.07 percent) according to the Rare Diseases Act of 2002 (House Resolution 4013). The low prevalence is most likely due to lack of recognition of this distinct clinical entity by urologists and pain specialists.

PATHOGENESIS — Multiple hypotheses have been proposed for the hematuria and pain associated with LPHS, including vascular disease of the kidney, coagulopathy, renal vasospasm (including microinfarction), and psychopathology [2]. There is no objective evidence supporting any of these factors.

Mechanism of hematuria — When kidney biopsy is performed, some patients with LPHS have a known cause of glomerular hematuria such as immunoglobulin A (IgA) nephropathy or thin basement membrane nephropathy (TBMN) [2,3]. Such patients are considered to have secondary LPHS, while patients without an underlying glomerular disease are considered to have primary LPHS. (See 'Primary versus secondary LPHS' below.)

Kidney biopsy in patients with primary LPHS shows evidence of glomerular hematuria, as manifested by red cells in the tubules. This finding is seen significantly more often in patients with LPHS than in normal kidneys from transplant donors (7.2 versus 1.6 percent of tubular cross-sections with red cells in a blinded assessment in our series of 34 patients), thereby precluding trauma from the biopsy as the cause [2]. Kidney biopsy also showed red cell casts in the tubules in some patients with LPHS but not in controls, another objective sign of glomerular hematuria. In addition, approximately 60 percent of biopsy specimens show abnormally thin or thick glomerular basement membranes on electron microscopy, suggesting an important role for glomerular basement membrane abnormalities in the pathogenesis of hematuria [2,4].

We consider glomerular hematuria to be present if the kidney biopsy shows red cell casts, or if more than 3 percent of tubular cross-sections contain red cells, which is approximately 2 standard deviations above the mean value in normal kidneys [2].

Some patients with the syndrome of LPHS do not have increased numbers of red cells in tubular cross-sections on kidney biopsy [2]. Possible explanations are that the patients did not have gross hematuria at the time that kidney biopsy was performed, which is usually the case, or sampling error. It is also possible that hematuria and pain originate from different sites in a subset of patients. Thus, the absence of glomerular hematuria on kidney biopsy should not exclude the diagnosis of primary LPHS.

Possible role of intratubular crystal formation — In as many as 50 percent of patients with primary LPHS (reported in one series), glomerular hematuria coexists with nephrolithiasis, as manifested by a history of passed stones and/or typical calcifications on imaging studies [2].

Similar findings have been described in patients with TBMN. In a study of 46 patients with TBMN or first-degree relatives with persistent microscopic hematuria, the 18 patients with risk factors for stone formation (hypercalciuria and/or hyperuricosuria) had, when compared with patients with normal urine calcium and uric acid excretion, significantly higher rates of episodes of both gross hematuria (44 versus 7 percent) and loin pain (27 versus 3 percent) [5]. (See "Thin basement membrane nephropathy (benign familial hematuria)", section on 'Gross hematuria and flank pain'.)

Thus, renal tubular injury and obstruction may be promoted by the simultaneous presence of red cells and microcrystals in the tubular lumen, leading to gross hematuria and loin pain (figure 1). Whether intratubular crystal formation can cause LPHS in the absence of glomerular hematuria is not clear.

Mechanism of loin pain — The pathogenesis of loin (flank) pain in patients with LPHS is incompletely understood. The following observations support the hypothesis that the pain of LPHS originates in the kidney:

●The pain is localized at the costovertebral angles and made worse by a gentle punch, features that are typical of kidney pain.

●LPHS pain can be stopped at least temporarily by denervating the kidney. The efficacy of renal denervation is discussed below. (See 'Surgical renal denervation' below.)

Despite the lack of certainty of the origin of pain, we propose the following sequence of events as a contributor to the loin pain in LPHS [2]:

●Glomerular hematuria, often in the presence of abnormal (thin or thick) glomerular basement membranes, is the initiating event, leading sequentially to tubular obstruction, backleak of glomerular filtrate, and local parenchymal edema that promotes compression of adjacent tubules.

●Both tubular obstruction and compression of adjacent tubules lead to glomerular hypertension and further bleeding into the tubules.

●The net effect is a vicious cycle that eventually results in diffuse parenchymal edema, stretching of the kidney capsule, and loin pain (figure 1).

As mentioned above, hypercalciuria and/or hyperuricosuria may contribute to tubular obstruction and, in patients with TBMN, are associated with significantly higher rates of episodes of loin pain than similar patients with normal urinary calcium and uric acid excretion (27 versus 3 percent in one study) [5].

However, the great majority of patients with glomerular bleeding or with urolithiasis (or its risk factors) do not have the severe and constant or frequently recurrent pain of LPHS. Thus, other factors are needed to explain the pathogenesis of pain that occurs in primary or secondary LPHS. As examples, patients with LPHS may have greater compliance of the kidney capsule or qualitative or quantitative differences in the innervation of the kidney capsule, each of which could enhance the susceptibility to kidney pain (figure 1). Alternatively, patients with LPHS may have central nervous system amplification of pain as in those with fibromyalgia (and many patients with LPHS also meet criteria for, and are being treated for, fibromyalgia) [6].

Possible somatoform pain disorder — A psychiatric component has been described in patients with LPHS, and some have suggested a type of somatoform pain disorder (ie, pain that cannot be explained by a known medical disease) and possible drug-seeking behavior [7,8]. (See "Somatic symptom disorder: Assessment and diagnosis", section on 'Terminology and DSM-5'.)

One report compared 15 patients with LPHS with 10 patients with complicated kidney stone disease who were matched for age, sex, and duration of illness [7]. The patients with LPHS were much more likely to have medically unexplained somatic symptoms, an adverse psychologic event preceding the onset of pain (8 versus 0), and a history of greater analgesic ingestion.

In another study that compared 24 patients with LPHS with 10 patients with isolated hematuria, those with LPHS were more likely to have irritable bowel syndrome (37 versus 10 percent), depression/anxiety (58 versus 20 percent), migraine (50 versus 20 percent), and a history of physical assault (29 versus 10 percent) [9].

Some of these patients have been managed successfully with antidepressants, anxiolytics, and supportive counseling, although the hematuria may persist [8]. On the other hand, effective nonnarcotic analgesic therapy may potentially lead to cessation of drug use and reversal of any psychiatric disturbances [10]. (See 'Other invasive modalities' below.)

CLINICAL FEATURES — LPHS is a poorly defined disorder characterized by recurrent or persistent loin (flank) pain and hematuria that appears to represent glomerular bleeding. Most patients present with both manifestations, but some present with loin pain or hematuria alone [11].

Affected patients are typically young (mean age of 31 years in one review, with some cases occurring in teenage children) and female (70 to 80 percent in most series); in addition, the disorder is primarily seen in White patients [2,9,11-13]. As many as 50 percent of patients with LPHS have nephrolithiasis, as defined by either a history of passing stones or, on imaging studies, kidney calcifications typical of stones [2,9].

The factors responsible for the predominance in women are not well understood. Women tend to have thinner glomerular basement membranes than men [14], which may predispose to glomerular hematuria [15]. (See "Thin basement membrane nephropathy (benign familial hematuria)", section on 'Microscopic hematuria'.)

Primary versus secondary LPHS — LPHS is considered primary when it occurs in the absence of an underlying acquired glomerular disease and secondary when it occurs with an acquired glomerular disease, most often IgA nephropathy. Among 43 consecutive patients that we saw with LPHS, all had a negative urologic evaluation; 34 had primary LPHS, and nine had secondary LPHS (associated with IgA nephropathy) [2]. We have also encountered two patients with LPHS who had fibrillary glomerulonephritis.

The diagnostic distinction between primary and secondary LPHS is made by kidney biopsy. (See 'Kidney biopsy' below.)

Hematuria — The hematuria in LPHS is typically characterized by dysmorphic red cells, primarily acanthocytes (picture 1 and picture 2), with or without red blood cell casts (picture 3), both of which indicate a glomerular origin [2,4,11]. (See "Etiology and evaluation of hematuria in adults", section on 'Glomerular versus nonglomerular bleeding' and "Etiology and evaluation of hematuria in adults", section on 'Acanthocytes'.)

However, the absence of acanthocytes and red cell casts does not exclude LPHS. In a minority of patients, intratubular crystal deposition may be primarily responsible for the flank pain and hematuria. An alternative explanation for the absence of acanthocytes is that the glomerular hematuria may be the result of focal glomerular "blow out," which would permit red cells to enter the renal tubular lumens without being distorted by the glomerular filtration barrier. (See 'Possible role of intratubular crystal formation' above.)

The hematuria can be microscopic but most patients have experienced at least one episode of gross hematuria (25 of 34 in our series) [2]. Episodes of gross hematuria are almost always accompanied by worsening pain. The episodes usually last a few days, but gross hematuria and pain can persist for weeks to months. We have also observed patients with kidney biopsy-documented primary LPHS who had severe gross hematuria, often painless, which lasted for many months. In some of these patients, the gross hematuria was sufficient to produce iron deficiency.

Between episodes of gross hematuria, the urinalysis typically shows microscopic hematuria [2]. However, in some patients, hematuria clears but pain persists.

Loin pain — Loin (flank) pain, often described as burning or throbbing, is localized at the costovertebral angles and made worse by a gentle punch. As with other causes of renal colic, the pain may radiate to the abdomen, inguinal area, or medial thigh [11].

At presentation, the pain is usually unilateral and, less often, bilateral (6 of 34 in the above series) [2]. However, the majority of patients eventually develop bilateral pain [11]. The pain can be induced or exacerbated by exercise in approximately one-half of patients, and even acts such as riding in a car can be extremely uncomfortable [2].

The pain is typically unrelenting, leading clinicians to consider or prescribe narcotic therapy. Sleep may be difficult since certain postures exacerbate pain. (See 'Approach to pain control' below.)

Some patients describe upper abdominal pain, but costovertebral angle punch tenderness is also present [2]. In addition, tenderness of the muscles overlying the costovertebral area is common because of chronic muscle spasm.

The onset of loin pain is often associated with nausea and vomiting, which are common in patients who require hospitalization for pain control. This can complicate management because the patient may be unable to control the loin pain with oral opioids (see 'Treatment of pain exacerbations' below). In many of these patients, nausea and vomiting are the reasons for hospitalization and can be recurring problems.

Kidney function — The glomerular filtration rate, as estimated from the serum creatinine concentration, generally remains normal. Protein excretion is typically normal or slightly elevated. Hypertension is not a feature of primary LPHS, although some patients have hypertension for other reasons.

Pathology — When kidney biopsy is performed in patients with primary LPHS, the glomeruli are normal on light microscopy [2,16]. The renal tubules may contain red cells or red cell casts, suggesting that glomerular bleeding is the source of hematuria [2,16].

It has been proposed that the glomerular hematuria is the result of structural abnormalities in the glomerular basement membrane that are not visible by light or immunofluorescence microscopy. In one study, approximately 60 percent of biopsy specimens showed thin or thick glomerular basement membranes on electron microscopy [2]. However, in a subsequent study, nearly all of 13 patients had normal-appearing glomerular basement membranes without structural irregularities; one patient had thick glomerular basement membranes [16]. Genetic testing of these patients identified no pathogenic variants in the type IV collagen genes (COL4A3, COL4A4, COL4A5).

Clinical presentations — We have observed three relatively distinct clinical presentations in patients with LPHS. Scenario 1 is most common, and scenario 3 is least common:

●Scenario 1 – A young woman presents to her primary care clinician with moderate to severe unilateral or bilateral flank pain, and microscopic hematuria is noted. Pyelonephritis is diagnosed, although pyuria and bacteriuria are absent. An antibiotic is administered, but the pain persists. Successive kidney imaging studies are normal or negative. An opioid is started with some pain relief.

The patient is referred to a urologist who repeats the imaging studies and then performs cystoscopy and retrograde examination, all of which are normal. The pain continues. The urologist then places ureteral stents, but the stents do not relieve the pain.

Symptomatic urinary tract infection ensues. The stents are removed and the infection resolves, but the patient is still miserable. She is then referred to a pain medicine specialist or, rarely, a nephrologist.

●Scenario 2 – A patient presents with unilateral flank pain and hematuria caused by an obstructing kidney stone. The kidney stone is eventually passed or removed, but the pain and hematuria persist. After multiple negative or normal urologic procedures, the patient is referred to a pain medicine specialist or a nephrologist. Narcotic-seeking behavior is suspected.

A variation of scenario 2 is the patient who has had kidney stones in the past and now has nephrocalcinosis consistent with medullary sponge kidney or the medullary calcifications that can be seen in patients with hypercalciuria (see "Medullary sponge kidney", section on 'Kidney stones and nephrocalcinosis' and "Nephrocalcinosis", section on 'High urine calcium without hypercalcemia'). Imaging studies show no evidence of obstruction to urine flow, but the patient has severe pain that is usually bilateral. Narcotic-seeking behavior is suspected.

●Scenario 3 – A serious athlete experiences flank pain and gross hematuria while playing or practicing his or her sport. The pain is of sufficient severity and the hematuria of sufficient alarm that the patient quits the sport. Numerous urologic procedures are performed, which are all normal or negative. Eventually, the patient is referred to a nephrologist.

DIAGNOSIS — Based upon the evaluation of more than 200 patients referred to a single center in the United States with unexplained loin (flank) pain and hematuria, we suggest the following step-wise approach. The diagnosis of LPHS requires exclusion of causes of nonglomerular bleeding, fulfillment of the diagnostic criteria for LPHS, and kidney biopsy if underlying acquired glomerular disease (eg, IgA nephropathy) is suspected in order to distinguish primary LPHS from secondary LPHS. (See 'Primary versus secondary LPHS' above.)

Exclusion of nonglomerular causes of loin pain and hematuria — Since LPHS is an uncommon disorder, the first step in the diagnostic approach to LPHS is to exclude nonglomerular causes of hematuria by examining the urine sediment for acanthocytes and red blood cell casts. (See 'Hematuria' above and "Etiology and evaluation of hematuria in adults", section on 'Glomerular versus nonglomerular bleeding'.)

The most common causes of chronic or recurrent nonglomerular bleeding and loin pain include:

●Obstructing nephrolithiasis (see "Kidney stones in adults: Diagnosis and acute management of suspected nephrolithiasis", section on 'Hematuria')

●Autosomal dominant polycystic kidney disease (see "Autosomal dominant polycystic kidney disease (ADPKD): Kidney manifestations", section on 'Hematuria' and "Autosomal dominant polycystic kidney disease (ADPKD): Kidney manifestations", section on 'Flank and abdominal pain')

●Renal cell carcinoma (see "Clinical manifestations, evaluation, and staging of renal cell carcinoma", section on 'Symptoms and signs')

●Recurrent renal thromboembolism, as with atrial fibrillation (see "Renal infarction", section on 'Clinical features')

Less common causes include:

●Endometriosis (see "Endometriosis: Clinical features, evaluation, and diagnosis", section on 'Clinical features')

●Left renal vein entrapment (nutcracker syndrome) (see "Etiology and evaluation of hematuria in adults", section on 'Nutcracker syndrome')

Renal vein thrombosis is not included in this list. Although it can be associated with hematuria and loin pain, the pain is neither chronic nor recurrent. (See "Renal vein thrombosis in adults".)

Hematuria and loin pain can also be factitious (self-induced), with blood being added to the urine after voiding (eg, from a finger stick). Factitious hematuria can be documented by the absence of hematuria in a urine specimen obtained under direct observation. (See "Etiology and evaluation of hematuria in adults", section on 'Etiology'.)

Diagnostic criteria — If nonglomerular causes of loin pain and hematuria have been excluded, as described in the preceding section, the next step is to document whether the patient has a syndrome consistent with LPHS. (See 'Clinical features' above.)

We use the following criteria [2]:

●The pain is typical of LPHS, being severe, unilateral or bilateral, constant or frequently recurrent, localized at the costovertebral angles, made worse by gentle punching, and present for a prolonged period (six months or more).

●If nephrolithiasis has occurred in the past, stones are not currently obstructing the urinary tract. The absence of obstruction should be confirmed by at least two kidney imaging procedures obtained during episodes of flank pain. Ultrasonography is preferred to minimize the cumulative dose of radiation.

●Hematuria, defined as more than five red cells per high-power field, is present in almost all urinalyses. In our experience, hematuria is absent in less than 5 percent of examinations and is almost invariably present in subsequent specimens.

Gross hematuria is almost always associated with worsening pain, but severe pain can occur in the absence of gross hematuria [2,4]. Blood clots are rarely seen in the urine of LPHS patients with gross hematuria, and their presence is highly suggestive of one of the causes of nonglomerular hematuria. (See 'Exclusion of nonglomerular causes of loin pain and hematuria' above and "Etiology and evaluation of hematuria in adults", section on 'Blood clots'.)

Kidney biopsy — Kidney biopsy is often difficult to justify in the absence of increased albumin excretion rate, abnormal kidney function, or hypertension. However, it may be warranted in patients in whom underlying acquired glomerular disease is suspected. These patients are considered to have secondary LPHS. (See 'Primary versus secondary LPHS' above.)

Identifying an elevation in serum creatinine can be difficult in patients with only mild elevations that are in or just above the normal range. This issue is discussed in detail elsewhere and will be briefly reviewed here. (See "Assessment of kidney function".)

Declining kidney function is likely to occur in patients with secondary LPHS due to progression of the underlying glomerular disease, such as IgA nephropathy. (See 'Natural history' below and "Assessment of kidney function".)

NATURAL HISTORY — The natural history of primary or secondary LPHS is not clear. We believe that LPHS eventually resolves in most patients. This conclusion is based upon our experience that LPHS is unusual in persons older than 60 years of age and that neither end-stage kidney disease nor premature death is a feature of LPHS.

A possible explanation for spontaneous resolution is that the glomeruli that bleed eventually become nonfunctional due to tubular damage. If the destroyed nephrons represent only a minority of the nephrons, the LPHS will resolve and the patient will be left with normal or near-normal kidney function.

TREATMENT — The management of LPHS is usually the same in primary LPHS (occurs in the absence of an acquired glomerular disease) and secondary LPHS (occurs in the presence of an acquired glomerular disease, most often IgA nephropathy). One exception is secondary LPHS that is due to a glomerular disease for which there is specific therapy. (See 'Clinical features' above.)

It is likely that LPHS is not a discrete disease but probably represents a common clinical endpoint for a diverse group of underlying disease processes, as reflected in the multitude of pathophysiologic bases for the disease. Thus, the following approach is largely based upon a single-center experience of over 200 patients with this disorder. The intensity of therapy varies with the severity of the pain. Patients with severe pain typically require high-dose opioids daily or almost daily, frequently visit the emergency department, and occasionally require hospitalization for intravenous opioid therapy.

General measures — Patients with LPHS generally have normal kidney function, and kidney ultrasonography excludes kidney stone disease and other disorders. Patients who fulfill these criteria should be reassured that their kidneys are functioning well and should continue to do so. The patients should also be advised to avoid activities that induce LPHS pain, such as exercise in approximately one-half of patients [2]. (See 'Loin pain' above.)

Angiotensin inhibition — Limited evidence suggests that administration of an angiotensin-converting enzyme (ACE) inhibitor or angiotensin II receptor blocker (ARB) may reduce both the frequency and severity of episodes of gross hematuria and loin pain. In a report of seven patients with LPHS who were treated with enalapril for 7 to 48 months, four reported fewer or less severe episodes [4]. A possible mechanism for such a benefit is that efferent arteriolar dilation induced by decreased angiotensin II activity reduces intraglomerular pressure and therefore the likelihood of glomerular rupture and hematuria. The reduction in intraglomerular pressure is less prominent or not seen with other classes of antihypertensive drugs. (See "Antihypertensive therapy and progression of nondiabetic chronic kidney disease in adults", section on 'Effect of antihypertensive drugs on proteinuria'.)

Reduce the risk of nephrolithiasis — As mentioned above, as many as one-half of patients with LPHS have nephrolithiasis, as defined by either a history of passing stones or kidney calcifications typical of stones on imaging studies [2]. (See 'Possible role of intratubular crystal formation' above.)

It is possible that renal tubular injury and obstruction is promoted by the simultaneous presence of red cells and microcrystals in the tubular lumen, leading to gross hematuria and loin pain. We have observed calcium oxalate microcrystals obstructing distal nephrons in the kidney biopsy from several patients with LPHS even though there was no history of nephrolithiasis.

Based upon these observations, we recommend a 24-hour urine collection for calcium, uric acid, oxalate, citrate, sodium, and creatinine (to estimate the completeness of the urine collection) in patients with LPHS, including those who have no history of stone disease. If an abnormality is found in patients with significant LPHS symptoms, a trial of corrective therapy (eg, increased fluid intake, low-salt diet for hypercalciuria, potassium citrate for hypocitraturia, allopurinol or reduced meat intake for hyperuricosuria) is reasonable to see if the frequency or severity of gross hematuria and pain is reduced. There are no confirmatory data supporting benefit from this approach.

●(See "Kidney stones in adults: Epidemiology and risk factors".)

●(See "Kidney stones in adults: Prevention of recurrent kidney stones".)

●(See "Kidney stones in adults: Uric acid nephrolithiasis", section on 'Treatment'.)

Approach to pain control — Medical (nonopioid and opioid) and interventional therapies for pain control in LPHS are generally similar to those in patients with other chronic pain syndromes. Every effort should be made to avoid opioid therapy. If opioids are necessary, particularly for daily therapy, consultation with a pain specialist is recommended. There are no randomized trials evaluating opioid therapy regimens in LPHS, and different regimens are likely to be equally effective.

The general approach to the treatment of chronic pain and issues related to prescription drug misuse are discussed in detail elsewhere:

●(See "Approach to the management of chronic non-cancer pain in adults".)

●(See "Prescription drug misuse: Epidemiology, prevention, identification, and management".)

Treatment of pain exacerbations — There is no high-quality evidence to guide the optimal treatment of pain exacerbations in patients with LPHS. The following approach is based upon our experience in the treatment of over 200 patients with LPHS. At our center, hospitalization is now rarely needed to manage severe pain exacerbations of LPHS, which may reflect improvement in our ability to control LPHS pain exacerbations with outpatient oral opioids.

In patients with LPHS who are experiencing a pain exacerbation, nonopioid therapy should be attempted first. If the patient does not respond to nonopioid therapy and requires opioids, we refer the patient to a pain specialist at a specialized pain clinic that uses a multidisciplinary and multimodal approach to pain management. (See "Use of opioids in the management of chronic non-cancer pain" and "Approach to the management of chronic non-cancer pain in adults".)

When the pain therapy has been stabilized, the patient may be returned to the nephrologist or primary care clinician to continue the analgesic therapy. Many of these patients will require doses of opioids that are higher than the daily morphine equivalents of specified state guidelines. In this situation, the therapy formulated by a pain medicine specialist will provide some protection for the nephrologist or primary care clinician if there is scrutiny by state or federal agencies.

In the United States, where there is computerized monitoring of the identity of the health care providers who prescribe the patient's opioids, it is important for each provider to consult this list each time the patient's opioids prescription is filled. The purpose is to determine whether others have prescribed opioids for the patient. If that is the case, the reasons for duplicate providers of the patient's opioids need to be reconciled in the patient's medical record. (See "Prescription drug misuse: Epidemiology, prevention, identification, and management", section on 'Prescription monitoring programs'.)

Maintenance therapy between pain exacerbations — Most patients with LPHS experience significant daily pain consistent with kidney pain. Many of these patients ask for and receive "maintenance" daily opioids between LPHS pain exacerbations.

We suggest the following regimen. Once the pain associated with the LPHS flare has been controlled, the opioid dose is tapered at the rate of approximately 20 percent per day until the patient's usual daily maintenance opioid dose is reached. This rate of taper should not cause symptoms of opioid withdrawal.

If the patient remains free of pain for three months or more, we recommend a trial of slow tapering of the maintenance opioid dose.

Invasive therapies for chronic refractory pain — A variety of invasive therapies have been used in the treatment of severe chronic pain syndromes. These approaches are discussed in detail elsewhere, but the limited experience in LPHS will be reviewed here.

●(See "Interventional therapies for chronic pain".)

●(See "Approach to the management of chronic non-cancer pain in adults", section on 'Interventional therapy for chronic pain'.)

●(See "Approach to the management of chronic non-cancer pain in adults", section on 'Interventional therapy for chronic pain'.)

Implantable drug delivery system — In patients who require large doses of opioids, the systemic side effects may become intolerable. Such patients may be candidates for an implantable drug delivery system (IDDS) that permits intrathecal administration of opioid, usually morphine [17]. The advantage of intrathecal administration is the ability to get the opioid directly to the opioid receptors in the spinal cord, thereby reducing the systemic concentration and minimizing systemic side effects. Intrathecally delivered morphine is approximately 300 times more powerful than oral morphine.

Of the invasive therapies we have used in patients with LPHS, the IDDS has been the most effective. Among more than 20 treated patients, pain was largely controlled and hospitalization and emergency department visits were substantially reduced (unpublished personal observation). Our longest-treated patient has been receiving intrathecal therapy for more than 20 years. Some patients treated with IDDS need occasional oral opioids for episodes of breakthrough pain.

Limitations to the IDDS include high cost and the risk of developing intrathecal catheter-tip inflammatory masses due to mast cell granulomas that are induced by morphine [18-20]. These masses can act as space-occupying lesions and produce neurologic symptoms. In our experience, switching from morphine to hydromorphone appears to prevent progression of the granulomas. Limited data suggest that cessation of opioid therapy through the catheter is associated with shrinkage or resolution of the mass over two to five months [18].

Although rare, infection can occur with IDDS use; this is more frequent in patients with diabetes, and therefore diabetes is a possible contraindication to use IDDS. In addition, in slender individuals, the subcutaneous pump is conspicuous and can be cosmetically objectionable.

Endovascular denervation of the renal artery — The nociceptive fibers that convey pain signals from the kidney flow through sympathetic nerve fibers that travel along the adventitia of the renal artery en route to the central nervous system. Endovascular ablation to interrupt these sympathetic nerve fibers has been used to successfully treat loin pain in patients with LPHS [21-23]. Compared with surgical options, this technique has the advantages of being catheter based, safe, rapid, and minimally invasive [22,23]. In the largest case series of 12 patients, the majority of patients were pain free and off opiates for nearly six months; in addition, there was concurrent improvement in mood, disability, and quality of life [23]. Endovascular denervation has also been successful in managing refractory chronic pain in patients with autosomal dominant polycystic kidney disease [24].

The success of endovascular ablation in the treatment of LPHS has been aided by the development of newer catheters that achieve better circumferential endothelial contact. One of the newer spiral catheters, which has been used in a randomized controlled trial of renal denervation in managing resistant hypertension [25], is currently being evaluated as part of a feasibility study for a larger randomized controlled trial of LPHS patients [26].

Surgical renal denervation — Surgical renal denervation can be accomplished by stripping the kidney capsule from the kidney (the capsule contains the stretch fibers that transmit pain sensation when the kidney parenchyma expands), by stripping the renal nerves from the renal artery (neurectomy), by percutaneous catheter-based radiofrequency ablation of the renal sympathetic nerves, or by kidney autotransplantation [11,12,21,27-30].

We do not typically recommend surgical renal denervation to control LPHS pain for the following reasons:

●LPHS eventually resolves.

●There is potential for harm from acute and chronic complications of the denervation procedure.

●Pain often recurs, presumably due to reinnervation of the kidney, even if steps are taken to prevent reinnervation. In two studies with a total of 42 patients who had adequate long-term follow-up after surgical renal denervation, the incidence of recurrent ipsilateral pain was 73 percent at a median of 11 months [27] and 67 percent at a mean of 8.4 years [12]. Other reports show similar outcomes [29,30].

Kidney autotransplantation — Kidney autotransplantation has been used in LPHS patients with chronic, severe pain that has been unresponsive to nonsurgical therapies. However, because of the risks associated with kidney autotransplantation and lack of long-term efficacy, this approach is now regarded as a last resort [13,31].

The long-term results are better with kidney autotransplantation than with surgical renal denervation. In two reports with 25 and 26 patients who underwent this procedure, the long-term rate of being free of pain was 76 percent at a mean of 8.4 years (including 8 of 10 patients who underwent bilateral autotransplantation and three of four patients who had developed recurrent pain after renal denervation) [12] and 69 percent at a mean follow-up of 7.1 years with another 12 percent having reduced analgesic requirements and improved quality of life despite recurrent pain [28].

However, some studies found a lower rate of being pain free after kidney autotransplantation (eg, 3 of 11 [27 percent] at two to four years) [32,33], and kidney autotransplantation may be associated with significant complications (including loss of the transplanted kidney) [28,32,33]. In the study of 26 patients cited above, two patients required nephrectomy because of complications, one due to renal vein thrombosis and one due to persistent kidney ischemia [28]. Another report described similar outcomes including loss of the autotransplanted kidney in 2 of 16 patients [33]. An ongoing concern is whether the reported results of kidney autotransplantation overestimate benefit because of publication bias.

Nephrectomy — Nephrectomy to control LPHS pain is not recommended, although it may initially be effective [27,28]. In one report, nine patients who had recurrent pain after renal denervation underwent unilateral nephrectomy [27]. Three of these patients developed loin pain in the contralateral kidney, and two developed disabling wound pain.

There are three case reports of LPHS patients who had bilateral nephrectomy for severe chronic pain [34-36]. Although the pain was controlled, the patients were hemodialysis dependent. One patient in whom the pain disappeared for the first time in 40 years underwent successful kidney transplantation and was doing well at four years although he had intermittent microscopic hematuria [36].

Other invasive modalities — A number of other invasive modalities have been evaluated in patients with LPHS, but none has proven to be clinically useful:

●Pulse radio frequency – The application of pulse radio frequency to the lower thoracic dorsal root ganglion has been used in some chronic pain syndromes. It disables the pain fibers for periods of up to six months but does not destroy them. We have had some success with this technique in 10 patients. However, proof of long-term benefit is lacking [37].

●Celiac plexus block – Celiac plexus block has been used to treat chronic upper abdominal pain, primarily in patients with cancer or chronic pancreatitis. We have not found this approach to be consistently effective in patients with LPHS, and formation of a retroperitoneal hematoma at the site of the injection can add to the pain burden. (See "Interventional therapies for chronic pain".)

Other therapies — On the assumption that the pain of primary LPHS might be related to ischemia (ie, "angina" of the kidney), we have tried therapies to increase renal blood flow with saline infusion, dopamine infusion, and oral sildenafil. None of these interventions have been successful in acutely relieving pain. Acupuncture has also been ineffective. However, one report showed an improvement in pain intensity in a woman treated with tadalafil [38]. Clinicians and patients may also explore the possibility of virtual reality as analgesic therapy, which has been used for other forms of severe acute and chronic pain [39].

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Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topic (see "Patient education: Blood in the urine (hematuria) in adults (The Basics)")

●Beyond the Basics topics (see "Patient education: Blood in the urine (hematuria) in adults (Beyond the Basics)" and "Patient education: Glomerular disease (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

●Overview – Loin pain-hematuria syndrome (LPHS) is a rare disease with an estimated prevalence in the population of approximately 0.012 percent. LPHS is considered primary when it occurs in the absence of an underlying acquired glomerular disease and secondary when it occurs with an acquired glomerular disease (eg, immunoglobulin A [IgA] nephropathy). (See 'Epidemiology' above and 'Clinical features' above.)

●Pathogenesis – The mechanisms for hematuria and pain in patients with LPHS are not known. The hematuria in primary LPHS may be due to functionally abnormal glomerular basement membranes, in which temporary gaps form that permit the passage of red blood cells into the urinary space. Glomerular hematuria may be the initiating event in the development of loin pain by causing tubular obstruction leading to backleak of glomerular filtrate, parenchymal edema, and stretching of the kidney capsule (figure 1). (See 'Pathogenesis' above.)

●Clinical features – There are several common clinical presentations of LPHS, but they all include the following clinical features characteristic of LPHS (see 'Clinical presentations' above):

•Recurrent or persistent loin (flank) pain − The pain, which may be described as burning or throbbing, is localized at the costovertebral angles and is associated with costovertebral angle tenderness. The pain can be unilateral or, less often, bilateral and is often induced or exacerbated by exercise and riding in a car. (See 'Loin pain' above.)

•Hematuria − The hematuria is usually microscopic and is characterized by dysmorphic red cells indicating a glomerular origin. Most patients experience at least one episode of gross hematuria, which is almost always accompanied by worsening pain. Between episodes of gross hematuria, the urinalysis ordinarily shows microscopic hematuria. (See 'Hematuria' above.)

•The glomerular filtration rate remains normal or near normal in patients with LPHS, and the incidence of hypertension is not increased compared with the general population. (See 'Kidney function' above.)

●Pathology – Kidney biopsy in patients with primary LPHS reveals normal glomeruli by light and immunofluorescence microscopy; red cells or red cell casts are present in the tubules, suggesting that glomerular bleeding is the source of hematuria. By electron microscopy, patients may have normal, thin, or thick glomerular basement membranes. (See 'Pathology' above.)

●Diagnosis – To make a diagnosis of LPHS, the following criteria should be met (see 'Diagnosis' above):

•Hematuria, defined as more than five red cells per high-power field, should be present in almost all urinalyses. (See 'Diagnostic criteria' above.)

•Recurrent or persistent pain (present for six months or more) should be severe, localized in the costovertebral angles, and associated with costovertebral angle tenderness. (See 'Diagnostic criteria' above.)

•Nonglomerular bleeding, for example nephrolithiasis, urinary infection, polycystic kidney disease, and tumors, must be excluded. (See 'Exclusion of nonglomerular causes of loin pain and hematuria' above.)

•Obstruction of the urinary tract should not be present and should be confirmed by at least two imaging procedures during episodes of pain. (See 'Diagnostic criteria' above.)

Kidney biopsy is warranted in patients in whom underlying acquired glomerular disease (eg, IgA nephropathy) is suspected. Patients with underlying acquired glomerular disease often have overt proteinuria and/or an elevation in serum creatinine, neither of which is likely in primary LPHS. (See 'Kidney biopsy' above.)

●Treatment – In the absence of substantial data, our treatment recommendations are experiential:

•Angiotensin inhibition with angiotensin-converting enzyme (ACE) inhibitors or angiotensin II receptor blockers (ARBs) may reduce the frequency and severity of hematuria and pain episodes. (See 'Angiotensin inhibition' above.)

•Given the associations with nephrolithiasis, patients with LPHS should undergo a metabolic stone workup to evaluate risk factors for kidney stones. Abnormalities that are uncovered should be treated appropriately; if none are revealed, then empiric therapy should be attempted to see if the frequency of symptoms can be reduced. (See 'Reduce the risk of nephrolithiasis' above.)

•Chronic and acute pain control, similar to that provided to patients with other chronic pain syndromes, should be provided. Nonopioid therapy should be attempted first. (See 'Approach to pain control' above.)

•A variety of invasive and experimental therapies have been used in the treatment of severe pain in patients with LPHS. Of these, an implantable drug delivery system and endovascular renal denervation have been the most effective. (See 'Invasive therapies for chronic refractory pain' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Dan N Spetie, MD, and Lee A Herbert, MD, who contributed to earlier versions of this topic review.